Cobalamin metabolism disorders

The phenotype varies and is shaped by the underlying defect. The cblC type (combined methylmalonic acidaemia and homocystinuria, caused by biallelic MMACHC variants) is the best-characterised subtype and serves as the clinical prototype for combined defects. Age of onset ranges from the prenatal period to adulthood, and the infantile presentation is the most frequently recognised.

Early-onset disease (before one year of age) typically presents with multisystem involvement. Reported features include failure to thrive, megaloblastic anaemia, neurological deterioration, maculopathy, cytopenias, and renal or hepatic dysfunction.

Later-onset forms may instead present with neuropsychiatric, thromboembolic, or ocular manifestations. A separate group of subtypes causes isolated homocystinuria rather than a combined defect, including methionine synthase reductase deficiency (cblE) and methionine synthase deficiency (cblG), which present with homocystinuria, megaloblastic anaemia, and neurological signs, as well as cblD-homocystinuria. These subtypes are not detected through routine newborn screening, which can contribute to delayed diagnosis.

Treatment commonly includes parenteral hydroxocobalamin, often in combination with betaine and supportive metabolic management, depending on the underlying subtype.

Most published figures for cblC come from newborn-screening cohorts and therefore report birth incidence rather than prevalence. In European and American newborn-screening populations, the reported birth incidence of cblC is approximately 1:46,000 to 1:200,000.

Cobalamin metabolism disorders are caused by pathogenic variants in several genes, which can be grouped into combined methylmalonic acidaemia and homocystinuria and isolated forms of either.

The most common genetic cause is the cblC type, due to biallelic MMACHC variants and typically associated with multisystem disease and maculopathy. Other subtypes include the cblA type (MMAA; cobalamin-responsive methylmalonic acidaemia) and the cblG type (MTR; methionine synthase deficiency causing homocystinuria with megaloblastic anaemia).

Inheritance varies by gene. Most subtypes within this spectrum follow autosomal recessive inheritance, including the cblC, cblA, and cblG types.

Most recognised subtypes are inherited in an autosomal recessive manner. HCFC1-related cblX is inherited as an X-linked disorder and represents a notable exception.

Diagnosis combines biochemical and molecular findings. Suggestive results include elevated methylmalonic acid, raised plasma homocysteine, and low methionine, with the specific pattern depending on the subtype. For the remethylation defects, including the cblC type, raised total homocysteine guides both diagnostic work-up and longer-term management. Molecular genetic testing of the panel genes confirms the subtype and identifies the causative pathogenic variant.

Main differential diagnoses include:

• Isolated methylmalonic acidaemia: raised methylmalonic acid without homocystinuria; MMUT, MMAB
• Isolated homocystinuria: raised homocysteine without methylmalonic acidaemia; CBS, MTHFR
• Nutritional vitamin B12 deficiency: acquired, non-genetic, with overlapping biochemical findings

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic variant, clarifying the genetic aetiology and providing a basis for genetic counselling.
• A confirmed result supports condition-specific surveillance and management options, which the treating physicians decide together with the affected individual.
• A known familial variant supports predictive testing of at-risk relatives, so they can clarify their personal risk and access surveillance and counselling where indicated.

• Sloan JL, Carrillo N, Adams D, Venditti CP. Disorders of intracellular cobalamin metabolism. 2008 Feb 25 [updated 2018 Sep 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID:.
• Olivieri G, Bordugo A, Burnyte B, Costetti A, Couce ML, Diogo L, et al. First revision of the guidelines for the diagnosis and management of remethylation disorders. J Inherit Metab Dis. 2026;49(4):e70177. doi:10.1002/jimd.70177. PMID:.
• Forny P, Hörster F, Ballhausen D, Chakrapani A, Chapman KA, Dionisi-Vici C, et al. Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: first revision. J Inherit Metab Dis. 2021;44(3):566-92. doi:10.1002/jimd.12370. PMID:; PMCID:PMC8252715.