Pathogenic Compound Heterozygous Mutations in a Mexican Mestizo Patient with Niemann-Pick Disease Type B

Area of Science:

• Biochemistry
• Genetics
• Pediatric Medicine

Background:

• Niemann-Pick disease type B (NPD type B) is a lysosomal storage disorder resulting from acid sphingomyelinase (ASM) deficiency.
• Early diagnosis and understanding of genetic mutations are crucial for managing rare inherited metabolic diseases.

Observation:

• A 16-year-old Mexican mestizo woman presented with hepatosplenomegaly, low HDL cholesterol, and thrombocytopenia, characteristic of NPD type B.
• A dengue fever episode revealed pancytopenia, prompting a bone marrow study that identified foamy histiocytes, leading to the suspicion of Niemann-Pick disease.

Findings:

• Biochemical and molecular testing confirmed NPD type B, identifying two novel missense mutations (c.1343 A>G and c.1426C>T) in the SMPD1 gene.
• The identified mutations, p.Tyr448Cys and p.Arg476Trp, have not been previously reported in the Mexican population.
• The combination of these mutations suggests a potential attenuator effect of the R474W allele on the Y446C mutation, which is typically associated with NPD type A.

Implications:

• This case represents the first documented instance of these specific SMPD1 mutations occurring together in a Mexican patient with NPD type B.
• Increased awareness and accessibility of specialized diagnostic tools are vital for the accurate and timely diagnosis of rare genetic disorders.
• Understanding genotype-phenotype correlations, including potential modifier effects of compound mutations, can improve patient management and genetic counseling for Niemann-Pick disease.