MMACHC Human

The cblC type is caused by mutations in the MMACHC gene located on chromosome 1p36.3 . This gene is responsible for the proper metabolism of vitamin B12 (cobalamin). The mutations lead to defects in the synthesis of two active forms of cobalamin: adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) . These forms are crucial for the conversion of methylmalonic acid to succinyl-CoA and homocysteine to methionine, respectively. The inability to convert these compounds results in the accumulation of methylmalonic acid and homocysteine in the body .

The clinical presentation of methylmalonic aciduria cblC type with homocystinuria can vary widely, but symptoms typically appear in infancy. Common signs include:

• Developmental delay and intellectual disability
• Failure to thrive and feeding difficulties
• Hypotonia (weak muscle tone)
• Seizures and other neurological problems
• Megaloblastic anemia, characterized by a low number of red blood cells that are larger than normal

In some cases, the condition can present later in life, leading to behavioral changes, psychiatric symptoms such as hallucinations and psychosis, and neurological decline .

Diagnosis is often based on clinical presentation and biochemical tests. Elevated levels of methylmalonic acid and homocysteine in the blood and urine are indicative of the disorder. Genetic testing can confirm mutations in the MMACHC gene .

Treatment typically involves dietary management and supplementation with vitamin B12. In some cases, additional treatments such as betaine and folate may be used to help reduce homocysteine levels . Early diagnosis and treatment are crucial for improving outcomes and preventing severe complications.

The incidence of methylmalonic aciduria cblC type with homocystinuria is estimated to be about 1 in 67,000 newborns in the United States . The condition is inherited in an autosomal recessive manner, meaning that both copies of the gene in each cell have mutations .