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Alpha-mannosidosis is an inherited lysosomal storage disorder characterized by immune deficiency, facial and skeletal abnormalities, hearing impairment, and intellectual disability. It occurs in approximately 1 of 500,000 live births. The children are often born apparently normal, and their condition worsens progressively. Some children are born with ankle equinus or develop hydrocephalus in the first year of life. Main features are immune deficiency (manifested by recurrent infections, especially in the first decade of life), skeletal abnormalities (mild-to-moderate dysostosis multiplex, scoliosis and deformation of the sternum), hearing impairment (moderate-to-severe sensorineural hearing loss), gradual impairment of mental functions and speech, and often, periods of psychosis. Associated motor function disturbances include muscular weakness, joint abnormalities and ataxia. The facial trait include large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. Slight strabismus is common. The clinical variability is significant, representing a continuum in severity. The disorder is caused by lysosomal alpha-mannosidase deficiency. Alpha-mannosidosis is inherited in an autosomal recessive fashion and is caused by mutations in the MAN2B1 gene located on chromosome 19 (19 p13.2-q12). Diagnosis is made by measuring acid alpha-mannosidase activity in leukocytes or other nucleated cells and can be confirmed by genetic testing. Elevated urinary secretion of mannose-rich oligosaccharides is suggestive, but not diagnostic. Differential diagnoses are mainly the other lysosomal storage diseases like the mucopolysaccharidoses. Genetic counseling should be given to explain the nature of the disease and to detect carriers. Antenatal diagnosis is possible, based on both biochemical and genetic methods. The management should be pro-active, preventing complications and treating manifestations. Infections must be treated frequently. Otolaryngological treatment of fluid in the middle ear is often required and use of hearing aids is invariably required. Early educational intervention for development of social skills is needed and physiotherapy is important to improve bodily function. Orthopedic surgery may be necessary. The long-term prognosis is poor. There is an insidiously slow progression of neuromuscular and skeletal deterioration over several decades, making most patients wheel-chair dependent. No patients manage to be completely socially independent. Many patients are over 50 years of age.
α-Mannosidosis, Lysosomal α-D-Mannosidase Deficiency, α-Mannosidase B Deficiency. OMIM 248500.
Hurler-like syndrome had been known for a number of years when the Swedish physician Öckerman in Lund described a 4 year old boy with a Hurler-like phenotype in 1967 [1]. He died at the age of 4 from pneumonia, and in his tissues appeared large amounts of oligosaccharide material with the dominance of mannose. Therefore, the term "Mannosidosis" was suggested as the name of the disorder [2]. In 1977 Loeb described an atypical form of mucopolysaccharidosis which later turned out to be α-mannosidosis [3].
In 1978, Gideon Bach described two Palestinian siblings with a mild clinical phenotype and residual mannosidase activity, which increased by 40% with the addition of zinc (Zn++) to cell extracts of both patients and control subjects [4]. It took 25 years before the molecular mechanism of this observation could be explained [5]. Meanwhile, this observation led to many therapeutic attempts with zinc substitution in cattle [6] and man [7], which all proved futile.
Since these early clinical descriptions, many research groups have contributed to the characterization of the enzyme and the corresponding gene in several species such as human, cow, cat, mouse and guinea pig. Furthermore, underlying genetic, biochemical and physiological mechanisms of the disease have been explored, and additional clinical aspects of the disease such as immunodeficiency and psychiatric complications of the disease have been described (see below). Subsequently, two EU Research Consortiums, EURAMAN 2002–2005 (A systematic and multidisciplinary approach towards understanding and therapy of the inborn lysosomal storage disease α-mannosidosis), and HUE-MAN 2006–2009 (Towards the Development of an Effective Enzyme Replacement Therapy for Human α-Mannosidosis) were established [8].
Alpha-mannosidosis is a genetic disorder of metabolism characterized by immune deficiency, facial and skeletal abnormalities, hearing impairment, and mental retardation. The disorder is caused by lysosomal α-mannosidase deficiency and is inherited in an autosomal recessive fashion.
Elevated urinary secretion of mannose-rich oligosaccharides is suggestive, but not diagnostic for α-mannosidosis. Diagnosis is made by measuring acid α-mannosidase activity in leukocytes or other nucleated cells, e.g. fibroblasts. Genetic diagnostics by mutation analysis is available from a few laboratories.
Alpha-mannosidosis has been described as two distinct phenotypes: one severe form with hepatomegaly and early death following severe infections (Type I), and a mild form with hearing loss, mental retardation, and survival into adulthood (Type II) [4,9,10].
However, when studying published cases, the patients present a continuum of clinical presentations, many of which probably can be influenced by background genetics or external factors like infectious diseases, educational opportunities, proactive initiatives, and quality of health services [11-13].
At present, three clinical types have been suggested [14-16]: Type 1: Mild form clinically recognized after 10 years of age, without skeletal abnormalities and very slow progression; Type 2: Moderate form, clinically recognized before 10 years of age, with skeletal abnormalities, and slow progression with development of ataxia at age 20–30; Type 3: Severe form, immediately recognized, with skeletal abnormalities, and obvious progression, leading to an early death from primary central nervous system (CNS) involvement or myopathy (Table (Table1).1). Most patients belong to clinical type 2.
The prevalence of the disease is not precisely known. A study from Norway reported six (later eight) patients in a population of 4.5 millions [17]. This corresponds with a study from Australia, reporting a disease frequency of one in 500,000 live births [18]. Mannosidosis is expected to be found in any ethnic group anywhere in the world.
Alpha-mannosidosis should be suspected in individuals with mental retardation, skeletal changes, hearing loss, and recurrent infections. The children are often born apparently normal, and their condition worsens progressively. Therefore, early diagnosis is important if bone marrow transplantation (BMT) is to be considered a therapeutic modality. Since inborn errors of lysosomal metabolism occur in approximately 1:5,000 live births, many have argued for screening of newborns for early diagnosis and initiation of treatment [18].
Early references have described that early psychomotor development appears normal, and that pathophysiology develops over time [4,19]. However, some children are born with ankle equinus or develop hydrocephalus in the first year of life [17,20].
