炭酸脱水酵素VA欠損症における、代謝クライシスを伴わない発達遅滞として発症する新規ホモ接合型CA5A遺伝子欠失症

Carbonic anhydrase VA deficiency is a rare autosomal recessive disorder caused by biallelic mutations in the CA5A gene. Patients present with acute metabolic decompensation including hyperammonemia in infancy albeit a good outcome.

We report three children from the same Saudi tribe with a novel homozygous deletion in CA5A gene, manifesting predominantly as developmental delay without hyperammonemia and major metabolic crises.

Diagnostic work-up included clinical, biochemical, neuroimaging, and genetic analyses through WES and WGS with family segregation analysis.

The first patient, a 3-year-old girl, presented with global developmental delay, corpus callosum thinning, and mild periventricular leukomalacia on brain MRI. The second patient, a 7-year-old girl born to consanguineous parents, had delayed motor and language milestones with persistent speech delay, microcephaly, and mild to moderate intellectual disability, but normal metabolic and neuroimaging findings. Her younger sister, aged 4 years, showed mild speech delay without additional clinical abnormalities with biochemical investigations in both siblings unremarkable. None presented with classic neonatal hyperammonemia. A pathogenic homozygous loss of 16.5 kb (exons 3-7) in CA5A gene (chr16:87921735-87,938,510 NM_001739.2) was identified in all the three children with the parents and healthy siblings carrying the variant in heterozygous state.

CA-VA deficiency may present with non-specific neurodevelopmental delay without metabolic decompensation. Genetic analysis remains the cornerstone for identifying atypical cases with novel mutations in a rare disease and recognition of this atypical presentation is essential for awareness of the disease.