What is Tay-Sachs disease?

From the Guidelines

Tay-Sachs disease is a rare, inherited genetic disorder that progressively destroys nerve cells in the brain and spinal cord, caused by mutations in the HEXA gene, leading to a deficiency of an enzyme called hexosaminidase A, and primarily affects infants of Eastern European Jewish (Ashkenazi), French-Canadian, and Cajun descent.

Key Characteristics of Tay-Sachs Disease

• It is an autosomal recessive lysosomal storage disease, meaning that a person must inherit two copies of the mutated gene (one from each parent) to develop the disease 1.
• The disease is characterized by progressive weakness and loss of motor skills, decreased attentiveness, and increased startle response, with a typical macular cherry red spot, and often leads to seizures, blindness, and death by age 3 to 5 years 1.
• There are milder variants of hexosaminidase A deficiency, including juvenile (chronic) and adult-onset forms, which have later onset and slower disease progression 1.

Diagnosis and Treatment

• Tay-Sachs disease is diagnosed by deficient activity of hexosaminidase A in serum or white blood cells, and molecular genetic testing can be used for clinical confirmation, carrier testing, and prenatal testing in Ashkenazi Jewish individuals 1.
• Treatment for Tay-Sachs disease is supportive and includes improvement of nutrition and hydration, treating seizures, managing infections, and protecting the airway, with no cure available and enzyme replacement therapy and bone marrow transplant being ineffective 1.

Screening and Genetic Counseling

• Carrier screening is recommended for individuals of Ashkenazi Jewish, French Canadian, and Cajun descent, with a carrier frequency of approximately 1 in 31 in these groups, and genetic counseling is recommended for families with a history of the disease or those from high-risk ethnic backgrounds 1.
• Prenatal diagnosis is possible for at-risk pregnancies, and screening can be performed by DNA testing or biochemical screening, with biochemical screening recommended for non-Jewish individuals or individuals of mixed ethnicity 1.

From the Research

Definition and Overview of Tay-Sachs Disease

• Tay-Sachs disease (TSD) is an autosomal recessive disease characterized by progressive neurodegenerative presentations 2, 3.
• It is caused by a deficiency of β-hexosaminidase A (HexA) enzyme due to various mutations in the α-subunit gene of this enzyme, resulting in GM2 ganglioside accumulation predominantly in lysosomes of nerve cells 3.
• The disease affects one in 100,000 live births and is characterized by acute neurodegeneration, muscle weakness, ataxia, speech, and mental disorders 2, 3.

Forms and Symptoms of Tay-Sachs Disease

• Tay-Sachs disease has different forms, including the infantile form, which is the most severe, and the juvenile and late-onset forms 3.
• The symptoms of the disease depend on the residual HexA enzymatic activity associated with some mutations, and clinical symptom severity varies among patients 3.
• Typical features of Tay-Sachs disease include muscle weakness, ataxia, speech, and mental disorders, with the disease often manifesting itself during infancy 3.

Current Treatment and Therapeutic Strategies

• Currently, there is no approved therapy or cure for Tay-Sachs disease, and treatment is based on symptom relief and, in some cases, delay of progression 2, 3.
• Various therapeutic strategies are being developed, including enzyme replacement therapy, pharmaceutical chaperone therapy, substrate reduction therapy, gene therapy, and hematopoietic stem cell replacement therapy 2, 3.
• Studies have reported the use of MALDI mass spectrometry to perform high-throughput screens of compound libraries, enabling the discovery of compounds that reduce GM2 and potentially leading to further development of a TSD therapy 2.

Genetic Basis and Diagnosis

• Tay-Sachs disease is caused by genetic variations in the HEXA gene leading to a deficiency of β-hexosaminidase A (HEXA) isoenzyme activity 4.
• Genetic testing, including targeted gene sequencing and whole-exome sequencing, can be used to identify causative gene variants and diagnose the disease 4.
• The study of Tay-Sachs disease has expanded the ethnic and mutational spectrum of the disease, emphasizing the usefulness of whole-exome sequencing as a diagnostic tool 4.