In α-mannosidosis guinea pigs, long before the onset of obvious neurologic abnormalities at 2 months, cerebral pathophysiology like neuronal lysosomal vacuolation, and reduced myelination of white matter was observed. Thus, complex neuropathologic changes in α-mannosidosis guinea pigs are already present at birth, long before clinical changes are evident, and similar events are likely to occur in humans with this disorder [21].
Facial traits may be subtle, but independent of race and background genetics, all patients have some degree of coarse Hurler-like features. This is classically a large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. The neck is usually short (Fig (Fig11).
According to Chester (1982), clinical or radiographic signs of mild-to-moderate dysostosis multiplex are present in 90% of the patients [14]. The most frequent abnormalities are scoliosis and deformation of the sternum [22] (Fig (Fig2).2). These changes are present at birth. Genu valgus (knucle knee) is common and, like the same complication in Gaucher disease, may be treated with epiphyseal arthrodesis at a young age before the epiphyseal lineation of the knee is closed [23]. Over time, from the second till the fourth decade of life the patients may develop destructive polyarthropathy, especially coxarthrosis (Fig (Fig3),3), but also gonarthrosis [24,25]. These are often so serious that orthopedic corrections are needed [26]. Patellar bilateral dislocation and severe synovial hypertrophy have also been described along with Charcot elbow and bilateral hip and elbow avascular necrosis in one patient [27].
Moderate or severe sensorineural hearing loss seems inevitable [12,22,28,29]. It is regularly worsened by otitis or accumulation of fluid in the middle ear, adding a mechanical component to the hearing deficit [17].
Slight strabismus is common and also hyperopia more frequently than myopia [14,30]. Blurred discs [31], superficial corneal opacities, and lenticular changes seem to be rare but have been reported [4].
As soon as the age of the patients makes intelligence quotient (IQ) measurements feasible, almost all patients show some degree of mental retardation. In a clinical study that included eight patients the age at onset of symptoms varied from 6 months to 3 years [10]. The first symptom was usually delayed development of speech or motor or mental functions. All the patients were mildly or moderately mentally retarded with an IQ of 60–80, with a declining tendency over later decades. With their poor ability to speak combined with sensorineural hearing loss, patients score generally better in nonverbal tests [10]. Although some have suggested the disease stabilises in puberty [32], most follow-up observations suggest gradual impairment of mental and motor functions and speech with age. Longitudinal assessments of three brothers have been done by testing of general intelligence, language, visual spatial skills, and overall adaptive abilities over two years. During the follow-up, the cognitive findings showed that the patients manifested mild cognitive deficits. Cognitive deficits were generally uniform with no signs of progressive deterioration, except receptive language abilities [33]. Other patients are described as having profound retardation even at young age [19,34]. Again, there can be remarkable differences in mental functioning among siblings [28,35,36].
Patients learn to speak late, sometimes in the second decade of life. This impaired development of language with limited vocabularies and poor pronunciation might be explained by their congenital and/or later-onset hearing loss. Many patients learn to read, but have difficulties in understanding abstracts (Malm D: personal observation).
The development of motor functions in affected patients is generally slow, and the children appear clumsy. This is caused by a combination of factors like muscular weakness, joint abnormalities and ataxia due to cerebral atrophy and cerebral demyelination [37].
The impairment is by nature progressive, with gradual worsening in the second and third decade of life [10]. However, as for mental retardation, there is a considerable variation in the clinical progression and in a long term observation of two patients, no progression of neurological function has been noted [28], whereas some investigators have suggested that the disease progression is halted after puberty [32]. Additional studies on the natural course of the disease are needed.
In intellectually disabled patients, psychiatric symptoms may be overlooked. However, a systematic survey found psychiatric symptoms in more than 25% of adult patients with mannosidosis [38]. It typically presented in adolescence or early adulthood. In mentally retarded patients, psychiatric symptoms form part of a more diffuse clinical picture with systemic, cognitive or motor neurological signs. It can present with acute and recurrent attacks of confusion, sometimes with anxiety, depressions or, hallucinations. These might be associated with loss of function, like decreased appetite with severe weights loss or incontinence for urine and feces. The periods of psychosis usually last 3 to 12 weeks, followed by a long period of hypersomnia and sometimes loss of abilities, like difficulty speaking or inability to read. Search for organic causes has been negative [38]. As specific treatments should be more effective at the initial stage before the occurrence of irreversible neurological lesions, clinicians should be aware of atypical psychiatric symptoms in patients with inborn errors of metabolism [39].
Mannosidosis patients suffer from recurrent infection, especially in the first decade of life. In one single patient, impaired leukocyte chemotaxis and reduced phagocytosis were found [9]. Malm and co-workers compared the humoral and cellular immunological functioning in six patients to that of six age- and sex-matched healthy controls [40]. They found that post-immunization levels of antibody were lower in patients, proving a decreased ability to produce specific antibodies after antigen presentation. More interestingly, there was a serum factor in patient plasma, inhibiting phagocytosis [40]. In mannosidosis, there are increased levels of oligosaccharides in plasma [41]. Oligomannosides with five and six mannose residues bind to interleukin-2 (IL-2) receptors disturbing the IL-2-dependent responses [42]. IL-2 activates T-, B-, and NK cells. It can therefore be speculated that blockage of this receptor is the mechanism causing the immune deficiency seen in mannosidosis.
The same mechanism could contribute to the increased prevalence of autoimmune disorders among mannosidosis patients ([13] and Malm D: personal observations). Interestingly, in a mice model, alpha-mannosidase II deficiency reduces complex-type N-glycan branching and induces an autoimmune disease similar to human systemic lupus erythematosus (SLE) with induction of antinuclear antibodies with reactivity towards histone, Sm antigen, and DNA [43].
End-stage kidney failure has been reported only once, where an Italian patient successfully received a kidney transplant [44]. In a study in mannosidosis mice, deposits of storage material in myocardium were reduced after enzyme replacement [45]. In some case descriptions, a murmur of the heart is mentioned, but so far, reports on manifest heart disease have not been reported.
