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)

Nadia Waheed,Ahmad Imran,Zafar Fayyaz

doi:10.1186/s43042-021-00197-2

Nadia Waheed, Ahmad Imran + Show 1 more

Open Access

https://doi.org/10.1186/s43042-021-00197-2

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Abstract

BackgroundMethylmalonic 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 presentationWe 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.ConclusionOur case report emphasizes that the diagnosis of inherited metabolic disorder in a child obviates the need to screen all siblings for the same disorder.

Highlights

Methylmalonic acidemia with homocystinuria is caused by a rare inborn error of vitamin B12 metabolism
We discussed a family of 6 siblings having symptomatic methylmalonic acidemia and homocystinuria with a novel combination of defects in the MMA DUE TO cobalamin c disease (cblC) deficiency (MMACHC) and CD 320 gene
Normal systemic examination was normal including the central nervous system. We performed her metabolic workup afterward which revealed elevated Methylmalonic level along with raised levels of homocysteine levels (240 umol/L) in serum confirming the diagnosis of methylmalonic acidemia with homocystinuria

Summary

Background

Cobalamin is vitamin B12, an essential water-soluble vitamin, which has a vital role in the functioning of several enzymes in our body [1]. All siblings presented with variable initial symptomatology, age of onset, and severity of symptoms and showed variable response to treatment Case presentation This family first sought medical attention when their eldest daughter suffered from behavioral changes at 6 years of life. Her gait became ataxic, and gradually she lost ambulation at 10 years of age Her magnetic resonance imaging of the thoracolumbar spine performed was normal, but MRI brain revealed bilateral symmetrical hyper-intensities in periventricular and peritrigonal areas suggestive of demyelination due to a metabolic disorder. Normal systemic examination was normal including the central nervous system We performed her metabolic workup afterward which revealed elevated Methylmalonic level (mean 625 nmol/L) along with raised levels of homocysteine levels (240 umol/L) in serum confirming the diagnosis of methylmalonic acidemia with homocystinuria.

Discussion

Conclusion