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Medicine in Malaysia: paediatrics

Sinniah D, Choy YS

Med J Malaysia, 1995 May;50 Suppl A:S65-8.
PMID: 10968019
Fulltext Morbidity in Alagille syndrome in 6 Malaysian children

Lim CB, Choy YS

Med J Malaysia, 2003 Dec;58(5):641-6.
PMID: 15190647 MyJurnal

We retrospectively studied the records of 6 Malaysian children who were diagnosed with Alagille Syndrome (AGS) according to this criteria from January 1999 to January 2001, at the Institute of Paediatrics, Kuala Lumpur Hospital. Four patients (66%) had a positive family history. Thirteen individuals (6 patients and 7 relatives) were diagnosed with AGS in these 5 families. Only 6/13 (46%) of them presented with liver involvement. All 6 patients presented with typical facies and cholestasis (100%). Three (50%) presented with portal hypertension (PHT) with synthetic liver dysfunction (1 died), 1/6 (17%) have PHT and normal synthetic liver function. Two have cleared their jaundice but have biochemical evidence of hepatitis and hepatomegaly, four have congenital heart disease 5/6 posterior embryotoxon, 2/6 butterfly vertebrae, 4/6 hyperlipidaemia and 4/6 failure to thrive. One patient has a Jagged-1 gene disruption at the translocation breakpoint locus 20p12.3 2n = 46,XX,t(12.20) (q22, p12.3). 5/6 (83%) are still alive. Two-thirds of our patients developed chronic liver disease by 3 years of age. Two-thirds of the index patients have a family history. Only 46% of individuals in these families have clinical evidence of liver involvement. Mortality depends on cardiac/renal disease, end-stage liver failure and intercurrent infection.
Fulltext Clinical and biochemical profiles of maple syrup urine disease in malaysian children

Yunus ZM, Kamaludin DA, Mamat M, Choy YS, Ngu L

JIMD Rep, 2012;5:99-107.
PMID: 23430924 DOI: 10.1007/8904_2011_105

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.
Dengue encephalitis: a true entity?

Lum LC, Lam SK, Choy YS, George R, Harun F

Am J Trop Med Hyg, 1996 Mar;54(3):256-9.
PMID: 8600761 DOI: 10.4269/ajtmh.1996.54.256

Involvement of the central nervous system in dengue fever and dengue hemorrhagic fever has always been thought to be secondary to vasculitis with resultant fluid extravasation, cerebral edema, hypoperfusion, hyponatremia, liver failure, and/or renal failure. Thus, the condition has been referred to as dengue encephalopathy. Encephalitis or direct involvement of the brain by the virus was thought to be unlikely. This paper reports on six children who were seen over a period of two years presenting on the second or third day of illness with dengue encephalitis. The diagnosis was based upon a clinical picture of encephalitis and confirmed by cerebrospinal fluid (CSF) microscopy and electroencephalography changes. All six cases were confirmed dengue infections. Dengue 3 virus was isolated from the CSF of four cases and in one case, dengue 2 was detected by the polymerase chain reaction in both the CSF and blood. In the sixth case, virologic evidence was negative but dengue immunoglobulin M was detected in the CSF and blood. Since the onset of encephalitis appears early in the course of illness coinciding with the viremic phase, we postulate that the virus crosses the blood-brain barrier and directly invades the brain causing encephalitis. This study provides strong evidence that dengue 2 and 3 viruses have neurovirulent properties and behave similarly to other members of the Flaviviridae.
Fulltext Infantile Progressive Hepatoencephalomyopathy with Combined OXPHOS Deficiency due to Mutations in the Mitochondrial Translation Elongation Factor Gene GFM1

Balasubramaniam S, Choy YS, Talib A, Norsiah MD, van den Heuvel LP, Rodenburg RJ

JIMD Rep, 2012;5:113-22.
PMID: 23430926 DOI: 10.1007/8904_2011_107

Mitochondrial disorders are a heterogeneous group of often multisystemic and early fatal diseases caused by defects in the oxidative phosphorylation (OXPHOS) system. Given the complexity and intricacy of the OXPHOS system, it is not surprising that the underlying molecular defect remains unidentified in many patients with a mitochondrial disorder. Here, we report the clinical features and diagnostic workup leading to the elucidation of the genetic basis for a combined complex I and IV OXPHOS deficiency secondary to a mitochondrial translational defect in an infant who presented with rapidly progressive liver failure, encephalomyopathy, and severe refractory lactic acidemia. Sequencing of the GFM1 gene revealed two inherited novel, heterozygous mutations: a.539delG (p.Gly180AlafsX11) in exon 4 which resulted in a frameshift mutation, and a second c.688G > A (p.Gly230Ser) mutation in exon 5. This missense mutation is likely to be pathogenic since it affects an amino acid residue that is highly conserved across species and is absent from the dbSNP and 1,000 genomes databases. Review of literature and comparison were made with previously reported cases of this recently identified mitochondrial disorder encoded by a nuclear gene. Although limited in number, nuclear gene defects causing mitochondrial translation abnormalities represent a new, rapidly expanding field of mitochondrial medicine and should potentially be considered in the diagnostic investigation of infants with progressive hepatoencephalomyopathy and combined OXPHOS disorders.
Fulltext Overcoming the barriers to diagnosis of Morquio A syndrome

Bhattacharya K, Balasubramaniam S, Choy YS, Fietz M, Fu A, Jin DK, et al.

Orphanet J Rare Dis, 2014;9:192.
PMID: 25433535 DOI: 10.1186/s13023-014-0192-7

Morquio A syndrome is an autosomal recessive lysosomal storage disease often resulting in life-threatening complications. Early recognition and proficient diagnosis is imperative to facilitate prompt treatment and prevention of clinical complications.
Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency

Brun L, Ngu LH, Keng WT, Ch'ng GS, Choy YS, Hwu WL, et al.

