Abstract
BackgroundCobalamin C deficiency (cblC) caused by the MMACHC mutations is the most common type of the disorders of intracellular cobalamin metabolism. While the c.609G > A mutation is most frequent in Chinese cblC patients, its correlation with phenotype has not been delineated. Here we aim to investigate the factors affecting variable phenotypes and outcomes associated with the MMACHC c.609G > A homologous mutation in 149 Chinese cases to have implications for treatment and prevention.MethodsWe assessed 149 cblC patients caused by MMACHC c.609G > A homozygous mutation. The clinical manifestations, complications, treatment, and outcomes were evaluated; 120 patients were followed-up till December 2019.ResultsTwo patients (1.3%) were prenatally diagnosed, treated after birth and consequently showed normal development. In 15 patients (10.1%) detected by newborn screening, 10 were treated at the age of 2 weeks and showed normal development, while the other 5 were treated after onset and showed neurologic disorders. All 132 clinically diagnosed patients (88.6%) developed symptoms at age from few minutes after birth to 72 months. Among them, 101 (76.5%) had early-onset (before the age of 12 months) and 31 (23.5%) had late-onset (after the age of 12 months). Totally 5 patients died and 24 were lost to follow-up. Of the 132 clinical diagnosed patients, 92 (69.7%) presented with developmental delay, 65 (49.2%) had seizures, 37 (28.0%) had anemia, 24 (18.2%) had feeding difficulty, 23 (17.4%) had ocular problems, and 22 (16.7%) had hydrocephalus. Compared with the non-developmental delay group, the onset age, the age at treatment initiation and the time from onset to treatment initiation were later in the developmental delay group. Seizure group showed significantly higher urinary methylmalonic acid concentration. During long-term follow-up, plasma total homocysteine (tHcy) levels were significantly higher in patients in the uncontrolled group than those in the seizure-free group.ConclusionsMost cblC patients caused by MMACHC c.609G > A homozygous mutation showed early-onset. The clinically diagnosed patients usually showed the presence of irreversible brain disorders. Patients treated from the pre-symptomatic stage showed favorable outcomes. Therefore, newborn screening, prenatal diagnosis and early treatment are crucial and the c.609G > A mutant allele should be listed in the pre-pregnancy carrier screening panel in China.
Highlights
Cobalamin C deficiency caused by the MMACHC mutations is the most common type of the disorders of intracellular cobalamin metabolism
During long-term followup, plasma total homocysteine levels were significantly higher in patients in the uncontrolled group than those in the seizure-free group
Most Cobalamin C deficiency (cblC) patients caused by MMACHC c.609G > A homozygous mutation showed early-onset
Summary
Cobalamin C deficiency (cblC) caused by the MMACHC mutations is the most common type of the disorders of intracellular cobalamin metabolism. The most common MMACHC pathogenic variant previously reported, c.609G > A (p.Trp203X), results in a premature termination codon that is predicted to cause a truncated or absent MMACHC protein due to nonsense mediated decay and accounts for 48.1% of mutant alleles in 79 Chinese patients with cblC [3] This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.004% and has been reported in numerous affected individuals in the homozygous and compound heterozygous state, and there is evidence that the variant may be a founder mutation in the Chinese population [3, 7]
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