During normal turnover and catabolism glycoproteins are digested by proteinases and glycosidases within the lysosomes. These enzymes degrade glycoproteins into fragments small enough to be excreted or transported to the cytosol for reuse. Lack or deficiency of such hydrolases results in the multi-systemic accumulation of undigested material in the lysosomes. Consequently, the lysosomes swell resulting in severe impairment of cellular functions (Fig (Fig4).4). However, the pathophysiology of lysosomal storage disorders is complex, and accumulation of storage material alone cannot fully explain the cause of disease.
Lysosomal α-mannosidase is an exoglycosidase which cleaves the α-mannosidic linkages during the ordered degradation of N-linked oligosaccharides. The enzyme has the capacity to cleave α(1 → 2), α(1 → 3) and α(1 → 6) mannosidic linkages found in high mannose and hybrid type glycans [46,47]. Deduced from the analyses of mannose rich fractions from urine of affected individuals the major lysosomal storage products are the oligosaccharides:
Man(α1 → 3)Man(β1 → 4)GlcNac, Man(α1 → 2)Man(α1 → 3)Man(β1 → 4)GlcNac and Man(α1 → 2)Man(α1 → 2)Man(α1 → 3)Man(β1 → 4)GlcNac [48].
However, several additional, but apparently less abundant urinary oligosaccharides have been identified [49], all of them with GlcNac at the reducing end (reviewed by [50]).
Alpha-mannosidosis is caused by mutations in the MAN2B1 (LAMAN) gene encoding lysosomal α-mannosidase. The MAN2B1 is located on chromosome 19 (19p13.2-p13.11) and is composed of 24 exons spanning 21.5 kb [51,52]. The MAN2B1 mRNA has the capacity to encode a polypeptide of 988 [53] or 1011 [54] amino acids depending on the start site of translation (Genebank accession numbers U68382/U68567 and U60266.1). As judged by Northern blot analyses, the level of MAN2B1 expression appears to be highest in lung [54], kidney, pancreas [53,54], and peripheral blood leukocyte [53]. In CNS the highest level of expression appears to be in corpus callosum and spinal cord, whereas considerably lower levels are observed in the larger structures, which include cerebellum, cerebral cortex, frontal and temporal lobes [54]. The significance (if any) of this variation is not clear.
The enzyme is synthesized as a single chain precursor that is processed into three glycopeptides of 70, 42 and 15 kDa [54]. In humans, the 70 kDa peptide is further partially proteolysed into three more peptides that are joined by disulfide bridges – constituting all together 5 peptides (a-e) [54]. α-mannosidase contains 11 potential N-linked glycosylation sites all of which are occupied with either high mannose or complex type oligosaccharides [54]. Based on electron microscopy, X-ray diffraction data and the structure of D. melanogaster Golgi II α-mannosidase, the structure of the bovine lysosomal α-mannosidase was resolved at 2.7 Å resolution [5]. α-mannosidase is a di-mer and the 3-dimensional structure of bovine lysosomal α-mannosidase (which shares 80% identity to its human counterpart) nicely defines the fold of each peptide, identifies the active site and provide clues to understand lysosomal transport and low pH activation (Fig (Fig5).5). Furthermore, the 3-dimensional structure provides the basis for understanding α-mannosidosis at the atomic level.
A total of 40 different disease-causing mutations have been reported over the last 10 years. Except for two unrelated patients from Japan and one patient of Arabian origin [13,54,55], the patients studied originate from Europe [11,15,54,56-60]. The genetic aberrations reported are scattered all over the MAN2B1 gene and include missense, nonsense, small and large deletions, small insertions and splice site mutations. Most mutations are private as they occur in single or in a few families only. However, missense mutation c.2248C>T resulting in the replacement of arginine with tryptophane at amino acid position 750 (p.R750W) appears to be frequent among mannosidosis patients, as it has been reported from most European populations studied, accounting for more than 30% of all disease alleles detected by Berg et al. (1999) [15]. Haplotyping based on 5 internal single nucleotide polymorphisms (SNP) markers showed that a common haplotype was shared by Finnish, Polish and Italian homozygotes, whereas a second haplotype, deviating at one marker, was observed in a Turkish patient [15]. These findings indicate that the frequency and wide geographical distribution of the "p.750W" allele may result both from founder effects and from recurrent mutational events. However, further analysis including patients of other origins must be carried out in order to explore this fully.
Altogether 12 missense mutations have been functionally characterized by expression analysis in mammalian cell lines followed by enzyme activity measurements and modeling into the MAN2B1 3-dimensional structure. Missense mutations affect residues located in the active site, in the dimer interphase as well as in the interior of the protein [5,58,59,61]. Based on pulse chase experiments and immune fluorescence microscopy, Hansen et al. (2004) monitored the intracellular transport of mutant enzymes. They concluded that mutant enzymes (missense) could be divided into two groups: Group 1 that was correctly sorted to the lysosomes and group 2 that was retained (transport arrested) in the endoplasmic reticulum (ER) [61].
There is no apparent correlation between MAN2B1 genotype and clinical phenotype in α-mannosidosis [15]. Clinical variation within sib ships has been observed [17,28,35,36], and patients characterized as less severely or moderately affected were shown to be homozygous for null mutations [15]. However, attempts to predict genotype/phenotype relationships often suffer from lack of data. Case reports on clinical findings are few and often include few patients and variability of methods used. Likewise, mutation reports often lack sufficient clinical data.
Enzyme activity measurements from patient leukocytes or fibroblast cells provide no clue either to a MAN2B1 genotype/phenotype correlation as these values range from 5% to 15% of normal levels. Using a refined method Berg et al. (1999) demonstrated that the level of cross-reacting α-mannosidase activity was less than 1.3% of that in controls, with no consistent variation among affected individuals. However, one cannot rule out the existence of MAN2B1 genotypes ("mild" mutations) that cause sub-clinical symptoms associated with residual enzyme activity. Such cases would likely escape detection as they will not be severe enough to arouse the suspicion of α-mannosidosis.
Environmental factors and other genetic factors may contribute to the clinical heterogeneity seen in α-mannosidosis. Environmental factors might be exposure to pathogens causing recurrent infections and thereby worsening of the disease symptoms. Other genetic factors might be those that encode other mannosidases like cytosolic α-mannosidase that potentially might contribute to the intra cellular clearance of undigested oligosaccharides [14,41,62-64]. However, no such salvage pathway has yet been proven to contribute to the clinical variability.
