Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision

Abstract

Isolated methylmalonic acidaemia (MMA) and propionic acidaemia (PA) are rare inherited metabolic diseases. Six years ago, a detailed evaluation of the available evidence on diagnosis and management of these disorders has been published for the first time. The article received considerable attention, illustrating the importance of an expert panel to evaluate and compile recommendations to guide rare disease patient care. Since that time, a growing body of evidence on transplant outcomes in MMA and PA patients and use of precursor free amino acid mixtures allows for updates of the guidelines. In this article, we aim to incorporate this newly published knowledge and provide a revised version of the guidelines. The analysis was performed by a panel of multidisciplinary health care experts, who followed an updated guideline development methodology (GRADE). Hence, the full body of evidence up until autumn 2019 was re‐evaluated, analysed and graded. As a result, 21 updated recommendations were compiled in a more concise paper with a focus on the existing evidence to enable well‐informed decisions in the context of MMA and PA patient care.

Severe anemia in patients with Propionic acidemia is associated with branched-chain amino acid imbalance

“…The SMAA contains no Val, Ile, Met and Thr, but a normal-high Leu levels and they are recommended if natural protein tolerance is below FAO/WHO/UNU safe levels [ 2 ]. The actual amount of medical food versus intact protein intakes are not detailed by the current guidelines and protein tolerance should be titrated individually [ 2 , 14 ].…”

Current Perspectives on Neonatal Screening for Propionic Acidemia in Japan: An Unexpectedly High Incidence of Patients with Mild Disease Caused by a Common PCCB Variant

“…Guidelines for the diagnosis and management of PA based on the clinical features of patients studied in large scales were published in 2014 [ 10 ] and revised in 2021 [ 1 ]. It has become clear that cardiac complications, mainly cardiomyopathy and QT prolongation, are quite specific to PA compared with other similar organic acid disorders and that these complications are primary causes of death during the chronic phase of PA [ 1 , 11 , 12 , 13 , 14 ].…”

“…Guidelines for the diagnosis and management of PA based on the clinical features of patients studied in large scales were published in 2014 [ 10 ] and revised in 2021 [ 1 ]. It has become clear that cardiac complications, mainly cardiomyopathy and QT prolongation, are quite specific to PA compared with other similar organic acid disorders and that these complications are primary causes of death during the chronic phase of PA [ 1 , 11 , 12 , 13 , 14 ]. Though precise pathophysiology has not been fully understood, mitochondrial impairment is suggested for the development of cardiomyopathy [ 2 , 15 ], and acute reduction of the repolarizing potassium currents in cardiomyocytes due to toxic metabolites for the prolonged QTc interval [ 2 , 16 ].…”

“…Prevention of disease progression in patients with PA requires a dietary restriction of precursor amino acids (i.e., valine, isoleucine, methionine, threonine, and glycine) accompanied with l -carnitine supplementation. Liver transplantation is considered in patients with poor disease control [ 1 , 2 ].…”

“…Aiming at improving the prognosis, several countries list PA as one of the target diseases for neonatal screening, but its utility is not established [ 1 , 3 ]. This review outlines the current perspectives on neonatal screening for PA in Japan.…”