Methylmalonic acidemia with homocystinuria is an inborn error of vitamin B12 (cobalamin) metabolism that occurs mostly in neonatal age, with megaloblastic anemia, lethargy, growth /development delay, cognitive deficiency and seizures, acute visual and neurological deterioration. More rarely it occurs during childhood or adolescence, with psychiatric symptoms or with marrow degeneration.
It is a metabolic disorder belonging to the group of organic acidurias characterized by a dysfunction of the metabolism of some amino acids . Specifically, such defects are clustered within the remethylation disorders and have in common the inability to convert properly homocysteine into methionine: the methionine cycle (derived from foods, converted into homocysteine and then re-converted into methionine) is interrupted. As a consequence, blood levels of homocysteine are high while methionine is low, entailing that many important functions of the body are disturbed.
The cblC, cblF and cblJ defects affect both the homocysteine-methionine and the methylmalonic acid (MMA) cycle. Thus, in such cases also the elimination of MMA from the body cells is compromised , potentially causing further complex health problems.
CblC type methylmalonic acidemia with homocystinuria (hereinafter simply cblC) is the most common inborn cobalamin metabolism error due to the inability to convert cobalamin into active forms (adenosylcobalamin and methylcobalamin), cofactors of enzymes that counteract the accumulation of methylmalonic acid and homocysteine in the blood and urine.
The age of onset and clinical manifestations are heterogeneous. Early onset with acute metabolic decompensation is more frequent and can arise as multi-systemic disease with myocardiopathy, acidosis, hypotonia, failure to thrive, acute neurological deterioration, intellectual deficit, lethargy, seizures, microcephaly, retinopathy, signs of megaloblastic anemia (pallor, fatigue, anorexia), hypercholesterolemia and haemolytic-uremic syndrome.
Late onset, during childhood or adolescence, may be acute-intermittent or chronic-progressive with psychiatric symptoms (dementia and psychosis) or with ataxia and subacute marrow degeneration.
CblC is one of about 600 Inherited Metabolic Diseases and is transmitted in an autosomal recessive manner: when both parents are carriers of a mutation in one of the involved genes, they have a 1 in 4 (25%) chance in each pregnancy that the child will have the disease. There is also a 1 in 2 (50%) chance that the baby is a carrier, like the parents, and a 1 in 4 (25%) chance for the baby to have inherited two normal genes.
Molecular analysis of the gene MMACHC (recently identified and responsible of cblC) is crucial for identifying the carrier status in families at risk and to provide adequate genetic counseling for prenatal diagnosis and shorter times of response than classical biochemical-enzymatic investigations based on blood and urine laboratory tests.
Prenatal diagnosis is possible and early diagnosis is possible thanks to neonatal metabolic screening.