Acute decompensation of isovaleric acidemia induced by Graves' disease.

Sir, We present the first report of a metabolic exacerbation in a late onset form of isovaleric acidaemia (IVA, MIM 243500) due to hyperthyroidism. A 24-year-old woman was hospitalized for vomiting, drowsiness and a weight loss of 5 kg in 3 months. She had been treated since 7 years old for IVA with oral L-carnitine and had not experienced IVA decompensation since diagnosis. Despite an anabolic therapy [IV glucose (400 g/day) and lipids (40 g/ day)], a low protein diet and IV L-carnitine and PO L-glycine, her neurological state worsened in 24 h (Glasgow coma score of 11) and she was transferred to the ICU. The clinical examination showed tachypnea, paroxysmal atrial fibrillation and flapping tremor. Laboratory findings, at admission, revealed metabolic ketoacidosis: (pH 7.25, bicarbonates 9.8 mmol/l), normal glycaemia 5 mmol/l and hyperammonemia 100 lmol/l (controls \30 lmol/l). Additionally, her plasma amino acid profile found hypoalaninemia 122 lmol/l (controls 218–474 lmol/ l) and hyperleucinemia 157 lmol/l (controls 98–142 lmol/l). These metabolic abnormalities normalized within the first 24 h. However, despite biological improvement, she developed severe confusional syndrome and permanent atrial fibrillation. Hyperthyroidism was then diagnosed: TSH 0.005 mU/l (controls 0.3–4 mU/l), T4 43 pmol/l (controls 10–26 pmol/l), T3 11.7 pmol/l (controls 3–7 pmol/l). A high level of circulating antibodies to TSH-receptor led to the diagnosis of Graves’ disease. Clinical recovery was achieved after initiating treatment with carbimazole and propanolol in conjunction with Lcarnitine, L-glycine and a low protein diet. IVA is a rare autosomal recessive inborn error of metabolism due to isovaleryl CoA dehydrogenase deficiency (EC 1.3.99.10), an enzyme of the leucine catabolism pathway (Fig. 1) [1]. Its deficiency will cause the accumulation of intermediate metabolites (Fig. 1). These accumulated toxic substrates are responsible for the primary pathological effects seen in IVA [1]. In organic acidemias, an inadequate gluconeogenic response has been suggested to partly account in the pathophysiology of the hyperketotic hypoglycaemia linked to relative hypoalaninemia [2]. Moreover, the accumulation of acyl-CoAs can inhibit the urea cycle, resulting in hyperammonemia [3]. Patients with isovaleric acidemia must be treated during acute attack with glucose and lipids infusion without proteins for 48 h [1]. The administration of Lglycine and L-carnitine is designed to help the removal of isovalerate through excreting the non-toxic byproducts: isovalerylglycine and isovalerylcarnitine [4]. While the emergency treatment is administered, the factor triggering decompensation (infection, fasting, poor diet compliance and accidental high protein intake) which has induced the metabolic exacerbation must be treated [1]. As leucine constitutes about 10% of the amino acid content of the Leucine