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Return to: Twitter Facebook Linkedin Reddit Get Citation Citation AMA Citation Wenger DA, Escolar ML, Luzi P, Rafi MA. Wenger D.A., Escolar M.L., Luzi P, Rafi M.A. Wenger, David A., et al.Krabbe disease (Globoid Cell Leukodystrophy). In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G. Valle D, Beaudet A.L., Vogelstein B, Kinzler K.W., Antonarakis S.E., Ballabio A, Gibson K, Mitchell G Eds. David Valle, et al.eds. The Online Metabolic and Molecular Bases of Inherited Disease New York, NY: McGraw-Hill; 2014. http://ommbid.mhmedical.com/content.aspx?bookid=971§ionid=62644214. Accessed May 26, 2017. MLA Citation Wenger DA, Escolar ML, Luzi P, Rafi MA. Wenger D.A., Escolar M.L., Luzi P, Rafi M.A. Wenger, David A., et al.. "Krabbe disease (Globoid Cell Leukodystrophy)." The Online Metabolic and Molecular Bases of Inherited Disease Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G. Valle D, Beaudet A.L., Vogelstein B, Kinzler K.W., Antonarakis S.E., Ballabio A, Gibson K, Mitchell G Eds. David Valle, et al. New York, NY: McGraw-Hill, 2014, http://ommbid.mhmedical.com/content.aspx?bookid=971§ionid=62644214. Download citation file: RIS (Zotero) EndNote BibTex Medlars ProCite RefWorks Reference Manager © Copyright Tools Search Book Top Return Clip New! 147: Krabbe disease (Globoid Cell Leukodystrophy) David A. Wenger; Maria L. Escolar; Paola Luzi; Mohammad A. Rafi DOI: 10.1036/ommbid.178 + Print Section Abstract Infantile globoid cell leukodystrophy (GLD, also called Krabbe disease; OMIM #245200) is a rapidly progressive, invariably fatal disease. It is transmitted as an autosomal recessive trait. The disease usually begins between 3 and 6 months of age with nonspecific symptoms such as stiffness, feeding difficulties, and irritability, but soon progresses to motor deterioration and cognitive decline. Clinical manifestations are limited to the nervous system, with prominent corticospinal tract signs. Patients experience hypertonia with decreased deep tendon reflexes in the early stages, but later become flaccid and hypotonic. Visual deficits are common. Peripheral neuropathy is almost always detectable. Patients rarely survive the second year. While the infantile form is the most common, later onset forms are also recognized. While there is no clear delineation of subtypes, clinical manifestations can begin at any age after infancy. Patients with later onset forms usually present with ataxia, weakness, blindness, spastic paraparesis, behavioral problems, and dementia. The presence of numerous, often multinucleated, globoid cells, the almost total loss of myelin and oligodendroglia, and astrocytic gliosis in the white matter are the morphologic basis for diagnosis. The globoid cells are hematogenous macrophages that contain undigested galactosylceramide. Segmental demyelination, axonal degeneration, fibrosis, and histiocytic infiltration are common in the peripheral nervous system. It is postulated that accumulation of a toxic metabolite, psychosine (galactosylsphingosine), which is also a substrate for the missing enzyme, leads to the death of myelin-forming cells. However, the extensive globoid cell reaction indicates that impaired catabolism of galactosylceramide is also an important factor in the pathogenesis. Consistent with the myelin loss, the white matter is severely depleted of all lipids, particularly glycolipids. However, the ratio of galactosylceramide to sulfatide is abnormally high. Galactosylceramide, a sphingoglycolipid consisting of sphingosine, a fatty acid, and galactose, is an important component of the myelin sheath. The primary cause of Krabbe disease is a genetic deficiency of galactocerebrosidase (GALC; EC 220.127.116.11) activity. This lysosomal enzyme normally degrades galactosylceramide to ceramide and galactose. A few infants with a clinical picture similar to Krabbe disease have been found to have mutations in saposin A, an activator protein that assists in the action of GALC on galactosylceramide. Assays of GALC activity in leukocytes or cultured fibroblasts using an appropriate substrate can readily establish a definitive diagnosis. Intrauterine diagnosis of affected fetuses in at-risk couples is available using amniotic fluid cells or biopsied chorionic villi by mutation analysis when the parents' genotypes have been identified. Knowing the mutation(s) also opens the possibility of preimplantation genetic diagnosis. In an attempt to arrive at an early diagnosis, newborn screening for Krabbe disease has been initiated in New York State. The method involves an enzyme-based assay using dried blood spots and tandem mass spectrometry followed by conventional testing and sequencing in the event of a low GALC value. Treatment at this time is limited to hematopoietic stem cell transplantation, often using umbilical cord blood stem cells, in asymptomatic individuals and those with only minimal neurologic involvement. This seems to slow the expected course of the disease with improved neurological function and magnetic resonance imaging findings and decreased cerebrospinal fluid protein. The human GALC gene (OMIM *606890) has been mapped to chromosome 14q31. The human cDNA and gene have been cloned. The cDNA encodes a protein of 643 amino acids following cleavage of the leader sequence. The gene is about 56 kb, consisting of 17 exons. Over 140 disease-causing mutations have been found in patients with all types of GLD. However, a few specific mutations are found in a significant number of unrelated patients with European ancestry and within some inbred communities. In addition, a number of polymorphisms in this gene have been identified. Some of these polymorphisms can result in significantly lowered GALC activity resulting in wide "normal" and "carrier" ranges. These polymorphisms may also play a role in modifying the effect of other disease-causing mutations on the same allele. GALC deficiency also occurs in other mammalian species, most notably in certain breeds of dogs, monkeys, and mice. Clinical and pathologic features are similar to those in the human disease. These animal models are currently being used in therapy trials. + History Print Section ++ ++ In 1916, Knud Krabbe described clinical and histologic findings in 5 infants who died of an "acute infantile familial diffuse sclerosis of the brain."1 He noted familial occurrence, early onset of spasticity, and a rapidly progressive course to death. He gave a detailed description of the globoid cells, the histologic hallmark of the disease. A retrospective search of the neuropathologic literature found 2 earlier descriptions of similar abnormal cells.2,3 Collier and Greenfield4 were the first to coin the term globoid to describe the numerous abnormal cells found in white matter. ++ An earlier suggestion5 that globoid cells might contain kerasin (a cerebroside) was supported by subsequent chemical6,7 and histochemical7– 10 studies. The experimental induction of the globoid cell reaction by intracerebral injection of galactocerebroside, but not by any other lipids tested,11– 13 further supported the close relationship between globoid cells and cerebroside. Analytically, the most consistent abnormality in the white matter appeared to be an increased ratio of cerebroside to sulfatide.14,15 In 1970-71, a deficiency of galactocerebrosidase (GALC) activity was established as the disease's underlying genetic defect.337,16,17,18 Prenatal diagnosis of an affected fetus was first accomplished in 1971.19 The toxic effect of a related metabolite, galactosylsphingosine (psychosine), was first proposed in 1972 as the critical biochemical pathogenetic mechanism.20 The accumulation of psychosine in this disease has been generally substantiated in both human patients and animal models.21 However, there is little evidence that psychosine accumulates in later-onset forms of GLD or that lower levels of psychosine following treatment completely correct the disease. In 1990, human GLD was mapped to chromosome 14.22 The human enzyme was first purified and partially characterized in 1993 by Chen and Wenger.23 The cDNA for human GALC has been cloned and sequenced, revealing the complete amino acid structure.24,25 The gene organization and exon-intron boundaries have been determined.26 With this information, a large number of disease-causing mutations have been identified in all types of patients, allowing carrier identification within families and within inbred communities as well as in utero diagnosis and preimplantation genetic diagnosis. Treatment of some patients with hematopoietic stem cell transplantation has been accomplished, with some degree of success. + Incidence and Heredity Print Section ++ ++ Infantile Form ++ Globoid cell leukodystrophy is an autosomal recessive disorder with a wide geographic distribution. The incidence in the United States is estimated as 1 in 100,000 births in individuals with European ancestry. A recent study based on death rates estimates the birth prevalence at about 1 per 250,000.394 However, the incidence appears to be higher in the Scandinavian countries. Hagberg et al27 reported 32 Swedish cases from 1953 through 1967 and calculated the incidence as 1.9 per 100,000 births. In Japan the incidence was estimated to be approximately 1 in 100,000-200,000 births. A very high incidence has been found in a Druze kindred in Israel.28 Between 1969 and 1983, during which approximately 2000 people were born, 12 children were diagnosed by enzymatic testing. The calculated incidence was 6 in 1000 live births and the carrier frequency was 0.15 in this community. No Jewish patients were found in a subsequent report from the same investigators.29 ++ Late-Onset and Adult Forms ++ Increasing numbers of patients with the later onset forms of GLD are being diagnosed. The classification of patients considered to have later onset GLD varies among different publications, from onset-after-walking to adulthood. It is difficult to delineate a clear separation between late infantile, juvenile, and adult forms. Fifty patients with late-onset Krabbe disease were summarized by Lyon et al,30 including 27 patients reported in response to a survey conducted by the European Federation of Child Neurology Societies in 1987, and 23 other cases reported in the literature between 1906 and 1987. Of the 50 patients, 39 were of European origin, with the countries of origin as follows: Italy (9, including 8 from Sicily), France (5), Germany (4), Belgium (3), the UK (2), Norway (2), Portugal (2), Greece (1), and others. Similarly, 15 late-onset cases from the United States, with an age distribution between 4 and 73, were described.31 Although distributed throughout the world, the late-onset cases appear to be more common in southern Europe; 7 of 10 patients reported by Fiumara et al32 had a late onset. In another report, 9 of 11 patients who developed gait disturbance and vision loss were over 2 years of age.33 The frequency of late-onset cases was estimated by one of us (DAW) to be approximately 10 percent of over 700 patients with GLD diagnosed in this laboratory. In a recent publication from another laboratory, 8 percent of the patients diagnosed with GLD had adult onset.433 + Clinical Manifestations Print Section ++ ++ Infantile Globoid Cell Leukodystrophy ++ The typical clinical picture of infantile GLD was described by Hagberg et al.27 Affected infants typically develop the first clinical signs and symptoms at 3 to 6 months after birth. Stiffness with clenched fists and hyperextension of extremities have also been observed during the neonatal period.34 In addition, pronounced irritability and twitching may appear soon after birth.35 Vomiting, feeding difficulties, and gastroesophageal reflux can also be present from the first weeks of life.36,404 The patients lose weight and grow poorly unless they are fed through a gastrostomy tube. Visceromegaly is not commonly found. The head size varies from small62– 65 to large38,66 depending on stage of disease progression and whether there is hydrocephalus or brain atrophy.67 Convulsive seizures occur frequently, but infantile spasms are unusual.68,69,417 ++ Hagberg60 divided the steady and rapidly progressive clinical course into 3 stages. Stage I is characterized by generalized hyperirritability, hyperesthesia, episodic fever of unknown origin, and some stiffness of the limbs. Slight retardation or regression of psychomotor development, vomiting with difficulty feeding, and convulsive seizures may be among the initial clinical signs. There is already an increase in cerebrospinal fluid (CSF) protein level. In stage II, rapid and severe motor and mental deterioration develops. There is marked hypertonicity, with extended and crossed legs, flexed arms, and arched back. Tendon reflexes are hyperactive. Minor tonic or clonic seizures occur. Optic atrophy and sluggish pupillary reactions to light are common. Stage III is the "burnt-out" stage, sometimes reached within a few weeks or months. The infant is decerebrate and blind and has no contact with his or her surroundings. Hypertrophy of the optic nerves has been observed in the late stages of the disease.61,414–416 Deafness may occur. Patients rarely survive for more than 2 years. ++ More recently, based on evaluations of 26 patients with early infantile onset, Escolar et al404 described a staging system based on symptoms of disease progression. Stage 1 was characterized by the presence of at least 2 of the following signs: weak feeding, hypotonia of the shoulder girdle, intermittent thumb clasp, or gastroesophageal reflux. In stage 2, patients developed prolonged periods of irritability, fixed thumb clasp, spasticity of extremities with predominant extensor tone (arching back), severe feeding difficulties with uncoordinated suck and swallowing, and trunk weakness. In stage 3, clinical seizures became evident, deep tendon reflexes are absent, infants show exaggerated startle and other abnormal primitive reflexes, and there are visual deficits including jerky eye movements, poor tracking, and sluggish pupillary responses. In stage 4, infants become unresponsive and severely flaccid or hypotonic, develop blindness and hearing deficit, and have signs of autonomic instability manifested by random temperature abnormalities, abnormal heart and respiratory rate, and capillary leakage. Patients with the early infantile form generally die within the first 2 years of life, but can live longer if intense supportive care is provided. ++ In addition to the features typical of infantile patients, other findings have been reported. Macular cherry-red spots have been reported in one patient.70 Bouts of hyperthermia, possibly caused by involvement of the hypothalamic system, have been reported in the absence of infection.1,36,71 Generalized ichthyosis was present from early infancy in one patient.72 ++ Krabbe noted that knee jerks could not be elicited in his original 5 patients and that stiffness passed into a flaccid state toward the end of the disease.1,418 Since the first report of the peripheral nervous system pathology by Matsuyama et al,73 several authors have reported absent or depressed tendon reflexes62,65,69,74,75,404 or disappearance of tendon reflexes over the course of the disease.42,50,51,63,75. 