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RANBP2 susceptibility to infection-induced encephalopathy: Clinicoradiologic and molecular description in a Malaysian family

Chew HB, Ngu LH

Mol Genet Metab Rep, 2020 Sep;24:100627.
PMID: 32760653 DOI: 10.1016/j.ymgmr.2020.100627

Pathogenic variants in RANBP2 cause autosomal dominant familial and recurrent Acute Necrotizing Encephalopathy of Childhood (ANEC). Affected children typically experience a 3-stage disease: a 3 to 5 days prodrome of non-specific febrile illness, acute encephalopathy, and recovery with or without neurological sequelae or death. Neuroradiological finding of bilateral symmetrical thalamic lesions raise the suspicion of this diagnosis. A devastating disease, reported mortality approaches 1/3 of those affected and only approximately 10% of patients recover completely without sequelae. We report a Malaysian family with RANBP2 pathogenic variant c.1754C>T (p.Thr585Met). The clinical presentation and course over a maximum of 7 years, as well as neuroradiological features of the 3 affected children are described. In contrast to the reported high mortality and morbidity, our patients have recovered with minor sequelae. We would like to highlight the absence of pathogenic variants in both parents' blood, raising the possibility of germline mosaicism in one of the parents as the underlying genetic mechanism of inheritance. To our knowledge, this is the first report of germline mosaicism in RANBP2 Susceptibility to Infection-induced Encephalopathy.
Fulltext Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD): a case with additional features and review of the literature

Chew HB, Ngu LH, Keng WT

BMJ Case Rep, 2011;2011.
PMID: 22715259 DOI: 10.1136/bcr.02.2010.2706

A rare syndrome of rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) has been recently described. We report the first patient with this syndrome in Southeast Asia and review reported cases to date. Our patient was good health with normal development until the age of 2. He then developed hyperphagic obesity, hypersomnolence, seizures, alveolar hypoventilation, central hypothyroidism, sodium and water dysregulation, gastrointestinal dysmotility, strabismus, disordered temperature and irregular heart rate, altered sweating, delayed puberty, mental retardation and recurrent respiratory tract infections. The cardiomyopathy with heart failure and abnormal cerebral spinal fluid (CSF) neurotransmitter analysis present in our patient have not been reported previously. Tumours of the sympathetic nervous system are known to be associated with this syndrome but had not been found in our patient at the time of reporting. We highlight the difficulty of achieving the diagnosis of ROHHAD syndrome and its overlap with other well-established disease entities. The mortality and morbidity resulting from the high incidence of cardiorespiratory arrest may be prevented by early ventilatory support.
Dairy manure pellets and palm oil mill effluent as alternative nutrient sources in cultivating Sporosarcina pasteurii for calcium carbonate bioprecipitation

Omoregie AI, Muda K, Ngu LH

Lett Appl Microbiol, 2022 Jan 14.
PMID: 35032053 DOI: 10.1111/lam.13652

Microbially induced carbonate precipitation (MICP) is a process that hydrolysis urea by microbial urease to fill the pore spaces of soil with induced calcium carbonate (CaCO3 ) precipitates, which eventually results in improved or solidified soil. This research explored the possibility of using dairy manure pellets (DMP) and palm oil mill effluent (POME) as alternative nutrient sources for Sporosarcina pasteurii cultivation and CaCO3 bioprecipitation. Different concentrations (20-80 g l-1 ) of DMP and POME were used to propagate the cells of S. pasteurii under laboratory conditions. The measured CaCO3 contents for MICP soil specimens that were treated with bacterial cultures grown in DMP medium (60%, w/v) was 15·30 ± 0·04 g ml-1 and POME medium (40%, v/v) was 15·49 ± 0·05 g ml-1 after 21 days curing. The scanning electron microscopy showed that soil treated with DMP had rhombohedral structure-like crystals with smooth surfaces, whilst that of POME entailed ring-like cubical formation with rough surfaces Electron dispersive X-ray analysis was able to identify a high mass percentage of chemical element compositions (Ca, C and O), whilst spectrum from Fourier-transform infrared spectroscopy confirmed the vibration peak intensities for CaCO3 . Atomic force microscopy further showed clear topographical differences on the crystal surface structures that were formed around the MICP treated soil samples. These nutrient sources (DMP and POME) showed encouraging potential cultivation mediums to address high costs related to bacterial cultivation and biocementation treatment.
Fulltext Supernumerary derivative (22) syndrome resulting from a maternal balanced translocation

