Clinical, Biochemical and Molecular Features of a Cohort of 8 Patients with Inherited Disorders of Vitamin B12 Metabolism in a Metabolic Reference Center

Gonçalo Padeira; Sandra Jacinto; Augusto Ribeirinho; Ana Cristina Ferreira

doi:10.2174/0118715303272253231004094018

Clinical, Biochemical and Molecular Features of a Cohort of 8 Patients with Inherited Disorders of Vitamin B12 Metabolism in a Metabolic Reference Center

Endocr Metab Immune Disord Drug Targets. 2023 Oct 11. doi: 10.2174/0118715303272253231004094018. Online ahead of print.

Authors

Gonçalo Padeira¹, Sandra Jacinto², Augusto Ribeirinho³, Ana Cristina Ferreira¹

Affiliations

¹ Centro Hospitalar de Lisboa Central Metabolic Diseases Unit, Pediatric Department, Reference Center of Inherited Metabolic Diseases Lisbon Portugal.
² Centro Hospitalar de Lisboa Central Neuropediatric Service, Pediatric Department, Reference Center of Inherited Metabolic Diseases Lisbon Portugal.
³ Centro Hospitalar de Lisboa Central Internal Medicine Service 3-2. Medicine Department, Reference Center of Inherited Metabolic Diseases Lisbon Portugal.

PMID: 37861032
DOI: 10.2174/0118715303272253231004094018

Abstract

Background: Vitamin B12, or cobalamin (Cbl), undergoes a complex series of absorptive and intracellular processing steps before serving as a cofactor for the enzymes methylmalonyl-CoA mutase and methionine synthase. Disorders of intracellular cobalamin metabolism have variable phenotypes and age of onset related to the location of the defect in the metabolic pathway leading to a combined methylmalonic acidemia and homocystinuria (cblC, cblD, cblF and cblJ), Isolated methylmalonic acidemia (cblA, cblB and cblDv2) and isolated homocystinuria (cblDv1, cblE and cblG).

Objective and methods: We conducted a retrospective study of the clinical biochemical and molecular features of a cohort of patients with disorders of intracellular Cbl metabolism followed in our Reference Centre of Inherited Metabolic Diseases (CR-IMD) for the last 23 years (2000-2023).

Results: CblC: P1 and P2, pré-newborn screening (NBS), had an early and severe presentation evolving to multiorgan failure and death. P3 was asymptomatic at NBS with an excellent evolution except for nystagmus and retinitis pigmentosa. P4 presented at 19Y with an atypical hemolytic uremic syndrome and is presently on hemodialysis. CblD: P5 had a developmental delay (DD) and hypotonia and presented at 14m with seizures. CblDv2: P6 had DD and failure to thrive (FTT) and presented at 4Y with acute metabolic acidosis. CblDv1: P7 had DD, FTT, and hypotonia and presented at 16m with seizures and anemia. CblG: P8 had DD and FTT and presented at 15m with macrocytic anemia. In all, characteristic biochemical profiles guided the diagnosis, afterward confirmed by genetic analysis (4 MMACHC, 3 MMADHC, 1 MTR). All patients received either betaine, hydroxycobalamin, or both (P3 is on a very high dosage).

Conclusion: Our cohort of patients has similar clinical and biochemical characteristics to the ones described in the literature. Outcomes of patients reinforce the importance of newborn screening and the need for consensus guidelines for optimal doses of parenteral hydroxocobalamin.

Keywords: Disorders of intracellular cobalamin metabolism; homocystinuria; methylmalonic acidemia.