Publications by authors named "Bee-Chin Chen"

7 Publications

  • Page 1 of 1

Inherited metabolic disorders presenting as hypoxic ischaemic encephalopathy: A case series of patients presenting at a tertiary care hospital in Pakistan.

J Pak Med Assoc 2019 Mar;69(3):432-436

Department of Paediatrics & Child Health, Aga Khan University Hospital, Karachi.

In spite of the efforts and interventions by the Government of Pakistan and The World Health Organization, the neonatal mortality in Pakistan has declined by only 0.9% as compared to the global average decline of 2.1% between 2000 and 2010. This has resulted in failure to achieve the global Millennium Development Goal 4. Hypoxic-ischaemic encephalopathy, still birth, sepsis, pneumonia, diarrhoea and birth defects are commonly attributed as leading causes of neonatal mortality in Pakistan. Inherited metabolic disorders often present at the time of birth or the first few days of life. The clinical presentation of the inherited metabolic disorders including hypotonia, seizure and lactic acidosis overlap with clinical features of hypoxic-ischaemic encephalopathy and sepsis. Thus, these disorders are often either missed or wrongly diagnosed as hypoxicischaemic encephalopathy or sepsis unless the physicians actively investigate for the underlying inherited metabolic disorders. We present 4 neonates who had received the diagnosis of hypoxic-ischaemic encephalopathy and eventually were diagnosed to have various inherited metabolic disorders. Neonates with sepsis and hypoxic-ischaemic encephalopathy-like clinical presentation should be evaluated for inherited metabolic disorders.
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March 2019

Mitochondrial Neurogastrointestinal Encephalomyopathy Disease in Three Siblings from Pakistan with a Novel Mutation.

J Pediatr Genet 2019 Mar 30;8(1):15-19. Epub 2018 Jun 30.

Department of Paediatrics and Child Health, Aga Khan University Hospital, Karachi, Pakistan.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare multisystem autosomal recessive disorder. The disease is clinically heterogeneous with gastrointestinal symptoms of intestinal dysmotility and cachexia as well as neurological symptoms of ophthalmoplegia, neuropathy, sensorineural hearing impairment, and diffuse leukoencephalopathy being most prominent. MNGIE is caused by mutations in , a gene that encodes thymidine phosphorylase (TP)-a cytosolic enzyme. Mutations in lead to very low TP catalytic activity, resulting in dramatically increased thymidine and deoxyuridine in plasma. We describe the clinical, biochemical, and neuroimaging findings of three boys with MNGIE from a Pakistani family with a novel homozygous mutation, c.798_801dupCGCG p. (Ala268Argfs*?), in exon 7 of .
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http://dx.doi.org/10.1055/s-0038-1661411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375719PMC
March 2019

Fructose-1,6-bisphosphatase deficiency as a cause of recurrent hypoglycemia and metabolic acidosis: Clinical and molecular findings in Malaysian patients.

Pediatr Neonatol 2018 08 13;59(4):397-403. Epub 2017 Nov 13.

Department of Genetics, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia. Electronic address:

Background: Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare autosomal recessive inborn error of gluconeogenesis. We reported the clinical findings and molecular genetic data in seven Malaysian patients with FBPase deficiency.

Methods: All patients diagnosed with FBPase deficiency from 2010 to 2015 were included in this study. Their clinical and laboratory data were collected retrospectively.

Results: All the patients presented with recurrent episodes of hypoglycemia, metabolic acidosis, hyperlactacidemia and hepatomegaly. All of them had the first metabolic decompensation prior to 2 years old. The common triggering factors were vomiting and infection. Biallelic mutations in FBP1 gene (MIM*611570) were identified in all seven patients confirming the diagnosis of FBPase deficiency. In four patients, genetic study was prompted by detection of glycerol or glycerol-3-phosphate in urine organic acids analysis. One patient also had pseudo-hypertriglyceridemia. Seven different mutations were identified in FBP1, among them four mutations were new: three point deletions (c.392delT, c.603delG and c.704delC) and one splice site mutation (c.568-2A > C). All four new mutations were predicted to be damaging by in silico analysis. One patient presented in the neonatal period and succumbed due to sepsis and multi-organ failure. Among six survivors (current age ranged from 4 to 27 years), four have normal growth and cognitive development. One patient had short stature and another had neurological deficit following status epilepticus due to profound hypoglycemia.

Conclusion: FBPase deficiency needs to be considered in any children with recurrent hypoglycemia and metabolic acidosis. Our study expands the spectrum of FBP1 gene mutations.
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http://dx.doi.org/10.1016/j.pedneo.2017.11.006DOI Listing
August 2018

Dihydropyrimidine dehydrogenase deficiency in two malaysian siblings with abnormal MRI findings.