Afroze B, Ngu LH, Roziana A, Aminah M, Noor Shahizan A

Singapore Med J, 2008 Dec;49(12):e372-4.
PMID: 19122939

Supernumerary derivative (22) syndrome is one of the rare genomic syndromes. It is characterised by severe mental retardation, microcephaly, failure to thrive, ear anomalies, preauricular tags or sinus, cleft palate or high arch palate, microganathia, renal anomalies, congenital cardiac defects and genital abnormalities in males. In 99 percent of the cases, one of the parents is a balanced carrier of a translocation between chromosome 11 and chromosome 22. We report the first known case, a female neonate, of supernumerary derivative (22) syndrome from Malaysia.
Oil droplets and solid particles removal using circular separator with inclined coalescence mediums: comparison between co-current and counter-current flow

Ngu LH, Law PL, Wong KK, Yusof AA

Water Sci Technol, 2010;62(5):1129-35.
PMID: 20818055 DOI: 10.2166/wst.2010.407

This research investigated the effects of co- and counter-current flow patterns on oil-water-solid separation efficiencies of a circular separator with inclined coalescence mediums. Oil-water-solid separations were tested at different influent concentrations and flowrates. Removal efficiencies increased as influent flowrate decreased, and their correlationship can be represented by power equations. These equations were used to predict the required flowrate, Q(ss50), for a given influent suspended solids concentration C(iss) to achieve the desired effluent suspended solids concentration, C(ess) of 50 mg/L, to meet environmental discharge requirements. The circular separator with counter-current flow was found to attend removal efficiencies relatively higher as compared to the co-current flow. As compared with co-current flow, counter-current flow Q(ss50) was approximately 1.65 times higher than co-current flow. It also recorded 13.16% higher oil removal at influent oil concentration, C(io) of 100 mg/L, and approximately 5.89% higher TSS removal at all influent flowrates. Counter-current flow's better removal performances were due to its higher coalescing area and constant interval between coalescence plate layers.
Arterial thrombosis and critical limb ischaemia in a case of nephrotic syndrome

Koh KH, Tan C, Tan S, Ngu L

Nephrology (Carlton), 2009 Sep;14(6):622.
PMID: 19712262 DOI: 10.1111/j.1440-1797.2008.01001.x
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.
Fulltext Utilization of Point-of-Care Ultrasound to Detect Splenic Microabscesses in Pediatric Melioidosis

Sakulchit T, Ngu L, Chor YK, Ong GY

Cureus, 2021 Mar 08;13(3):e13760.
PMID: 33842136 DOI: 10.7759/cureus.13760

Melioidosis is an infectious disease most commonly found in places with tropical climates. Definitive diagnosis can be confirmed by culture or pathological results of blood or infected organ. However, imaging study is helpful in providing early provisional diagnosis and guiding therapy. Point-of-care ultrasound can be currently performed bedside by non-radiological staff such as emergency physicians or intensivists. We present the case of a pediatric patient who got diagnosed with melioidosis after detection of multiple splenic and hepatic abscesses by point-of-care ultrasound, leading to early diagnosis and appropriate empirical antibiotic selection, resulting in good treatment outcome.
Fulltext Molybdenum cofactor deficiency in a Malaysian child

Ngu LH, Afroze B, Chen BC, Affandi O, Zabedah MY

Singapore Med J, 2009 Oct;50(10):e365-7.
PMID: 19907877

Molybdenum cofactor deficiency is a rare autosomal recessive disorder with devastating neurological manifestations, characterised by neonatal-onset encephalopathy mimicking hypoxic-ischaemic insult, intractable seizure, and feeding and respiratory difficulties. It is often fatal in the early life. We report an affected 8-year-old boy, who presented with severe neurological manifestations since birth, but without clinically-significant seizure. Molybdenum cofactor deficiency must be included in the differential diagnosis of patients presenting with unexplained encephalopathy in the newborn period, and whose neuroimaging findings are consistent with hypoxic ischaemic encephalopathy. The classic laboratory hallmark of this disorder is low serum uric acid, positive urine sulphite dipstick test, and elevated urinary S-sulphocysteine, hypoxanthine and xanthine.
Fulltext Mowat-Wilson syndrome: the first two Malaysian cases

