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.

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

Fragile X syndrome (FXS) is a neurodevelopmental disorder commonly found worldwide, caused by the silencing of fragile X mental retardation 1 (FMR1) gene on the X-chromosome. Most of the patients lost FMR1 function due to an expansion of cytosine-guanine-guanine (CGG) repeat at the 5’ untranslated region (5’UTR) of the gene. The purpose of this study is to identify the prevalence of FXS and characterize the FMR1 gene CGG repeats distribution among children with developmental disability in Malaysia. Genomic DNA of 2201 samples from different ethnicities (Malays, Chinese, Indian and others) of both genders were PCR-amplified from peripheral blood leukocytes based on specific primers at 5’UTR of FMR1 gene. Full mutations and mosaics were successfully identified by triple methylation specific PCR (ms-PCR) and subsequently verified with FragilEase kit. The findings revealed for the first time the prevalence of FXS full mutation in children with developmental disability in Malaysia was 3.5%, a slightly higher figure as compared to other countries. Molecular investigation also identified 0.2% and 0.4% probands have permutation and intermediate alleles, respectively. The CGG repeats length observation showed 95% of patients had normal alleles within 11 to 44 CGG repeats; with 29 repeats found most common among Malays and Indians while 28 repeats were most common among Chinese. In conclusion, this is the first report of prevalence and characterisation of CGG repeats that reflects genetic variability among Malaysian ethnic grouping.

Purpose: To compare patient care multipliers estimated from subjective evaluation against work sampling (WS) techniques in genetic nursing activities. Methods: An observational WS technique was conducted from November to December 2019 with nine genetic nurses in a tertiary referral center in Malaysia. The WS activity instrument was devised, validated, and pilot tested. All care- and non-care-related activities were sampled at 10-minute intervals within 8 hours of working over 14 days, followed by a subjective evaluation of activities survey over the same period. Bonferroni correction was undertaken for multiple testing with a p value of 0.0025. Results: The two techniques produced significant differences in genetic nurses’ activities categorization. The WS showed that compared with subjective evaluation, direct care (19.3% vs. 45.0%; p < .001) was estimated to be significantly lower, and indirect care (40.4% vs. 25.6%; p < .001) and unit-related activity (28.5% vs. 16.9%; p < .001) were higher. Both techniques produced a similar proportion of time spent in other non-care activities (12.0%) but differed in genetic meetings and information-gathering activities. While the multipliers for patient face-to-face contact were significantly larger between WS (4.57) and the survey (1.94), the multipliers for patient care time were smaller between WS (1.47) and the survey (1.24), indicating that caution should be taken when multiplying for patient contact time compared to patient care activity to determine the cost of care provision. Conclusion A considerable proportion of time spent away from the patient needs to be allocated to patient-related care time. Thus, estimating the paid cost solely based on direct time with patients considerably underestimates the cost per hour of nurses' care. It is recommended to employ ‘patientrelated activity’ instead of the ‘face-to-face contact’ multiplier because the former did not significantly differ from the one estimated using WS.

Labrune’s syndrome, or leukoencephalopathy with brain calcifications and cysts (LCC), is a rare genetic syndrome with variable neurological presentations. Psychiatric manifestations and involuntary movements are uncommonly reported. We report the case of a 19-year-old female, initially diagnosed with Fahr’s syndrome, who presented to us with acute psychosis, abnormal behavior and involuntary movements. Her brain computed tomography showed extensive bilateral intracranial calcifications without cysts. Genetic testing detected two compound heterozygous variants, NR_033294.1 n.*9C>T and n.24C>T, in the SNORD118 gene, confirming the diagnosis of LCC. We discuss the expanding phenotypic spectrum of LCC and provide a literature review on the current diagnosis and management of this rare syndrome.