A thorough clinical and molecular investigation of many patients is warranted in order to explore the clinical variability of α-mannosidosis. Indeed, a study on the natural history of mannosidosis was recently initiated by HUE-MAN – a multinational research project supported by the sixth framework program of the European Union [8].
Light microscopy or transmission electron microscopy (TEM) demonstrates vacuoles in bone marrow smears and lymphocytes from peripheral blood in most affected individuals (Fig (Fig4)4) (reviewed in [14]). Although detection of vacuoles by microscopy is a useful screening test, supplementary investigations are necessary when α-mannosidosis is suspected.
Elevated urinary excretion of mannose-rich oligosaccharides can be demonstrated by thin-layer chromatography [41] or high performance liquid chromatography (HPLC) [65]. This finding is suggestive of α-mannosidosis, but not diagnostic.
The most efficient and reliable method of establishing the diagnosis of α-mannosidosis is the assay of acidic α-mannosidase activity in leukocytes or other nucleated cells. This fluorometric assay is performed at low pH (usually at pH 4) with the substrate 4-methylumbelliferyl α-D-mannopyranoside. In affected individuals, acid α-mannosidase enzyme activity in peripheral blood leukocytes is 5%–15% of normal activity. Residual enzyme activity could possibly represent α-mannosidase activity from other organelles or compartments (e.g., Golgi apparatus; MAN2A1, cytosol; MAN2C1 or ER; MAN1B1), showing some activity also at low pH. Following immunoprecipitation with anti-acid α-mannosidase polyclonal antibodies, acid α-mannosidase enzyme activity ranges from 0.1% to 1.3% of normal [15]. Such testing is not performed routinely. In carriers, acid α-mannosidase enzyme activity is usually 40%–60% of normal, and is therefore unreliable for carrier detection because of the overlap between carriers and non-carriers.
Identification of disease causing mutations is carried out on DNA from peripheral blood cells, by polymerase chain reaction (PCR) amplification of all 24 MAN2B1 exons followed by DNA sequencing.
The main symptoms of mannosidosis, like dysmorphic traits, dysostosis, and mental retardation, are shared with the symptoms in many lysosomal storage diseases like mucopolysaccharidosis.
According to autosomal recessive inheritance, offspring of carrier parents have 25% risk of being affected whereas 50% will be non-symptomatic carriers.
Prenatal testing is available for pregnancies of carrier parents. Prenatal testing may be performed by analysis of acid α-mannosidase enzyme activity in fetal cells obtained by chorionic villus sampling at 10–12 weeks gestation or by amniocentesis at 15–18 weeks. DNA from the same sources can be used for mutation analysis. Preferably, mutation analysis should be carried out in the parents in advance of pregnancy. Genotype does not allow prediction of severity of disease.
In general, the approach to the patients should be pro-active, searching for emerging complications. After a full physical examination, focusing on the known complications of mannosidosis like hydrocephalus, otitis media, hearing loss, dental state, joint status, kyphoscoliosis, and mental state, a plan should be made to limit the health consequences for the patient.
This would also include examination by an ophthalmologist, an otolaryngologist, audiometry and neuropsychological assessment, blood tests, and skeletal evaluation with radiographs, especially of the head, spine, knees or other skeletal sites displaying symptoms.
Early diagnosis with measurement of head circumference, diagnosis with ultrasound, skull radiographs or computed tomography (CT) [20]. Ventriculocaval shunt should be preferred before ventriculoperitoneal shunt due to reduced ability of resorption in the peritoneal cavity in mannosidosis (Malm D: personal observation).
Diagnosis is simple and insertion of pressure-equalizing tubes will reduce the impact of the mechanical component of reduced hearing. There is a variety of tubes, and tubes with long-term stability should be preferred, since the condition is usually long lasting [29].
Diagnosis is made with audiometry in cooperating patients, but can be difficult in young children and severely retarded patients. In some cases the brainstem auditory evoked response (BAER) test measuring brain wave activity that occurs in response to clicks or certain tones, can be useful. For speech therapy to be effective, hearing aids should be provided.
Caries seem frequent because of reduced dental quality combined with tooth grinding or acid reflux from the stomach. Regular dental support and good dental hygiene is obviously important.
Goniometry is used in the measurement of joint pathology. Kyphoscoliosis is measured according to Cobb, and can be corrected with orthopedic surgery (Fig (Fig2).2). Genu valgum deformity can be treated with epiphyseal stapling in growing children, but must be performed early to be effective [23].
Can be monitored with various tests, such as Wechsler. Nonverbal tests can compensate for the hearing deficit.
In α-mannosidosis all cells are devoid of α-mannosidase activity. Early observations showed that cells producing α-mannosidase were able to transfer the enzyme to mannosidosis cells [63,66]. The rationale for bone marrow transplantation (BMT) in mannosidosis is that enzyme-producing donor cells repopulate the host tissues and transfer enzyme to nearby enzyme-deficient host cells.
In 1987 Will et al. performed BMT in a patient with α-mannosidosis. However, the patient died 18 weeks after successful grafting due to procedure related complications. The post mortem examination showed that transplantation reversed the somatic changes of α-mannosidosis, but did not affect lysosomal storage within brain tissue. It was therefore concluded that BMT may not be a suitable treatment for α-mannosidosis [67]. However, the findings of nil effect in the brain could be explained by the only 50% activity in donor cells which came from the mother (being a carrier of alpha-mannosidosis), the treatment of prednisone which could have influenced synthesis of protein, or the short observation period. Because of the blood-brain barrier, the main question remained whether BMT could improve the pathology of the central nervous system. In 1994, Steven Walkley reported that an early BMT could prevent neurological deterioration in a cat model [68]. A possible explanation of the neuronal benefits of BMT could be migration of donor-derived cells to the CNS of the recipient [69]. Later, Wall et al. (1998) presented a single case with BMT, claiming complete resolution of the recurrent infectious disease and organomegaly, improvement in the bone disease, and stabilization of neurocognitive function during a 2 year observation period [70].