PMID: 20505134 DOI: 10.1212/WNL.0b013e3181e620ae

Neurology. 2010 Jul 6;75(1):64-71
OBJECTIVE: To describe the current treatment; clinical, biochemical, and molecular findings; and clinical follow-up of patients with aromatic l-amino acid decarboxylase (AADC) deficiency.
METHOD: Clinical and biochemical data of 78 patients with AADC deficiency were tabulated in a database of pediatric neurotransmitter disorders (JAKE). A total of 46 patients have been previously reported; 32 patients are described for the first time.
RESULTS: In 96% of AADC-deficient patients, symptoms (hypotonia 95%, oculogyric crises 86%, and developmental retardation 63%) became clinically evident during infancy or childhood. Laboratory diagnosis is based on typical CSF markers (low homovanillic acid, 5-hydroxyindoleacidic acid, and 3-methoxy-4-hydroxyphenolglycole, and elevated 3-O-methyl-l-dopa, l-dopa, and 5-hydroxytryptophan), absent plasma AADC activity, or elevated urinary vanillactic acid. A total of 24 mutations in the DDC gene were detected in 49 patients (8 reported for the first time: p.L38P, p.Y79C, p.A110Q, p.G123R, p.I42fs, c.876G>A, p.R412W, p.I433fs) with IVS6+ 4A>T being the most common one (allele frequency 45%).
CONCLUSION: Based on clinical symptoms, CSF neurotransmitters profile is highly indicative for the diagnosis of aromatic l-amino acid decarboxylase deficiency. Treatment options are limited, in many cases not beneficial, and prognosis is uncertain. Only 15 patients with a relatively mild form clearly improved on a combined therapy with pyridoxine (B6)/pyridoxal phosphate, dopamine agonists, and monoamine oxidase B inhibitors.
Identifying the need for a multidisciplinary approach for early recognition of mucopolysaccharidosis VI (MPS VI)

Choy YS, Bhattacharya K, Balasubramaniam S, Fietz M, Fu A, Inwood A, et al.

Mol Genet Metab, 2015 May;115(1):41-7.
PMID: 25892708 DOI: 10.1016/j.ymgme.2015.03.005

Mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome) is caused by deficient activity of the enzyme, N-acetylgalactosamine-4-sulfatase, resulting in impaired degradation of the glycosaminoglycan dermatan sulfate. Patients experience a range of manifestations including joint contractures, short stature, dysostosis multiplex, coarse facial features, decreased pulmonary function, cardiac abnormalities, corneal clouding and shortened life span. Recently, clinicians from institutions in the Asia-Pacific region met to discuss the occurrence and implications of delayed diagnosis and misdiagnosis of MPS VI in the patients they have managed. Eighteen patients (44% female) were diagnosed. The most common sign presented by the patients was bone deformities in 11 patients (65%). Delays to diagnosis occurred due to the lack of or distance to diagnostic facilities for four patients (31%), alternative diagnoses for two patients (15%), and misleading symptoms experienced by two patients (15%). Several patients experienced manifestations that were subtler than would be expected and were subsequently overlooked. Several cases highlighted the unique challenges associated with diagnosing MPS VI from the perspective of different specialties and provide insights into how these patients initially present, which may help to elucidate strategies to improve the diagnosis of MPS VI.
Fulltext ASPP2 deficiency causes features of 1q41q42 microdeletion syndrome

Zak J, Vives V, Szumska D, Vernet A, Schneider JE, Miller P, et al.

Cell Death Differ, 2016 Dec;23(12):1973-1984.
PMID: 27447114 DOI: 10.1038/cdd.2016.76

Chromosomal abnormalities are implicated in a substantial number of human developmental syndromes, but for many such disorders little is known about the causative genes. The recently described 1q41q42 microdeletion syndrome is characterized by characteristic dysmorphic features, intellectual disability and brain morphological abnormalities, but the precise genetic basis for these abnormalities remains unknown. Here, our detailed analysis of the genetic abnormalities of 1q41q42 microdeletion cases identified TP53BP2, which encodes apoptosis-stimulating protein of p53 2 (ASPP2), as a candidate gene for brain abnormalities. Consistent with this, Trp53bp2-deficient mice show dilation of lateral ventricles resembling the phenotype of 1q41q42 microdeletion patients. Trp53bp2 deficiency causes 100% neonatal lethality in the C57BL/6 background associated with a high incidence of neural tube defects and a range of developmental abnormalities such as congenital heart defects, coloboma, microphthalmia, urogenital and craniofacial abnormalities. Interestingly, abnormalities show a high degree of overlap with 1q41q42 microdeletion-associated abnormalities. These findings identify TP53BP2 as a strong candidate causative gene for central nervous system (CNS) defects in 1q41q42 microdeletion syndrome, and open new avenues for investigation of the mechanisms underlying CNS abnormalities.
Fulltext Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes

Himmelreich N, Bertoldi M, Alfadhel M, Alghamdi MA, Anikster Y, Bao X, et al.

Mol Genet Metab, 2023 Jul;139(3):107624.
PMID: 37348148 DOI: 10.1016/j.ymgme.2023.107624

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic.
Corrigendum to: Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes

Himmelreich N, Bertoldi M, Alfadhel M, Alghamdi MA, Anikster Y, Bao X, et al.

Mol Genet Metab, 2023 Aug;139(4):107647.
PMID: 37453860 DOI: 10.1016/j.ymgme.2023.107647