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Objective: Sudden arrhythmia death syndrome (SADS) accounts for about 30% of causes of sudden cardiac death (SCD) in young people. In Hong Kong, there are scarce data on SADS and a lack of experience in molecular autopsy. We aimed to investigate the value of molecular autopsy techniques for detecting SADS in an East Asian population., Methods: This was a two-part study. First, we conducted a retrospective 5-year review of autopsies performed in public mortuaries on young SCD victims. Second, we conducted a prospective 2-year study combining conventional autopsy investigations, molecular autopsy, and cardiac evaluation of the first-degree relatives of SCD victims. A panel of 35 genes implicated in SADS was analysed by next-generation sequencing., Results: There were 289 SCD victims included in the 5-year review. Coronary artery disease was the major cause of death (35%); 40% were structural heart diseases and 25% were unexplained. These unexplained cases could include SADS-related conditions. In the 2-year prospective study, 21 SCD victims were examined: 10% had arrhythmogenic right ventricular cardiomyopathy, 5% had hypertrophic cardiomyopathy, and 85% had negative autopsy. Genetic analysis showed 29% with positive heterozygous genetic variants; six variants were novel. One third of victims had history of syncope, and 14% had family history of SCD. More than half of the 11 first-degree relatives who underwent genetic testing carried related genetic variants, and 10% had SADS-related clinical features., Conclusion: This pilot feasibility study shows the value of incorporating cardiac evaluation of surviving relatives and next-generation sequencing molecular autopsy into conventional forensic investigations in diagnosing young SCD victims in East Asian populations. The interpretation of genetic variants in the context of SCD is complicated and we recommend its analysis and reporting by qualified pathologists., Competing Interests: All authors have disclosed no conflicts of interest.

A 21-year-old female had recurrent presentations to the emergency department with myalgia, vomiting, abdominal pain and subsequently developed generalized seizures. She was volume depleted with a plasma sodium of 125 mmol/L (reference interval: 135-145) and she had fluctuating hypertension. Acute porphyria was suspected and confirmed with raised urine porphobilinogen/creatinine ratio of 12:4 μmol/mmoL (reference interval < 1:5) and she was treated with intravenous haem arginate. Urinary porphyrin/creatinine ratio was 673 nmol/mmoL (reference interval <35) and faecal porphyrins 2430 μmol/kg dry weight (reference interval: <200) were markedly elevated, with raised faecal CIII:CI ratio, consistent with acute coproporphyria. Diagnosis was confirmed by the demonstration of a novel missense variant in the coproporphyrinogen oxidase gene c.863T > G (p.Leu288Trp) predicted to be deleterious and which segregated with three other affected family members. Although CT head was normal, magnetic resonance imaging scan revealed symmetrical signal abnormalities and swelling in the parietal and occipital lobes consistent with posterior reversible encephalopathy. Over several days, her seizures ceased and sodium and blood pressure normalized. The aetiology of the acute porphyric attack was likely multifactorial with contributions from a recent viral illness and caloric deprivation. No drug precipitant was identified. We postulate that untreated hypertension played a key role in the development of posterior reversible encephalopathy. Early clinical suspicion and urine porphobilinogen testing are the key components in preventing morbidity and mortality in acute porphyrias.

Introduction: Hereditary channelopathies and cardiomyopathies are potentially lethal and are clinically and genetically heterogeneous, involving at least 90 genes. Genetic testing can provide an accurate diagnosis, guide treatment, and enable cascade screening. The genetic basis among the Hong Kong Chinese population is largely unknown. We aimed to report on 28 unrelated patients with positive genetic findings detected from January 2006 to December 2015., Methods: Sanger sequencing was performed for 28 unrelated patients with a clinical diagnosis of channelopathies or cardiomyopathies, testing for the following genes: KCNQ1, KCNH2, KCNE1, KCNE2, and SCN5A, for long QT syndrome; SCN5A for Brugada syndrome; RYR2 for catecholaminergic polymorphic ventricular tachycardia; MYH7 and MYBPC3 for hypertrophic cardiomyopathy; LMNA for dilated cardiomyopathy; and PKP2 and DSP for arrhythmogenic right ventricular dysplasia/cardiomyopathy., Results: There were 17 males and 11 females; their mean age at diagnosis was 39 years (range, 1-80 years). The major clinical presentations included syncope, palpitations, and abnormal electrocardiography findings. A family history was present in 13 (46%) patients. There were 26 different heterozygous mutations detected, of which six were novel-two in SCN5A (NM&#95;198056.2:c.429del and c.2024-11T>A), two in MYBPC3 (NM&#95;000256.3:c.906-22G>A and c.2105&#95;2106del), and two in LMNA (NM&#95;170707.3:c.73C>A and c.1209&#95;1213dup)., Conclusions: We have characterised the genetic heterogeneity in channelopathies and cardiomyopathies among Hong Kong Chinese patients in a 10-year case series. Correct interpretation of genetic findings is difficult and requires expertise and experience. Caution regarding issues of non-penetrance, variable expressivity, phenotype-genotype correlation, susceptibility risk, and digenic inheritance is necessary for genetic counselling and cascade screening.