Subsequently, a number of unpublished BMTs were performed, and in 2004, Grewal et al. could present results from four patients, aged 3 to 23 years, that had undergone BMT [69]. In short, they claimed that intellectual function stabilized, with improvement in adaptive skills and verbal memory function in 3 of 4 patients. Especially hearing improved to normal or near normal, but for speech frequencies only.
The possible benefits of BMT must be weighed against the overall risk of procedure related morbidity and mortality. The benefits are greater in younger patients before complications have developed, and also transplant related complications are more frequent and severe in older patients. Therefore, BMT is an option in the first decade of life which makes early identification of affected patients critical.
The long-term prognosis is poor. There is an insidiously slow progression of neuromuscular and skeletal deterioration over several decades, making most patients wheel-chair dependent. No patients manage to be completely socially independent. Many patients are over 50 years of age.
Enzyme replacement therapy (ERT) is a therapeutic modality in other lysosomal storage diseases, like Gaucher, Fabry or Pompe disease. In α-mannosidosis, experiments with ERT have been performed in an artificial knock-out mouse model [45], and in a naturally occurring guinea pig model [71]. The reduction in storage material was evident in almost all tissues in both models. However, whereas the first study found a reduction of mannose containing oligosaccharides in the brain to less than 30% of that in control mice with α-mannosidosis [45], a similar cerebral improvement was not found in guinea-pigs [71]. The development of ERT in human is the long term objective of the European HUE-MAN project [8].
Central nervous system: CNS; bone marrow transplantation: BMT; intelligence quotient: IQ; interleukin-2: IL-2; systemic lupus erythematosus: SLE; single nucleotide polymorphisms: SNP; endoplasmic reticulum: ER; polymerase chain reaction: PCR; computed tomography: CT; brainstem auditory evoked response: BAER; Enzyme replacement therapy: ERT.
The authors declare that they have no competing interests.
The authors equally contributed to this review article. They read and approved the final version of the manuscript.
Written consent for publication of photographs was obtained from the patients or legal guardians where required.
The authors wish to thank Professor Pirko Heikinheimo, University of Helsinki, Finland, for contributing the α-Mannosidose 3-D model (Fig (Fig5).5). Also, we wish to thank Dr. Hilde Monica Stensland, University Hospital of North Norway, and President of the ISMRD, John Forman, New Zealand, for valuable comments to the manuscript. We appreciate the European HUE-MAN project [8] enabling us to work in this field.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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HEMPSTEAD, N.Y. -- The New York Jets and first-round draft
pick Darrelle Revis were closing in on a deal Tuesday night that
would end the touted cornerback's lengthy training camp holdout.
"We've made major, substantial progress," Revis' agent, Neil
Schwartz, told The Associated Press. "We're working on it right
Schwartz was at the Jets' headquarters at Hofstra University
late Tuesday night discussing a deal with general manager Mike
Tannenbaum. Schwartz was uncertain if an agreement would be struck
sometime Tuesday night or early Wednesday.
"That, I don't know," Schwartz said. "I don't want to put the
cart before the horse, but we're working. We're making progress."
About an hour after Tannenbaum, Schwartz and his partner,
Jonathan Feinsod, released a joint statement that said talks were
moving along, the Jets general manager met briefly with the media.
"We have some more work to do, but I'm optimistic," Tannenbaum
said. "Neil's here and we're committed to seeing this thing
through. So, barring something unforeseen, hopefully we'll have a
resolution here soon."
Tannenbaum said Revis was not present during the negotiations,
and wouldn't speculate whether the cornerback would be signed in
time to practice Wednesday afternoon.
"It could happen," Tannenbaum said. "It's certainly a
possibility, but I don't want to mislead you and say that's
certainly going to happen."
Revis, taken 14th overall after New York traded up to select
him, became the Jets' first unsigned pick at the start of training
camp since linebacker James Farrior in 1997. He has missed 21
practices and the team's preseason opener last Friday against
Atlanta since camp opened July 27.
The holdup in the negotiations reportedly stemmed from the
length of the contract. The Jets are looking to sign Revis to a
six-year deal, while the cornerback wants a five-year contract.
"I wouldn't comment on that," Tannenbaum said when asked if
the sides came up with an agreement on the length of the deal.
Once he signs, the Jets expect Revis to compete for the starting
job at right cornerback, a position Justin Miller, David Barrett,
Hank Poteat and Drew Coleman all took turns at last season. He
could also serve as the team's punt returner.
Revis was considered one of the best overall cornerbacks in the
draft, and had an outstanding college career at Pittsburgh,
finishing with 129 tackles and eight interceptions.
"Neil's been great," Tannenbaum said. "We've had a lot of
dialogue, a lot of meetings, a lot of communication and it's just
been both sides committed to trying to do something that's good for
both sides."
If Revis signs soon, the only first-round holdout would be top
overall pick JaMarcus Russell, the LSU quarterback selected by


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- Ice
- 1 1/2 ounces amber rum
- 1/2 ounce dark crème de cacao
- 1 1/2 ounces heavy cream
- 1/2 ounce vanilla syrup
- Finely grated zest of 1/2 small orange
- 1 ounce chilled club soda
- Pinch each of unsweetened cocoa and freshly grated nutmeg, for garnish
Fill a cocktail shaker with ice. Add all of the remaining ingredients except the club soda and garnishes; shake well. Strain into an ice-filled highball glass; stir in the soda. Garnish with cocoa and nutmeg.


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Welcome to the
Old Lyme Historical Society
Since its beginning in 2005, the Old Lyme Historical Society has produced exhibits, published books, conducted cemetery tours, held dinner lectures, and hosted Antiques Appraisal Fairs – all in pursuit of our mission to preserve and analyze Old Lyme's past. In 2014 we bought the old Grange Hall at 55 Lyme Street. Thanks to our volunteer "Tuesday Morning Work Crew"- and with help from local contractors, updates to the circa 1900 building are nearly done. The lobby is now an office, the original ceiling in the main hall has been revealed, and an archive storage area has been completed. A new, handicapped-accessible entrance will be next.
Thank you for your support in helping to bring Old Lyme's history to life for new generations!
Old Lyme Historical Society Memorial Day Open House
starts at 10 am
Come to the parade, visit us,
See the recently restored Stage Curtain Backdrop.
