Disclaimer: This newsletter is intended to enrich the insights related to genetic disorders from a laboratory perspective. The objective of this newsletter is to share knowledge from a lab perspective to facilitate the dialogue of genetic disorders diagnosis. We want to sincerely thank the physicians whose dedication, knowledge and intelligence helps arrive at answers through diagnosis enabling timely and effective prevention.


Tay-Sachs disease is a rare, inherited neurodegenera-tive disease. People with Tay-Sachs disease do not have enough of an enzyme called beta-hexosamini-dase A1.The severity of expression and the age at onset of Tay-Sachs varies from infantile and juvenile forms that exhibit paralysis, dementia, blindness and early death to a chronic adult form that exhibits neuron dysfunction and psychosis.
In the general population, the carrier rate for Tay-Sachs disease is approximately 1 in 250-300 people.Tay-Sachs is an autosomal recessive disease caused by mutations in both alleles of a gene (HEXA) on chromosome 15. HEXA codes for the alpha subunit of the enzyme β-hexosaminidase A.

This enzyme is found in lysosomes, organelles that break down large molecules for recycling by the cell2.
The diagnosis of Tay-Sachs disease involves a blood test that detects absent or very low levels of beta-hexosaminidase A enzyme activity3. Molecu- lar genetic testing of the HEXA gene may be used to identify the specific mutations present, or to rule out the disease if a false-positive blood test result is sus- pected.
Treatment options aim to control some of the symp- toms. For example, your provider may prescribe medication to control seizures. Other treatment measures include providing proper nutrition and hy- dration.


A 5-months male child born of non-consanguineous marriage presented with:

  1. Global developmental delay
  2. IUGR
  3. Floppy Baby
  4. Bulbar weakness
  5. Failure to thrive
  6. Muscular hypotonia
  7. Sepsis
  1. Respiratory Distress (O2 Support @7 days)
  2. Opisthotonos
  3. Hyperreflexia
  4. Congenital myopathy
  5. Gliosis
  6. B/L Undescended testis
  7. Upper motor neuron signs

Facial Dysmorphism: Dolichocephaly,Retrognathia, Broad Nasal Bridge.

Previous Tests Reports

Gliosis along left inferior temporal gyrus, mild thinning of the cortex Normal study Patchy myopathic process involving proximal upper limb and tongue

Tests Prescribed : Whole Exome Sequencing

  1. Whole Exome Sequencing
  2. Enzyme Analysis

About the Prescribed Tests

Test Name Sample Type Method Description
Whole Exome Sequencing 2-4 EDTA Blood Next Generation Sequencing Mean coverage of 80-100X coverage. Target coverage 200X
Enzyme Assay 2-4 EDTA Blood Fluorometry assay Enzyme Analysis of Beta Hexosaminidase A by fluorometry assay with artificial substrate

Test Results

  1. Whole Exome Sequencing: A homozygous variant was found in the HEX4 gene which is classified as variant of uncertain significance. (Table.1).
  2. A heterozygous variant was found in the CACNA1G gene which is classified as variant of uncertain significance. (Table.1)
  3. A heterozygous variant was found in the MORC2 gene which is classified as variant of uncertain significance. (Table.1)

Table 1. Whole Exome Sequencing result

TGene & Transcript Variant Location Zygosity Disorder (OMIM) Inheritance Classification
CACNA1G c.164G>A(p.Ala550Thr) Exon 8 Heterozygous Spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits Autosomal Dominant VOUS
HEX4 c.134A>C(p.Gln45Pro) Exon 1 Homozygous GM2-gangliosidosis, several forms; Tay-Sachs disease Autosomal Recessive VOUS
MORC2 c.598A>G(p.lie200val) Exon 8 Heterozygous Charcot-Marie-Tooth disease, axonal, type 2Z;cancer

Table 2. Enzyme Assay results

Test (Units) Disorder Results Reference Status
Beta Hexosaminidase A (nmol/hr/mg) Tay-Sachs 14.8 62-310 Low
Beta Galactosidase (nmol/hr/mg) GM1-gangliosidosis 141.0 70-324 Normal

Result Interpretation:- Low enzyme activity of ß-Hexosaminidase A in leukocytes may be consistent with the diagnosis of Tay-Sachs disease. (Table.2)


  1. The clinical suspicion of Tay Sach disease should lead to the immediate analysis of blood to measure the hexosaminidase A followed by mutation analysis.
  2. Ophthalmic evaluation should be done to check classic cherry red spot in the eye.
  3. Treatment may require the coordinated efforts of a team of specialists (Pediatricians, neurologists, speech pathologists).
  4. The early prenatal diagnosis of Tay Sach disease is possible by molecular analysis of chorionic villus cells or cultured amniocytes.
  5. Exome sequencing along with measurement of enzyme activity analysis can significantly improve the diagnostic yield.
  6. Genetic counseling is recommended for affected individuals and their families. Psychosocial support is recommended for the entire family.

This bulletin is compiled by

Name Designation Contribution
Mr. Nadir Aman Genetic Counselor Compilation
Ms. Vineeta Singh Vice President-Scientific Affairs Exome Analysis
Ms. Divya Borkar Manager - Biochemical Genetics Enzyme Assay


  1. Rare Diseases, here
  2. OMIM, here
  3. NCBI, https://www.ncbi.nlm...Click here
  4. here