Publications by authors named "Hencher Han Chih Lee"

13 Publications

  • Page 1 of 1

In-house multiplex ligation-dependent probe amplification assay for citrin deficiency: analytical validation and novel exonic deletions in SLC25A13.

Pathology 2021 Dec 25;53(7):867-874. Epub 2021 May 25.

Kowloon West Cluster Laboratory Genetic Service, Chemical Pathology Laboratory, Department of Pathology, Princess Margaret Hospital, Hong Kong, China. Electronic address:

Citrin deficiency is one of the most common inborn errors of metabolism in East Asians, which may manifest as neonatal cholestasis, failure to thrive and dyslipidaemia, or recurrent hyperammonaemic encephalopathy. Its molecular diagnosis requires confirmation of the presence of biallelic pathogenic variants in SLC25A13 gene by sequencing, and analysis for a common insertion IVS16ins3kb. However, patients with compatible biochemical features but only one monoallelic pathogenic variant have remained a diagnostic challenge. Here we report the development, validation and application of a multiplex ligation-dependent probe amplification (MLPA) assay using an in-house oligonucleotide probemix and a customised Coffalyer.NET worksheet for detection of exonic copy number variations in SLC25A13. With this MLPA assay, we successfully identified the presence of a heterozygous exonic deletion in SLC25A13 in three of 15 (20%) unrelated individuals with only one monoallelic pathogenic variant detected using conventional methods. Three exonic deletions, two novel involving exon 14 and one reported involving exon 5, were subsequently confirmed with Sanger sequencing. In summary, we developed, evaluated, and demonstrated the clinical utility of an in-house MLPA assay to look for exonic deletions in SLC25A13 in patients with citrin deficiency. With the discovery of novel deletions, MLPA should be considered a test of choice for molecular diagnosis of citrin deficiency when the sequencing result is inconclusive.
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http://dx.doi.org/10.1016/j.pathol.2021.02.010DOI Listing
December 2021

Movement disorders associated with thiamine pyrophosphokinase deficiency: Intrafamilial variability in the phenotype.

Clin Neurol Neurosurg 2020 12 30;199:106258. Epub 2020 Sep 30.

Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region.

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http://dx.doi.org/10.1016/j.clineuro.2020.106258DOI Listing
December 2020

Toxicity from illegitimate slimming agents - a 10-year case series at a tertiary toxicology laboratory in Hong Kong.

Clin Toxicol (Phila) 2021 May 22;59(5):426-432. Epub 2020 Sep 22.

Hospital Authority Toxicology Reference Laboratory, Princess Margaret Hospital, Kowloon, Hong Kong.

Context: This retrospective case-series study aims to provide an overview of the clinical, biochemical and analytical findings in patients who presented with toxicity related to the use of illegitimate slimming agents in Hong Kong from the perspective of a tertiary referral toxicology laboratory.

Methods: All clinical cases referred to the Hospital Authority Toxicology Reference Laboratory, Hong Kong with clinical suspicion of illegitimate slimming agent-related toxicity between January 2008 and December 2017 were reviewed retrospectively. The use of illegitimate slimming agents included the use of (1) deregistered slimming agents, (2) drug analogues that were not registered drugs, (3) registered drugs not approved for the indication of weight reduction (whether prescribed by a doctor or not), and (4) prescription-only slimming agents without a doctor's prescription. Patients taking registered weight-reducing drugs prescribed by a doctor were excluded. Patient demographics, clinical features, relevant laboratory investigations, and toxicological findings were analyzed.

Results: From 2008 to 2017, a total of 346 patients were analytically confirmed by our laboratory to have clinical toxicity related to the use of illegitimate slimming agents. The median age of the patients was 27 years and 92.5% of the patients were female. The most common clinical presentations included psychiatric features, sympathomimetic toxicity, hypokalemia, and abnormal thyroid function tests. Fatal or severe clinical toxicity was observed in 10% of the cases. The major classes of drugs detected on our analytical platforms were stimulants (e.g., sibutramine), laxatives (e.g., anthraquinones), diuretics (e.g., hydrochlorothiazide), and thyroid hormones (e.g., animal thyroid tissue). These illegitimate slimming agents were obtained from various sources including the Internet, over-the-counter in community pharmacy, or unspecified local sources.

