Methylmalonic Aciduria and Homocystinuria: Type cblC

Combined methylmalonic aciduria and homocystinuria, cblC type (Cobalamin C deficiency) is an inherited disorder where the body cannot use vitamin B12 correctly. This is due to the deficiency of multiple enzymes. Onset of symptoms can begin before birth all the way to adulthood. Babies often have restricted growth during development before birth. Heart and brain defects, as well as small head size are present at birth. After birth, infants with this disorder can have poor feeding, poor weight gain, seizures, developmental delay and intellectual disability, a blood problem that results in very large red blood cells, and weak muscles. They may also develop vision problems and skin rashes. Individuals with cobalamin C deficiency can be treated with hydroxycobalamin to help with some of these problems, especially if treatment begins early in life. However, treated individuals may still have motor and language delays and intellectual disability. Cobalamin C deficiency is caused by pathogenic variants in the MMACHC gene.

Cobalamin C deficiency is inherited in an autosomal recessive manner. This type of inheritance requires the presence of two copies of a pathogenic variant in the gene for a person to have the genetic disease. Both parents must be carriers of a pathogenic variant in the gene in order to be at risk to have an affected child. The child must inherit a pathogenic variant from each carrier parent in order to be affected. There is a 1 in 4 chance that a baby will inherit two mutated copies of the gene and be affected when both parents are carriers.

There are generally no signs or symptoms associated with being a carrier for cobalamin C deficiency. However, the risk to have a child affected with cobalamin C is increased. Testing of reproductive partners is recommended for carriers of cblC.

The population frequency of cobalamin C deficiency is highly variable. It is estimated to occur in about 1 in 200,000 newborns; however, in New York State it occurs in 1 in 100,000 newborns and in California 1 in 60,000 newborns. In the Californian Hispanic population cobalamin C deficiency occurs in 1 in 37,000 newborns.

Newborn Screening Info: Methylmalonic Acidemia with Homocystinuria (http://www.newbornscreening.info/)
Orphanet: Methylmalonic academia with homocystinuria (http://www.orpha.net)

GeneReviews: Disorders of Intracellular Cobalamin Metabolism (http://www.ncbi.nlm.nih.gov/books/NBK1116/)

• Full gene sequencing