Clinical spectrum of intracellular cobalamin metabolism disorders: a single-center retrospective study from the United Arab Emirates

Abstract

Cobalamin is essential for DNA synthesis and for methylmalonyl-CoA mutase and methionine synthase activity. Inherited disorders of intracellular cobalamin (Cbl) metabolism are single-gene defects affecting absorption, transport, or intracellular processing, with variable phenotypes depending on the severity and location of the defect. Data from high consanguinity populations, such as the UAE, are limited. To describe the clinical, biochemical, and molecular characteristics of patients with intracellular Cbl metabolism disorders at Tawam Hospital, UAE. Retrospective review of patients followed between January 2010 and December 2025. Data included demographics, clinical features, laboratory and radiological findings, molecular results, treatment, and outcomes. Twelve patients were identified: 8 CblC, 1 CblE, 1 CblG, and 2 unclassified. Consanguinity was present in 75%. The earliest diagnosis was at 8 days; 91.6% were symptomatic. Presentations included seizures (58%), apparent life-threatening events (33%), hydrocephalus and cytopenia (25% each), global developmental delay, osteoporosis, hypothyroidism, hypogonadism, multicystic kidney, and psychiatric symptoms. Homocysteine was elevated in all. The MMACHC c.271dupA variant was common; a novel variant in the MTRR gene was identified. All received parenteral hydroxocobalamin, betaine, and carnitine with partial biochemical improvement. The newborn-screened patient had a favorable outcome. This cohort broadens the phenotypic spectrum to endocrine, renal, and psychiatric manifestations. Early diagnosis and hydroxocobalamin treatment improve outcomes, though neurocognitive and ophthalmologic complications persist.