Discussion And Conclusions: The use of slimming agents is common worldwide; apart from taking registered slimming agents prescribed by registered practitioners, many users obtain slimming agents from various illegitimate sources. The unregulated use of these drugs can be associated with significant clinical toxicity. This study provides a current landscape of illegitimate slimming agent toxicity in Hong Kong to frontline clinicians and other toxicology professionals. Collaboration between clinicians, laboratories, and government authorities would be imperative to prevent further health adversities related to the misuse of these agents.
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http://dx.doi.org/10.1080/15563650.2020.1822529DOI Listing
May 2021

Case Report: The first probable Hong Kong Chinese case of -related acute recurrent rhabdomyolysis in a boy with two novel variants.

F1000Res 2019 2;8:1566. Epub 2019 Sep 2.

Kowloon West Cluster Laboratory Genetic Service, Chemical Pathology Laboratory, Department of Pathology, Princess Margaret Hospital, Hong Kong, Laichikok, Hong Kong.

Recurrent rhabdomyolysis is frequently ascribed to fatty acid ß-oxidation defects, mitochondrial respiratory chain disorders and glycogen storage-related diseases. In recent years, autosomal recessive mutations have been identified as a prevailing cause of severe rhabdomyolysis in children in Western countries. We report the first probable Hong Kong Chinese case of recurrent severe rhabdomyolysis in early childhood caused by variants. Compound heterozygous novel variants NM_145693.2(LPIN1):c.[1949_1967dupGTGTCACCACGCAGTACCA]; [2410G>C] (p.[Gly657Cysfs*12];[Asp804His]) were detected. The former variant was classified as likely pathogenic while the latter variant was classified as a variant of uncertain significance (VUS) based on the guideline published by the American College of Medical Genetics and Genomics (ACMG) in 2015. Although the genetic findings were inconclusive, the patient's presentation was compatible with LPIN1-related acute recurrent rhabdomyolysis, and the patient was treated as such. The early recognition, timely diagnosis and management of this condition are important to avoid fatal consequences. To our knowledge, there has been no previous report in the English-language literature of a child with Chinese ethnicity and -related acute recurrent rhabdomyolysis (MIM #268200).  Functional characterization of the novel variants detected in this study are warranted in future studies.
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http://dx.doi.org/10.12688/f1000research.20343.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823901PMC
June 2020

Performance evaluation of five commercial assays for detection of acetaminophen.

J Clin Lab Anal 2019 Feb 4;33(2):e22683. Epub 2018 Oct 4.

Department of Pathology, Chemical Pathology Laboratory, Princess Margaret Hospital, Kowloon, Hong Kong.

Background: To evaluate the analytical performance of five commercial acetaminophen assays and select the best method for routine use.

Methods: Imprecision, accuracy, linearity, and interferences of three enzymatic assays (Beckman Coulter AU Paracetamol, Abbott MULTIGENT Acetaminophen, and Sekisui Acetaminophen L3K) and two immunoassay-based assays (Beckman Coulter SYNCHRON ACTM (Acetaminophen) Reagent and Siemens SYVA Emit-tox Acetaminophen) were evaluated on a Beckman Coulter AU680 chemistry analyzer. Hook effect for immunoassay-based assays and recovery in ultrafiltrate for enzymatic methods were studied.

Results: Within-run and between-run imprecision of the enzymatic assays ranged 0.26%-0.82% and 0.53%-2.86%, respectively, while that for the immunoassay-based methods ranged 0.96%-6.34% and 1.50%-11.33%, respectively. All assays except the SYNCHRON assay fell within the program analytical performance specifications (±20 µmol/L or 10%) for external quality assurance (EQA) samples, with the highest positive bias (31.7%) observed in the SYNCHRON assay. Icteric interference was demonstrated most significantly in the Abbott assay (up to 88 μmol/L positive bias in blank serum). The lipemic interference on the SYNCHRON was significant (up to 110% positive bias at level of 100 μmol/L). The immunoassay-based methods were less susceptible to hemolytic interference, while the Abbott and AU assays were more susceptible to N-acetylcysteine interference. Both immunoassay-based methods showed no hook effect up to 18 000 μmol/L. Ultrafiltration recoveries for enzymatic methods were satisfactory, ranging from 80.0% ± 5.1% to 89.5% ± 3.0%.

Conclusions: Proportional bias was observed in the SYNCHRON assay, while the Siemens and Sekisui assays were minimally affected by bilirubin interferences.
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http://dx.doi.org/10.1002/jcla.22683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818599PMC
February 2019

First case of genetically confirmed CLN3 disease in Chinese with cDNA sequencing revealing pathogenicity of a novel splice site variant.

