Clinical, phenotypic and genetic landscape of case reports with genetically proven inherited disorders of vitamin B12 metabolism: A meta-analysis

Abstract

Inherited disorders of B₁₂ metabolism produce a broad spectrum of manifestations, with limited knowledge of the influence of age and the function of related genes. We report a meta-analysis on 824 patients with a genetically proven diagnosis of an inherited disorder of vitamin B₁₂ metabolism. Gene clusters and age categories are associated with patients' manifestations. The "cytoplasmic transport" cluster is associated with neurological and ophthalmological manifestations, the "mitochondrion" cluster with hypotonia, acute metabolic decompensation, and death, and the "B₁₂ availability" and "remethylation" clusters with anemia and cytopenia. Hypotonia, EEG abnormalities, nystagmus, and strabismus are predominant in the younger patients, while neurological manifestations, such as walking difficulties, peripheral neuropathy, pyramidal syndrome, cerebral atrophy, psychiatric disorders, and thromboembolic manifestations, are predominant in the older patients. These results should prompt systematic checking of markers of vitamin B₁₂ status, including homocysteine and methylmalonic acid, when usual causes of these manifestations are discarded in adult patients.

Keywords: MMACHC; cobalamin; inherited metabolic disorders; methionine synthase; methylmalonyl-CoA mutase; vitamin B(12); vitamin B(12) deficiency.

Graphical abstract

Figure 1

The four clusters are defined according to the function and metabolic consequences of genes involved in inherited disorders of vitamin B₁₂ metabolism The cluster “B₁₂ bioavailability” includes gene defects involved in B₁₂ absorption, blood transport, and cellular uptake, with an expected abnormal level of blood vitamin B₁₂ and/or transport proteins and a combined increase of homocysteine and methylmalonic acid. Note that gene defects in lysosome export may also produce vitamin B₁₂ deficit through impaired vitamin B₁₂ absorption. The “cytoplasmic transport” cluster includes gene defects of cytoplasmic transport with an expected normal blood level of vitamin B₁₂ and/or transport proteins and a combined increase of homocysteine and methylmalonic acid. The “remethylation” cluster includes gene defects of the remethylation pathway of homocysteine with an expected normal blood level of vitamin B₁₂ and/or transport proteins and methylmalonic acid and an increased level of homocysteine. The “mitochondrion” cluster of the B₁₂ mitochondrion pathway includes gene defects involved in the mitochondrion processing of B₁₂ and conversion of L-methylmalonyl-CoA to succinyl-CoA. The complementation groups corresponding to vitamin B₁₂ metabolism defects are indicated in blue font (icons made by flaticon, flaticon.com; CC-BY-3.0).

Figure 2

Influence of age in the manifestations reported by the Cochran-Armitage test for trend in the three age categories, “0 to 1 year,” “1 to 14 years,” and “over 15 years” (A) Neuropsychiatric manifestations include hypotony, abnormal EEG findings, seizures, peripheral neuropathy, extrapyramidal syndrome, pyramidal syndrome, walking difficulty, and cerebral atrophy reported on head MRI. (B) Ophthalmological manifestations include nystagmus and strabismus. (C) Cardiovascular and renal manifestations include thrombosis, blood pressure, and chronic kidney disease.

Figure 3

Predictors of inherited disorders of vitamin B12 metabolism according to "Cytoplasmic transport" and "Mitochondrion" functional gene clusters (A) Forest plot illustrating the logistic regression analysis results that assessed the predictors of the “cytoplasmic transport” gene cluster compared with the remaining functional gene clusters. Only binary variables are shown in the Forest plot. The gene cluster “cytoplasmic transport” regroups all patients with MMACHC variants and MMADHC variants responsible for combined mitochondrion and remethylation abnormalities. The black square represents the OR and the horizontal line indicates the 95% CI. (B) Forest plot illustrating the results of the logistic regression analysis that assessed the predictors of the “mitochondrion” gene cluster in comparison with the remaining functional gene clusters. Only binary variables are shown in the Forest plot. The gene cluster “mitochondrion” regroups all patients with MMAA, MMAB, or MUT variants and MMADHC variants responsible for mitochondrion abnormalities. OR, odds ratio; EMG, electromyography; EEG, electroencephalography. The black square represents the OR and the horizontal line indicates the 95% CI.