Clinical and biochemical profiles of maple syrup urine disease in malaysian children

Abstract

Introduction: Maple Syrup Urine Disease (MSUD) is an autosomal recessive disorder caused by defects in the branched-chain α-ketoacid dehydrogenase complex resulting in accumulation of branched-chain amino acids (BCAAs) and corresponding branched-chain ketoacids (BCKAs) in tissues and plasma, which are neurotoxic. Early diagnosis and subsequent nutritional modification management can reduce the morbidity and mortality. Prior to 1990s, the diagnosis of MSUD and other inborn errors of metabolism (IEM) in Malaysia were merely based on clinical suspicion and qualitative one-dimensional thin layer chromatography technique. We have successfully established specific laboratory diagnostic techniques to diagnose MSUD and other IEM. We described here our experience in performing high-risk screening for IEM in Malaysia from 1999 to 2006. We analysed the clinical and biochemical profiles of 25 patients with MSUD.

Methods: A total of 12,728 plasma and urine samples from patients suspected of having IEM were received from physicians all over Malaysia. Plasma amino acids quantitation using fully automated amino acid analyzer and identification of urinary organic acids using Gas Chromatography Mass Spectrometry (GCMS). Patients' clinical information were obtained from the request forms and case records Results: Twenty-five patients were diagnosed MSUD. Nineteen patients (76%) were affected by classical MSUD, whereas six patients had non-classical MSUD. Delayed diagnosis was common among our case series, and 80% of patients had survived with treatment with mild-to-moderate learning difficulties.

Conclusion: Our findings suggested that MSUD is not uncommon in Malaysia especially among the Malay and early laboratory diagnosis is crucial.

Fig. 1

Metabolic pathway of branched-chain amino acids degradation. In MSUD, the degradation of the essential branched-chain amino acids leucine, valine and isoleucine and their derived 2-ketoacids is impaired because of deficiency of BCKAD. Alloisoleucine which is a by-product of isoleucine transaminatione significantly elevated

Fig. 2

Special request form for investigation of Inborn Errors of Metabolism

Fig. 2

Special request form for investigation of Inborn Errors of Metabolism

Fig. 3

Plasma amino acid chromatograms of (a) a normal control and (b) a patient with MSUD. (a) Plasma amino acid chromatogram from a normal control. Peak 1, valine; 2, isoleucine; 3, leucine; 4, internal standard (norleucine). Alloisoleucine is not detected. (b) Plasma amino acid chromatogram from a patient with MSUD showing markedly increased leucine. Plasma isoleucine and valine were also elevated. Alloisoleucine was detected. Peak 1, valine; 2, alloisoleucine; 3, isoleucine; 4, leucine; 5, internal standard (norleucine)

Fig. 4

Urinary organic acids chromatogram of (a) a normal control (b) a patient with MSUD. (a) Urine organic acids chromatogram from a normal control. Peak 1, lactate; 2, pyruvate; 3, 3-hydroxybutyrate; 4, 2-hydroxyisovalerate; 5, 2-keto-3-methylvalerate; 6, 2-keto-isocaproate; 7 and 8 are internal standard and external standard respectively. (b) Urine organic acids chromatogram from a patient with MSUD showing branched-chain ketoacids were excreted in large quantity in urine. Peak 1, lactate; 2 and 8, 2-keto-isocaproate (2 peaks); 3, 3-OH butyrate; 4, 2-hydroxyisovalerate; 5, 2-ketoisovalerate; 6, 2-hydroxy-isocaproate; 7, 2-keto-3-methylvalerate; 9 and 10, internal standard and external standard, respectively