Tay–Sachs Disease Establish rapport with small talk Assess the understanding for the referral to genetics Assess the concerns of the family and what they hope to learn today Ascertain the level of understanding of Tay–Sachs for those members present Discuss topics to be covered during the appointment Ask if anyone has any questions Also called Hexosaminidase A deficiency A genetic disorder that commonly affects the Ashkenazi Jewish population Hexosaminidase A is a lysosomal enzyme that is required to catalyze one step in the catabolism of gangliosides. The lack of hexosaminidase A results in the faulty metabolism of sphingolipids A specific sphingolipid, GM2 ganglioside accumulates in the cells, especially nerve and brain cells Death usually occurs before age 4 in the infantile type of disease Juvenile, chronic, and adult onset forms of the disorder also exist No specific therapy is currently available. Inherited in an autosomal recessive fashion The chromosomal locus of HEXA is 15q23-q24 Mutations in the HEXA gene are associated with the Tay–Sachs phenotype The HEXA gene is ~35 kb, has 14 exons and both 5' and 3' UTRs The normal gene product is Beta-hexosaminidase alpha chain The gene encodes the alpha chain of the heterodimeric protein, beta-hexosaminidase A (HEX A) The protein has a single alpha chain and a single beta chain; both HEX A and HEX B show GM2 ganglioside cleaving acitivity, but that of HEX A is 8x greater than HEX B The gene for HEX B is located on chromosome 5; this subunit is responsible for most of the catalytic activity More than 90 HEXA mutations have been identified The majority are associated with the infantile phenotype 2 null mutations result in 90-95% of the cases of infantile Tay–Sachs disease in the Ashkenazi Jewish population. The abnormal gene product: mutations result in many effects ranging from processing or subunit assembly to defective catalytic activity 1:3600 Ashkenazi Jewish live births. The carrier rate is 1:25-30 Ashkenazi Jewish persons The carrier rate for the French-Canadian population is 1:50 Among non-Jews, the disease incidence is about 100 times less common and the carrier rate is 1:250-1:300. As the result of extensive genetic counseling of carriers identified through screening programs and the monitoring of at risk pregnancies, the incidence of TSD has been reduced by greater than 90%. If both parents are carriers, the risk of occurrence is 25% with each pregnancy If either or both parents are carriers, the risk to have a carrier child is 50% for each pregnancy When both parents are carriers, unaffected children have a 67% risk of being carriers. Onset at age 3-6 months Death before the age of 4 Hexosaminidase A deficiency is characterized by: Progressive weakness and loss of motor skills beginning between 3-6 months Decreased attentiveness Increased startle response A cherry red spot of the fovea centralis of the macula of the retina can be seen in >90% of cases Hyperreflexia with sustained ankle clonus These signs are followed by: Progressive neurodegeneration Seizures Blindness, typically by the end of the 8th month of life Spasticity of the limbs An increase in head circumference often reaches 3 standard deviations above normal due to an enlargement of the brain NOT hydrocephalus Progressive inability to swallow Breathing difficulties Juvenile, chronic and adult-onset forms have later onset, slower progression, and more variable neurologic findings Diagnostic (Biochemical) The diagnosis of TSD relies upon the absence or near absence of HEX A in the serum or WBC of a symptomatic individual in the presence of normal or elevated activity of HEX B isoenzyme If the HEX A activity is undetectable= homozygote, affected Carrier (Biochemical) In population screening, assay of HEX A activity in serum or leukocytes using synthetic substrates provides a simple, inexpensive and accurate method for heterozygote identification Serum is used for males and women who are not pregnant and not using oral contraceptives Leukocytes are used for testing pregnant women, women using oral contraceptives and any individual whose serum activity level was in the inconclusive range. If the HEX A activity is ~1/2 the normal level=heterzygote, carrier Molecular Genetic Testing: Used to identify specific disease-causing alleles in affected individuals and to distinguish pseudodeficiency