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]