Argininosuccinic aciduria is an inborn error of the urea cycle caused by deficiency of argininosuccinate lyase (ASL). ASL-deficient patients present with progressive intoxication due to accumulation of ammonia in the body. Early diagnosis and treatment of hyperammonemia are necessary to improve survival and prevent long-term handicap. Two clinical phenotypes have been recognized--neonatal acute and milder late-onset form. We investigated patients with hyperammonemia by a stepwise approach in which quantitative amino acids analysis was the core diagnostic procedure. Here, we describe the clinical phenotypes and biochemical characteristics in diagnosing this group of patients. We have identified 13 patients with argininosuccinic aciduria from 2003 till 2009. Ten patients who presented with acute neonatal hyperammonemic encephalopathy had markedly elevated blood ammonia (> 430 micromol/L) within the first few days of life. Three patients with late-onset disease had more subtle clinical presentations and they developed hyperammonemia only during the acute catabolic state at two to twelve months of age. Their blood ammonia was mild to moderately elevated (> 75-265 micromol/L). The diagnosis was confirmed by detection of excessive levels of argininosuccinate in the urine and/or plasma. They also have moderately increased levels of citrulline and, low levels of arginine and ornithine in their plasma. Two patients succumbed to the disease. To date, eleven patients remained well on a dietary protein restriction, oral ammonia scavenging drugs and arginine supplementation. The majority of them have a reasonable good neurological outcome.
Age of Onset ; Amino Acids/analysis ; Argininosuccinic Acid/blood ; Argininosuccinic Acid/urine ; Argininosuccinic Aciduria/*diagnosis ; Argininosuccinic Aciduria/*metabolism ; Argininosuccinic Aciduria/*physiopathology ; Malaysia ; Phenotype

Citrin defi ciency is an autosomal recessive disorder caused by mutation in the SLC25A13 gene. It has two major phenotypes: adult-onset type II citrullinemia (CTLN2) and neonatal intrahepatic cholestatic caused by citrin defi ciency (NICCD). NICCD is characterized by neonatal/infantile-onset cholestatic hepatitis syndrome associated with multiple amino acidemia and hypergalactosemia. NICCD is self-limiting in most patients. However, some patients may develop CTLN2 years later, which manifests as fatal hyperammonemia coma. We report three unrelated Malay children with genetically confi rmed NICCD characterised by an insertion mutation IVS16ins3kb in SLC25A13 gene. All 3 patients presented with prolonged neonatal jaundice which resolved without specifi c treatment between 5 to 10 months. Of note was the manifestation of a peculiar dislike of sweet foods and drinks. Elevated plasma citrulline was an important biochemical marker. NICCD should be considered in the differential diagnosis of cholestatic jaundice in Malaysian infants regardless of ethnic origin.

Mucopolysaccharidoses (MPS) are a group of inherited disorders caused by the defi ciency of specifi c lysosomal enzymes involved in glycosaminoglycans (GAGs) degradation. Currently, there are 11 enzyme defi ciencies resulting in seven distinct MPS clinical syndromes and their subtypes. Different MPS syndromes cannot be clearly distinguished clinically due to overlapping signs and symptoms. Measurement of GAGs content in urine and separation of GAGs using high-resolution electrophoresis (HRE) are very useful initial screening tests for isotyping of MPS before specifi c enzyme diagnostics. In this study, we measured total urinary GAGs by a method using dimethylmethylene blue (DMB), and followed by isolation and separation of GAGs using high resolution electrophoresis (HRE) technique. Of 760 urine samples analyzed, 40 have abnormal GAGs HRE patterns. Thirty-fi ve of these 40 cases have elevated urinary GAGs levels as well. These abnormal HRE patterns could be classifi ed into 4 patterns: Pattern A (elevated DS and HS; suggestive of MPS I, II or VII; 16 cases), Pattern B (elevated HS and CS; suggestive of MPS III; 17 cases), and Pattern C (elevated KS and CS; suggestive of MPS IV, 5 cases), and Pattern D (elevated DS; suggestive of MPS VI; 2 cases). Based on the GAGs HRE pattern and a few discriminating clinical signs, we performed selective enzymatic investigation in 16 cases. In all except one case with MPS VII, the enzymatic diagnosis correlated well with the provisional MPS type as suggested by the abnormal HRE pattern. Our results showed that GAGs HRE is a useful, inexpensive and practical fi rst-line screening test when MPS is suspected clinically, and it provides an important guide to further enzymatic studies on a selective basis.

Lysinuric protein intolerance (LPI) is an inborn error of dibasic amino acid transport due to a defect in the dibasic amino acid transporter in the renal and intestine and has a heterogenous presentation. Three Malaysian patients with LPI were studied and their biochemical and molecular findings compared. There were differences and similarities in the biochemical and molecular findings. Molecular analysis of SLC7A7 gene revealed a novel mutation c.235G>A; p.(Gly79Arg) in exon three in Patient 1 and a mutation c.1417C>T; p.(Arg473*) in exon 10 in patient 2 and 3. The degree of concentration of dibasic amino acids may determine the type of disease of the cell membrane transport, however, a positive molecular confirmation will secure the diagnosis.

We report the biochemical profiling in two siblings with mitochondrial 2-methylacetoacetyl-CoA thiolase deficiency. Organic aciduria typical of this rare inborn error metabolism was found when the elder sibling presented with an episode of severe ketoacidosis at 20 months of age, which consisted of excessive excretion of ketones, tiglylglycine, 2-methyl-3-hydroxybutyrate, and 2-methylacetoacetate. Blood acylcarnitiness profile showed elevation of C5OH-carnitine, which represents 2-methyl-3-hydroxybutyrylcarnitine. A similar biochemical profile was identified in the younger sibling during screening although he had only mild clinical symptoms. Both patients reported a favourable outcome on follow-up.
2-methylacetoacetyl-coenzyme A ; deficiency ; Acetyl-CoA C-Acetyltransferase ; Biochemical ; Siblings

Homocystineimia is an Inborn Errors of Metabolism (IEM) which can occur due to accumulation of homocysteine. Homocysteine is one of the sulfur-containing amino acid with thiol group that is formed by demethylation of methionine. Deficiency of enzymes involves in homocysteine metabolism can give rise to seven types of homocystinemia subject to total homocysteine level. Therefore reference ranges are needed to differentiate between normal and abnormal population as well as the type of homocystineimia depending on the enzymes defect in the pathway. Hence, homocysteine reference ranges in children for the Malaysian population were postulated. 3 mL of blood was collected from 86 normal individuals (52 boys and 34 girls) and then subsequently processed and analysed using High Performance Liquid Chromatogrphy – Ion Exchange Chromatography (HPLC-IEC). The calculated mean total homocysteine for the population was 8.1 ± 3.89 µM (95% confidence interval, l 7.3-8.9 µM). Reference range was 2.5 – 16.2 µM with lower and upper cut-off were 1.0 µM dan 21.0 µM, respectively. The newly developed reference range of total homocysteine for Malaysian children is able to reduce false negative cases in the laboratory.