Indian Pediatrics - Editorial

Letters to the Editor

Indian Pediatrics 2002; 39:704-706

Prenatal Diagnosis of Tay-Sachs B1 Variant In A Maharashtrian Family

We describe an Indian family with Tay-Sachs disease (B1 variant). The proband born to a non-consanguineous Maharashtrian couple was brought to our center for the investigation of lysosomal storage disorder. The child presented at 6 months of age with the complaints of regression in milestones, cherry-red spot on fundus examination, hypotonia, and breathing problem. There was no hepatosplenomegaly. He was clinically suspected as having Tay-Sachs disease and for biochemical confirmation, enzyme study for Hex-A and Hex-T was carried out using flurogenic substrate (4 MU-2 acetamide-2 deoxy-b-D Glucopyranoside), while b-Hex-A was studied using same substrate but by denaturing the cell suspension. During subsequent pregnancy prenatal diagnosis of Tay Sachs B1 variant was carried out in chorionic villus cells at 10 weeks of pregnancy. b-Galactosidase enzyme estimation was carried out in all the study subjects as a control measure. The results are shown in Table 1.

Table I- Enzyme Estimation in a Family with Tay-Sachs Disease

Study subject	b-Hex Total nmoles/hr/mg of protein	b-Hex A %	b-Galactosidase nmoles/hr/mg of protein
Proband	186	24	85.56
	(189-1621)+	(10-52)+	(97.9 ± 19.8)*
Mother	264	40	88.43
	(801 ± 190)*	(55 - 72)*	(97.9 ± 19.8)*
Father	300	44	90.9
	(801 ± 190)*	( 55 - 72)*	(97.5 ± 19.8)*
CVS	2000	33.33	366.0
	(1908 ± 900)*	(28 - 63)*	(350 ± 147)*

*Values in parenthesis are normal range
+Values in parenthesis are patient’s range for Tay-Sachs B1 variant

The proband showed reduced acitivity of Hex-A (24%) and Hex-T (186 nmoles/hr/mg protein) which was within the carrier range as has been observed in Tay-Sachs variant B1(1). An important class of mutation is represented in "B1 variant" of Tay-Sachs disease, which has been elucidated largely by Suzuki and Vanier(2). There was a marginal reduced activity of Hex-T in our case, which is likely to be due to reduced activity of Hex-A in the proband. Based on clinical findings and biochemical results the proband was diagnosed as having Tay-Sachs disease (B1 variant).

Previous studies have shown that the 4MUG activity in B1 variant lies within the carrier range in compound heterozygotes with a functionally null second allele and can be near normal in homozygotes(2,3). This shows that there is a a mutation that inactivate the polypeptides but does not interfere with subunit association and processing to the lysosome. This suggests that the Hex-A activity is derived from the activity of b-subunit(4). Due to this residual activity, the proband might have developed the clinical symptoms after 6 months of age. Rapin et al(5) also described a similar case of a brother and 2 sisters with progressive deterioration of gait and posture. Though we did not carry out mutation study, it was shown by earlier reports that Tay-Sachs disease B1 variants have mutation in exon 5 of HEXA gene at nucleotide 533 that results in a change from arginine to histidine at amino acid 178(6). Another new mutation at nucleotide 987 in exon 9 was also demonstrated by Mules et al(7).

During prenatal diagnosis chorionic villus cells have shown normal activity for both the enzymes (Hex-A and Hex-T) suggesting non-affected fetus and were counseled to continue the pregnancy. Similar study has been made by Conselmann et al.(8) confirming the usefulness of b-Hex-A and b-Hex-T in prenatal diagnosis of Tay Sachs disease and its variants. The present report affirms that with comprehensive genetic counseling and biochemical study prenatal diagnosis can be made in Tay-Sachs disease B1 variant. This relieves the affected family from psychological/mental stress by reassuring them of having the normal baby.

Jayesh Sheth,

Raktima Bhattacharya,

Frenny Sheth,

Foundation for Research in Genetics and Endocrinology (FRIGE),

Genetic Center, 20/1 Bimanagar,

Satellite Road,

Ahmedabad 380 015, India

E-mail: [email protected]

References

1. Wenger DA, Williams C. Screening for Lysosomal Disorders. In: Techniques in Diagnostic Human Biochemical Genetics, Ed. Hommes FA, Willey-Liss, New York, 1991, pp 587-617.

2. Suzuki K, Vanier MT. Biochemical and molecular aspects of late-onset GM2-gangliosidosis: B1 variant as a prototype. Dev Neurosci 1991; 13: 288-294.

3. Cashman NR, Antel JP, Hancock LW, Dawson G, Horowitz AL, Johnson WG. et al.N-Acetyl - b-hexosaminidage b-locus defect and juvenile motor neuron disease. A case study. Ann Neurol 1986; 19: 568-572.

4. Kytzia JH, Hinrichs U, Marie I, Suzuki K, Sandhoff K. Variant of GM2-gangliosidosis with hexosaminidase A having a severely changed substrate specificity. EMBO J 1983; 2: 1201-1205.

5. Rapin I, Suzuki K, Valsamis MP. Adult (chronic) GM2 gangliosidosis. A typical spinocerebellar degeneration in a Jewish sibship. Arch Neurol 1976; 33: 120-130.

6. Whitley CB, Anderson RA, McIvor RS. Hetrozygosity for the DN allele (G533-to-A) of the beta-hexosaminidase alpha subunit gene identified by direct DNA sequencing in a family with the B1 variant of GM2-gangliosidosis. Neuropediatrics 1992; 23: 96-101.

7. Mules EH, Hayflicsk S, Miller CS, Reynolds LW, Thomas GH. Six novel deleterious and three neutral mutations in the gene encoding the alpha subunit of hexosaminidase A in non Jewish individuals. Am J Hum Genet 1992; 50: 834-841.

8. Conselmann E, Nehrkorn H, Kytzia JH, Sandhoff K, Macek M, Lehovsky M, et al. Prenatal diagnosis of GM2 gangliosidosis with high residual hexosaminidase A activity (variant B1: pseudo AB variant). Pediatr Res 1985; 19: 1220-1224.