Introduction: Newborn screening is important for early diagnosis and effective treatment of inborn errors of metabolism (IEM). In response to a 2008 coroners' report of a 14-year-old boy who died of an undiagnosed IEM, the OPathPaed service model was proposed. In the present study, we investigated the feasibility of the OPathPaed model for delivering expanded newborn screening in Hong Kong. In addition, health care professionals were surveyed on their knowledge and opinions of newborn screening for IEM., Methods: The present prospective study involving three regional hospitals was conducted in phases, from 1 October 2012 to 31 August 2014. The 10 steps of the OPathPaed model were evaluated: parental education, consent, sampling, sample dispatch, dried blood spot preparation and testing, reporting, recall and counselling, confirmation test, treatment and monitoring, and cost-benefit analysis. A fully automated online extraction system for dried blood spot analysis was also evaluated. A questionnaire was distributed to 430 health care professionals by convenience sampling., Results: In total, 2440 neonates were recruited for newborn screening; no true-positive cases were found. Completed questionnaires were received from 210 respondents. Health care professionals supported implementation of an expanded newborn screening for IEM. In addition, there is a substantial need of more education for health care professionals. The majority of respondents supported implementing the expanded newborn screening for IEM immediately or within 3 years., Conclusion: The feasibility of OPathPaed model has been confirmed. It is significant and timely that when this pilot study was completed, a government-led initiative to study the feasibility of newborn screening for IEM in the public health care system on a larger scale was announced in the Hong Kong Special Administrative Region Chief Executive Policy Address of 2015.

Background: Chromosomal microarray offers superior sensitivity for identification of submicroscopic copy number variants (CNV) and it is advocated to be the first tier genetic testing for patients with autism spectrum disorder (ASD). In this regard, diagnostic yield of array comparative genomic hybridization (CGH) for ASD patients is determined in a cohort of Chinese patients in Hong Kong., Methods: A combined adult and paediatric cohort of 68 Chinese ASD patients (41 patients in adult group and 27 patients in paediatric group). The genomic DNA extracted from blood samples were analysed by array CGH using NimbleGen CGX-135K oligonucleotide array., Results: We identified 15 CNV and eight of them were clinically significant. The overall diagnostic yield was 11.8 %. Five clinically significant CNV were detected in the adult group and three were in the paediatric group, providing diagnostic yields of 12.2 and 11.1 % respectively. The most frequently detected CNV was 16p13.11 duplications which were present in 4 patients (5.9 % of the cohort)., Conclusions: In this study, a satisfactory diagnostic yield of array CGH was demonstrated in a Chinese ASD patient cohort which supported the clinical usefulness of array CGH as the first line testing of ASD in Hong Kong.

Palliative chemotherapy is increasingly used in cancer patients near end of life. With the development of newer anticancer agents which have less side effects and higher expected efficacy, the decision on palliative chemotherapy in patients near end of life is complex. This article illustrates how oncologist and palliative care physicians can work together effectively. This article also gives an overview about the risks of palliative chemotherapy near end of life, patients' and physicians' perspectives in choosing the aggressive treatment and describes what an oncologist should do when facing this challenging situation.

