Propionic acidemia

Baumgartner MR, et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis. 2014 Sep 2;9:130.

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.

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Grünert SC, et al. Propionic acidemia: clinical course and outcome in 55 pediatric and adolescent patients. Orphanet J Rare Dis. 2013 Jan 10;8:6.

Propionic acidemia (PA) is a rare autosomal recessively inherited inborn error of propionate metabolism. The biochemical defect involves the conversion of propionyl-coenzyme A (propionyl-CoA) to methylmalonyl-coenzyme A (methylmalonyl-CoA) by the mitochondrial enzyme propionyl-CoA carboxylase (PCC, EC 6.4.1.3). Thus, the metabolism of branched-chain amino acids, odd-numbered fatty acids, cholesterol side chains, thymine and uracil is impaired.

Most patients with this disorder present in the neonatal period with severe metabolic acidosis and hyperammonemia. However, late presentations with predominantly neurological symptoms as well as asymptomatic individuals have also been described [13]. With progression of the disease, patients are prone to complications affecting the neurologic, cardiologic, hematologic, immunologic and gastrointestinal system. As underlined in the proceedings of a recently held consensus conference on PA, the understanding of the disease course in PA is rather limited, with most information deriving from case reports and small retrospective case series [4]. Although few authors have reported data on larger groups of patients [2,59] information on the long-term outcome of affected individuals is still limited.

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Rafique M. Clinical spectrum of propionic acidaemia. J Nutr Metab. 2013;2013:975964.

Objectives. To evaluate the clinical features, physical findings, diagnosis, and laboratory parameters of the patients with propionic acidaemia (PA). Methods. The records of diagnosed cases of propionic acidaemia were reviewed, retrospectively. Results. Twenty-six patients with PA had 133 admissions. The majority (85%) of the patients exhibited clinical manifestations in the 1st week of life. Regarding clinical features, lethargy, fever, poor feeding, vomiting, dehydration, muscular hypotonia, respiratory symptoms, encephalopathy, disturbance of tone and reflexes, and malnutrition were observed in 51-92% admissions. Metabolic crises, respiratory diseases, hyperammonaemia, metabolic acidosis, hypoalbuminaemia, and hypocalcaemia were observed in 30-96% admissions. Pancytopenia, ketonuria, hypoproteinemia, hypoglycaemia, and mildly disturbed liver enzymes were found in 12-41% admissions. Generalised brain oedema was detected in 17% and cerebral atrophy in 25% admissions. Gender-wise odd ratio analysis showed value of 1.9 for lethargy, 1.99 for respiratory diseases, 0.55 for anaemia, and 1.82 for hypocalcaemia. Conclusion. Propionic acidaemia usually presents with wide spectrum of clinical features and disturbances of laboratory parameters in early neonatal age. It is associated with significant complications which deteriorate the patients’ quality of life. Perhaps with early diagnosis of the disease and in time intervention, these may be preventable.

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Rafique M. Propionic acidaemia: demographic characteristics and complications. J Pediatr Endocrinol Metab. 2013;26(5-6):497-501.

Of 24 patients, 16 (67%) were male. Consanguineous parents were 16 (67%). Ten (42%) patients had diseased siblings. Mean age at diagnosis was 0.13±0.27 year. Twenty-two (92%) patients had early onset and 2 (8%) had late onset disease. Eighteen (75%) patients had developmental delay, 11 (46%) had hypotonia, 3 (12%) had hypertonia, 13 (54%) had hyperreflexia and 12 (50%) had seizures. Two (8%) children each, had intracranial haemorrhage, spastic quadriplegia, hemiplegia and 1 (4%) had paraplegia. Cerebral atrophy and nasogastric/gastrotomy, tube feeding, each was found in 6 (25%) patients. Under nutrition was revealed in 20 (83%), short stature in 18 (75%), rickets in 1 (4%) and pancreatitis in 2 (8%) patients. During metabolic crisis, cerebral oedema and pancytopenia each were found in 4 (17%), hypoglycaemia in 6 (25%), hyperglycaemia in 2 (8%), hyperammonaemia in all 24 (100%) and metabolic acidosis in 20 (83%) cases.

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Carrillo-Carrasco N, Venditti C. Propionic Acidemia. 2012 May 17. In: Pagon RA, et al, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.

The spectrum of propionic acidemia (PA) ranges from neonatal-onset to late-onset disease. Neonatal-onset PA, the most common form, is characterized by poor feeding, vomiting, and somnolence in the first days of life in a previously healthy infant, followed by lethargy, seizures, coma, and death. It is frequently accompanied by metabolic acidosis with anion gap, ketonuria, hypoglycemia, hyperammonemia, and cytopenias. Late-onset PA includes developmental regression, chronic vomiting, protein intolerance, failure to thrive, hypotonia, and occasionally basal ganglia infarction (resulting in dystonia and choreoathetosis) and cardiomyopathy. Affected children can have an acute decompensation that resembles the neonatal presentation and is precipitated by a catabolic stress such as infection, injury, or surgery. Isolated cardiomyopathy and arrhythmia can be observed on rare occasion in the absence of clinical metabolic decompensation or neurocognitive deficits. Manifestations of neonatal and late-onset PA over time can include growth impairment, intellectual disability, seizures, basal ganglia lesions, pancreatitis, and cardiomyopathy. Other rarely reported complications include optic atrophy, hearing loss, premature ovarian insufficiency (POI), and chronic renal failure.

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