Save the Date for Old Lyme's Midsummer Festival! Saturday, July 29, 2017
The Old Lyme Historical Society will be part of the fun, with music, exhibits,
and demonstrations by the Handweavers.


text: Well, my fine flowered friends. Pikmin 3 has been announced. Officially. We have waited many years for the legacy to continue! I would just like to welcome wiki users, both old and new, to our humble wiki. We will still need help, but we can get it done! Well, captains, dismissed!


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A recent Reuters / Ipsos poll finds that 51 percent of Americans are spooked by Internet companies and their growing ambitions, "with a majority worried that Internet companies are encroaching too much upon their lives."
Clearly, users are increasingly concerned about privacy, including healthcare workers and patients. This will likely be exacerbated going forward by new powerful apps and devices, health and wellness devices, medical devices, social media, wearables, and the Internet of Things.
However, many users don't know what to do about it, and feel the situation is hopeless, as can be seen by widespread sentiment that "privacy is dead." I assert that if privacy were dead, and all of our personal information was available to anyone who wanted it, including malicious individuals that would seek to abuse it, then we would be much worse off than we currently are.
In a prior blog, I discussed Viewing Health IT Privacy as a Purchase Decision. From this standpoint, privacy is far from dead, and we are not "privacy broke," but rather many users are currently spending too much of their privacy in online engagements, given the benefits they are receiving, and there is a growing need to help users find more "privacy cost effective" solutions to meet their needs.
In many forms of online engagement, whether apps or social media, there is a natural privacy "give" required for the benefit or "get." For example, if one wants to get live traffic information one must share one's location history since this is a critical input used to calculate the live traffic information. Similarly, if a patient wants health and wellness advice he/she must be willing to share personal health and wellness information with apps and organizations that have the big data/analytics to collect, analyze and derive knowledge from raw health and wellness data and present it to the patient to help them make better choices.
However, in many online engagements there is an unnecessary privacy "give," not required for the benefit the user is receiving. An example may include a flashlight app that has ad network libraries in it tracking the user's location and other personal information – clearly not required for the user to get the function of the flashlight app providing light, and especially considering that there are many other functionally equivalent flashlight apps out there that do not require this unnecessary privacy "give."
In many cases, there are simple actions users can use to achieve their goals while reducing or minimizing unnecessary privacy "give." These could include changing configuration settings of their apps and devices – for example unchecking opt-outs, replacing privacy intrusive apps with safer alternatives such as in the flashlight example above, changing the type of information they share in specific online engagements, or in a worst case uninstalling privacy intrusive apps.
In many cases users, are unaware of the privacy "give" in online engagements. To really help users with privacy, beyond raising the alarm … helping them actually improve their privacy posture, we need to first increase users awareness of their unnecessary privacy "give" and then guide them to viable alternative actions that achieve their goals while significantly reducing or eliminating the unnecessary privacy "give." This is no easy task with the rapidly changing technology landscape especially in the exploding ecosystem of health and wellness apps and online services, but critical if we are to maintain users trust and confidence in the privacy safety of new technology, and their willingness to adopt it and use it.
Are you concerned about your privacy online? What solutions do you see to address these concerns?
David Houlding, MSc, CISSP, CIPP is a senior privacy researcher with Intel Labs and a frequent blog contributor.
Find him on LinkedIn
Keep up with him on Twitter (@davidhoulding)
Check out his previous posts


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Dr. Timothy Gibson MD Patient Reviews
- Orthopedic Surgery Huntington Beach, CA
Overall Rating
24 Patient Reviews
- Friendly Staff
- Promptness
- Wait Time 20 minutes
- Appropriate Followup
- Spends Time With Patients
- Bedside Manner
- Fair and Accurate Diagnosis
- Easy Appointments
Showing 1 - 12 reviews
4.0 of 5
July 11th, 2016
I had bilateral arthroscopic knee surgery awhile back. I found Dr. Gibson to be curt and insulting about losing weight without alot of discussion. I wish he explained to me how important it may have been to lose weight although my health issues make it impossible. The surgery lasted about six years and now I need knee replacements but I will find a doctor that is a little more empathetic and takes time with patients. Also, I couldn't get a hold of the Dr. after surgery and he should have made better arrangements for me to be mobile so I wasn't chasing down wheelchairs and walkers since I couldn't use crutches.
1.0 of 5
May 4th, 2016
Dr. Gibson review.
He spent 5 minutes with me, even cut me off when I was describing my symptoms. Since I wasn't a candidate for surgery he had no time for me. Would ...
2.3 of 5
July 16th, 2013
If you don't need surgery, probably not for you.
Dr. Gibson is not mean. However, if you do not have a problem that requires surgical management, he won't spend much time on you. When I first went to see him, he made me feel stupid for coming. He told me to stop running and come back in one month if I didn't improve. When I came back a month later he seemed befuddled and told me he was going to refer me to an "intellectual orthopedist." What was he saying about himself? The cold hard facts are, insurance doesn't pay enough to try and figure out problems that don't require surgery. But the experience was unsatisfying enough that if I ever needed surgery, I wouldn't go to him.
1.0 of 5
September 30th, 2011
Found him to be very cold and uncaring. If you're not a surgical candidate, he and his staff make you feel like you are wasting their time. Very discouraging. Doesn't really listen and has a very condescending attitude.
5.0 of 5
September 10th, 2010
Dr. Gibson repaired both my elbows a couple years apart. He was sent from God to work miracles! He is awesome and know his stuff for sure. Highly recommended!
5.0 of 5
March 25th, 2010
Dr. Gibson did my Total Knee Replacement. He did a wonderful job and I'm very satisfied. He's a very caring and compassionate person. I will continue to treat with him.
5.0 of 5
March 22nd, 2010
Great Person, Great Surgeon
He did my ACL surgery and my knee feels great now for the 2nd year running. I plan on following up for other surgeries I may have in the future...
5.0 of 5
May 8th, 2017
4.0 of 5
January 28th, 2017
5.0 of 5
December 12th, 2016
5.0 of 5
September 12th, 2016
5.0 of 5
June 12th, 2016
Health Guides
Dupuytren's Contracture
Dupuytren's contracture is a thickening of the tissue beneath the skin of the palm of your hand
Nearby Doctors
Dr. Timothy Gibson, MD is similar to these 3 Doctors near Huntington Beach, CA.
