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cobalamin deficiency type C

Monday 14 March 2011

Definition: Cobalamin C (cblC) defect is the most common inborn error of cobalamin metabolism. It is a multisystem disorder usually presenting with progressive neurological, haematological and ophthalmological signs.

Clinical synopsis

- early-onset disease, presenting in the first year of life

  • feeding difficulty (88.9%)
  • recurrent vomiting (66.7%)
  • hypotonia (77.8%)
  • lethargy (44.4%)
  • seizures (50%)
  • progressive developmental delay (88.9%)
  • mental retardation (55.6%)

- milder clinical phenotype manifesting after 1 year of age (late onset)

  • progressive neurological symptoms
  • behavioral disturbance

Routine laboratory tests

anemia (83.3%)
lactic acidemia (66.7%)
severe metabolic acidosis (22.2%)
hyperammonemia (5.6%)
impaired functions of liver (22.2%), kidneys (5.6%), and cardiac muscle (44.4%)


- severe neonatal hyperammonemia (21153419)
- severe hyperpyrexia (20926213)
- thrombotic microangiopathy of the kidneys and lungs
- diffuse hepatic steatosis
- megaloblastic changes in the bone marrow
- fetal dilated cardiomyopathy (19248038)
- hemolytic uremic syndrome (HUS) (17874135)
-  retinal degeneration (16543196)
- late-onset thrombocytic microangiopathy (association with a factor H mutation) (15754282)
- severe gastritis

  • cystic dysplastic mucosal changes
  • total absence of parietal and chief cells


Cobalamin C (Cbl-C) defect is the most common inborn cobalamin metabolism error. Cobalamin C (Cbl-C) defect causes impaired conversion of dietary vitamin B12 into its two metabolically active forms, methylcobalamin and adenosylcobalamin.

Cobalamin C disease is an intracellular defect of cobalamin metabolism with possible recessive inheritance that can result in multiorgan failure early in life, with a thrombotic microangiopathy and unusual changes in the gastric mucosa.

Cbl-C defect causes the accumulation of methylmalonic acid and homocysteine and decreased methionine synthesis.

The most frequent change was the known c.271dupA mutation, which accounts for 85% of the mutant alleles characterized in this cohort of patients. Cell lines bearing this mutation present a significant increase of intracellular reactive oxygen species (ROS) content, and also a high rate of apoptosis, suggesting that elevated ROS levels might induce apoptosis in cblC patients. (19760748)

ROS levels decreased in hydroxocobalamin-incubated cells, indicating that cobalamin might either directly or indirectly act as a scavenger of ROS. ROS production might be considered as a phenotypic modifier in cblC patients, and cobalamin supplementation or additional antioxidant drugs might suppress apoptosis and prevent cellular damage in these patients. (19760748)

Methylmalonic acidemia combined with hyperhomocysteinemia is a biochemical phenotype caused by a number of inherited autosomal recessive defects in cobalamin [vitamin B12 (VitB12)] metabolism resulting in impaired synthesis of adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl).

AdoCbl and MeCbl are essential coenzymes for both the intramitochondrial isomerization of methylmalonyl-coenzyme A (CoA) to succinyl-CoA (catalyzed by methylmalonyl-CoA mutase) and the cytosolic remethylation of homocysteine to methionine (catalyzed by methionine synthase).

Deficiency of these two coenzymes result in reduced activity of methylmalonyl-CoA mutase and methionine synthase, which consequently lead to increased concentrations of methylmalonic acid (MMA) and homocysteine in plasma and urine, together with normal or decreased concentration of methionine in plasma (Thiele and Van Raamsdonk 2006).

Three distinct groups of combined methylmalonic acidemia and hyperhomocysteinemia are identified by complementation studies; namely, cobalamin C (cblC), cblD, and cblF, with the cblC disorder (MIM.277400) being the most common.

Cusmano-Ozog et al. reported the incidence of cblC disorder by newborn screening to be in the range of 1:67,000 for an ethnically diverse population in California, USA, contrasting with a previous estimate of 1:200,000 births by clinical ascertainment (Cusmano-Ozog et al. 2007).

The estimated incidence of methylmalonic acidemia ranges between 1:48,000 and 1:250,000 worldwide.

The MMACHC gene responsible for cblC disorder is located on chromosome 1p34.1. It encodes a polypeptide of 282 amino acids. Exons 1–4 are coding exons and exon 5 is noncoding.