76 However, patients with normal37 or hyperactive77 tendon reflexes at age 15 months have been described. ++ While most patients develop normally for the first few months, others show slow development from soon after birth.7,38,39,78 One patient, whose diagnosis had been established in utero,79 was normal neurologically during the neonatal period, but deep tendon reflexes were already absent at 5 weeks of age, even though the movement and muscle tone of the extremities were apparently normal. Electromyography (EMG) revealed reduced insertional activity, and at 7 weeks, peripheral nerve conduction velocity was markedly reduced. Clinically, psychomotor development was normal for the first 2 months, and weakness of neck muscles was first observed at 3 months of age. These findings suggest that other patients described in the literature may have had clinical manifestations detected earlier than the reported age of onset if they had been examined more carefully. ++ Some patients have atypical clinical histories with disease onset after an infectious event. Wallace et al80 reported a patient who experienced mental deterioration at 5 months of age, apparently after mumps, and convulsions beginning at 7 months of age. The clinical diagnosis was mumps encephalitis, and the final diagnosis was established only at autopsy. Another patient with a rapid course (total 3 months) was diagnosed as having encephalitis.81 ++ Recently, a 6-month-old Arab female presented with progressive neurodegeneration after 3½ months of normal development. The child was unresponsive to external stimuli, and muscle tone in her extremities was significantly increased. Deep tendon reflexes were markedly depressed after an initial period with exaggerated reflexes. Magnetic resonance imaging (MRI) revealed enlarged cerebral ventricles and bilateral white matter dysmyelination. The patient died at about 8 months of age with no autopsy. CSF protein was elevated (108 mg/dL) and although GALC activity in leukocytes was low, it was in the low-normal range in cultured skin fibroblasts. A homozygous mutation in saposin A, a protein activator of GALC, was identified in this patient.338 ++ Late-Onset Globoid Cell Leukodystrophy ++ Until enzymatic diagnosis became possible, the diagnosis of GLD was made on the basis of the characteristic neuropathology.37– 41 With the availability of enzymatic testing, there have been an increasing number of reports describing later onset forms of GLD.30– 33,42– 59,82– 90,339– 341,433 Clinical manifestations in these patients are highly variable and differ significantly from those of typical infantile patients. ++ Most patients with late-onset GLD developed initial clinical signs and symptoms before 10 years of age, but some developed neurologic signs only after 40 years of age. Loonen et al48 divided 18 patients with late-onset disease into 2 types: late infantile (early childhood) and juvenile (late childhood). In the first group (onset from 6 months to 3 years), irritability, psychomotor regression, stiffness, ataxia, and loss of vision were the common initial symptoms. In most cases the course of the disease was progressive, and in some cases deterioration ensued within months, resulting in death approximately 2 years after onset. In the second group (onset from 3 to 8 years), patients developed loss of vision, together with hemiparesis, ataxia, and psychomotor regression. The course was generally protracted, and none of the patients died during the follow-up period, which varied from 10 months to 7 years. Most patients with late-onset disease initially showed rapid deterioration, followed by a more gradual progression lasting for years. Developmental delay was observed in some cases prior to the onset of deterioration.38,42,43,45 In 4 patients,44,47,82,419 seizures were observed. Hemiparesis was present in 2 patients. Glioma was suspected in a 3½-year-old girl with left hemiparesis and hemianopsia because of an infiltrating high-density lesion crossing the splenium of the corpus callosum.89 A 4-year-old boy developed left paraparesis that progressed to quadriplegia.85 The symptoms responded to steroids but worsened after withdrawal. A case described by Goebel et al82 included a remission of clinical symptoms around 10 years of age. A Swedish patient who was followed for 15 years from the onset of symptoms at 8 years of age was still functioning in a sheltered environment at 24 years of age.51 ++ One female patient developed slowly progressive spastic paraparesis at 38 years of age, and MRI findings of demyelination were confined to the corticospinal tract.90 This patient, reported as case 15 by Kolodny et al,31 had been "shaky" in childhood and walked slowly with a stiff, wide-based gait throughout life. Progressive and generalized neurologic deterioration was observed after 40 years of age. She died of pneumonia at age 73. In addition, a 64-year-old female was hospitalized for slowly progressive intention tremor and postural hand tremor lasting for 4 years.58 She had been healthy until age 60 and had worked as a nurse. Her parents were consanguineous, but there was no family history of similar diseases. On admission, mild vision loss, opsoclonus, bilateral optic atrophy, and slightly decreased central flicker score were observed. Speech was slow and scanning. Total IQ score on the Wechsler Adult Intelligence Scale was 66. Deep tendon reflexes were hyperactive, with a positive Babinski sign. Vibration sense was mildly disturbed in the legs. Cerebellar signs and symptoms were present, and the patient was unable to walk without support. A recent publication described the clinical, radiological, electrophysiological, and genetic features of 11 adult patients plus a review of 30 additional patients from the literature.433 In 96 percent of patients, presenting symptoms indicated pyramidal tract dysfunction. Spastic paraparesis or tetraparesis was common while other features including dysarthria, cerebellar ataxia, optic atrophy, and cognitive decline were found less often. In most cases the decline was very gradual, over 10 or more years, although a few patients declined rapidly after diagnosis. The authors also mention the considerable variability in onset and course among some patients, even siblings, with the same mutations. This has been reported in other publications. For example, a girl developed loss of vision at 5½ years of age, whereas her brother became ataxic and irritable at 2¾ years.38,43 They would be classified as juvenile and late infantile types, respectively, by the criteria of Loonen et al.48 Another report described 2 siblings, one with the adult form (onset at 19 years) and the other with a late infantile form (brother, onset at 14 months), although no enzymatic confirmation was available for the brother who died at age 4.88 Other factors that could modify the onset of disease and clinical course in older individuals is documented systemic infection or a blow to the head shortly before symptoms result in diagnostic evaluation.32,38,44,49,52,80,82,432 It should be noted that there are no instances with one sibling having infantile GLD and another having adult GLD disease. + Clinical Diagnosis Print Section ++ ++ Infantile GLD should be strongly suspected if the following clinical features are present: onset early in infancy, irritability, feeding difficulties, fisting and muscle hypertonicity with progressive neurologic deterioration, signs of peripheral neuropathy, and elevated CSF protein level. In rare cases muscle hypotonia and weakness appear before CNS deterioration.91 These findings, together with evidence of white matter disease by neuroimaging, should strongly indicate testing for GLD. The disease can be distinguished from non-progressive CNS disorders of congenital or perinatal origin by a history of normal development during the first few months after birth, followed by psychomotor deterioration. Rarely, the disease may first appear to be of traumatic, inflammatory, or neoplastic origin, but careful evaluation of the clinical picture and appropriate laboratory tests usually exclude these possibilities. ++ Clinical differentiation from other degenerative diseases of infancy can be challenging. Metachromatic leukodystrophy (MLD, Chapter 148) usually begins in the second year of life, with slowly progressive motor disturbance as the initial symptom. Spongy degeneration of white matter begins in early infancy and is characterized by an enlarged head, initial hypotonia, and a normal CSF protein concentration. Alexander disease includes megalocephaly as a characteristic sign, but has no other specific clinical manifestations. Pelizaeus-Merzbacher disease (Chapter 228) can also occur in the first year of life. The disease has a slowly progressive course and is characterized by abnormal involuntary eye movements, often described as nystagmus, which are prominent and useful for diagnosis. The CSF protein concentration is normal and inheritance is X-linked recessive. Canavan disease (Chapter 229) is characterized by evidence of developmental delay by five months of age with severe hypotonia, macrocephaly and failure to achieve independent sitting, ambulation, or speech. Hypotonia evolves into spasticity and assistance with feeding becomes necessary. However, survival is longer than in patients diagnosed with infantile Krabbe disease. MRI shows prominent involvement of subcortical white matter. The finding of elevated N-acetylaspartic acid concentration in urine confirms the diagnosis of Canavan disease. The GM2-gangliosidoses (Chapter 153) usually manifest themselves in the first year of life; developmental delay, startle to sharp sounds, and macular cherry-red spots are commonly present. The initial clinical finding is sluggishness or apathy rather than hyperirritability. Patients with GM1-gangliosidosis (Chapter 151) of early onset often present with coarse facial features, hepatosplenomegaly, developmental delay, and radiological findings that may resemble a mucopolysaccharidosis. Finally, patients with Gaucher disease (Chapter 146) and Niemann-Pick disease (Chapters 144, 145) can present in the first year of life with developmental delay but almost always have visceromegaly. ++ It is almost impossible to make a clinical diagnosis of GLD in patients with atypical symptoms and in patients with the late-onset form of the disease. Presenting signs in later onset patients may be similar to Charcot-Marie-Tooth disease (Chapter 227). Patients of any age who show progressive deterioration of the central or peripheral nervous systems should be tested for GLD. Measurement of GALC activity in leukocytes or cultured skin fibroblasts can easily make the diagnosis. + Laboratory Findings Print Section ++ ++ Blood, Cerebrospinal Fluid, and Urine ++ No specific abnormalities can be detected in routine blood chemistry tests or urinalysis. However, assay of GALC activity in leukocytes isolated from whole blood can result in a definitive diagnosis. CSF protein concentration is high in patients with infantile and late infantile GLD, but normal or only moderately elevated in juvenile or adult patients.82,84,86,89 The CSF cell count is normal. The electrophoretic pattern may be of some diagnostic help; albumin and α2-globulin levels are elevated, and β1- and γ-globulin levels are decreased.36,75 This pattern remains constant throughout the course of the disease and is found only in MLD and GLD.92 In one patient with late-onset GLD, the protein pattern indicated blood-brain barrier damage with additional intrathecal IgG synthesis.85 ++ Neuroimaging ++ Progressive, diffuse, and symmetric cerebral atrophy can be detected with neuroimaging techniques. However, asymmetry is rarely demonstrated by computerized tomography (CT) or MRI.93,94 CT scans in the early stage of the disease can be normal87,95; diffuse cerebral atrophy involving both gray and white matter in the third stage develops later.93 Diffuse hypodensity of the white matter may be present, particularly in the parieto-occipital region.55,96 However, these findings are nonspecific and can be observed in many white matter diseases. Localized lesions have been described in some reports: hypodensity of periventricular parieto-occipital white matter87; high density in the thalamus,97 corona radiata,98 and cerebellar cortex98,99 (Figure 147-1); high density in the globus pallidus changing to low density with disease progression100; and necrosis of the corpus callosum.101 Discrete and symmetric dense areas on CT were found in the deep gray matter of the hemispheres, thalamus, posterior limb of the internal capsule, quadrigeminal plate, and cerebellum, and also in periventricular and capsular white matter.102 In many patients with early infantile Krabbe disease, intracranial calcification in the white matter and thalamus has been observed and is associated primarily with high concentrations of globoid cells.434 ++ Fig. 147-1 CT and MRI images of an infant with GLD. A-C: CT of a 5-month-old patient shows symmetrically increased density in (A) cerebellar cortex, (B) thalami, and (C) corona radiata. D-F: T2-weighted images on MRI. TR: 2100 ms; TE 100 ms. There is an abnormally high signal intensity in cerebellar white matter (D), and slightly high signal intensity in the posterior limbs of the internal capsules (E) and periventricular cerebral white matter (F). (From Pediatr Neurol98 with permission.) Graphic Jump Location+View Full Size|Favorite Figure|Download Slide (.ppt) ++ In general, MRI detects demyelination in the brainstem and cerebellum more clearly than CT in the early stage of the disease (Figure 147-2).97 However, one 5-month-old infant had a deceptively normal MRI scan when CT already revealed symmetric hyperdensity involving the cerebellum, thalami, caudate, corona radiata, and brainstem.103 Another patient had a deceptively normal initial MRI scan at 3 months of age, with progression of the white matter disease over the subsequent 9 months.104 The T1 value was decreased, with normal or slightly decreased T2 in white matter of the centrum semiovale.102 A plaque-like high signal intensity in T2-weighted images and low signal intensity in T1-weighted images in the periventricular and cerebellar white matter were reported in 3 infants (Figure 147-1).98 On the other hand, T2-weighted and fluid-attenuated inversion recovery (FLAIR) MRI showed symmetric high intensity of the pyramidal tract and optic radiation in an adult patient who developed initial clinical manifestations at 60 years of age (Figure 147-3). Enhancement of multiple cranial nerves or lumbosacral nerve roots has been observed in some patients (Figure 147-4).420– 423 In one family, 3 members developed adult-onset disease with GALC deficiency and gait disturbance but MRI findings were normal.424 Calculation of the T2 value in the central white matter provides a basis for objective judgment for demyelinating diseases.105 T2 values increased gradually in the occipital deep white matter and posterior part of central semiovale in late-onset disease. MRI was also useful for differentiation between dysmyelination