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Tay-Sachs disease

  • Tay-Sachs disease is an autosomal recessive condition caused by deficiency of the enzyme hexosaminidase A (HEX A).
  • The carrier frequency for Tay-Sachs disease is about 1 in 30 amongst Jews of Ashkenazi ancestry, which in that population group gives a disease incidence of 1 in 3600 children born. In the majority of other populations the carrier frequency is between 1 in 250 and 1 in 300.

Clinical features

  • Tay-Sachs disease is characterised by a normal early infancy, followed by a cessation and then loss of motor skills beginning between three and six months of age. Seizures, initially as myoclonic jerks, and visual problems develop, accompanied by a characteristic cherry-red spot on the macula of the retina.
  • The child shows progressive neurodegeneration, including worsening seizures, and blindness, developing spasticity and decerebrate posturing, and leading to death usually before four years of age.
  • There are also milder juvenile (subacute) and chronic and adult-onset variants of hexosaminidase A deficiencies; the latter often demonstrating long-term survival.

Diagnosis

  • Clinical suspicion in an infant or child who shows cessation and/or decline of an initially normal motor developmental progress, and develops other neurological signs, but not an enlarged liver or spleen.
  • Family history enquiry specifically to include questions about Ashkenazi Jewish ancestry.
  • Eye examination to detect cherry-red spot on the macula of the retina.
  • Blood sample for serum and white cell lysosomal enzyme assay, specifically hexosaminidase A and B (HEX A is deficient; HEX B is normal).
  • DNA testing for HEXA gene mutation analysis.

Genetic basis

  • Tay-Sachs disease is caused by mutations in the alpha subunit of the HEXA (hexosaminidase A) gene on chromosome 15.
  • More than 100 HEXA mutations causing Tay-Sachs disease have been identified to date. Amongst Ashkenazi Jewish people, two of these mutations account for 90-95% of all affected chromosomes.
  • At least one of these HEXA DNA variants is a pseudo-deficiency allele, leading to apparent low Hex-A enzyme activity in the biochemical test, but not in vivo, and does not cause clinical disease.

Clinical management

  • Management of infants and children with Tay Sachs disease should be by or under the guidance of a paediatric neurologist, or inherited metabolic disease specialist.
  • Management is largely supportive and palliative. Seizure control may be achieved initially with standard anti-convulsant drugs, but progression of neurodegeneration will necessitate alterations in the types and dose of anti-convulsant regime required.
  • In juveniles or adults with the later-onset presentations there can be psychiatric manifestations, but response to antipsychotic treatments is unpredictable, and often poor.

Genetic testing

  • In the biochemical laboratory test for HEX A activity, a pseudodeficiency allele (which does not cause HEX A enzyme deficiency in vivo) accounts for 36% of apparent HEX A deficiency heterozygotes in non-Jewish populations, and for 2% in Jewish populations. A diagnosis of Tay-Sachs disease, or a biochemical carrier test, should therefore be supported by molecular genetic confirmation.
  • Carrier testing is possible by direct mutation detection if known, or assay of HEX A enzymatic activity (provided there is no confounding pseudodeficiency).
  • Prenatal diagnosis is possible (from chorion villus biopsy from 11 weeks gestation, or by later amniocentesis) by direct mutation detection if known, or by enzyme analysis otherwise. If a family is considering prenatal diagnosis for the first time, referral to Obstetrics/Fetal medicine or to the local Clinical Genetics service should be made prior to a pregnancy if at all possible. This can ensure that pseudodeficiency should not be a confounding issue. Referral to Clinical Genetics can also facilitate the offer of appropriate advice and carrier test investigation to family members.
  • Preimplantation genetic diagnosis (PGD) is licensed in the UK for couples who are both carriers for Tay Sachs Disease.

 

This information is intended for educational use and was current in February 2014. For clinical management, it is recommended that local guidelines and protocols are used.