Homozygosity for the double D409H+H255Q allele in type II Gaucher disease

Area of Science:

• Genetics and Molecular Biology
• Neurology
• Rare Diseases

Background:

• The D409H mutation in the GBA gene is linked to a Type III subtype of a rare disease, characterized by severe cardiovascular issues and minimal neurological symptoms.
• Previous understanding suggested a specific phenotype associated with D409H homozygosity, primarily impacting the cardiovascular system.

Purpose of the Study:

• To investigate the genetic basis and clinical phenotype of patients identified with the D409H/D409H genotype.
• To characterize the specific GBA gene mutations and their combined effect on disease presentation.

Main Methods:

• Polymerase Chain Reaction (PCR) amplification and restriction enzyme analysis were used to identify the D409H/D409H genotype in patients.
• Full coding region sequencing of the GBA gene was performed to identify additional mutations.
• Parental DNA analysis was conducted to confirm the co-inheritance of mutations on the same allele.

Main Results:

• Three patients (Greek and Albanian) with the D409H/D409H genotype presented with a severe, early-onset neurological phenotype, classifying them as Type II.
• These patients were found to be homozygous for both D409H and H255Q mutations, with both present on the same GBA gene allele.
• The D409H+H255Q allele was found in heterozygotes in Greek, Bulgarian, and Argentinian populations, but not in Spanish patients with D409H.

Conclusions:

• Homozygosity for the combined D409H and H255Q mutations on the same GBA allele results in a distinct and severe neurological phenotype (Type II).
• This finding expands the genotypic and phenotypic spectrum associated with GBA mutations, highlighting the importance of considering combined mutations.
• The prevalence of the D409H+H255Q allele varies geographically, suggesting potential founder effects or differing population genetics.