and demyelination.106 GLD with severe demyelination shows high-intensity lesions on T2-weighted images, with a loss of diffusional anisotropy and relatively high signal intensity on diffusion-weighted images. The Loes scoring system, developed to monitor disease progression in X-linked adrenoleukodystrophy, is also useful for determining brain involvement in GLD, with some modifications.405 The Loes score has been shown to correlate with findings of neurophysiologic tests (eg, visual evoked potentials, brainstem auditory evoked potentials, electroencephalogram, nerve conduction velocity)406 and neurobehavioral development (cognitive ability and motor skills),407 and can therefore be used to assess prognosis and response to treatment. ++ Fig. 147-2 MRI images of a patient with late infantile GLD. (A) Linear structures of low signal intensity are seen in a radiating pattern (arrows), suggesting spared perivascular white matter similar to MLD. (B) Gliosis of the corticospinal tracts (upper right, arrows) and (C) midline structure atrophy (arrow, bottom right) is also noted. (Courtesy of Dr. G. Zuccoli, NDRD Program, Children's Hospital of Pittsburgh of UPMC.) Graphic Jump Location+View Full Size|Favorite Figure|Download Slide (.ppt) ++ Fig. 147-3 MRI images of an adult patient with GLD. (A) Axial T2-weighted images. TR 4000 ms; TE 98 ms. (B) Corresponding planes of FLAIR images. TR 10,002 ms; TE 138 ms. Bilateral pyramidal tract and optic radiation exhibits symmetrical high intensity on both images. (Courtesy of Dr M Takahashi, Sumitomo Hospital, Osaka, Japan.) Graphic Jump Location+View Full Size|Favorite Figure|Download Slide (.ppt) ++ Fig. 147-4 MRI of the brain of a patient with infantile GLD. The finding of multiple cranial nerve enhancements is not common, but when found it is pathognomonic for Krabbe disease. This case shows increased signal of all the cranial nerves (arrows) plus enhancement and enlargement of the optic nerves (blue arrows). (Courtesy of Dr. G. Zuccoli, NDRD Program, Children's Hospital of Pittsburgh of UPMC.) Graphic Jump Location+View Full Size|Favorite Figure|Download Slide (.ppt) ++ Unlike conventional T2-weighted MRI, diffusion tensor imaging (DTI) is a quantitative and reproducible method for evaluating myelination. Because DTI is more sensitive than conventional MRI, changes in diffusional anisotropy may appear before changes in T2-weighted images.425,426 Diffusion tensor imaging can be used to assess response to treatment by comparing anisotropy measurements in well-defined white matter structures with those of age-matched controls.408,409 Results of serial imaging (up to 4 years after treatment) showed that anisotropy measurements correlate with neurodevelopmental scores (cognitive ability, language, and motor skills).408 In addition, diffusion tensor imaging with fiber tracking can detect early changes in corticospinal tracts before symptoms are apparent.410 This technique can be used to determine which infants who screen positive for GLD have the early infantile form of the disease and would consequently benefit from immediate treatment. Magnetic resonance spectroscopy can also be used to document the demyelination, gliosis, and axonal loss in white matter of typical and atypical patients with GLD.427,428 A study evaluating metabolic changes in 7 patients reported that infantile GLD was characterized by increased myo-inositol and choline-containing compounds (indicating demyelination and glial proliferation) and decreased N-acetylaspartate (indicating neuroaxonal loss) in white matter and, to a lesser extent, in gray matter. In juvenile GLD, smaller changes in myo-inositol and N-acetylaspartate in white matter indicated astrocytosis with minor neuroaxonal damage, but in adult GLD brain metabolites were near normal.411 ++ Eeg, EMG, and Evoked Potentials ++ The electroencephalogram (EEG) is normal in the initial stages, but the cerebral rhythms gradually become abnormal. Background activity slows and becomes disorganized,34,37,62,64,66,77 with changes that may be asymmetric.66 This is often accompanied by multifocal paroxysmal or epileptic discharges.34,37,62,68,78,107 In accord with the clinical and pathologic observations of peripheral neuropathy, various abnormal results have been obtained by electrophysiological procedures. These include a mild increase in polyphasic motor unit potentials,64 presence of high-amplitude neuromuscular units with a decrease in the number of units,68 and a few fibrillations62,64 on routine EMG. Motor nerve conduction velocity is consistently low.42,62,64,68,71,72,107,108 Distal sensory latency of the median nerve was also prolonged in one patient.65 EMG and nerve conduction studies were normal in an adult patient with enzymatically confirmed diagnosis,86 but there was EMG evidence of demyelinating neuropathy in another adult.87,88 ++ One study reported that multimodal evoked potential testing was useful for the diagnostic differentiation of various types of leukodystrophies.109 Three GLD patients had an abnormal auditory brainstem response (ABR), with a loss of rostral waves accompanied by delayed I-III interpeak latencies. Sensory evoked potentials (SEPs) were abnormal; the cortical SEP was absent and cervical SEP showed peripheral slowing. Visual evoked potentials (VEPs) were also abnormal and correlated with disease progression. Another study reported prolongation of each wave component and interpeak latency in the early stages of the disease,110 but later components eventually disappeared.99,110 Abnormal brainstem auditory evoked responses (BAERs) tend to occur early in the course of infantile disease and can appear before clinical signs and symptoms.429,404 An adult patient showed prolonged I-III interpeak latency in ABR and prolonged N9-N19 interpeak latency in SEPs, although VEPs were normal.88 ABR was normal in another adult patient at age 29.86 + Pathology Print Section ++ ++ Although there are some isolated reports describing pathological findings outside the nervous system,74,111– 114 the pathology of GLD is limited, for all practical purposes, to the nervous system. In a study on a muscle biopsy sample, fiber-type disproportion has been described.115,116 Goebel et al117 have described typical inclusions in eccrine sweat gland epithelial cells. An infant was hospitalized at 8 weeks of age because of progressive feeding difficulty, generalized weakness, tachypnea, respiratory failure, and minor motor seizures.35 A lung biopsy revealed widespread distension of alveoli and alveolar ducts by numerous large macrophage-like cells containing amorphous, electron-dense, membrane-bound cytoplasmic inclusions. ++ Central Nervous System ++ Gross Pathology ++ The brain is usually small and atrophic, with shrunken gyri and widened sulci. The white matter is firm, reduced in volume, and of whitish-gray appearance. The ventricles are dilated. In contrast to the grossly abnormal white matter, the gray matter appears relatively normal except for a moderate reduction of cortical thickness. The junction of the gray and white matter is ill-defined. ++ Histopathology ++ The major histopathologic changes are extensive demyelination, gliosis, and presence of unique macrophages, the globoid cells, in the white matter. The subcortical arcuate fibers (U-fibers) tend to be spared except in unusually severe or protracted cases, in which practically no myelin can be demonstrated within the cerebral hemispheres. Among the various white matter systems, phylogenetically newer nerve fiber tracts are usually more severely involved by the demyelinating process. Thus, the fornix, the hippocampus, the mamillothalamic tract, and the nerve fiber bundles in the basal ganglia tend to be less involved than the centrum semiovale or the cerebellar white matter.112,118,119 In the spinal cord, the pyramidal tracts are more severely affected than the dorsal columns. In the areas of demyelination, the oligodendroglial cell population is severely diminished and globoid cells are often clustered around blood vessels (Figure 147-5). Secondary axonal degeneration is a consistent finding. In some clinically protracted cases, the white matter may be totally gliotic, without any globoid cells.42 If present, globoid cells have abundant cytoplasm, which stains positive with periodic acid-Schiff (PAS) stain. Characteristically, there is no sudanophilia. Intense acid phosphatase activity was demonstrated in these cells.63,80,112,120,121 The similarities in morphologic and histochemical characteristics between the globoid cells and the glucosylceramide-containing abnormal cells in Gaucher disease were often pointed out.5,8 There had been a long-lasting controversy as to the origin and nature of globoid cells,4,7,122– 125 but the current consensus is that these are cells of the mononuclear phagocyte lineage,126 which may become multinucleated as the unique response to free galactosylceramide.11– 13,127 (For more details, refer to the sixth edition of this text.) ++ Fig. 147-5 Typical light microscopic appearance of the white matter in GLD. Conspicuous clusters of globoid cells occupy a considerable portion of whole white matter. Globoid cells are PAS-positive and often contain multiple nuclei. The remainder of the tissue is mostly occupied by reactive astrocytes. Periodic acid-Schiff (PAS) stain; magnification ×120. Graphic Jump Location+View Full Size|Favorite Figure|Download Slide (.ppt) ++ In contrast to the devastated white matter, the gray matter is generally much less affected, although neuronal degeneration in the cerebral cortex, thalamus, cerebellar nuclei, and brainstem has been reported in some cases.7,81,122,128,129 A Golgi study indicated remarkably well-preserved dendritic processes of pyramidal neurons in the cerebral cortex.130 ++ Evolution of the Histopathologic Changes ++ It is difficult to determine the chronologic sequence of the various histologic changes, because it is rarely possible to follow morphologic changes in the same patient through the course of the illness. In their classic study, D'Agostino et al78 attempted to reconstruct the chronologic evolution of the morphologic changes through multiple sections from 3 different patients. Utilizing the degree of demyelination as the criterion, they divided the course into 4 stages: early, advanced, late, and final. In the early lesions, mononuclear globoid cells containing PAS-positive materials are present in the white matter, with only a slight decrease in the intensity of myelin staining. In the advanced stage, myelin and axons decrease and astrocytic gliosis becomes prominent. The globoid cells are more numerous and tend to cluster around blood vessels. Many become multinucleated. In the late stage, the globoid cells become fewer in number and are mostly clumped around blood vessels. Myelin and axons are markedly diminished at this stage. The final stage is characterized by predominant astrocytic gliosis, with a few remaining globoid cells, and a total loss of myelin and axons. Later chronologic investigations using canine or murine models of GLD support accuracy of this earlier study in human patients (see the "Animal Models" section). ++ Ultrastructure ++ There are many reports describing the ultrastructural pathology of GLD.35,37,40,62,66,75,107,108,125,131–140 Mononuclear and multinucleated globoid cells are similar ultrastructurally, except for the number of nuclei. They have prominent pseudopods, moderately electron-dense granular cytoplasm containing prominent rough endoplasmic reticulum, many free ribosomes, abundant fine filaments of approximately 9-10 nm, and scattered or clustered abnormal cytoplasmic inclusions (Figure 147-6). The inclusions have moderately electron-dense straight or curved hollow tubular profiles in longitudinal sections and appear irregularly crystalloid in cross sections (Figure 147-7). These tubular inclusions are often scattered among the normal intracellular organelles, but sometimes they are clustered within an electron-lucent space or within an electron-dense matrix. They often have longitudinal striations of variable density, approximately 6 nm in width. Other inclusions have a structure of slender twisted tubules with rectangular or irregularly round cross sections, resembling the tubular inclusions of Gaucher disease.66 Yunis and Lee135 pointed out the morphologic similarities of the abnormal inclusions to negatively stained pure brain galactosylceramide. Intracerebral injection of pure galactosylceramide into rat brain produced cells that have a morphology essentially identical to that of human globoid cells, containing both types of the tubular inclusions.141,142 Inclusions are also reported, though infrequently, in astrocytes and oligodendrocytes. Degeneration of myelin, with or without associated axonal degeneration, is widespread in the white matter, but the remaining myelin has normal multilamellar configuration with normal periodicity. ++ Fig. 147-6 A low-magnification electron micrograph of a globoid cell. Only one nucleus is visible. There are numerous tortuous pseudopods (arrows), which characterize this cell as a macrophage. Within the cytoplasm, near the center of the picture, there are many abnormal tubular inclusions (for details see Figure 147-5). Graphic Jump Location+View Full Size|Favorite Figure|Download Slide (.ppt) ++ Fig. 147-7 A high-magnification electron micrograph of a globoid cell. The image shows abnormal hollow tubules with longitudinal striations approximately 6 nm wide. Graphic Jump Location+View Full Size|Favorite Figure|Download Slide (.ppt) ++ Peripheral Nervous System ++ The peripheral nerves are commonly affected in GLD.62,64,73,75,133,135,143–148 The affected nerves are firm and often abnormally thick and white on gross inspection. The major pathologic features are marked endoneurial fibrosis, proliferation of fibroblasts, demyelination, and infiltration or perivascular aggregation of histiocytes/macrophages containing PAS-positive materials. Teased fiber preparations clearly demonstrate segmental demyelination, increased variations in internodal length, and osmiophilic lipid droplets in paranodal Schwann cell cytoplasm.144,148 Thinly myelinated fibers suggestive of remyelination may be present. Quantitative analysis has demonstrated a severe loss of large myelinated fibers, but the number of unmyelinated fibers was not diminished.141 Axonal degeneration of varying degrees has been reported.62,64,116,127,148 Ultrastructurally, inclusions similar to those in globoid cells in the brain are found in the cytoplasm of histiocytes and macrophages, as well as in the Schwann cells.135,145,147 ++ Pathology of Late-Onset GLD ++ Despite the increasing clinical reports on late-onset cases in recent years, only limited information is available on their neuropathology. In late infantile and juvenile cases, neuropathologic changes are similar to those in typical infantile-onset patients. The only available description of the CNS pathology of adult-onset GLD is the one by Choi et al.149 The patients were 18-year-old identical twins. Their symptoms developed 12 and 7 months prior to death. Two months after allogeneic bone marrow transplantation, both