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text: This extension will read any website out loud for you in most languages. It intelligently parses which portion of the page to read. The voices it uses are high quality. You have the option of changing the playback speed, as well as selecting which portion of the page to read. It has keyboard shortcuts for accessibility. The instruction will show up right after you install the extension.


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Jaws Revisited
Divers are Pulling Together to Save Sharks
Most people are afraid to share the water with sharks. But not the scuba divers who make a point of seeking them out. Instead, they call the sharks they encounter "graceful," "compelling," even "beautiful."
Ty Sawyer, long-time diver and editorial director for Sport Diver Magazine, encountered his first shark at 15. In the 32 years since, his passion for diving with sharks has only grown.
"Given any opportunity, I will jump in the water with sharks," says Sawyer. "It is absolutely thrilling to see this well-honed ancient predator in the water doing its thing. When you see them in action the water becomes electrified and it is hard to take your eyes off of them."
As with many terrestrial apex predators like tigers and lions, sharks have a bad reputation. The truth is, it's humans who pose a major threat to sharks, not the other way around.
Breaking the Myth
There is no better way to gain a real understanding of sharks than by seeing them in their own habitat. It's only after diving with sharks that you discover these powerful animals are more curious than ferocious.
"Almost all the sharks that I have encountered have shown more interest than aggression," says veteran diver and underwater photographer Budd Riker. "They're very curious. They are really quite beautiful. One flick of their tail that you'd hardly notice, and they're moving quickly through the water."
Riker had his first encounter with about 20 blue sharks off the coast of San Diego in 1982. At that time, few people dived with sharks and popular consensus was that they were dangerous predators (the huge popularity of the movie Jaws in 1975 probably lent some weight to the vicious shark myth).
"They came up and nosed the camera, but they made no aggressive moves," says Riker. "I learned very quickly that everything I thought about the blue shark was wrong."
The Awe-Inspiring Experience
Christopher Robinson, Editorial Director of Outdoor Photographer Magazine, is fairly new to diving. He began in 2006, taking a PADI (Professional Association of Diving Instructors) open water diver course. On a PADI trip to Tahiti, he was soon diving with lemon and black tip sharks.
"I found the experience to be completely magical," says Robinson. "There is something very different about being in the water with a shark for the first time; you suddenly realize that you are not on top of the food chain. For me, they are simply the most graceful, elegant animals that I have ever seen, under water or above," he says. "The more diving I did, the more I wanted to go back and dive with sharks. What we learn when we get past the myth is that they are powerful and vibrant creatures, and are a vital part of the ecosystems in which they live."
Magical Creatures
So why do these divers, and so many others, love sharks? All three divers relate their experiences with sharks to the world through photography — depicting the beauty of the animal, not sensationalizing the perceived terror of them.
Scientists say that sharks are among the oldest inhabitants of the ocean, with the earliest known species dating from more than 420 million years ago. With seven senses (two more than humans), they have the ability to feel water pressure changes and to sense tiny electrical charges, such as muscle movements.
Because most species will sink if they stop swimming, sharks are also in constant motion. Floating in the ocean among them, part of their world, divers experience first hand their energy and power.
Species in Peril
Most divers also share a concern for the health of shark populations and marine ecosystems. Both Sawyer and Riker have witnessed a decline in certain shark species over time. According to the Project AWARE Foundation, which has been working around the world with divers and decision-makers to close loopholes in shark legislation and management and secure international protection, some species have declined as much as 90% in the last 20 years.
Sharks are vulnerable to extinction from overfishing because they have long life spans and low birth rates. It's estimated that 100 million sharks are killed each year, with 73 million of those destroyed through shark finning. Shark finning is the practice of cutting off the fins and dumping the animal back in the ocean to die—only the fins are kept to sell for shark fin soup and medicines across Asia.
Despite the threat to shark populations, in March 2010 the Convention on International Trade in Endangered Species (CITES), an international agreement between governments, failed to accept proposals for regulating trade of the four shark species facing threats.
"The reason the CITES decision is a real disappointment is because it is one of the few international conventions that has a means of enforcement because it works through the trade regulations of each country that is a party," says Jenny Miller Garmendia, executive director of Project AWARE. "So, short-term economic interests won out over the advice of science in a meeting devoted to regulating trade in endangered species."
What Divers Can Do
Why protect sharks? Besides the loss of a majestic animal, as an apex predator their declining numbers already threaten the balance and health of the marine ecosystem. And divers can play a critical role in their survival. "As a group, divers have greater awareness and sensitivity for the underwater world in general, and sharks in particular," says Dr. Drew Richardson, president of PADI Worldwide and chairman of the Project AWARE Foundation. "From refusing to buy shark products, and encouraging friends to boycott them, to reporting violations of shark fishing, divers can use their individual influence, as well as their group voice, to reverse the trend toward shark over-exploitation and extinction."
Recently, Palau and the Maldives, popular shark-diving destinations, have declared their waters as shark sanctuaries. Divers, such as Riker, Robinson and Sawyer, share their love of sharks and capture their grace and power through articles and photographs.
But, to appreciate and protect sharks, nothing is as powerful as the personal experience of diving with sharks in their own habitat. As Robinson, a PADI instructor, encourages dive students: "if you're lucky enough to be in the water with a shark, relax and enjoy the moment—it will be a dive experience you"ll never forget."
CONTACTS: PADI; Project AWARE Foundation.
MARGO MALCOLM is a freelance travel writer based in Victoria, British Columbia.


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After days of sold-out hotel rooms and crowded bars and restaurants, tourism officials said the one-two punch this week that coupled New Year's Eve festivities with a high-profile Sugar Bowl game was a boon for New Orleans' hospitality industry, calming some jitters about how college football's new playoff format will play out in coming years.
Under the new system, Thursday's Allstate Sugar Bowl this year served as a national semifinal game, a feeder for the Jan. 12 title game in Arlington, Texas.
That will be the case once every three years under the new format. In other years, the Sugar Bowl will pit the best-available teams from the Southeastern Conference and the Big 12 against one another after the four national semifinalists are chosen.