Balasubramaniam S, Keng WT, Ngu LH, Michel LG, Irina G

Singapore Med J, 2010 Mar;51(3):e54-7.
PMID: 20428734

Mowat-Wilson syndrome (MWS) is a recently delineated mental retardation; a multiple congenital anomaly syndrome characterised by a typical facial gestalt, Hirschsprung disease or severe constipation, genitourinary anomaly, congenital heart defects, agenesis of corpus callosum and eye defects. Some cases also present with epilepsy, growth retardation with microcephaly and speech impairment. MWS was first described in 1998 by Mowat et al, and approximately 180 cases have been reported as of August 2008. The syndrome occurs as a result of heterozygous mutations or deletions in the zinc finger E-box-binding homeobox 2 gene, ZEB2, previously called ZFHX1B (SIP1). Most cases reported so far were sporadic occurrences; however, rare cases of sibling recurrence have been cited. The facial phenotype is particularly important for the initial clinical diagnosis and provides the hallmark, warranting ZEB2 mutational analysis even in the absence of Hirschsprung disease. We present the first two molecularly confirmed Malaysian MWS patients, one of whom has a novel mutation.
Severe central airway stenosis and tracheomalacia in hunter syndrome

Tan HL, Abd Rahman R, Md Tarekh NA, Kassim M, Sathiamurthy N, Nik Mohamad Kamil A, et al.

Med J Malaysia, 2021 05;76(3):441-445.
PMID: 34031351

Hunter Syndrome is a genetic disease characterized by deficiency of Iduronate-2-Sulfatase enzyme activity, resulting in accumulation of glycoaminoglycans in various organs including the central airways. We report a case of severe tracheomalacia and airway stenosis at Hospital Sultanah Aminah, Johor Bahru, Malaysia requiring mechanical ventilation in a middle aged gentleman who was previously undiagnosed of mucopolysaccharidosis. The patient underwent emergency tracheostomy for failed intubation, when he presented with shortness of breath and acute respiratory failure. A contrast-enhanced computed tomography of the neck and thorax revealed that the trachea distal to the tracheostomy tube had collapsed with narrowed right and left main bronchus. These findings were confirmed via direct visualization of the airway through a flexible bronchoscopy. Eventually, a tracheal stenting were performed to maintain the airway patency and assist in weaning off from mechanical ventilation. Further investigations to identify the aetiology of the central airway stenosis revealed elevated urinary glycoaminoglycans and the absence of iduronate-2-Sulfatase activity tested on dried blood spots, thus confirming the diagnosis of Hunter Syndrome. Managing mucopolysacharidosis with central airway obstruction requires multidisciplinary team effort in handling the difficult airway, anaesthesiology risk, potential comorbidities and providing genetic counselling.
Fulltext Molecular analysis of fragile X syndrome (FXS) among Malaysian patients with developmental disability

Ali EZ, Yakob Y, Md Desa N, Ishak T, Zakaria Z, Ngu LK, et al.

Malays J Pathol, 2017 08;39(2):99-106.
PMID: 28866690 MyJurnal

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.
Detection of copy number variations in epilepsy using exome data

Tsuchida N, Nakashima M, Kato M, Heyman E, Inui T, Haginoya K, et al.

Clin Genet, 2018 03;93(3):577-587.
PMID: 28940419 DOI: 10.1111/cge.13144

Epilepsies are common neurological disorders and genetic factors contribute to their pathogenesis. Copy number variations (CNVs) are increasingly recognized as an important etiology of many human diseases including epilepsy. Whole-exome sequencing (WES) is becoming a standard tool for detecting pathogenic mutations and has recently been applied to detecting CNVs. Here, we analyzed 294 families with epilepsy using WES, and focused on 168 families with no causative single nucleotide variants in known epilepsy-associated genes to further validate CNVs using 2 different CNV detection tools using WES data. We confirmed 18 pathogenic CNVs, and 2 deletions and 2 duplications at chr15q11.2 of clinically unknown significance. Of note, we were able to identify small CNVs less than 10 kb in size, which might be difficult to detect by conventional microarray. We revealed 2 cases with pathogenic CNVs that one of the 2 CNV detection tools failed to find, suggesting that using different CNV tools is recommended to increase diagnostic yield. Considering a relatively high discovery rate of CNVs (18 out of 168 families, 10.7%) and successful detection of CNV with <10 kb in size, CNV detection by WES may be able to surrogate, or at least complement, conventional microarray analysis.
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.

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