patients died of severe graft-versus-host disease. The neuropathologic changes, almost identical in the 2 patients, included degeneration of the optic radiation and of the frontoparietal white matter, with secondary corticospinal tract degeneration. The frontoparietal lesions consisted of multiple necrotic foci with calcified deposits and active degeneration of the surrounding white matter with globoid cell infiltration. Small satellite foci of degeneration with globoid cells were also noted. In the peripheral nerves of patients with late-onset forms, demyelination and the abnormal inclusions in Schwann cells have been described.38,44,47,53,82,150 A 73-year-old woman, who was the oldest person reported to have a case of GALC deficiency, showed loss of myelinated fibers, with disproportionately thin myelin sheaths, and Schwann cells containing needle-like inclusions.150 Two siblings, who died at 59 and 61 years of age, also were found to have hypomyelination with some lamellar inclusions in their sural nerves.430 ++ Pathology of Fetal Globoid Cell Leukodystrophy ++ Neuropathologic studies have reported GALC deficiency in fetuses of 20-23 weeks' gestation.151– 153 Scattered globoid cells with typical inclusions were found in the spinal cord, being more numerous in the dorsal column. Globoid cells were found in the pons in one fetus but were not found in the brainstem in other fetuses. No globoid cells were detected in the cerebrum or cerebellum. These findings are consistent with the normal sequence of myelination in the developing brain in that, at this gestational age, the telencephalon has not begun to myelinate. One report indicated a delay in myelination of both the central and peripheral nervous systems.151 However, a comparison of an affected fetus with its unaffected fraternal twin showed no differences in degree of myelination.153 Abnormal inclusions were found in the Schwann cells and endoneurial fibroblasts of peripheral nerves.152 + Biochemistry of Galactosylceramide Print Section ++ ++ Chemistry of Galactosylceramide and Related Compounds ++ Galactosylceramide (galactocerebroside) is a sphingoglycolipid consisting of a long-chain base, sphingosine, and a galactose (Figure 147-8). The amino group of sphingosine is acylated with long-chain fatty acid (C14-C26). N-acylsphingosine, generically called ceramide, is the basic common building block of almost all sphingolipids. Generally, the fatty acids of galactosylceramide and sulfatide in the brain are characterized by the predominance of longer-chain fatty acids (C20-C26), the lack of polyunsaturated fatty acids, and the presence of α-hydroxy acids. Approximately two-thirds of the fatty acids in cerebrosides and one-third of those in sulfatides are α-hydroxy fatty acids. Cerebroside is defined as a monohexosyl ceramide, the hexose being linked to the C-1 of ceramide by a glycosidic linkage. The hexose is either D-glucose or D-galactose. Depending on the nature of the hexose, cerebroside is named glucocerebroside (glucosylceramide) or galactocerebroside (galactosylceramide). Both the glucose and galactose are in the β anomeric configuration. Glucosylceramides alone and as a component of complex glycosphingolipids occur predominantly in systemic tissues outside of the nervous system and are present only at very low concentrations in normal human brain after one year of age. They are present in small amounts in the brains of normal human fetuses and newborns154 and in the brains of older children with certain diseases, notably ganglioside storage disorders.155,156 In contrast, galactosylceramide is characteristically a lipid of the nervous system, particularly of the myelin sheath. Sulfatides are derived from galactosylceramide, having a sulfate group ester-linked to the C-3 of galactose. Sulfatides are also present at high concentrations in myelin. ++ Fig. 147-8 Structure of galactocerebroside (galactosylceramide). The molecule consists of sphingosine, fatty acid, and galactose. R = -(CH2)nCH3. Graphic Jump Location+View Full Size|Favorite Figure|Download Slide (.ppt) ++ There is another related compound that is important in the pathogenesis of GLD: Psychosine (galactosylsphingosine, ceramide minus fatty acid) is essentially absent in normal brain,157– 159 but it is increased in the nervous system of individuals with Krabbe disease. ++ Though detailed structures of the individual moieties, such as fatty acids or sphingosines, differ among these glycosphingolipids, the simplified notations are convenient for purposes of most discussions in this chapter. Figure 147-9 depicts chemical and metabolic relationships among galactosylceramide and related compounds using such simplified notations. ++ Fig. 147-9 Structural relationships between galactosylceramide and related compounds. It should be understood that the arrows between the sphingolipids do not represent reversible enzymatic reactions. Graphic Jump Location+View Full Size|Favorite Figure|Download Slide (.ppt) ++ Metabolism of Galactosylceramide and Related Compounds ++ Galactosylceramide is biosynthesized first by acylation of sphingosine to ceramide and then by galactosylation of ceramide catalyzed by UDP-galactose: ceramide galactosyltransferase (CGT)160,161 (Figure 147-9). The activity of this enzyme increases significantly during the period of active myelination. Sulfatide is then synthesized from galactosylceramide with 3′-phosphoadenosine-5′-phosphosulfate (PAPS) as the sulfate donor.162 In addition, it has been long known that sphingosine can be directly galactosylated to form psychosine.163 This reaction appears to be a dead-end pathway metabolically, because the possible alternate pathway for the synthesis of galactosylceramide, namely the acylation of psychosine, has not been conclusively established. However, this dead-end pathway appears to play a role in the pathogenesis of GLD. ++ The initial step in the lysosomal degradation of sulfatide is removal of the sulfate group to convert it to galactosylceramide. This reaction is catalyzed by cerebroside sulfate sulfatase (arylsulfatase A).164 Deficiency of this enzyme results in another inherited leukodystrophy, MLD, in which abnormal accumulation of sulfatide occurs165,166 (see Chapter 148). Galactosylceramide is subsequently degraded to ceramide and galactose by a lysosomal hydrolytic enzyme, galactocerebrosidase (GALC, EC 22.214.171.124). ++ Purification and Characterization of GALC ++ GALC, initially called cerebroside galactosidase, was first studied in detail by Radin and coworkers.167– 170 In rat brain, GALC activity is present at 4 days of age, before myelination, when little galactosylceramide is present. The enzyme activity then rises 3 to 4 times above this level during the period of active cerebroside deposition and myelination. Activity remains high in mature animals. In 1993 Chen and Wenger23 succeeded in purifying GALC from human urine and brain using a series of hydrophobic affinity columns to take advantage of its extremely hydrophobic nature. As shown in Figure 147-10, the most pure fraction from human brain consisted of bands with approximate molecular weights of 80 kDa, 50-52 kDa, and 30 kDa based on migration on sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE). Studies also showed that these polypeptides could aggregate into a very large complex with an estimated molecular weight greater than 800,000. The purified enzyme had high activity toward galactosylceramide and psychosine and also had significant activity when measured using the water-soluble fluorescent substrate 4-methylumbelliferyl-β-D-galactopyranoside.23 N-terminal amino acid sequence analysis helped to confirm the relationship between the bands identified on SDS-PAGE. The band migrating near 80 kDa and all of the bands between 50 and 52 kDa shared the same N-terminal amino acids, while the sequence of the 30-kDa band was different. An antipeptide antibody prepared against the N-terminal amino acid sequence could detect the 80- and 50- to 52-kDa bands.23 Treatment with endoglycosidase F to remove N-linked sugar chains indicated that the multiple bands near 50 kDa are not due to glycosylation differences, but probably reflect proteolytic trimming during processing of the mature enzyme. Using information provided by those sequences probes were prepared and the cDNA for human GALC was cloned.24 The cDNA sequence provided direct evidence that the 80-kDa band was the precursor of the 50- to 52-kDa and 30-kDa bands. The coding region for the 50- to 52-kDa sequences is at the 5′ end of the gene and the coding region for the 30-kDa subunit is at the 3′ end of the gene. Both subunits are required for the production of active enzyme. Subsequently, Sakai and coworkers173 purified this enzyme from human lymphocytes and reached similar conclusions, although there are some differences in the estimated molecular weights of the bands identified after gel electrophoresis of the purified fractions. ++ Fig. 147-10 SDS-PAGE of the most active fractions of GALC purified from human brain. G denotes the active GALC fraction, and S denotes the molecular weight standards. The gel was stained with Coomassie blue. (From Biochim Biophys Acta,23 with permission of Elsevier Science.) Graphic Jump Location+View Full Size|Favorite Figure|Download Slide (.ppt) ++ Recently Deane and colleagues described the crystal structures of mouse GALC and GALC-product complex, revealing 3 domains necessary for activity.395 Two domains are common to other hydrolases and the third is a lectin-binding domain, not previously observed in other hydrolases. Both subunits are necessary for enzymatic activity. This structural information may be useful in predicting the effects of mutations and assisting in the development of novel therapies. ++ Substrate Specificity of GALC ++ While galactosylceramide is clearly the main natural substrate, GALC is also active in catalyzing hydrolysis of terminal galactose from psychosine,20,171–176 monogalactosyldiglyceride,177 and lactosylceramide under specific assay conditions.178– 184 Knowing the substrate specificity of the enzyme provides important information related to possible pathogenetic mechanisms, as well as to enzymatic diagnosis of the disease. It has been demonstrated that phosphatidylserine can specifically activate human brain GALC activity toward natural substrates.185 The hydrolysis of galactosylceramide by GALC is stimulated by the presence of certain so-called sphingolipid activator proteins (saposins) in the presence of acidic lipids, such as phosphatidylserine186 (see Chapter 134). Transgenic mice with an amino acid substitution in the saposin A domain of prosaposin have pathological changes similar to those observed in the later onset forms of GLD.431 In addition, a few patients with white matter disease were found to have mutations in the saposin gene.338,unpublished communications ++ Glycolipid Distribution ++ The distribution of galactosylceramide is mainly limited to the nervous systems and kidneys.187,188 Brain tissue, particularly white matter, is rich in galactosylceramide and its sulfate ester, sulfatide. Galactosylceramide is mostly, if not exclusively, located in the myelin sheath and synthesized in the oligodendroglia and the Schwann cells. Thus, galactosylceramide is virtually absent in the brain before myelination and is present at abnormally low concentrations in any pathologic conditions in which a severe loss of myelin occurs. The amounts of total brain galactosylceramide correlate precisely with the amounts of myelin that can be isolated from the brain, whereas amounts of other lipids do not.189 ++ Myelin of adult mammalian brain generally contains galactosylceramide at a concentration of 15-18 percent of dry weight. The content of galactosylceramide in myelin from peripheral nerves is somewhat less than that of CNS myelin.190 The most significant metabolic features of CNS myelin are its high rate of formation during a relatively short developmental period of active myelination and its slow turnover in the adult brain. The period of most active myelination in humans probably extends from the perinatal period to about age 18 months, but it may not be complete until 20 years of age.191 The amount of galactosylceramide in immature brain is very low compared to the concentrations of cholesterol and phospholipids. When measured by incorporation of labeled galactose administered in vivo, the rate of galactosylceramide synthesis in rat brain reaches a peak at 15-20 days, coinciding well with the most active period of myelination.192 This corresponds to a sharp increase in the activity of CGT, an enzyme that catalyzes the last step of galactosylceramide synthesis.193 The recent cloning of rat and mouse CGT confirms that peak levels of the corresponding mRNA occur during the period of most active myelination and that relatively high mRNA levels are found in brain and kidney.194– 197 ++ The metabolism of galactosylceramide involves many enzymes related to both its biosynthesis and degradation. The deficiency of one of these enzymes that could result in a change in the optimal glycolipid composition could lead to hypomyelination, dysmyelination, or demyelination. Critical levels of GALC activity appear to be necessary during the initial myelination period and for repair following an environmental insult. + Chemical Pathology Print Section ++ ++ Hallervorden was the first to point out the morphologic similarities of the globoid cells in GLD to the storage cells in Gaucher disease and to suggest that the globoid cells also might contain cerebroside in excess.5 Austin6 obtained fractions enriched in globoid cells from 7 patients with GLD. He concluded that globoid cells contain unusually large amounts of galactosylceramide but little sulfatide. Because of myelin loss, both galactosylceramide and sulfatide levels are usually lower than normal in the white matter overall.9,14,15,36,77,157–159,198–206 ++ An increase in the amount of psychosine, primarily in the white matter but also in other organs, is seen in infants with GLD.157– 159,207,208 It should be noted that the absolute amounts of psychosine found in the white matter of patients are still very small—approximately 2 orders of magnitude less than those of galactosylceramide. Even such small amounts are significant, because psychosine is essentially undetectable in normal tissues. Evidence for the cytotoxicity of psychosine and its role in the pathophysiology of GLD will be discussed later. ++ Besides the glycolipid abnormalities, white matter in GLD typically shows increased water content and a drastic reduction of proteolipid protein and total lipid content, with a consequently relative, but not absolute, increase in protein. Cholesterol, lecithin, sphingomyelin, and ethanolamine and serine phospholipids are all relatively reduced to similar degrees. These findings merely reflect the devastating myelin loss. In contrast to that of the white matter, the chemical composition of the gray matter is relatively normal. In keeping with the normal histologic appearance, non-neural tissues do not show conspicuous compositional changes except for the large relative increase in psychosine.207 