And with New Orleans failing in bids to land the big three sporting events later this decade — the 2016 college football title game, the 2017 NCAA Men's Final Four and the 2018 Super Bowl — the Sugar Bowl, the second-oldest college football bowl game, appears set to be the city's marquee sporting event for at least the next few years.
Early returns suggest this year's game paid off handsomely for hotels, bars and restaurants, with some estimates that more than 100,000 people converged on the city to watch the game, either in person or elsewhere.
That type of crowd typically brings an economic impact of $150 million to the region, officials say. That's big money, though still far from the financial windfall of hosting a Super Bowl, where the extra spending on the lavish event can push the economic impact close to $500 million.
In fact, nearly all of the 21,000 hotel rooms within a few miles of the Mercedes-Benz Superdome were booked this week, some officials said, largely by guests who committed to staying at least three nights.
Brett Forshag, head of sales and marketing for HRI Lodging — which includes the Hyatt French Quarter, Hyatt Place New Orleans and Hilton Garden Inn hotels — said the city's hospitality industry also caught a break by hosting a match-up between Alabama and Ohio State, two schools boasting loyal fan bases willing to travel to support their team.
The Sugar Bowl, Forshag said, is "New Orleans' bread and butter when it comes to major sporting events," noting that demand for hotel rooms was "really just off the charts."
"Sometimes you kind of take it for granted because it's always such a solid event, but you really realize how important it is to the local economy when you have a situation like this," he said.
Forshag said HRI's three hotels required a three-night stay for their 600 rooms because the game fell on New Year's Day. If it had been held a few days later, as has sometimes been the case, the hotels might have been able to demand only a two-night minimum for the game and a single night for New Year's Eve.
"Before the college football season started, I think a lot of us were kind of wondering how this playoff situation was going to affect the hotels," he said. "If you're a fan, can you afford to go to the first playoff game and follow it up with a trip to the championship? That's quite a bit of spending early in the year for a lot of families right after Christmas."
A lot of hoteliers, not just in New Orleans but throughout the U.S., were guarded about whether the extra semifinal games on the schedule would cause some fans to stay home, instead saving their money to potentially attend the final title game, he said. That wasn't the case this year.
By hosting the Sugar Bowl under the new format, New Orleans no longer is guaranteed a national championship game, which it held four times in the 16-year BCS era — which was replaced by the new playoff format — and twice before that in the Bowl Alliance/Bowl Coalition period.
New Orleans lost out to Phoenix for the 2016 college championship game and will not compete for another one until at least 2019. Some local bowl organizers, including Allstate Sugar Bowl CEO Paul Hoolahan, warn that New Orleans will have to loosen its purse strings even more to compete with the rising cost of bidding on big games like the college football title match.
Next year's title game will be held in Glendale, Arizona, home of the Fiesta Bowl; in 2017, it will go to Tampa, Florida. Those cities reportedly bid $13 million, more than twice what New Orleans ponied up for the 2016 game.
City officials had hoped to land the title game in 2016, followed by the Final Four in 2017 and the Super Bowl in 2018, but they ended up empty-handed in their pursuit of that trifecta.
Meanwhile, the success enjoyed by the hospitality industry from future Sugar Bowl games may depend to a large extent on which teams are playing, whereas many consider the championship game as a sure thing, financially.
"The first playoff game could sometimes be not as successful," Forshag said. "You're always guaranteed to have tremendous demand for (the title game). If you would've had two schools in this game that were maybe from much farther away, it could've negatively impacted the game, but I think you're always guaranteed a solid sellout when you have the championship game itself."
Dennis Waldron, who was president of this year's Sugar Bowl Committee, said Friday that the process of bidding to host a title game is something that's "still evolving, and we want to see how the first-ever championship game plays out."
"We certainly will always be committed to doing all we can to bring sporting events to the city that are good for the economy of the city and the state, and we remain focused and try to do the best we can," said Waldron, a recently retired Criminal District Court judge who has been on the committee for two decades. "These are challenging times, and we're on uncharted waters, so to speak."
Even though the city has hosted nearly two dozen national championships, Mark Romig, president of the New Orleans Tourism Marketing Corp., agreed that the bidding process has become a costly endeavor for a cash-strapped city like New Orleans to undertake "because more and more of the games are expecting more and more from the cities."
"It gets competitive," he said. "More and more cities have kind of read our playbook, and they're doing the same thing to try to help build their location as a college football site, but New Orleans is what it is. It's a walkable city, it treats its guests so well. We're just been known to crown many champions here."
From his perspective, the city gains more than just filling its rooms and restaurants by hosting a major sports event. It's also about the national exposure it receives as viewers watch the game on television and as sportscasters and others set up shop in Jackson Square and elsewhere, offering the city plenty of camera-time as its iconic setting serves as a backdrop, "talking about New Orleans like a 24-7 love letter," Romig said.
"Whether or not we're going to participate in the college football championship again, I think that's a decision that we have to make as a group with the city, because with that there comes some expenses," he said. "It's becoming much more expensive to compete, and that's a decision that we all have to make together as community, and decide whether the good outweighs the expense."
He said hosting a Super Bowl is far more lucrative for the local economy because "the parties are bigger, the exposure is greater."
Follow Richard Thompson on Twitter, @rthompsonMSY.


text:
To the Editor:
The United States now needs public investment more than tax cuts, and not only because of the new spending required for security. Yes, we also need improvements in education (including early childhood education and child care), health care, surface transportation and technology for state and local governments. We also need to extend unemployment pay. Such investment can stimulate the economy at least as well as tax cuts -- and result in greater fairness and a stronger future.
Tarrytown, N.Y., Sept. 24
The writer is a senior associate at the Institute of Public Administration, which studies government management, and is secretary of the Regional Research Consortium.Continue reading the main story


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How to Make a tums and bums juice
Ranish Jansari shows how to make a Tums and Bums at Fushi, London - a holistic health and beauty specialist in London. This juice is designed to aid detox and slimming. Its ingredients relieve water retention and flush the system of toxins. All you need is celery sticks, beetroot, lemon, apples, large carrots, and detox tincture.