Mol Syndromol 2014 Dec 25;5(6):299-303. Epub 2014 Sep 25.

Laboratory of Genetic Metabolic Diseasess, University of Amsterdam, Amsterdam, The Netherlands.

Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disorder of the pyrimidine metabolism. Deficiency of this enzyme leads to an accumulation of thymine and uracil and a deficiency of metabolites distal to the catabolic enzyme. The disorder presents with a wide clinical spectrum, ranging from asymptomatic to severe neurological manifestations, including intellectual disability, seizures, microcephaly, autistic behavior, and eye abnormalities. Here, we report on an 11-year-old Malaysian girl and her 6-year-old brother with DPD deficiency who presented with intellectual disability, microcephaly, and hypotonia. Brain MRI scans showed generalized cerebral and cerebellar atrophy and callosal body dysgenesis in the boy. Urine analysis showed strongly elevated levels of uracil in the girl and boy (571 and 578 mmol/mol creatinine, respectively) and thymine (425 and 427 mmol/mol creatinine, respectively). Sequence analysis of the DPYD gene showed that both siblings were homozygous for the mutation c.1651G>A (pAla551Thr).
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http://dx.doi.org/10.1159/000366074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281573PMC
December 2014

Hyperexcretion of homocitrulline in a Malaysian patient with lysinuric protein intolerance.

Eur J Pediatr 2013 Sep 29;172(9):1277-81. Epub 2013 Jan 29.

Biochemistry Unit, Specialised Diagnostic Centre, Institute for Medical Research, Jalan Pahang, 50588 Kuala Lumpur, Malaysia.

Unlabelled: Lysinuric protein intolerance (LPI; MIM 222700) is an inherited aminoaciduria with an autosomal recessive mode of inheritance. Biochemically, affected patients present with increased excretion of the cationic amino acids: lysine, arginine, and ornithine. We report the first case of LPI diagnosed in Malaysia presented with excessive excretion of homocitrulline. The patient was a 4-year-old male who presented with delayed milestones, recurrent diarrhea, and severe failure to thrive. He developed hyperammonemic coma following a forced protein-rich diet. Plasma amino acid analysis showed increased glutamine, alanine, and citrulline but decreased lysine, arginine and ornithine. Urine amino acids showed a marked excretion of lysine and ornithine together with a large peak of unknown metabolite which was subsequently identified as homocitrulline by tandem mass spectrometry. Molecular analysis confirmed a previously unreported homozygous mutation at exon 1 (235 G > A, p.Gly79Arg) in the SLC7A7 gene. This report demonstrates a novel mutation in the SLC7A7 gene in this rare inborn error of diamino acid metabolism. It also highlights the importance of early and efficient treatment of infections and dehydration in these patients.

Conclusion: The diagnosis of LPI is usually not suspected by clinical findings alone, and specific laboratory investigations and molecular analysis are important to get a definitive diagnosis.
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http://dx.doi.org/10.1007/s00431-013-1947-1DOI Listing
September 2013

Argininosuccinic aciduria: clinical and biochemical phenotype findings in Malaysian children.

Malays J Pathol 2010 Dec;32(2):87-95

Department of Genetics, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia.

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.
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December 2010

Adenylosuccinate lyase deficiency in a Malaysian patient, with novel adenylosuccinate lyase gene mutations.

J Inherit Metab Dis 2010 Dec 23;33 Suppl 3:S159-62. Epub 2010 Feb 23.

Biochemical Genetic Unit, Department of Genetics, Kuala Lumpur Hospital, Jalan Pahang 50586, Malaysia.

Most cases of adenylosuccinate lyase (ADSL OMIM 103050) deficiency reported to date are confined to the various European ethnic groups. We report on the first Malaysian case of ADSL deficiency, which appears also to be the first reported Asian case. The case was diagnosed among a cohort of 450 patients with clinical features of psychomotor retardation, global developmental delay, seizures, microcephaly and/or autistic behaviour. The patient presented with frequent convulsions and severe myoclonic jerk within the first few days of life and severe psychomotor retardation. The high performance liquid chromatography (HPLC) profile of the urine revealed the characteristic biochemical markers of succinyladenosine (S-Ado) and succinyl-aminoimidazole carboximide riboside (SAICAr). The urinary S-Ado/SAICAr ratio was found to be 1.02 (type I ADSL deficiency). The patient was compound heterozygous for two novel mutations, c.445C > G (p.R149G) and c.774_778insG (p.A260GfsX24).
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http://dx.doi.org/10.1007/s10545-010-9056-zDOI Listing
December 2010
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