Suzuki210 examined galactosylceramide levels in the kidneys of 5 patients and found them to be approximately 30 percent higher than normal. Since the glucosylceramide level was similarly high in patients' kidneys, it was concluded that there was no specific abnormal increase of galactosylceramide in the kidney. There are no reports describing kidney failure in patients with GLD. + Enzymatic Defect Print Section ++ ++ The fundamental genetic defect of GLD is a deficiency of GALC activity.337,16,17,18 This enzyme catalyzes the lysosomal degradation of galactosylceramide to galactose plus ceramide. The deficient activity of this enzyme can also be demonstrated with the other natural substrates psychosine,20,175 monogalactosyldiglyceride,177 or lactosylceramide.178– 184,212 ++ Mammalian tissues contain 2 genetically distinct lysosomal β-galactosidases, GALC and GM1-ganglioside β-galactosidase (commonly referred to simply as acid β-galactosidase; EC 188.8.131.52). They have different but overlapping substrate specificities. Deficiencies of the respective enzymes result in entirely different disorders because of the different natural substrates involved. Deficiency of acid β-galactosidase activity results in GM1 gangliosidosis or Morquio syndrome type B (Chapter 151). Both β-galactosidases share lactosylceramide as a substrate, and consequently lactosylceramide accumulation does not occur to any significant degree in either GLD or GM1 gangliosidosis. It can further be predicted that under these circumstances a specific disorder with accumulation of lactosylceramide probably does not occur in humans.213 Kobayashi et al214 demonstrated that under certain assay conditions, particularly in the presence of sodium cholate, acid β-galactosidase could also hydrolyze galactosylceramide, but not psychosine. However, purified GALC could hydrolyze both galactosylceramide and psychosine.23 + Pathophysiology Print Section ++ ++ Because a genetic defect of GALC is the underlying cause of GLD, we should be able to understand the morphologic and biochemical characteristics of the disease on the basis of this deficiency. These include: (1) an almost total loss of myelin and oligodendroglia; (2) normal chemical composition of the remaining myelin209; (3) morphologic evidence of decrease in the amount of myelin during the illness78; (4) massive infiltration of globoid cells; (5) absence of excess accumulation of galactosylceramide in the brain despite a block in the degradative pathway; and (6) a high concentration of psychosine, especially in nervous tissues. ++ In 1970, Suzuki and Suzuki16 proposed a plausible hypothesis on the evolution of the disease based on the 2 unique features of galactosylceramide: (1) galactosylceramide is almost exclusively a constituent of myelin and oligodendroglia; and (2) galactosylceramide is unique among sphingoglycolipids in its ability to elicit the globoid cell reaction when injected into normal rat brain.11– 13 According to this hypothesis, the following sequence of steps could occur in the brain of a patient with infantile GALC deficiency. Before myelination, there is practically no galactosylceramide in the brain. Therefore, lack of enzyme activity is of little consequence, although it is normally present at low activity even at the premyelination stage.170 As soon as myelination begins, just before birth in humans, newly formed myelin begins to undergo normal turnover. This period coincides with a rise of GALC activity in normal brain.170 In the brains of patients with GLD, galactosylceramide from catabolized myelin cannot be degraded because of the lack of the enzyme. This undegraded galactosylceramide causes globoid cell formation following macrophage infiltration. However, myelination cannot proceed normally, because the oligodendroglial cells disappear rapidly. With the significant death of oligodendroglial cells, myelin rapidly breaks down, contributing more free cerebrosides, which prompt a further rapid increase in the number of globoid cells. Finally, a majority of oligodendroglial cells die, and much of the myelin is degraded. No further increase in the number of globoid cells or galactosylceramide can occur because there is no longer any cellular source for new galactosylceramide and myelin. Therefore, the total amount of cerebroside that can accumulate in the brain during the short lifespan of the patient is limited by the small amount of myelin produced before the death of most oligodendroglial cells, which takes place at an early stage of myelination. ++ In 1972, Miyatake and Suzuki formulated a hypothesis to explain the unusually rapid and complete destruction of the oligodendroglia in GLD.20 Psychosine can be formed from UDP-galactose and sphingosine via the action of CGT, the same enzyme that catalyzes the addition of galactose to ceramide. Psychosine, with its free amino group, is known to be highly cytotoxic and induce apoptosis in vivo and in vitro.216,217,218,342–346 Psychosine is a substrate for GALC, and therefore patients with GLD are unable to degrade it. So it is conceivable that psychosine generated within oligodendroglia during the period of active myelination might reach a toxic level. Oligodendroglia are selectively destroyed because psychosine accumulation occurs primarily in these cells. In the white matter of human patients with infantile GLD and the animal models, psychosine has been shown to be greatly increased (see "Animal Models" section).21,219,220 This may explain the early destruction of oligodendroglial cells and the resultant cessation of myelination. The "psychosine hypothesis" was discussed in detail in a review by Suzuki.355 Apoptotic depletion of oligodendrocytes has been noted in the brains of twitcher mice and humans.344,346 The mechanisms for psychosine-induced cell death have been investigated by several laboratories, and a number of important steps related to normal cell functioning have been shown to be affected. These include inhibition of protein kinase C, activation of initiator and effector caspases, disruption of peroxisomal functioning, and activation of phospholipase A2 and several cytokines.347– 351 In addition, a role for psychosine in cytokinesis and the formation of the multinucleated globoid cells has been proposed.352 Recent studies have shown accumulation of psychosine in lipid rafts, which results in disruption of the rafts, providing a mechanism for inhibition of protein kinase C.353 Psychosine has also been shown to induce axonal defects and cell death in cultures of isolated neurons.354 ++ Involvement of the peripheral nervous system is to be expected because the myelin sheath also contains galactosylceramide. Histiocytes in peripheral nerves contain abnormal inclusions similar to those in the brain, but it is not clear why they are not transformed into the typical multinucleated globoid cells. The absence of discernible morphologic and functional abnormalities outside the nervous system is understandable, because normally galactosylceramide is practically absent in most non-neural tissues except for the kidney. Either a small amount of residual GALC activity or the action of acid β-galactosidase might be adequate to account for the normal turnover of renal galactosylceramide. In addition, there is little evidence that patients with late-onset GLD accumulate psychosine. ++ A unique feature of GLD is the lack of increase in the total galactosylceramide content in the brain despite the genetic defect in its catabolism. In MLD, an analogous genetic disorder, the amount of sulfatide in white matter becomes excessive as a result of defective sulfatide degradation (Chapter 148). The early disappearance of the oligodendroglia and the consequent early cessation of myelination therefore still appear to be the only explanation for the lack of abnormally high galactosylceramide accumulation. + Molecular Genetics Print Section ++ ++ In 1990 Zlotogora et al22 mapped the gene for GLD to human chromosome 14 using large informative families and information localizing the gene for the twitcher mouse model to chromosome 12.222 In 1993 the human gene was further localized to region 14q24.3-q32.1 by multipoint linkage analysis.223 In situ hybridization using the GALC cDNA mapped this gene to 14q31.224 Using probes generated from N-terminal amino acid sequence information from purified GALC, Chen et al24 were able to clone the human GALC cDNA. The cDNA consisted of 3795 bp, including 2007 bp of coding region, 47 bp of 5′ untranslated sequence, and 1741 bp of 3′ untranslated sequence. The coding region encodes a protein consisting of 669 amino acids with 6 potential glycosylation sites. It also encodes a 26-amino-acid leader sequence. Another potential initiation codon has been identified located 48 nucleotides upstream from the one initially reported. This would result in a leader sequence of 42 amino acids. Expression studies using constructs with the 2 different leader sequences showed no difference in GALC expression (unpublished data). Because of this, we are using the original numbering system when reporting mutations in this chapter. Note that some recent publications reporting mutations in patients number from the more upstream ATG as the start of the coding region. This would add 48 nucleotides and 16 amino acids to the original numbering system. The precursor protein is approximately 80-85 kDa and is processed into 50- to 52-kDa and 30-kDa subunits. The coding sequence for the 50- to 52-kDa subunit is at the 5′ end of the coding region, and the 30-kDa subunit is at the 3′ end. The initiation codon is less than optimum based on the sequences described by Kozak.225 Sakai et al25 also published the cloning of the human GALC cDNA with several nucleotide changes present at polymorphic sites. ++ In 1995 Luzi et al26 described the organization of the human gene encoding the enzyme GALC. It consists of 17 exons spread over about 56 kb (Figure 147-11). Other than exons 1 and 17, they ranged in size from 39 to 181 nucleotides. The introns ranged in size from 247 nucleotides in intron 2 to about 12 kb in intron 10. The 200 nucleotides preceding the initiation codon and the 5′ end of intron 1 were very GC-rich, including 13 GGC trinucleotides. Analysis of the 5′ flanking region revealed the presence of a YYI element and one potential SP1 binding site.226 No consensus TATA box or CAAT box was detected in the 800 nucleotides preceding the initiation codon. A construct containing nucleotides −176 to −24 had the strongest promoter activity. However, evidence for inhibitory sequences was found just upstream of the promoter region and at the 5′ end of intron 1. Sakai and coworkers227 also analyzed the human gene, with similar findings, although they did not note the presence of inhibitory elements in the 5′ flanking region. ++ Fig. 147-11 Organization of the human GALC gene. This shows the 17 exons and 16 introns and their exact or approximate sizes. The vertical bars represent the exons. Graphic Jump Location+View Full Size|Favorite Figure|Download Slide (.ppt) ++ Mutation Analysis ++ With the nucleotide sequence available, it was possible to analyze the mutations in patients with GLD, some of which were described in a review article.228 Table 147-1 provides a list of more than 140 published and unpublished mutations found in patients with GLD. Some mutations, designated NYS, were identified at the New York State Department of Health using DNA samples supplied by one of us (DAW) from diagnosed patients. For some mutations, comments suggest whether a mutation is severe or mild. As many patients are compound heterozygotes, having 2 different mutations in the GALC gene, it is sometimes difficult to determine which, if any, mutation is responsible for a milder phenotype. Even one copy of a "mild" mutation can result in a non-infantile onset. Sometimes assignment of mutation severity is possible if a number of patients have a shared mutation and different second alleles. Obviously, some mutations involving deletions or insertions, a premature stop codon, or missplicing will result in little if any mature protein. While missense mutations can result in inactive enzyme, unstable enzyme, and improperly processed enzyme, measurement of GALC activity after expression studies cannot reliably quantify the small amount of activity produced. Also, as is noted in Table 147-1, some mutations are more frequent among certain populations. However, with the analysis of more patients and more ethnic diversity in the sample population, some mutations thought to be in one group have been found in others. From looking at the wide distribution of disease-causing mutations, it is obvious that both subunits are necessary for activity. ++Table Graphic Jump LocationTable 147-1. Mutations found in patients with globoid cell leukodystrophyView Large|Favorite Table|Download (.pdf) Table 147-1. Mutations found in patients with globoid cell leukodystrophy Number Mutation designation b Location Base Change Effect Comments Reference 1 13delG Ex1 GGCCGC>GGCCC FS, PS Severe 339 2 C20A Ex1 TCG>TAG S7X Severe 228 3 G121A Ex1 GGC>AGC G41S Mild 398 4 G127A Ex1 GGC>AGC G43S Severe NYS d 5 G127C Ex1 GGC>CGC G43R 356 6 127delG Ex1 TCGGCG>TCGCG FS, PS Severe 396 7 G130A Ex1 GCG>ACG A44T 398 8 C131T Ex1 GCG>GTG A44V Mild NYS 9 G147C Ex1 GGG>GGC G49G, missplicing 238 10 delEx1-6 Ex1-6 delEx1-6 no protein made Severe 396 11 C152T Ex2 ACC>ATC T51I Mild 433 12 T154C Ex2 TCC>CCC S52P Severe 402 13 C155T Ex2 TCC>TTC S52F Severe, Japanese 356 14 C157T Ex2 CGA>TGA R53X Severe 339 15 G188A Ex2 CGT>CAT R63H Mild 238 16 A198G Ex2 ATA>ATG I66M Mild, Japanese 58 17 A214T Ex2 AAG>TAG K72X Severe 339 18 216+2t>g Int2 AAGgta>AAGgga missplicing Severe NYS 19 G226A Ex3 GGT>GAT G76D 402 20 254-260dup Ex3 AAATAGGdup FS, PS Severe 339 21 A277G Ex3 ACA>GCA T93A Severe 402 22 280+1g>t Int3 CAGgta>CAGtta missplicing Severe NYS 23 G283A Ex4 GGC>AGC G95S Mild 238 24 G284A Ex4 GGC>GAC G95D Severe 228 25 A286G Ex4 ACT>GCT T96A e Mild 55 26 A301T Ex4 ATG>TTG M101L Mild 228 27 C331T Ex4 CGA>TGA R111X Severe 339 28 G340A Ex4 GAG>AAG E114K Severe 339 29 G344A Ex4 TGG>TAG W115X Severe 399 30 360delA Ex4 AGAAGC>AGAGC FS, PS Severe 339 31 363delTAA Ex4 GCTAAG>GCG K122 del (?) Mild 402 32 382delA Ex4 ATATTA>ATTTA FS, PS #125 on same allele, low mRNA 228 33 384insA Ex4 ATTACA>ATTAACA FS, PS Severe 400 34 393delT Ex4 CATTGG>CATGG FS, PS Severe 399 35 C413G Ex5 CCT>CGT P138R Mild 433 36 G441A Ex5 TGG>TGA W147X Severe 400 37 C443G Ex5 CCT>CGT P148R Severe U 38 473delA Ex5 TTATGT>TTTGT FS, PS Severe 339 39 A512T Ex5 GAT>GTT D171V 55 40 T530C Ex5 ATT>ACT I177T NYS 41 G533C Ex5 GGA>GCA G178A 228 42 534+1g>a Int5 GGAgtt>GGAatt Splicing error Severe NYS 43 535del39 Ex6 del39nts Skip Ex6 Mild, Japanese 58 44 C551A Ex6 TCA>TAA S184X Severe, Chinese 436 45 563del5 Ex6 del5nts FS, PS Severe 401 46 G573A Ex6 AAG>AAA K191K, missplicing Severe 402 47 573ins34 Ex6 ins34nts from intron FS, PS Severe 238 48 574-1g>t Int6 aagATA>aatATA Loss of splice acceptor, del 8 bp Ex7, FS, PS Severe, #133 on same allele 228 49 A580T Ex7 AGA>TGA R194X NYS 50 602del8 Ex7 del8nts FS, PS Severe 400 51 C610T Ex7 CGA>TGA R204X Severe 399 52 G625A Ex7 GCA>ACA A209T