Abstract
Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC). MMA has an estimated incidence of ~ 1: 50,000 and PA of ~ 1:100’000 -150,000. Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture, leading to early death or to severe neurological handicap in many survivors. Mental outcome tends to be worse in PA and late complications include chronic kidney disease almost exclusively in MMA and cardiomyopathy mainly in PA. Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine. This may be related to under recognition and delayed diagnosis due to nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity.These guidelines aim to provide a trans-European consensus to guide practitioners, set standards of care and to help to raise awareness. To achieve these goals, the guidelines were developed using the SIGN methodology by having professionals on MMA/PA across twelve European countries and the U.S. gather all the existing evidence, score it according to the SIGN evidence level system and make a series of conclusive statements supported by an associated level of evidence. Although the degree of evidence rarely exceeds level C (evidence from non-analytical studies like case reports and series), the guideline should provide a firm and critical basis to guide practice on both acute and chronic presentations, and to address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues. Furthermore, these guidelines highlight gaps in knowledge that must be filled by future research. We consider that these guidelines will help to harmonize practice, set common standards and spread good practices, with a positive impact on the outcomes of MMA/PA patients.
Highlights
Methylmalonic and propionic acidemia (MMA/PA) are autosomal recessive disorders of propionate catabolism caused by defects in the enzymes methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC) characterized by accumulation of metabolites of branchedchain amino acid catabolism such as 3-hydroxypropionic acid, methylcitric acid and/or methylmalonic acid in plasma, urine and other body fluids
Mitochondrial propionyl-CoA carboxylase (PCC, EC 6.4.1.3) is an α6β6 dodecamer composed of PCCA and PCCB subunits catalyzing the reversible biotin-dependent conversion of propionyl-CoA to D-methylmalonyl-CoA
This is racemised to its L-enantiomer, L-methylmalonylCoA which is reversibly isomerised to succinyl-CoA, catalyzed by L-methylmalonyl-CoA mutase (MUT, EC 5.4.99.2) which requires vitamin B12 in the form of adenosylcobalamin (AdoCbl) as cofactor (Figure 1)
Summary
Methylmalonic and propionic acidemia (MMA/PA) are autosomal recessive disorders of propionate catabolism caused by defects in the enzymes methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC) characterized by accumulation of metabolites of branchedchain amino acid catabolism such as 3-hydroxypropionic acid, methylcitric acid and/or methylmalonic acid in plasma, urine and other body fluids. Mitochondrial propionyl-CoA carboxylase (PCC, EC 6.4.1.3) is an α6β6 dodecamer composed of PCCA and PCCB subunits catalyzing the reversible biotin-dependent conversion of propionyl-CoA to D-methylmalonyl-CoA This is racemised to its L-enantiomer, L-methylmalonylCoA which is reversibly isomerised to succinyl-CoA, catalyzed by L-methylmalonyl-CoA mutase (MUT, EC 5.4.99.2) which requires vitamin B12 (cobalamin) in the form of adenosylcobalamin (AdoCbl) as cofactor (Figure 1). These reactions represent crucial steps in propionate catabolism, funneling metabolites from the breakdown of the amino acids valine, isoleucine, methionine and threonine, odd-chain fatty acids and the side chain of cholesterol into the tricarboxylic acid cycle. The aim of this consensus guideline is to standardize, systematize and harmonize the diagnosis, therapy and long-term management of MMA/PA in Europe based on the highest level of evidence, by pooling all the published evidence and experience of leading centers from several European countries and the U.S These guidelines, developed using the SIGN methodology (Scottish Intercollegiate Guideline Network, http://www.sign.ac.uk), are intended for metabolic specialists, pediatricians, dietitians, neonatologists, intensive care specialists, adult physicians, obstetricians, nurses and psychologists involved in the care of MMA/PA patients
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