Clin Chim Acta 2018 Nov 24;486:151-155. Epub 2018 Jul 24.

Kowloon West Cluster Laboratory Genetic Service, Chemical Pathology Laboratory, Department of Pathology, Princess Margaret Hospital, Hong Kong. Electronic address:

Background: Juvenile neuronal ceroid lipofuscinosis (CLN3 disease) is a hereditary progressive neurodegenerative disease well documented among Caucasians, but such clinical data and genetic characterization is lacking among Asian populations.

Patient And Methods: A 13-year-old Chinese girl presented for diagnostic evaluation with retinitis pigmentosa, generalised tonic-clonic seizure and cerebellar ataxia. Electron microscopy of whole blood and skin biopsy, and mutation analysis of CLN3 gene with genomic DNA and cDNA, were performed.

Results: Electron microscopy showed vacuolated lymphocytes, and characteristic patterns in eccrine glands suggestive of neuronal ceroid lipofuscinosis. Sequencing of genomic DNA showed homozygous splice site variant NM_000086.2(CLN3):c.906+6T>G, and the pathogenicity of which was confirmed by cDNA sequencing to demonstrate the deletion of a transmembrane domain of the CLN3 protein. The mutant protein was predicted to adversely affect ligand binding of CLN3 as a lysosomal membrane protein.

Conclusions: Here we report the first genetically confirmed CLN3 disease in Chinese, with a novel splice site variant with proposed pathogenetic mechanism relating gene and protein, and highlights the potential ethnic differences in the mutation spectrum. We wish to establish the importance of clinical awareness and laboratory diagnosis of CLN3 disease, especially in the promising age of gene therapy.
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http://dx.doi.org/10.1016/j.cca.2018.07.040DOI Listing
November 2018

Adulteration of proprietary Chinese medicines and health products with undeclared drugs: experience of a tertiary toxicology laboratory in Hong Kong.

Br J Clin Pharmacol 2018 Jan 4;84(1):172-178. Epub 2017 Oct 4.

Hospital Authority Toxicology Reference Laboratory, Princess Margaret Hospital, Hong Kong.

Aims: Proprietary Chinese medicines (pCMs) and health products, generally believed to be natural and safe, are gaining popularity worldwide. However, the safety of pCMs and health products has been severely compromised by the practice of adulteration. The current study aimed to examine the problem of adulteration of pCMs and health products in Hong Kong.

Methods: The present study was conducted in a tertiary referral clinical toxicology laboratory in Hong Kong. All cases involving the use of pCMs or health products, which were subsequently confirmed to contain undeclared adulterants, from 2005 to 2015 were reviewed retrospectively.

Results: A total of 404 cases involving the use of 487 adulterated pCMs or health products with a total of 1234 adulterants were identified. The adulterants consisted of approved drugs, banned drugs, drug analogues and animal thyroid tissue. The six most common categories of adulterants detected were nonsteroidal anti-inflammatory drugs (17.7%), anorectics (15.3%), corticosteroids (13.8%), diuretics and laxatives (11.4%), oral antidiabetic agents (10.0%) and erectile dysfunction drugs (6.0%). Sibutramine was the most common adulterant (n = 155). The reported sources of these illicit products included over-the-counter drug stores, the internet and Chinese medicine practitioners. A significant proportion of patients (65.1%) had adverse effects attributable to these illicit products, including 14 severe and two fatal cases. Psychosis, iatrogenic Cushing syndrome and hypoglycaemia were the three most frequently encountered adverse effects.

Conclusions: Adulteration of pCMs and health products with undeclared drugs poses severe health hazards. Public education and effective regulatory measures are essential to address the problem.
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http://dx.doi.org/10.1111/bcp.13420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736835PMC
January 2018

Clinical manifestation of late onset Pompe disease patients in Hong Kong.

Neuromuscul Disord 2016 Dec 13;26(12):873-879. Epub 2016 Sep 13.

Department of Pathology, Princess Margaret Hospital, Hong Kong.