Mild NYS 53 C626A Ex7 GCA>GAA A209E Severe NYS 54 635del+ins Ex7 del12nts+ins3nts del5aa+ins2aa Severe, Japanese 233 55 G643A Ex7 GAG>AAG E215K f Mild 238 56 T668C Ex7 CTT>CCT L223P Mild 398 57 T701C Ex7 ATA>ACA I234T Severe 228 58 727delT Ex8 CCATTC>CCATC FS, PS Severe, Turkish 435 59 G739A Ex8 GCA>ACA A247T 228 60 C770T Ex8 TCT>TTT S257F Severe 399 61 G772C Ex8 GAA>CAA E258Q Severe NYS 62 G775C Ex8 GAC>CAC D259H Severe 402 63 C785T Ex8 ACT>ATT T262I Severe 356 64 G802A Ex8 GGT>AGT G268S 238 65 G809A Ex8 GGC>GAC G270D Mild 228 66 G818A Ex8 GGT>GAT G273D Severe NYS 67 C820T Ex8 CGC>TGC R274C Severe 400 68 A836C Ex8 AAT>ACT N279T 228 69 A836T Ex8 AAT>ATT N279I Severe 402 70 C860T Ex8 TCC>TTC S287F Severe 228 71 860+1g>a Int8 TTCgta>TTCata missplicing Severe 400 72 del6.9kb Int7-Int8 Ex8del FS, PS Severe 396 73 A893G Ex9 TAT>TGT Y298C Severe 238 74 C904G Ex9 CCT>GCT P302A Severe 233 75 C905G Ex9 CCT>CGT P302R Mild 339 76 906delT Ex9 CTTATG>CTATG FS, PS Severe 228 77 A908G Ex9 TAT>TGT Y303C e Mild 402 78 G919A Ex9 GGG>AGG G307R 339 79 G919T Ex9 GGG>TGG G307W NYS 80 G920A Ex9 GGG>GAG G307E Severe NYS 81 A925G Ex9 ATG>GTG M309V Mild NYS 82 C934T Ex9 CAA>TAA Q312X Severe 398 83 A956G Ex9 TAC>TGC Y319C 356 84 964delG Ex9 TAGAAT>TAAAT FS, PS Severe 228 85 1026del10 Ex10 del10nts FS, PS Severe 228 86 C1060G Ex10 TAC>TAG Y354X Severe 399 87 T1091G Ex10 CTC>CGC L364R Severe 399 88 T1103C Ex10 ATT>ACT I368T Mild 339 89 G1105T Ex10 GAA>TAA E369X Severe 25 90 1110del10 Ex10 del10nts FS, missplicing (?) Severe NYS 91 1113+2t>g Int10 ATGgta>ATGgga missplicing Severe NYS 92 Int10del Int10/Ex11 delinInt10 and 26bpEx11 FS, PS Severe 228 93 502T/del Int10/end del 30 kb short mRNA Severe 229 94 1123del5insA Ex11 del5insA FS, PS Severe 339 95 T1126C Ex11 TCT>CCT S376P NYS 96 C1138T Ex11 CGG>TGG R380W Severe 228 97 G1139T Ex11 CGG>CTG R380L Severe 401 98 C1151T Ex11 CCT>CTT P384L 228 99 Ex11-14dup Ex11-14 DupEx11-14 FS, PS Severe 396 100 T1228G Ex12 TGG>GGG W410G Severe 356 101 1314insT Ex13 insT FS, PS Severe NYS 102 A1334T Ex13 GAT>GTT D445V Severe NYS 103 C1355G Ex13 ACT>AGT T452S #120 on same allele 228 104 C1355T Ex13 ACT>ATT T452I NYS 105 1357del3insT Ex13 delCTCinsT FS, PS Severe 339 106 T1420A Ex13 TAT>AAT Y474N Severe 402 107 1424delA Ex13 ATAAGG>ATAGG FS, PS #141 on same allele 228 108 1441+1g>a Int13 TTGgtg>TTGatg missplicing Severe 339 109 C1480A Ex14 CAA>AAA Q494K Severe NYS 110 G1486A Ex4 GGT>AGT G496S Mild 403 111 T1493A Ex14 TTT>TCT F498S 228 112 C1538T Ex14 ACG>ATG T513M Severe 228 113 C1543T Ex14 CGC>TGC R515C Mild 228 114 G1544A Ex14 CGC>CAC R515H Severe, Japanese 356 115 G1582A Ex14 GAT>AAT D528N Severe, Israeli Arab 235 116 G1609A Ex14 GGA>AGA G537R Mild 402 117 A1616G Ex14 TAC>TGC Y539C NYS 118 T1649G Ex15 GTT>GGT V550G 233 119 A1652C Ex15 TAC>TCC Y551S Severe 228 120 1675insT Ex15 GGT>GTGT FS, PS #103 on same allele 228 121 C1688A Ex15 GCA>GAA A563E Severe 401 122 G1705T Ex15 GGT>TGT G569C Mild NYS 123 G1705A Ex15 GGT>AGT G5695 Mild 403 124 1719insT Ex15 TTA>TTTA FS, PS Severe 399 125 G1726T Ex15 GCC>TCC A576S #32 on same allele 228 126 1739delT Ex15 ATTTTC>ATTTC FS, PS 401 127 T1748G Ex15 ATT>AGT I583S Severe, Israeli Druze 235 128 A1766C Ex15 TAC>TCC Y589S Mild NYS 129 1767insA Ex15 TACAGG>TAACAGG Y589X Severe NYS 130 1771-1778dup Ex15 GTTACAGdup FS, PS Severe 339 131 A1781C Ex15 GAT>GCT D594A Mild 402 132 1788insT Ex16 AGCTGG>AGCTTGG FS, PS Severe, Chinese 436 133 1822del17 Ex16 del17nts FS, PS Mexican, #48 on the same allele 228 134 1848del5 Ex16 del5nts FS, PS Severe 396 135 C1850T Ex16 ACG>ATG T617M Mild 401 136 1852delT Ex16 TTAACT>TAACT L618X Severe 228 137 T1853C Ex16 TTA>TCA L618S Mild, Japanese 58,90 138 1863+1del5 Int16 AGgtaagta>AGta Splicing error Mild, Chinese 436 139 G1864A Ex17 GGT>AGT G622S Mild 433 140 G1865T Ex17 GGT>GTT G622V NYS 141 G1873A Ex17 GCC>ACC A625T #107 on same allele 228 142 T1886G Ex17 CTG>CGG L629R Mild 228 143 1914delC Ex17 CATCCC>CATCC V640X Severe NYS 144 G1941A Ex17 TGG>TGA W647X Severe 356 145 A1954C Ex17 ACT>CCT T652P Severe 356 146 1957del4 Ex17 del4nts FS Severe 402 147 G1993A Ex17 GTG>ATG V665M Mild, Chinese 436 a Mutations found in patients with globoid cell leukodystrophy. In some cases more than one mutation (excluding polymorphisms) was found on the same allele. b Numbering refers to the cDNA starting from the orginally published ATG.24 This is 48 nts and 16 aa shorter than the numbering system used in some publications. c The assignment of severity to a mutation is based on the review of multiple patients where the onset of disease was available. d Mutations identified in confirmed patients at the New York State, Department of Health Laboratory. e May only be disease-causing when the second allele is severe. f This may not be disease-causing since expressions studies showed significant GALC activity. Abbreviations: Ex=exon, Int=intron, del=deletion, ins=insertion, dup=duplication, nts=nucleotides, aa=amino acid, bp=base pairs, FS=frame shift, PS=premature stop codon, U=unpublished. Nucleotides given in capital letters refer to exonic sequence and lower case letters refer to intronic sequence. ++ One mutation, called 502T/del, was found to be quite common in patients from northern Europe and the United States, including those with Mexican ancestry.229,230 A survey conducted in patients within the Dutch population and from other parts of Europe confirmed that the 502T/del mutation comprises about 50 percent of total mutant alleles.231 In infant Swedish patients, this mutation makes up 75 percent of the mutant alleles.435 This mutation probably occurred initially in Sweden and traveled from there throughout Europe, Near Asia, and the United States. It has never been detected in Japanese patients. This mutation, consisting of a 30-kb deletion starting near the middle of intron 10 and continuing beyond the end of the gene, is always found with a known polymorphism consisting of a C-to-T transition at cDNA position 502, designated c.C502T (p.R168C). The 30-kb deletion eliminates the coding region for the 30-kDa subunit and about 15 percent of the coding region for the 50- to 52-kDa subunit. Some shortened polypeptide may be synthesized through the use of a cryptic polyadenylation sequence located at the 5′ end of intron 10. As expected, all patients homozygous for this mutation have the severe infantile form of GLD. However, this mutation has also been found heterozygous in a significant number of patients with late onset, including adult-onset, GLD. In a recent study, 60 percent of adult-onset patients were found to be heterozygous for this mutation.433 (See Table 147-1.) ++ While no other mutation is found at such high frequency among patients with GLD, a number of other mutations have been found in more than one unrelated family. Two other mutations, c.C1538T (p.T513M) and c.A1652C (p.Y551S), make up an additional 10-15 percent of the mutant alleles in infant patients with European ancestry.228,231 Within certain populations, some mutations causing GLD have been found in more than one family. Four mutations (635del + ins; c.A198G (p.I66M); c.G1544A (p.R515H) and c.T1853C (p.L618S)) have been found in unrelated Japanese patients.58,90,233,356 In Israel there are 2 populations with extremely high carrier rates for GLD,234 and they have different mutations.235 All infant patients in the Druze population in northern Israel are homozygous for c.T1748G (p.I583S), and patients from an Arab (non-Druze) village near Jerusalem are homozygous for c.G1582A (p.D528N). Carrier testing based on the identification of the mutation in these populations has been offered to interested individuals. ++ A G-to-A transition at nucleotide 809, designated c.G809A (p.G270D), has been found heterozygous in a significant number of patients with late-onset GLD.58,228,232,433 In fact, one copy of c.G809A, even when found together with a very severe second mutation, will result in a late-onset phenotype. This mutation has been reported in patients with both Japanese and European ancestry. So far, all non-Japanese patients with this mutation also have a c.T1637C polymorphism on the same allele. This important fact was not mentioned in the paper of Furuya et al,58 who reported the only patient homozygous for this mutation. Their patient was from consanguineous parents and presented with spastic gait in the second decade. Although the presence of c.G809A does indicate a late onset of disease, it does not predict a characteristic phenotype. In fact, within families having more than one patient with the identical genotype, involving at least one copy of c.G809A, there can be a very wide range of clinical presentations. In 2 unrelated families with a total of 5 patients, having c.G809A on one allele and 502T/del on the other allele, the symptoms vary from significant neurologic impairment and cognitive disability within the first decade to normal intelligence and only mild spastic paraparesis noted in the second or third decade. This clearly points to the role of other genetic or environmental factors in the clinical presentation of the later onset forms of GLD. Two other mutations, c.A286G (p.T96A) and c.A908G (p.Y303C) have been found in a significant number of patients with late-onset Krabbe disease. In all cases the second mutant allele would be considered severe; no confirmed patients were homozygous for these mutations. The 2 mutations have also been found in high frequency in newborns with low GALC activity using dried blood spots (see "Newborn Screening"). Some of these individuals are homozygous for the mutations. At this time, these individuals are clinically normal, and it is not known whether they will ever develop GLD. It is possible that these mutations are only disease-causing when found with certain specific second alleles. ++ Sometimes 2 mutations other than polymorphisms have been found on the same allele. Three infant patients of Mexican heritage were found to be heterozygous for one allele containing 2 changes, 1424delA and c.G1873A (p.A625T).228 Kolodny et al232 reported only the c.G1873A mutation in a woman who died at age 73 with GLD. It is unknown whether the 1424delA mutation, which results in a frameshift and a premature stop codon, was present in that individual or whether the c.G1873A alone would cause the disease. Since the other allele in the older woman is c.G809A, it is probable that the presence of one copy of the G809A mutation would be enough to explain the relatively mild phenotype. ++ While it is common to identify 2 disease-causing mutations in confirmed patients, in some individuals this has not been accomplished. Recently Tanner et al396 applied the use of array-based comparative genomic hybridization (CGH) deletion/duplication analysis to 5 patients with Krabbe disease where the second pathogenic mutation was not identified. In 3 of these patients the second mutation, a deletion or duplication, was identified by this technique. These are included in Table 147-1. ++ The newly reported crystal structure of mouse GALC protein provides insight into the role of disease-causing mutations identified in Krabbe disease.395 About 70 percent of the missense mutations identified involve residues that are buried within the structure of the enzyme. These mutations are likely to result in protein instability or misfolding, leading to premature degradation. Examples of such mutations are E114K, S257F, L364R, W410G, G537R, and L629R. Other mutations might interfere with the binding of activating factors. E215K confers an opposite charge on the same surface of the substrate-binding pocket, suggesting that it could interfere with the binding of an activating factor such as saposin. Also, proline 302 is located very close to the substrate-binding pocket, and a mutation coding for arginine will significantly change the surface properties of this region. In addition, arginine 380 is located at the tip of a long loop of the β-sandwich domain that represents an integral part of the substrate-binding site. Mutation of this arginine to tryptophan results in an infantile form of Krabbe disease, confirming the importance of this residue for GALC activity. While interesting, it should be noted that this study was done placing mutations found in human patients in the mouse GALC, which is 83 percent similar to human GALC. ++ Several recurring polymorphisms have also been found in this gene. They play a significant role in producing the wide range of GALC values measured in the general population and the family members of affected individuals. In addition, some mutations in the GALC gene may only be disease-causing when one or more polymorphisms are found on the same allele. For families in which the mutation(s) in the proband has been identified, carrier testing by mutation analysis of related individuals is relatively simple. However, this does not help to identify carrier status in an unrelated individual who plans to have a child with a known carrier. Complete sequencing of the GALC gene is available in certain specialized laboratories. ++ Polymorphisms ++ As discussed earlier, there is a very wide range of GALC activities in the "normal" population and among obligate heterozygotes when measured in leukocytes or cultured skin fibroblasts.57,211,236,237 This makes enzyme-based carrier testing in the general population almost impossible. The polymorphic mutations that result in amino acid changes are shown in Table 147-2. While the c.C502T polymorphism was found in the non-Japanese population,229 a c.A865G (p.I289V) polymorphism was reported only in the Japanese population.58,90 Expression of these mutations using COS-1 cells has demonstrated that they do result in less GALC activity than the most common genotype (Table 147-2). It has been observed by several groups that these polymorphisms occur on the same alleles as disease-causing mutations in a higher-than-expected percentage of cases.228,231,238,433 In fact, some "disease-causing" mutations may be deleterious only when the polymorphism is present on the same allele. Furuya et al58 demonstrated by expression studies that the c.A198G mutation (p.I66M) resulted in low GALC activity only when the c.A865G polymorphism was present. The "late-onset" mutation, c.G809A, occurs on the c.T1637C (p.I546T) background, and expression studies (MA Rafi and DA Wenger, unpublished) show that there is significantly less GALC activity when this mutation is on the c.T1637C background. Therefore, the presence of polymorphic changes in the GALC gene affects the measured activity, having implications related to carrier testing and interpretation of newborn screening results. In addition, some mutations may be disease-causing only when certain polymorphisms are present on the same allele. ++Table Graphic Jump LocationTable 147-2. Polymorphisms in the GALC gene that result in amino acid changesView Large|Favorite Table|Download (.pdf) Table 147-2. Polymorphisms in the GALC gene that result in amino acid changes Nucleotide change (cDNA) Amino acid change Expression a Minor allele frequency C502T R168C 80-90% 4-5% G694A D232N 60-70% 8-10% A865G I289V 80-90% b ? T1637C I546T 30-40% 40-45% C520T/T1637C c R168C/I546T 10-20% 2-3% aExpression after