Background: Autism spectrum disorders (ASD) are neurodevelopmental disorders with a high degree of heritability, but the genetic basis is exceedingly heterogeneous. Microdeletions of chromosome 15q24 have been demonstrated to be recurrent genomic alterations in ASD patients. Of interest, neuronal migration genes are of particular relevance to the pathogenesis of ASD. NEO1 is located in 15q24 and encodes for neogenin, a membrane receptor involved in cortical interneuron migration and axon guidance. We postulated that the ASD patient has one copy of the NEO1 gene deleted and the other copy disrupted by intragenic mutation., Results: We identify genetic changes in both alleles of NEO1 in two individuals from a cohort of 66 Han Chinese patients with ASD. In one patient, we detected a hemizygous 1.97-Mb deletion at 15q23q24.1 encompassing the NEO1 gene, a missense variant in NEO1, c.3388C>T (p.Arg1130Cys), and a duplication, c.2204-14&#95;2204-2dup, in the acceptor splice site of intron 14 of NEO1. Furthermore, we identified a second patient was a compound heterozygote for NEO1. A novel missense variant in NEO1, c.302G>A (p.Arg101His), in addition to c.3388C>T and c.2204-14&#95;2204-2dup was detected in the second patient. The c.3388C>T is a single nucleotide polymorphism with allele frequency of 0.045 in Han Chinese individuals. In silico and functional analyses indicated that p.Arg1130Cys, located at the nuclear localization signal (NLS) domain of neogenin led to defective nuclear translocation of neogenin., Conclusions: The hemizygous 15q deletion unmasks the recessive functional polymorphism in NEO1 which plays a pivotal role in cortical interneuron development. Our study provides the first evidence linking NEO1 with ASD in humans., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Breathlessness is common in patients with advanced cancer. Using a multidisciplinary approach for relieving this challenging symptom was believed to be just a theory. The "SOB Program" was implemented in our institution in March 2013., Measures: An audit of medical records before and after implementation of the "SOB Program" was performed to identify any changes in practice after implementation, specifically in the use of nonpharmacologic interventions., Intervention: The "SOB Program" is a multidisciplinary service in our department, using both pharmacologic and nonpharmacologic interventions for all patients with advanced cancer who have dyspnea., Outcomes: There was a marked increase in the use of nonpharmacologic interventions after the "SOB Program" (26.86% preimplementation vs. 89.35% postimplementation). Patients joining the program also had satisfactory improvement in breathlessness., Conclusions/lessons Learned: A multidisciplinary approach for breathlessness control is both feasible and practical. Similar services can be promoted in other palliative care centers., (Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

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&#95;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., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The monoamine neurotransmitter disorders are a heterogeneous group of inherited neurological disorders involving defects in the metabolism of dopamine, norepinephrine, epinephrine and serotonin. The inheritance of these disorders is mostly autosomal recessive. The neurological symptoms are primarily attributable to cerebral deficiency of dopamine, serotonin or both. The clinical presentations were highly variable and substantial overlaps exist. Evidently, laboratory investigations are crucial for accurate diagnosis. Measurement of neurotransmitter metabolites in cerebral spinal fluid (CSF) is the key to delineate the metabolic defects. Adjuvant investigations including plasma phenylalanine, urine pterins, urine 3-O-methyldopa (3-OMD) and serum prolactin are also helpful to establish the diagnosis. Genetic analyses are pivotally important to confirm the diagnosis which allows specific treatments, proper genetic counselling, prognosis prediction, assessment of recurrent risk in the family as well as prenatal diagnosis. Early diagnosis with appropriate treatment is associated with remarkable response and favourable clinical outcome in several disorders in this group.

Background: The efficacy and safety of using combination chemotherapy with cetuximab as first-line treatment in patients with K-ras wild-type colorectal cancers has been well established. In general, weekly cetuximab was given with biweekly chemotherapy FOLFOX-4 or FOLFIRI, synchronizing them would be appealed to both patients and health care professionals., Materials and Methods: This Phase II, prospective study investigated the efficacy and safety of using biweekly cetuximab 500 mg/m(2) with chemotherapy FOLFOX-4 or FOLFIRI as first-line treatment for Chinese patients with K-ras wild-type metastatic colorectal cancer. The study endpoints included overall objective response (OR), progression-free survival (PFS), overall survival (OS) and safety., Results: Total 15 Chinese patients (male: 10 [67%]; median age: 60 [range 41-80]) were enrolled. Patients received median 12 cycles (range 2-12) of chemotherapy + cetuximab (FOLFOX-4 + cetuximab: 9 [60%]; FOLFIRI + cetuximab: 6 [40%]). Six patients (40%) with non-progressive disease after 12 cycles of chemotherapy + cetuximab carried on maintenance cetuximab. Median duration of follow-up (FU) was 23.7 months. The OR was 40% (complete response: 0%; partial response: 40%) for a disease control rate of 87%. Median PFS and OS were 7.8 months and 17.9 months respectively. For maintenance cetuximab phase, median PFS since the start of maintenance cetuximab was 6.8 months and median OS was 17.0 months. The only grade 3-4 toxicities were neutropenia (26.7%) in chemotherapy phase and acneiform rashes (16.7%) in maintenance phase., Conclusions: Biweekly cetuximab with combination chemotherapy was effective and safe as weekly dose. Further studies are warranted for the role of maintenance cetuximab.