alleles from disease-causing alleles in individuals with apparent deficiency of HEX A activity identified through screening programs Mutation analysis is available for the 6 most common mutations at most clinical laboratories Comprised of three null alleles (non expressing) +TATC1278, +1IVC12, +1IVS9, which in the homozygous state or in compound heterozygosity are associated with TSD The G269S allele, which is associated with the adult onset form of TSD in the homozygous state or in compound heterozygosity with a null allele And two pseudodeficiency alleles R247W and R249W, which are not associated with the neurological disease, but are associated with reduced degradation of synthetic substrate when HEX A activity is determined Pseudodeficiency alleles reduce HEX A activity toward synthetic substrates, but not toward the natural substrate GM2 ganglioside Since all assays use artificial substrate, a potential problem arises when distinguishing between a true deficient allele and a pseudodeficient allele. Problem avoided by using a DNA-based test on any individual who had abnormal activity to identify the disease causing mutation Prenatal Available when: HEX A enzyme assay has shown both parents to be carriers for TSD and molecular genetics has ruled out the possibility of pseudodeficient alleles in either parent If one parent is known to be a heterozygote and the other parent has inconclusive enzymatic activity and no disease-causing mutation can be found And if the mother is a known carrier and the father's status is unknown or he is unavailable for testing Testing can be performed by assay of the HEX A activity in fetal cells obtained by CVS or amniocentesis If the mutation has been identified in both parents, then mutational analysis of the HEXA gene in fetal DNA (extracted from fetal cells removed by CVS or amniocentesis) can be done. Treatment for TSD is primarily supportive Provide adequate nutrition and hydration Manage infectious disease Protect the airway Control seizures with anticonvulsant medications, alter dose based on severity and type of seizure As the patient becomes more disabled, good bowel management is important Older patients with the adult-onset form may need antidepressants or antipsychotic therapy Enzyme and gene therapy: Attempts have been unsuccessful Infusions and bone marrow transpantation have had no benefit CNS enzyme replacement are in the experimental stage at this time Activator deficient TSD The enzymatic activity of both HEX A and HEX B is normal GM2 ganglioside accumulation occurs due to a deficit of the intralysosomal glycoprotein "GM2 activator" that is required for the degradation of GM2 ganglioside. The phenotype is identical to TSD The cherry red spot of the fovea centralis of the macula of the retina is seen during the first year of life in patients with Gaucher disease, GM1 gangliosidosis, galactosialidosis, Niemann-Pick type A, and Sandhoff disease Neurologic regression during the first 6 months of life is seen in many disorders including: Krabbe disease, Canavan disease, Alexander disease, infantile Gaucher disease, and both infantile and late infantile forms of neuronal ceroid-lipofuscinosis. Sandoff disease presents with the same neurological findings as TSD, although it is rarely seen in Jewish infants. For the adult form- SMA3, Friedreich ataxia, ALS and other lysosomal storage diseases should be considered Impending death Devastating disease Contemplation of pregnancy termination Guilt Heterozygote detection Population-based screens for Ashkenazi Jews Therapeutic termination National Tay–Sachs and Allied Diseases Association, Inc 2001 Beacon Street, Suite 204 Brighton, MA 02135 Phone: 1-800-906-8723 Email: NTSAD-boston@worldnet.att.net www.ntsad.org National Foundation for Jewish Genetic Diseases 250 Park Ave, Suite 1000 New York, NY 10177 Phone: 212-371-1030 Email: NFJGD@aol.com www.nfjgd.org Robinson A, Linden MG. (1993). Clinical Genetics Handbook. 2nd edition. Boston: Blackwell Scientific Publications Lyon G, Adams RD, Kolodny EH. (1996). Neurology of Hereditary Metabolic Diseases of Children. 2nd edition. Goodman, RM. (1979). Genetic disorders among the Jewish People. Baltimore: The Johns Hopkins University Press. www.geneclinics.org The information in this outline was last updated in 2002.
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