transfection of COS-1 cells as a percentage of activity obtained with the most common allele bAn estimate based on the information published by Furuya et al59 cBoth on the same allele + Diagnosis Print Section ++ ++ Assays of GALC activity in peripheral leukocytes or cultured fibroblasts offer the best and most reliable means for the definitive diagnosis of GLD. These tests are best performed using radiolabeled galactosylceramide. Enzymatic diagnosis with the natural lipid substrate requires care, and the procedure should be done in laboratories experienced with the assay. Leukocytes and cultured fibroblasts are equally reliable, with the former having a clear advantage in the rapidity with which the diagnosis can be established after the specimen is obtained. The first prenatal detection of the disease and confirmation of the diagnosis by histologic examination followed by additional enzymatic assays on the fetal specimens was accomplished in 1970, within a few months of the identification of the enzymatic defect in GLD.19,151 While prenatal testing by enzyme assay is reliable when performed by an experienced laboratory, most prenatal testing for at-risk couples is currently being done by molecular analysis. Because of the broad specificity of GALC, other natural substrates can, in principle, also be used for enzymatic diagnosis of GLD. However, psychosine,20,174–176 monogalactosyl diglyceride,177 and lactosylceramide,180,212 do not provide a practical advantage over the original assay for galactosylceramide hydrolysis. Conditions of assays with natural sphingolipid substrates have been carefully examined in several laboratories.184,212,214,215,236,237,243–250 ++ Several methods for measuring GALC activity using artificial substrates have been published.357,358 However, they add little to the sensitivity of the natural substrate assay and their use has resulted in missed diagnoses of Krabbe disease (unpublished information). In order to utilize tandem mass spectrometry to assay GALC activity on dried blood spots for large-scale newborn screening, galactosylceramide with a shorter fatty acid residue was synthesized.359 ++ With the currently available assay procedures using the natural substrate, there is no consistent difference in residual GALC activity measured in individuals with the classic infantile form and the late-onset forms. Although a profound deficiency (less than 5 percent of the normal mean) of GALC activity is almost always diagnostic for GLD, some healthy individuals have also been found to have lower than normal GALC activity (15-20 percent of the normal mean).251,252 In addition, newborns with GALC activity lower than normal, but not as low as typical confirmed patients with Krabbe disease, have been identified following newborn screening. The probable cause of this finding is the presence of multiple polymorphisms in the GALC gene with or without one copy of a disease-causing mutation. This should be kept in mind when enzymatic diagnosis is attempted. While it is a rare occurrence, some families may require additional studies, such as a molecular analysis, to clarify the situation. ++ Assay of GALC activity can be useful for the identification of carriers within a family. For example, knowing the leukocyte GALC values in both heterozygous parents of a patient can make carrier testing in other offspring possible in a skilled laboratory. As stated earlier, there is a large amount of overlap between the "normal" range and the carrier range. Carrier detection is inherently less reliable than diagnosis of affected patients.211,236,237 Some studies have suggested a bimodal distribution of the "normal" activity.57,180 With the cloning of the GALC gene and identification of disease-causing and polymorphic changes, the reason for this variability in activity could be tested.228 Table 147-2 shows the expression of GALC activity of several common polymorphisms. It can be seen that the common polymorphism p.I546T has a pronounced effect on GALC activity. + Newborn Screening for GLD Print Section ++ ++ In an attempt to identify individuals who may develop Krabbe disease before they are symptomatic so that treatment can be instituted, newborn screening was initiated in New York State in August 2006.360,361 This has resulted in the testing of nearly 1,700,000 newborns as of this writing. An automated tandem mass spectrometry method for measuring GALC activity was developed to analyze dried blood spots collected soon after birth.359 Using this automated system, approximately 1,000 samples could be tested each day. The algorithm calls for retesting samples with activity below a certain cutoff and, if necessary, stipulates additional testing including enzyme assay by the conventional method and sequencing of the GALC gene. Infants with low activity are then referred for neurodiagnostic testing, with the length and frequency of follow-up evaluation based on the risk category. ++ To identify infants likely to benefit from transplantation, a point system has been developed that takes into account findings from the neurologic examination, neurodiagnostic tests (MRI, CSF levels, nerve conduction, BAERs, VEPs), and mutational analysis.361 This testing has resulted in the identification of 12 high-risk individuals who have GALC activities within the range found in patients with Krabbe disease. Only 5 of these newborns were predicted to have infantile Krabbe disease. Therefore, only 1 in about 300,000 screened infants had early-infantile GLD, suggesting that later-onset forms of the disease may not be as rare as previously thought. Part of the explanation may be the ethnic makeup of people giving birth in New York State, especially in New York City. These 5 individuals predicted to develop infantile Krabbe disease were recommended for blood stem cell transplantation. The outcome of 4 individuals who received umbilical cord transplantation has been variable, with 2 dying of complications from the transplant, and 2 surviving with moderate to significant deficits in speech and motor function. The other high-risk individuals with low GALC activity and unreported mutations or mutations previously found in late-onset patients have raised the question of whether they will ever develop Krabbe disease and, if they do, when. These patients are being followed by neurodiagnostic evaluation. A staging system has been developed to help clinicians unfamiliar with infantile GLD identify those patients likely to benefit from transplantation.404 This study showed that the number and types of pretransplant clinical indicators (eg, abnormal reflexes, exaggerated startle, gastroesophageal reflux) predict posttransplant outcomes. In contrast, outcomes did not correlate with pretransplant CSF levels, conventional MRI scans, or neurophysiologic measures (EEGs, NCVs, VEPs, BAERs). This clinical tool can also be used to monitor disease progression in untreated patients. Although it is agreed that earlier diagnosis will result in earlier treatment and possible prevention of neurological damage, newborn screening for Krabbe disease has raised questions that are difficult to answer at this time.362 + Treatment Print Section ++ ++ At this time the treatment option for patients with GLD is limited to hematopoietic stem cell transplantation in certain individuals who have either a slowly progressive later onset form of GLD or are asymptomatic (as occurs in some families who have prenatal testing and elect not to terminate an affected fetus or in which the diagnosis is made at birth because of family history or newborn screening). The publication of Krivit and coworkers253 described the successful stabilization and possible improvement in the clinical picture of 4 patients with late-onset disease who were followed for up to 9 years after transplantation. CSF protein levels decreased, and MRI showed improvement with evidence of remyelination. Umbilical cord blood transplantation was performed on 11 asymptomatic newborns confirmed to have low GALC activity at birth because of previously affected siblings.363 However, older patients transplanted after symptoms were apparent did not show significant improvement. The treated asymptomatic newborns did much better than their untreated affected siblings. They showed progressive central myelination and continued to gain developmental skills and age-appropriate cognitive function. Some problems remained with expressive language and gross motor function. This cohort has been followed for more than 7 years, with the oldest patient turning 13. Most patients are still alive and derived significant neurological benefits despite a wide range of motor compromise. Although a 9-year-old patient is able to walk, run, and jump and is in regular school, others walk independently but have gait abnormalities. Some patients walk with walkers, and some use wheelchairs (Escolar, personal communication). ++ Siddiqi et al assessed peripheral neuropathy in 12 patients (9 early infantile onset, 2 juvenile onset, and 1 late onset) after transplantation.412 Most patients showed improvement, suggesting that remyelination had occurred. Among patients with the early infantile form, presymptomatic infants (treated within the first month of life) showed greater improvement than symptomatic patients (treated at 4 to 6 months) at the 1-year follow-up.412 The phase II multicenter Cord Blood Transplantation Study (COBLT)413 included 16 presymptomatic patients with early infantile GLD, eleven of whom were previously reported.363 In these patients, unrelated umbilical cord blood transplantation in the first 8 weeks of life improved survival and neurologic outcomes. Two patients died in transplant; the remaining patients all showed normal cognitive function but poor growth, abnormal expressive language, and feeding problems, with half requiring gastrostomy tubes (mean follow-up, 5 years). Gross motor function was the most affected area; only 25 percent were able to walk independently (Escolar, personal communication). Another 9 patients with GLD underwent transplantation in Pediatric Bone Marrow Transplantation Consortium centers in the United States and Canada. Of the 6 presymptomatic infants with early infantile disease, one died from transplant complications, and the remaining 5 children showed delayed development and neurologic abnormalities. The children older than 3 years at the last reported follow-up showed poor growth, and only one was able to walk independently. In a presymptomatic patient predicted to have later onset GLD, neurologic findings were normal but growth was poor. Two symptomatic children with later onset disease exhibited cognitive impairment, seizures, and neurologic abnormalities. Patients with later onset disease (both presymptomatic and symptomatic) generally improved with treatment.361 ++ With the institution of newborn screening for Krabbe disease, additional presymptomatic individuals have been treated with umbilical cord stem cells with variable results (see above). The question of when to institute such treatment in individuals with previously unreported mutations or mutations found in later onset patients remains unanswered. Improvements in conditioning regimens and the isolation of transplantable hematopoietic stem cells from umbilical cord blood, peripheral blood, and bone marrow have increased survival. The increase in the number of cord blood units banked improves the chances of finding a suitable donor for patients considered candidates for transplantation. ++ Unfortunately, about 85 to 90 percent of patients identified with GLD are infants who already have significant neurologic impairment at the time of laboratory diagnosis. Only supportive care can be provided when diagnosis occurs too late for hematopoietic stem cell transplantation. Patients with early infantile presentation who are already symptomatic benefit from treatment of spasticity, reflux, and peripheral neuropathy. Patients usually respond to baclofen and gabapentin and should have a Nissan fundoplication to prevent reflux when a gastrostomy is placed. Gastrostomy placement should be done early in the disease process to prevent dehydration and aspiration pneumonia. Seizures present later in the disease progression and are usually easy to manage. Irritability responds to prompt management of spasticity and gastroesophageal reflux. Stewart and colleagues reported that low-dose morphine resulted in a significant improvement in the irritability frequently reported in infantile patients with Krabbe disease.364 Diazepam and lorazepam can be used as adjunctive therapy. Assistive devices for communication can prolong the child's ability to communicate since receptive language and hearing are only affected late in the disease process, while speech is impaired earlier. Hip dysplasia, hip subluxation, and scoliosis are commonly seen and can be prevented or delayed by using a stander and a well-fitted wheelchair. Respiratory care, secretion management, apnea monitoring, and oxygen supplementation may be needed in stage 4 of the disease when apneic episodes increase in duration and frequency. Other symptoms that may be present in stages 3 and 4 are temperature instability, poor perfusion, and paroxysmal autonomic instability with dystonia. Supportive care and prompt response to infection can keep children out of the hospital and improve quality of life. Families are very vulnerable and often sleep deprived and exhausted from providing care around the clock. They benefit from respite care and home-based nursing care (Escolar, personal communication). ++ A fetus predicted to be affected with GLD by CVS testing at 9 weeks of age received in utero bone marrow transplantation using the father as the donor.254 This fetus died at about 20 gestational weeks, but examination of the fetal tissues revealed significant engraftment of the donor T-cell-depleted, CD34+ selected cells. As it was postulated that too many donor cells were injected in the first case, one-thousandth the number of cells were used in the 2 subsequent pregnancies (Karin Blakemore, personal communication). Unfortunately, there was little, if any, engraftment detected at birth in the newborns. Both underwent postnatal transplantation of hematopoietic stem cells; the outcome is not known. ++ There is mounting evidence that only a small increase in GALC activity may be needed to significantly improve clinical outcomes. Studies involving transplantation of stem cells and injection of viral vectors containing the GALC gene or recombinant GALC protein are in progress using animal models. It is hoped that these studies will lead to additional treatment options. + In Vitro Model Systems Print Section ++ ++ With the availability of the GALC gene and cDNA, it was possible to begin preliminary studies to evaluate delivery of GALC activity to deficient cells by several methods. Several publications have described the retroviral transfer of GALC cDNA into cultured cells from human and animal models.239– 241 Transduced cultured skin fibroblasts from patients with Krabbe disease can reach very high levels of GALC activity (100 times normal), and, more important, these cells were able to secrete GALC that