Late onset Pompe disease is a rare inherited metabolic disease with diverse clinical manifestation. However, there is a lack of local data in Hong Kong. We aimed at performing an in-depth review of natural history of all patients in Hong Kong. Eleven patients were diagnosed to have the disease in Hong Kong from 2000 to 2013. All case records were reviewed and face-to-face interviews were conducted to complete a questionnaire regarding the clinical manifestation and diagnosis of the disease. The estimated birth incidence was 1/300,000. The age of diagnosis ranged from 9 to 44 years; all patients were ethnic Chinese. The median ages of first symptoms and first medical attention were 20.5(6-44) and 29(9-44) years respectively. The most common initial complaint was decreased exercise tolerance. Two patients' first complaint was difficulty with getting up from lying position and failure to perform sit up. The mean time from first medical attention to diagnosis was 1.3 years but one patient was diagnosed 8 years later. Half of the patients sought medical attention due to progressive shortness of breath and all of them developed type 2 respiratory failure requiring ventilator support during the first admission. Two patients became chair-bound and seven patients required assisted ventilation. Late onset Pompe disease tends to have an earlier and more aggressive clinical presentation in Chinese and lower birth incidence was found in Hong Kong.
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http://dx.doi.org/10.1016/j.nmd.2016.09.004DOI Listing
December 2016

Novel POLG mutation in a patient with sensory ataxia, neuropathy, ophthalmoparesis and stroke.

Clin Chim Acta 2015 Aug 11;448:211-4. Epub 2015 Jul 11.

Department of Pathology, Princess Margaret Hospital, Hong Kong, China.

Background: Clinical diagnosis of POLG-related disorders can be challenging because the phenotypic spectrums are heterogeneous which can mimic different types of mitochondrial disorders.

Case: We report a case of POLG-related disorder in an 18y Chinese girl who had been diagnosed as MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) for the past 8y. She first presented at 10y with sudden onset of headache, repeated focal seizures and visual loss, complicated with residual sensory and motor neuropathy, ophthalmoparesis and cortical blindness. MRI brain showed extensive cytotoxic edema and ischemia in bilateral parietal-occipital lobes. Mutation analysis for common point mutations in the mitochondrial DNA and muscle biopsy was negative. She was referred to us for mitochondrial whole genome analysis. However, no pathogenic variants can be determined. We initiated further genetic analysis for POLG which confirmed compound heterozygous mutations NM_002693.2:c.925C>T (p.Arg309Cys) and a novel mutation c.2244G>T (p.Trp748Cys). Both were determined to be pathogenic using in silico analysis.

Conclusions: The novel mutation contributes to the expanding spectrum of disease-causing mutations. A definitive diagnosis can benefit our patient and also the relatives by avoiding sodium valproate induced liver toxicity in POLG patients and also the heterozygotes.
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http://dx.doi.org/10.1016/j.cca.2015.06.028DOI Listing
August 2015

Cost-benefit analysis of hyperphenylalaninemia due to 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency: for consideration of expanded newborn screening in Hong Kong.

J Med Screen 2014 Jun 6;21(2):61-70. Epub 2014 May 6.

Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

Objectives: To evaluate the cost-benefit of implementing an expanded newborn screening programme for hyperphenylalaninemias due to 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency in Hong Kong.

Setting: Regional public hospitals in Hong Kong providing care for cases of inborn errors of metabolism.

Methods: Implementational and operational costs of a new expanded mass spectrometry-based newborn screening programme were estimated. Data on various medical expenditures for the mild and severe phenotypic subtypes were gathered from a case cohort diagnosed with PTPS deficiency from 2001 to 2009. Local incidence from a previously published study was used.

Results: Implementation and operational costs of an expanded newborn screening programme in Hong Kong were estimated at HKD 10,473,848 (USD 1,342,801) annually. Assuming a birthrate of 50,000 per year and an incidence of 1 in 29,542 live births, the medical costs and adjusted loss of workforce per year would be HKD 20,773,207 (USD 2,663,232). Overall the annual savings from implementing the programme would be HKD 9,632,750 (USD 1,234,968).

Conclusions: Our estimates show that implementation of an expanded newborn screening programme in Hong Kong is cost-effective, with a significant annual saving for public expenditure.
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http://dx.doi.org/10.1177/0969141314533531DOI Listing
June 2014

Hyperekplexia: a Chinese adolescent with 2 novel mutations of the GLRA1 gene.

J Child Neurol 2014 Jan 8;29(1):111-3. Epub 2012 Nov 8.

1Private Practice, Hong Kong.

