cblA Type Methylmalonic aciduria
The group of isolated methylmalonic acidemias are a group of metabolic diseases characterized by elevated levels of methylmalonic acid in blood, urine and other fluids. These pathologies are inherited in an autosomal recessive manner and directly affect the enzyme methylmalonyl-CoA mutase (mut) or indirectly through proteins that interact with this enzyme, such as the cofactors cblA and cblB.
The gene responsible for methylmalonic acidemia cblA is MMAA and is involved in the mitochondrial transport of cobalamin.
Symptoms
Individuals affected with this disease usually present with mild to severe symptoms from infancy and may experience crises of acidosis. Symptoms are generally milder than those of patients with other types of methylmalonic acidemias due to methylmalonyl-CoA mutase (mut) enzyme deficiency.
Early diagnosis and treatment can help to improve their symptomatology and prevent metabolic crises from occurring. In cases that are detected later, growth retardation and psychomotor development may occur. A complication, which occurs in less than half of the cases, is chronic kidney disease.
Disease management
The diagnosis of methylmalonic aciduria is based on biochemical tests. Increased production of methylmalonic acid and its metabolites is detected by chromatography in urine and blood samples. In many countries this pathology is included in newborn screening. In addition, it is often combined with mutation analysis and enzyme activity analysis to profile the type of acidemia involved. Defining the type of aciduria is important because mut-, cblA and cblB forms have a better prognosis and evolution.
The basic chronic treatment in patients with MMA is a diet free of certain amino acids that are "harmful" for these patients (valine, isoleucine, methionine and threonine). Patients with cblA are often treated with high-dose hydroxocobalamin to decrease methylmalonic acid levels in body fluids, but only in those who respond to such a procedure. Additionally, supplementation with L-carnitine is recommended, under control of its serum levels.
Genes analyzed
Bibliography
Hörster F, Tuncel AT, Gleich F, et al. Delineating the clinical spectrum of isolated methylmalonic acidurias: cblA and mut. J Inherit Metab Dis. 2021 Jan;44(1):193-214.
Lerner-Ellis JP, Dobson CM, Wai T, et al. Mutations in the MMAA gene in patients with the cblA disorder of vitamin B 12 metabolism. Hum Mutat, 2004; 24(6):509-16.
Merinero B, Pérez B, Pérez-Cerdá C, et al. Methylmalonic acidaemia: Examination of genotype and biochemical data in 32 patients belonging to mut, cblA or cblB complementation group. J Inherit Metab Dis, 2008; 31(1):55-66.
Wesół-Kucharska D, Kaczor M, Pajdowska M, et al. Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related to MMAA mutations. Mol Genet Metab Rep. 2020 Jan 8;22:100559.
