Propionic acidemia, the cardiomyopathy the screen cannot prevent

Propionic acidemia is on the newborn screening panel and has been for two decades. The screen catches affected infants before the first metabolic crisis. Standard care, when started in the first weeks of life, prevents the worst neurological outcomes that defined the condition before screening. Survival is measurably longer in screened cohorts. The condition is a clear screening success on most clinical metrics.

It is not a screening success on the cardiac metric. Cardiomyopathy in propionic acidemia, particularly dilated cardiomyopathy and arrhythmogenic conduction disease, develops in adolescent and young adult survivors at rates that current management does not consistently prevent. The screen identifies the disease at birth. The metabolic management controls the acute decompensations. The cardiac complication that emerges in the second and third decades sits outside what diet and emergency protocols can reach.

What propionic acidemia is

Propionic acidemia, PA, is an autosomal recessive organic acid disorder. The enzyme propionyl-CoA carboxylase is a mitochondrial biotin-dependent enzyme made of alpha and beta subunits encoded by PCCA on chromosome 13 and PCCB on chromosome 3. PCC catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA, a step in the catabolism of the branched-chain amino acids isoleucine and valine, of methionine and threonine, of odd-chain fatty acids, and of cholesterol side chains. Pathogenic variants in either PCCA or PCCB reduce or abolish enzyme activity. Propionyl-CoA and its derivatives accumulate, the resulting organic acidemia drives metabolic decompensation, and secondary inhibition of the urea cycle produces hyperammonemia.

Affected newborns typically present in the first days to weeks of life with poor feeding, vomiting, lethargy, hypotonia, tachypnea from metabolic acidosis, and progression to coma if untreated. Ammonia is often markedly elevated. Survivors of the neonatal crisis face a chronic course with recurrent metabolic decompensations triggered by infection or catabolic stress, failure to thrive, and developmental delay. Late complications across cohorts include cardiomyopathy (dilated and less commonly hypertrophic), prolonged QT interval and other arrhythmias, optic atrophy, basal-ganglia injury producing movement disorders, pancreatitis, and chronic kidney disease.

Reported live-birth incidence in US and European newborn screening programs runs roughly 1 in 100,000 to 1 in 150,000. Higher incidence is documented in several founder populations including the Greenlandic Inuit and parts of the Saudi Arabian population.

Detection

Newborn screening uses tandem mass spectrometry on the dried blood spot to flag elevated propionylcarnitine, C3, and an elevated C3 to acetylcarnitine (C2) ratio. The same screening signal identifies methylmalonic acidemia, and second-tier testing distinguishes the two through urine organic acid analysis: PA shows 3-hydroxypropionate, methylcitrate, and propionylglycine without the methylmalonic acid that defines MMA. Confirmation includes plasma acylcarnitines, plasma amino acids, and PCCA or PCCB sequencing.

What management looks like

Standard of care is lifelong protein-restricted diet using medical formula free of isoleucine, valine, methionine, and threonine, paired with measured natural protein, calorie support, and L-carnitine supplementation to clear propionyl groups as propionylcarnitine. Oral metronidazole or an alternative antibiotic is used in some centers to suppress propionate production by gut bacteria. Sick-day protocols use high-calorie low-protein intake, and acute decompensations are managed with intravenous dextrose, insulin when needed, ammonia scavengers including sodium phenylbutyrate or sodium benzoate, carglumic acid for hyperammonemia, and hemodialysis for severe acidosis or refractory hyperammonemia.

Carglumic acid, marketed as Carbaglu, was approved by the FDA in 2010 for N-acetylglutamate synthase deficiency and gained an additional indication in 2021 for adjunctive treatment of acute hyperammonemia in propionic acidemia and methylmalonic acidemia. The drug activates carbamoyl phosphate synthetase I, reactivating the urea cycle that propionyl-CoA inhibits.

Cardiac surveillance with periodic echocardiography and electrocardiography is part of routine follow-up, with intervals shortening through adolescence. The clinical question for adolescents and young adults with PA is increasingly the trajectory of cardiomyopathy and the timing of advanced cardiac interventions including device therapy and, in selected cases, heart transplantation alone or combined with liver transplantation.

Liver transplantation is offered at multiple centers and reduces the frequency and severity of metabolic crises by providing a partially functional source of PCC. It does not eliminate disease because the enzyme is required throughout the body and propionyl-CoA continues to be produced from non-protein substrates. Cardiomyopathy can develop or progress after transplant.

mRNA replacement therapy is in clinical development. Moderna's mRNA-3927 program, which encodes both PCCA and PCCB subunits in a single lipid nanoparticle delivery, entered Phase 1/2 trials in 2022 with interim data published in 2024 showing reductions in major metabolic decompensation events. AAV-delivered gene therapy programs are in earlier clinical and preclinical stages. The fundamental challenge of any proposed treatment is that the enzyme is required ubiquitously, which means liver-targeted approaches address some clinical problems and not others.

What this looks like for a family

A baby is born and the heel-prick is sent. On day 4, the state lab reports an elevated C3 and C3/C2 ratio. On day 5, urine organic acids confirm propionic acidemia. The metabolic team starts protein-restricted formula and carnitine. The neonatal period passes without a clinical crisis because the diagnosis was made before the crisis would have happened.

That child grows up. Annual or biannual cardiac evaluations begin in toddlerhood. Sick-day protocols are part of every febrile illness. Hospitalizations for metabolic decompensation happen, but at lower frequency and severity than in the unscreened cohorts of the 1990s. In the late teens, an echocardiogram shows reduced left ventricular function. The cardiology and metabolism teams begin the conversations the family has known were coming about whether and when an mRNA-based therapy or a transplant would change the trajectory.

That is what propionic acidemia care looks like in practice. The screen prevents the neonatal death. The medicine prevents the worst of the metabolic course. The cardiac complication is the part of the disease that the field has not yet been able to consistently reach.