Hyperekplexia is a rare neurologic disorder, characterized by excessive startle response to unexpected stimuli. There are 3 cardinal features: generalized stiffness immediately after birth that normalizes during the first year of life; excessive startle reflex to unexpected (particularly auditory) stimuli; and a short period of generalized stiffness following the startle response while patient cannot elicit voluntary movements. Awareness of this condition will avoid misdiagnosis of disorders like epilepsy. Clonazepam is an effective medical treatment. We report a patient whose frequent falls triggered by sudden noise or tactile stimuli was initially misdiagnosed as epilepsy. The clinical diagnosis was subsequently revised to hyperekplexia and confirmed by mutation analysis of the GLRA1 gene, which showed c.497G>C (p.Cys166Ser) and c.526delG (p.Asp176Metfs*16). Both of them are novel mutations. His response to clonazepam is dramatic and has been able to engage in sports and social activities.
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http://dx.doi.org/10.1177/0883073812465338DOI Listing
January 2014

Electronic chemical pathology consultation service and dried blood spot metabolic screening in hospital patients.

J Clin Pathol 2012 Dec 10;65(12):1141-5. Epub 2012 Aug 10.

Chemical Pathology Laboratory, Department of Pathology, Princess Margaret Hospital, Hong Kong SAR, China.

Aim: Inborn errors of metabolism (IEM) are an unpopular and difficult subject and most clinicians are unfamiliar with them. Although chemical pathologists have a long-standing practice in advising test strategy and result interpretation especially from primary care, such consultations are usually informal, unstructured and those related to IEM are infrequently requested. This study aims to provide a formal electronic consultation service and to apply tandem mass spectrometry-based dried blood spot metabolic screening (DBSM) as a rapid first-line test for patients suspected of IEM.

Methods: DBSM and a chemical pathology consultation were ordered through the hospital computer terminals. DBSM detected 29 metabolic disorders. The clinical data and metabolic results for the 12-month period were reviewed.

Results: There were 279 consultations of which 209 were initiated by paediatricians and 70 by adult physicians. The main reasons for consultation were developmental delay, neurological abnormalities, unexplained biochemical abnormalities and monitoring of patients with IEM. There were 158 DBSM requests. One positive case of isovaleric acidaemia was detected.

Conclusions: All high-risk paediatric patients should have a DBSM and a timely electronic chemical pathology consultation as a rapid and cost-effective first-line screening. Provision of a visible, accessible and helpful consultation service enables professional reimbursement.
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http://dx.doi.org/10.1136/jclinpath-2012-200837DOI Listing
December 2012

Young-onset parkinsonism in a Hong Kong Chinese man with adult-onset Hallervorden-Spatz syndrome.

Int J Neurosci 2011 Apr 4;121(4):224-7. Epub 2011 Jan 4.

Kowloon West Cluster Laboratory Genetic Service, Department of Pathology, Princess Margaret Hospital, Hong Kong SAR, China.

Neurodegeneration with brain iron accumulation (NBIA) is a heterogeneous group of disorders varied in genetic etiologies, clinical presentations, and radiological features. NBIA is an iron homeostasis disorder with progressive iron accumulation in the central nervous systems and is clinically characterized by extrapyramidal movement abnormalities, retinal pigmentary changes, and cognitive impairment. Panthothenate kinase-associated neurodegeneration (Hallervorden-Spatz disease) is the commonest disorder of NBIA with a prevalence of one-three per million. Clinically, it is classified into early-onset childhood, atypical late-onset, and adult-onset type. Adult-onset type is rarer. We report the first case of adult-onset panthothenate kinase-associated neurodegeneration in Hong Kong in a 28-year-old Chinese man who presented with pure young-onset parkinsonism. Magnetic resonance imaging (MRI) of the brain showed the presence of eye-of-the-tiger sign. Two compound heterozygous mutations PANK2 NM_153638.2: c.445G > T; NP_705902.2: p.E149X and PANK2 NM_153638.2: c.1133A > G; NP_705902.2: p.D378G were detected. Parkinsonism per se is a very heterogeneous phenotypic group. In view of the readily available genetic analysis of PANK2, panthothenate kinase-associated neurodegeneration should be considered in adult patients with young-onset parkinsonism with or without the eye-of-the-tiger sign. The exact diagnosis offers a different management approach and genetic counseling. NBIA is likely under- or misdiagnosed in Hong Kong Chinese.
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http://dx.doi.org/10.3109/00207454.2010.542843DOI Listing
April 2011
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