What are the risks and recommendations for a hexa (hexosaminidase A) gene carrier among Japanese individuals?

HEXA Gene Carrier Status Among Japanese Individuals: Risks and Recommendations

Japanese individuals who are carriers of HEXA gene mutations have no health risks themselves but should receive genetic counseling to understand their 25% risk of having a child with Tay-Sachs disease if their partner is also a carrier. 1, 2

Understanding HEXA Gene and Tay-Sachs Disease

• Tay-Sachs disease (TSD) is an autosomal recessive neurodegenerative disorder caused by mutations in the HEXA gene, resulting in deficiency of hexosaminidase A enzyme 1
• The HEXA gene encodes the alpha subunit of hexosaminidase A, which normally functions to hydrolyze GM2 ganglioside 1
• Deficient enzyme activity leads to accumulation of GM2 ganglioside in the nervous system, causing progressive neurodegeneration 1

Japanese-Specific HEXA Mutation

• The predominant mutation among Japanese patients with infantile Tay-Sachs disease is a G-to-T transversion at the acceptor site of intron 5 of the HEXA gene 2
• This mutation was found in 38 out of 48 mutant alleles (79%) in Japanese TSD patients, with 15 patients homozygous and 8 heterozygous for this mutation 2
• This mutation appears to be unique to the Japanese population and causes a splicing abnormality resulting in mRNA lacking exon 6 sequence 2

Carrier Status Implications

• Carriers (heterozygotes) have one normal and one mutated HEXA gene copy and typically show no symptoms of the disease 1
• Carrier frequency in the general population is approximately 1 in 300, compared to 1 in 31 in high-risk populations like Ashkenazi Jews 1
• The specific carrier frequency for the Japanese population is not explicitly stated in the evidence, but the Japanese-specific mutation is highly prevalent among Japanese TSD patients 2

Testing Recommendations

• For Japanese individuals concerned about carrier status, the following testing approach is recommended:
  • Initial screening with hexosaminidase A enzyme activity assay in serum or white blood cells 1, 3
  • If enzyme testing suggests carrier status, confirmatory DNA testing should be performed, specifically looking for the Japanese-specific G-to-T mutation at intron 5 2, 3
  • This two-step approach helps distinguish true carriers from individuals with pseudodeficiency alleles 1

Reproductive Considerations

• When both partners are carriers, there is a 25% risk of having a child affected with Tay-Sachs disease in each pregnancy 1
• For carrier couples planning pregnancy, options include:
  • Prenatal diagnosis through chorionic villus sampling or amniocentesis 1, 3
  • If parental mutations are known, DNA-based testing of fetal cells is preferred 1
  • If mutations are not fully characterized, enzyme activity testing of fetal cells can be performed 3

Important Caveats

• Pseudodeficiency alleles (R247W and R249W) can complicate biochemical screening by showing reduced enzyme activity without causing disease 1
• These pseudodeficiency alleles are more common in non-Jewish populations (32% and 4% respectively) but have not been specifically reported in Japanese populations 1
• The presence of a pseudodeficiency allele with a true disease-causing mutation can result in very low enzyme activity without disease symptoms 1
• DNA testing is essential to distinguish between true disease-causing mutations and pseudodeficiency alleles 1, 4

Clinical Implications for Offspring

• Infantile TSD is fatal, with affected children typically not surviving beyond 3-5 years of age 1
• The disease is characterized by progressive weakness, loss of motor skills, decreased attentiveness, increased startle response, and a characteristic macular cherry red spot 1
• As the disease progresses, seizures and blindness develop 1
• Treatment is currently only supportive, focusing on nutrition, hydration, seizure management, and airway protection 1