Paeds · genetics-dysmorphology-and-metabolism
Organic acidaemias
Also known as Organic acidurias · Propionic acidaemia · Methylmalonic acidaemia · Isovaleric acidaemia · Glutaric aciduria type 1 · Branched-chain organic acidaemias
A fellowship approach to the organic acidaemias: recognise the high-anion-gap metabolic acidosis with ketosis that distinguishes them from the urea cycle disorders, treat on suspicion with calorie loading, carnitine and toxin removal before the enzyme diagnosis returns, distinguish the cofactor-responsive subtypes, and lock in long-term protein-restricted diet, transplantation, and an emergency sick-day plan.
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Red flags
- Any neonate who is well at birth then deteriorates after 24 to 72 hours of feeds with lethargy, vomiting, hypotonia and seizures AND a high-anion-gap metabolic acidosis with ketosis — think organic acidaemia
- Recurrent episodes of ketoacidosis, vomiting and encephalopathy in an older infant or child triggered by infection, fasting or a high-protein load
- High anion-gap metabolic acidosis with ketosis is the discriminating clue: a urea cycle disorder gives a normal anion gap and respiratory alkalosis
- A child with propionic or methylmalonic acidaemia who develops acute dystonia, choreoathetosis or altered consciousness during decompensation — basal-ganglia stroke is occurring
- Cardiomyopathy or prolonged QTc in a child with a known or suspected organic acidaemia, especially propionic acidaemia
- Chronic renal impairment with progressive intellectual disability and movement disorder — methylmalonic acidaemia causes tubulointerstitial nephropathy and basal-ganglia injury
- Macrocephaly in an infant with hypotonia, then acute encephalopathy and dystonia after an intercurrent illness — glutaric aciduria type 1 with acute striatal necrosis
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Board mappings
- Organic acidaemias as a cause of neonatal metabolic acidosis
- Differentiating organic acidaemias from urea cycle disorders on the metabolic panel
- Principles of acute metabolic decompensation management
- Biochemistry and classification of propionic, methylmalonic, isovaleric and glutaric acidurias
- Cofactor responsiveness (B12 in MMA, biotin in multiple carboxylase deficiency), carnitine therapy and transplantation
- Long-term dietary management, basal-ganglia injury and emergency sick-day planning
- Recognising and stabilising an organic acidaemia crisis in a neonate
- Interpreting acylcarnitines and urinary organic acids
- Trialling vitamin B12 responsiveness in methylmalonic acidaemia
- Acute case of a neonate with high-anion-gap metabolic acidosis and encephalopathy
- Long case of a child with methylmalonic acidaemia discussing renal failure, basal-ganglia injury and transplantation
- Metabolic emergencies in the neonate and infant
- Investigation of the acutely unwell child with metabolic acidosis
- Multisystem chronic disease and the family implications of inherited metabolic disease
- Branched-chain amino-acid catabolism and the major organic acidaemias
- Acute and long-term management of the organic acidaemias
- Newborn screening, cofactor responsiveness and transplantation
- Resuscitation of the metabolic collapse with ketoacidosis
- Communicating a chronic inherited metabolic diagnosis and emergency plan to parents
- Inborn errors of metabolism presenting with metabolic acidosis
- Propionic and methylmalonic acidaemia diagnosis and emergency management
- Glutaric aciduria type 1 and acute striatal necrosis
- Organic acidaemias
- Acute metabolic decompensation with high-anion-gap acidosis
- Multidisciplinary care and transplantation in inherited metabolic disease
- Neonatal metabolic emergency management
- Long-term outcomes, renal failure and transplantation in organic acidaemias