was rapidly and efficiently taken up by neighboring cells.240 This could provide a mechanism for the treatment of patients through the transplantation of cells, such as hematopoietic stem cells, that can be removed from the patient and successfully transduced by a viral vector containing GALC cDNA. In addition, other cell types, such as rat and mouse brain astrocytes, CD34+ hematopoietic cells, twitcher mouse brain oligodendrocytes and astrocytes, and mouse myoblasts, have also been transduced and produce high levels of GALC activity that can be exported and taken up by other cells. The uptake of this hydrophobic enzyme by other cells appears to be mostly by a non-mannose-6-phosphate-mediated mechanism.240 When oligodendrocytes from the brains of twitcher mice were transduced with GALC cDNA in a retroviral vector, they attained a normal morphology following differentiation.241Additional studies have demonstrated viral transduction of either oligodendrocyte progenitors or neural stem cells.383,384 Supplying sufficient GALC activity to oligodendrocytes isolated from twitcher mice results in lysosomal localization and phenotype correction. In a further study, retrovirally transduced neural progenitor cells over-expressing GALC activity were injected into the brains of twitcher mice.378 Although there was only a modest increase in the lifespans of these mice, there was an increase in body weight, correction of astrogliosis, normal appearing oligodendrocytes, and evidence for remyelination. In addition, the normal appearing oligodendrocytes show evidence for the uptake of GALC protein from donor cells. These studies provide evidence that supplying GALC activity to deficient brain cells in vivo could result in secretion and uptake of enzyme to neighboring cells and improvement in the typical pathology. Cultured cells, such as COS cells, can be transfected with plasmids containing wild-type and mutated GALC cDNA, and GALC activity can be measured. This has been used for many years to determine if a given mutation results in low GALC activity and, more recently, to determine if small chemical compounds can act as chaperones stabilizing GALC protein containing certain mutations.397 + Animal Models Print Section ++ ++ GLD caused by genetic deficiency of GALC activity also occurs in a number of animal models, including the mouse, the sheep, several breeds of dog, and the rhesus monkey.255– 263 The disease in the cat was not characterized enzymatically.264 The clinical and pathologic features are similar to those of the human disease. At this time, twitcher mice, Cairn and West Highland White terriers, and rhesus monkeys have been studied in the most detail and are available for research. A summary of the features of the available animal models has been published.365 In addition, a new mouse model with low GALC activity was generated by gene targeting.366 This mouse model with a missense mutation (p.H168C) lives about 10-15 days longer than the twitcher mouse. ++ Canine GLD ++ In 1963, Fankhäuser et al first reported that GLD occurs in certain breeds of dogs.263 The disease, which has been studied extensively from the clinical, pathologic, and biochemical standpoints,220,221,263,265–288 is transmitted as an autosomal recessive trait. The clinical and pathologic features are generally quite similar to those in the human disease, for example, deficient GALC activity284– 287,289 and the progressive accumulation of psychosine in the brain21,220 have been demonstrated in affected dogs. In 1996, Victoria et al289 cloned the canine GALC cDNA and determined that the mutation causing GLD in Cairn and West Highland White terriers is a transversion, c.A473C (p.Y158S). A rapid PCR-based test for this mutation has resulted in a North American screening program to identify carriers in these breeds. This has brought about the establishment of a colony of carrier dogs for research at the University of Pennsylvania School of Veterinary Medicine. Affected dogs from this colony are being used to evaluate treatment options as a bridge between studies in murine models and human patients. Treatment of these dogs can be followed by MRI, as in human patients.290 In addition, preliminary studies have demonstrated the usefulness of magnetization transfer imaging to investigate demyelination in the canine model of GLD.367 ++ Other breeds of dogs have been reported to have GALC deficiency, however none has been established as a usable colony. ++ Murine (Twitcher) GLD ++ A genetically and enzymatically authentic murine model of human GLD, known as twitcher (twi), was first identified at the Jackson Laboratory, Bar Harbor, Maine. The GALC gene has been mapped to mouse chromosome 12.222 Affected mice develop clinical signs at approximately 20 days, with stunted growth, twitching, and hind leg weakness. By 40 days, most reach the terminal stage, and even with intensive maintenance care, very few live beyond 50 days. Histopathologic findings are similar to those of human and canine GLD, both by light and electron microscopy.291– 293 Enzymatic studies using galactosylceramide and lactosylceramide as the substrates unequivocally demonstrated that GALC deficiency is the underlying lesion in this mutant.294,295 ++ In 1996 the mouse GALC gene was cloned and the mutation causing GLD in twi mice, c.G1017A (p.W339X), was determined.297 The genetic status of individual mice can be conveniently and reliably determined at birth by mutation analysis using small samples of the tail tip or toe.296,297 This permits the institution of treatment well before the clinical onset of disease. ++ While the pathologic findings of the brain and peripheral nerves are similar to those in human and canine disease,291– 293,298–303 a unique pathologic feature in the twi mouse is the abundant presence of the characteristic inclusions in the lymph nodes and kidney.304,305 This is consistent with biochemical analyses, which demonstrated a massive accumulation of galactosylceramide in the kidneys of affected mice.306,307 In addition, sperm abnormalities have also been identified in twitcher mice.368 Chronologic quantitative analyses of the central and peripheral nervous systems have shown that a brief period of hypomyelination and then demyelination follow early myelination that proceeds normally.299,300,308–312 However, the characteristic inclusions were already noted at day 5 in the Schwann cells and oligodendroglia, prior to morphologic evidence of demyelination or infiltration of macrophages.302,309,310 As the disease progresses, the tissue level of psychosine increases dramatically in both the brain21,310 and the peripheral nerves.308 The peripheral nerves of twitcher mice are abnormally thick, with marked endoneurial edema.301,309,313 A role for immunologic involvement in the pathology of murine GLD has been demonstrated.314– 319 In a series of studies, Suzuki and coworkers126,314,315 demonstrated a marked increase in Mac-1 immunopositive microglia and macrophages and major histocompatibility complex class II (Ia) antigen-expressing cells at the early stages of the demyelinating process. The major histocompatibility complex I antigen317 and cytokines such as TNF-α and IL-6318 have also been implicated in the development and progression of pathologic changes in twitcher mice. A recent study measuring the expression of several markers of the immune/inflammatory response in different regions of the CNS of GLD mice confirmed the increase in TNF-α and Il-6 plus additional markers.369 Treatment of these mice with anti-inflammatory drugs, including indomethacin and ibuprofen, and by BMT extended the lifespan of treated mice and reduced the levels of the immune-related factors studied. BMT produced the most dramatic response. ++ Psychosine inhibition of protein kinase C has been postulated to interfere with signal transduction and Schwann cell proliferation.319 In addition, expression of CGT (the enzyme involved in the synthesis of galactosylceramide and psychosine) was suppressed early in the disease process.320 The mechanism for this is not yet known. However, generation of twi mice with only one copy of the CGT gene results in a small increase in lifespan, indicating that decreased synthesis of these galactolipids could have therapeutic implications.370 ++ The twi mouse is uniquely suited for investigation of possible treatments for Krabbe disease,334,335 and there are many reports describing them. These include therapeutic effects of nerve grafts,321– 323,382 neural stem or progenitor cell transplantation,377– 379 bone marrow transplantation,324– 332,380 gene therapy,373– 376,381 enzyme replacement,333,371,372 mesenchymal stromal cells transplantation,386,387 and combination therapy.385,391 The first attempt to treat twi mice by BMT was in 1984.324 Although various studies have found differing results of BMT, in general, extended lifespan, accompanied by a moderate increase in GALC activity and a decrease in the psychosine level, has been consistently reported. However, none of the mice went on to live a normal lifespan in spite of evidence of remyelination in the CNS and PNS. It is possible that the ablation methods used to prepare the mice for transplantation were toxic to some stem cells, preventing normal remyelination. Other studies involving the direct injection into brain of cells, including neural stem cells, neural progenitor cells, and mesenchymal cells, resulted in only localized pathological correction and minimal extension of lifespan. Recombinant GALC enzyme injected either weekly intraperitoneally (IP) or once intracerebroventricularly (ICV) resulted in modest increases in lifespans and body weights, although no GALC activity was detected in brain following IP injections.371,372 The single ICV injection resulted in measurable GALC activity in brain and some reduction in the concentration of psychosine. While the use of ERT has been successful for other lysosomal disorders without a significant neurologic component, its use for the treatment of neurologic disorders is limited without significant improvements in delivery to the nervous system. A study using a twi mouse with very low expression of human GALC, supplied by mating with a transgenic mouse expressing human GALC, resulted in some improvement of certain parameters but limited usefulness in the treatment of human GLD.242 The finding that decreased synthesis of galactolipids prolonged the lives of twi mice370 resulted in attempts to treat these mice with L-cycloserine, an inhibitor of sphingolipid synthesis.388,389 Treatment with L-cycloserine also prolonged the lives of twi mice, but they still died with the pathologic findings of GLD. Concerns about the toxicity and side effects of L-cycloserine may prevent its use in young children. ++ Intraventricular administration of an adenoviral vector containing human GALC cDNA to neonatal twi mice resulted in some measurable GALC activity in brain and very small improvements in motor function, body weight, and lifespan.373 Recent studies indicate that adeno-associated viral vectors have properties that make them more suitable for gene therapy trials. With the identification of different serotypes having unique tropism for certain tissues, investigations of their use for treating different genetic disorders are increasing. In 2005, 2 papers described the use of different AAV vectors (AAV2/1 and AAV2/5) containing GALC cDNA in the treatment of twitcher mice.375,376 The lifespans of the treated affected mice were significantly extended, there was evidence for widespread expression of GALC activity, the concentration of psychosine dropped significantly, and there was normal myelination in some areas of the brain. In spite of the positive findings, the mice did not live a normal lifespan. Lin et al reported some additional extension of life when BMT was combined with AAV2/5 in twitcher mice.385 Recently, Rafi and colleagues reported a dramatic increase in lifespan with normalization of body weights, mating ability and behavioral parameters, and improved morphology of the CNS and PNS following intravenous, intracerebellar and intracerebroventricular injections of AAVrh10 containing GALC cDNA.390 The positive results with this vector could lead the way to studies in the larger animal models of GLD as a bridge to human trials and encourage the search for additional AAV vectors with tropism toward to CNS and PNS. While other laboratories investigate the use of lentiviral vectors for treating leukodystrophies,392,393 the results have not been as positive as with AAV vectors. ++ It is interesting that the saposin A-deficient mice lived much longer and had fewer globoid cells when they were kept pregnant or implanted with 17 beta-estradiol.431 Attempts to use estrogen therapy in twi mice did not result in a positive change in the clinical course or pathology (unpublished observation). There may still be a role for estrogen administration in some late-onset leukodystrophies. ++ Rhesus Monkey Globoid-Cell Leukodystrophy ++ In 1989, Baskin and coworkers259 described pathologic findings consistent with a diagnosis of globoid cell leukodystrophy in an 11-week-old rhesus monkey. An attempt to identify the disease-causing mutation using RNA from the obligate carrier mother was not successful. Subsequent matings produced 2 affected monkeys, as determined by their very low GALC activity in leukocytes and cultured skin fibroblasts. Sequencing of the GALC cDNA identified the mutation causing the low GALC activity336: a deletion of nucleotides A and C at cDNA positions 387 and 388 in exon 4. This results in a frameshift and stop codon after 46 nucleotides. Molecular screening of 45 monkeys in the colony resulted in the identification of 22 carriers. While both affected monkeys appeared normal at birth, one rapidly lost weight and developed volitional tremors, and was euthanized. The other monkey continued to nurse but became uncoordinated and hypertonic. That monkey developed volitional tremors at 92 days of age and had severely decreased nerve conduction velocities in all motor nerves tested. The monkey was euthanized at 158 days of age219; pathologic evaluation revealed enlarged, firm peripheral nerves. The cerebrum, cerebellum, and spinal cord tract were heavily infiltrated with PAS-positive multinucleated globoid cells and smaller mononucleated PAS-positive macrophages. A severe lack of myelin was also noted. Changes in the peripheral nerves were also observed, including a decrease in nerve fibers and in myelin sheaths around them. While there were some inflammatory cells between nerve fibers, no globoid cells were observed. Lipid analysis of the brains revealed that there was a very large increase in the amount of pyschosine in the white matter of the affected monkeys.219 There was an overall decrease in the level of galactosylceramide and other lipids associated with myelin; however, the galactosylceramide-to-sulfatide ratio was normal. The lipid profile of the gray matter appeared to be normal. The kidney from the older affected monkey showed a very high amount of psychosine, compared to undetectable levels in a control monkey. 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