Clinical, phenotypic and genetic landscape of case reports with genetically proven inherited disorders of vitamin B(12) metabolism: A meta-analysis

Inherited disorders of B(12) 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 B(12) 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 “B(12) 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 B(12) status, including homocysteine and methylmalonic acid, when usual causes of these manifestations are discarded in adult patients.