Spectrum of clinical manifestation of methylmalonic acidemia and homocystinuria in a family of six siblings: novel combination of transcobalamin receptor defect (CD320) and cblC deficiency (MMACHC)

Abstract Background Methylmalonic acidemia with homocystinuria is caused by a rare inborn error of vitamin B12 (cobalamin) metabolism. There are four complementation classes of cobalamin defects cblC, cblD, cblF, and cblJ that are responsible for combined methylmalonic acidemia and homocystinuria. Case presentation We report a case of a Pakistani family composed of six children diagnosed with methylmalonic acidemia and homocystinuria (MMA + HCU). Mutation analysis of siblings revealed a variable combination of c.394C>T mutation in the MMACHC gene and c.262_264del in CD320 gene. All siblings had variable age of onset, initial symptomatology, the severity of disease, and response to treatment. The maximum age of presentation was 6.5 years and the minimum age was at birth. The spectrum of symptoms ranged from a subtle learning disability to global developmental delay within the same family. None of them had a seizure disorder, megaloblastic anemia, visual disturbance, and vascular events.CD320 defect itself is very rare, and only 12 cases have been reported so far. We report six cases, four of them had homozygous MMACHC variant c.394C>T and the other two had heterozygous MMACHC mutations in c.394C>T and c.262_264del in CD 320 genes. To date, neither such case has been reported in the literature or this compound heterozygous mutation. Conclusion Our case report emphasizes that the diagnosis of inherited metabolic disorder in a child obviates the need to screen all siblings for the same disorder.