The newly identified MMACHC protein could have enzymatic function as a “cyanocobalamin decyanase”, catalyzing the reductive decyanation of cyanocobalamin and generating cob(II)alamin, a known substrate for assimilation into the active cofactor forms MeCbl and AdoCbl (Kim et al. 2008).

Moreover, it has recently been reported that the MMACHC protein could also catalyze the dealkylation of newly internalized MeCbl and AdoCbl, the naturally occurring alkylcobalamins present in the diet (Hannibal et al. 2009). The exact function of the MMACHC protein remains to be determined.

In 2010, more than 55 different mutations of the MMACHC gene have been identified (Lerner-Ellis et al. 2009). The most frequent is c.271dupA (p.R91KfsX14), which accounts for 42% of mutant alleles and has been associated with early-onset disease (Lerner-Ellis et al. 2006; Rossi et al. 2001; Smith et al. 2006).

The common nonsense mutation c.394 C > T (p.R132X), which was related to late-onset disease in previous studies (Ben-Omran et al. 2007; Morel et al. 2006; Nogueira et al. 2008; ), accounts for 20% of mutant alleles (Lerner-Ellis et al. 2009).

Lerner-Ellis et al. reported that no mutation was identified in 5.6% of alleles for 366 cblC patients proven by complementation studies.


The MMADHC gene responsible for the Cbl-C defect has been recently identified, and more than 40 MMADHC mutations have been reported.

MMACHC gene is located on chromosome 1p and catalyzes the reductive decyanation of CNCbl.

Clinical synopsis

Cbl-C patients present with a heterogeneous clinical picture and, based on their age at onset, can be categorized into two distinct clinical forms:
- Early-onset patients, presenting symptoms within the first year, show a multisystem disease with severe neurological, ocular, haematological, renal, gastrointestinal, cardiac, and pulmonary manifestations.
- Late-onset patients present a milder clinical phenotype with acute or slowly progressive neurological symptoms and behavioral disturbances.


To improve clinical course and metabolic abnormalities, treatment of Cbl-C defect usually consists of a combined approach that utilizes vitamin B12 to increase intracellular cobalamin and to maximize deficient enzyme activities, betaine to provide a substrate for the conversion of homocysteine into methionine through betaine-homocysteine methyltransferase, and folic acid to enhance remethylation pathway.

No proven efficacy has been demonstrated for carnitine and dietary protein restriction.

Despite these measures, the long-term follow-up is unsatisfactory especially in patients with early onset, with frequent progression of neurological and ocular impairment.

The unfavorable outcome suggests that better understanding of the pathophysiology of the disease is needed to improve treatment protocols and to develop new therapeutic approaches.


- Genetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC). Richard E, Jorge-Finnigan A, Garcia-Villoria J, Merinero B, Desviat LR, Gort L, Briones P, Leal F, Pérez-Cerdá C, Ribes A, Ugarte M, Pérez B; MMACHC Working Group. Hum Mutat. 2009 Nov;30(11):1558-66. PMID: 19760748

- cblC: advances in defining the MMACHC mutation spectrum. Kraus JP. Hum Mutat. 2009 Jul;30(7):v. PMID: 19551759

- Fetal dilated cardiomyopathy: an unsuspected presentation of methylmalonic aciduria and hyperhomocystinuria, cblC type. De Bie I, Nizard SD, Mitchell GA. Prenat Diagn. 2009 Mar;29(3):266-70. PMID: 19248038

- Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations. Lerner-Ellis JP, Anastasio N, Liu J, Coelho D, Suormala T, Stucki M, Loewy AD, Gurd S, Grundberg E, Morel CF, Watkins D, Baumgartner MR, Pastinen T, Rosenblatt DS, Fowler B. Hum Mutat. 2009 Jul;30(7):1072-81. PMID: 19370762

- Cobalamin C defect presenting as severe neonatal hyperammonemia. Martinelli D, Dotta A, Massella L, Picca S, Di Pede A, Boenzi S, Aiello C, Dionisi-Vici C. Eur J Pediatr. 2010 Dec 10. PMID: 21153419

- A congenital anomaly of vitamin B12 metabolism: a study of three cases. Russo P, Doyon J, Sonsino E, Ogier H, Saudubray JM. Hum Pathol. 1992 May;23(5):504-12. PMID: 1568746