The fellowship mark goes to the candidate who holds three ideas at once. The first is the acid-base discriminator: a urea cycle disorder gives a normal anion gap with a respiratory alkalosis, while an organic acidaemia gives a high anion-gap metabolic acidosis with ketosis — this single difference rewrites the differential and the diet. The second is the cofactor trial: methylmalonic acidaemia may respond to vitamin B12, and multiple carboxylase deficiency responds to biotin, so a labelled "mild" or "treatment-responsive" variant can still hide behind a dangerous first presentation. The third is the chronic burden: these are multisystem diseases of basal-ganglia injury, cardiomyopathy and renal failure that persist between crises, and the emergency sick-day plan is what keeps the child alive. [1] [7]
Overview & Definition
The organic acidaemias are a family of autosomal recessive inherited metabolic diseases caused by deficiency of an enzyme in the catabolism of the branched-chain amino acids (isoleucine, leucine and valine) and related substrates. A block at any step halts the pathway, and the intermediate immediately upstream accumulates as a toxic organic acid that circulates and injures tissues. The classic disorders are propionic acidaemia (PA), methylmalonic acidaemia (MMA), isovaleric acidaemia (IVA) and glutaric aciduria type 1 (GA1), with multiple carboxylase deficiency a treatable cousin. [1] [7]
Clinically, the organic acidaemias are the archetype of the intoxication-type inborn errors of metabolism: the disease is the accumulating toxin, and the priority is toxin removal and source control, not enzyme replacement. The toxic acids inhibit the urea cycle, producing secondary hyperammonaemia; they impair mitochondrial oxidative phosphorylation, producing lactic acidosis; and they are selectively neurotoxic to the basal ganglia, producing the choreoathetosis, dystonia and intellectual disability that dominate long-term morbidity. This framing dictates the whole management. [1] [6]
References12ShowHide
- [1]Baumgartner MR, Hörster F, Dionisi-Vici C, Haliloglu G, Karall D, Chapman KA, et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis, 2014.PMID 25205257
- [2]Reischl-Hajiabadi AT, Schnabel E, Gleich F, Mengler K, Lindner M, Burgard P, et al. Outcomes after newborn screening for propionic and methylmalonic acidemia and homocystinurias. J Inherit Metab Dis, 2024.PMID 38563533
- [3]Nizon M, Ottolenghi C, Valayannopoulos V, Arnoux JB, Barbier V, Habarou F, et al. Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias. Orphanet J Rare Dis, 2013.PMID 24059531
- [4]Boy N, Mühlhausen C, Maier EM, Ballhausen D, Baumgartner MR, Beblo S, et al. Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision. J Inherit Metab Dis, 2023.PMID 36221165
- [5]Kölker S, Christensen E, Leonard JV, Greenberg CR, Boneh A, Burlina AB, et al. Diagnosis and management of glutaric aciduria type I--revised recommendations. J Inherit Metab Dis, 2011.PMID 21431622
- [6]Head PE, Meier JL, Venditti CP. New insights into the pathophysiology of methylmalonic acidemia. J Inherit Metab Dis, 2023.PMID 37078237
- [7]Forny P, Hörster F, Baumgartner MR, Kölker S, Boy N. How guideline development has informed clinical research for organic acidurias (et vice versa). J Inherit Metab Dis, 2023.PMID 36591944
- [8]Sen K, Burrage LC, Chapman KA, Ginevic I, Mazariegos GV, Graham BH, et al. Solid organ transplantation in methylmalonic acidemia and propionic acidemia: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med, 2023.PMID 36534118
- [9]Molema F, Martinelli D, Hörster F, Kölker S, Tangeraas T, de Koning B, et al. Liver and/or kidney transplantation in amino and organic acid-related inborn errors of metabolism: An overview on European data. J Inherit Metab Dis, 2021.PMID 32996606
- [10]Schumann A, Belche V, Schaller K, Grünert SC, Kaech A, Baumgartner MR, et al. Mitochondrial damage in renal epithelial cells is potentiated by protein exposure in propionic aciduria. J Inherit Metab Dis, 2021.PMID 34297429
- [11]Thimm E, Riederer A, Vockley J, Dobbelaere D, Williams M, MacDonald A, et al. Practical Considerations for the Diagnosis and Management of Isovaleryl-CoA-Dehydrogenase Deficiency (Isovaleric Acidemia): Systematic Search and Review and Expert Opinions. Int J Neonatal Screen, 2025.PMID 41133704
- [12]Tuncel AT, Boy N, Morath MA, Hörster F, Mütze U, Kölker S. Organic acidurias in adults: late complications and management. J Inherit Metab Dis, 2018.PMID 29335813