A macrocephalic girl presented with generalised epilepsy due to focal cortical dysplasia. She later developed multiple hamartomatous lesions and was diagnosed to have Cowden syndrome. The diagnosis was confirmed by identification of a novel frameshift mutation in the PTEN gene of the patient.

Background: Glycogen storage disease (GSD) is a group of inherited metabolic disorders due to enzymatic deficiency involved in glycogen breakdown. In various subtypes of GSD, GSD IXa is an X-linked recessive disorder, which only manifested in males. Here, we report a case of X-linked GSD IXa manifested in a female Chinese patient accompanying a skewed X-chromosome inactivation (XCI)., Methods: A 29-y-old Chinese female was admitted to evaluate mild hepatomegaly, which was repeatedly observed in serial abdominal ultrasonographic examinations. GSDIXa was suspected. To identify the mutation and the disease mechanism, we performed sequencing analysis of the PHKA2 gene, XCI assay and cDNA expression analysis., Results: Sequencing analysis revealed a heterozygous mutation in the PHKA2 gene (c.3614C>T; p.P1205L) of the patient. In XCI assay, the proband showed a skewed XCI pattern cDNA expression analysis showed a preferential expression of the mutant allele in leukocytes of the patient., Conclusions: This is a rare report of X-linked GSD IXa manifested in a female carrier with skewed XCI. Skewed XCI can play a key role in the manifestation of X-linked recessive disorders in female carriers., (© 2013 Elsevier B.V. All rights reserved.)

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.

Objectives: Classical inborn errors of metabolism (IEM) affect about 1 in 4000 in Hong Kong. Despite the widespread implementation of expanded newborn screening in most countries, Hong Kong only screen for three conditions and the awareness of public has not been evaluated. This is the first study to examine the parental knowledge and attitudes towards expanded newborn screening in Hong Kong., Methods: A cross-sectional survey was conducted in the Princess Margaret Hospital. Parents with babies born from 1st July to 31st October 2010 were randomly recruited. Fifteen questions relating to the knowledge of newborn screening and biochemical genetic disorders, preferences about the features of newborn screening, the economic values, and attitudes toward false positive results were asked., Results: In total, 172 subjects were interviewed by phone (overall response rate 97.2%). There were 87.8% parents who had never heard of expanded newborn screening; 99.4% demanded more parental education; 83.5% thought the programme should be implemented immediately; 97.7% supported population screening, even though the diseases are incurable; 93.9% accepted the possibility of false positive and false negative results; 70.4% preferred a voluntary basis; 83.2% believed that the programme should be fully government funded as basic primary care; 98.8% agreed that Hong Kong should follow mainland China's policy on expanded newborn screening; 98.2% required pre-test counseling; and 96.4% required an explicit parental consent before blood sampling., Conclusions: The response from parents overwhelmingly favoured having expanded newborn screening in Hong Kong. Parental tolerance was high. Parents valued the parental autonomy with informed consent and pre-test counseling the most. The success of any screening programme requires the public participation and this study is the first to prove the parental call for an expanded newborn screening in Hong Kong., (Copyright © 2012 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is one of the most common fatty acid oxidation defects that cause sudden unexpected deaths in infants. The death attributed to VLCAD deficiency can be prevented by early diagnosis with expanded newborn screening using tandem mass spectrometry. A favorable outcome can be achieved with early diagnosis and prompt treatment. However, such newborn screening has not yet been available in Hong Kong. We report a 2-month-old boy who succumbed 5 hours after admission with the diagnosis of VLCAD deficiency confirmed by genetic analysis performed after death. The patient was compound heterozygous for a novel splicing mutation ACADVL NM&#95;000018.2:c.277+2T>G; NC&#95;000017.10:g.7123997T>G and a known disease-causing mutation ACADVL NM&#95;000018.2:c.388&#95;390del; NP&#95;000009.1: p.Glu130del. Family screening was performed for at-risk siblings. The rapid downhill course of the patient clearly illustrates the need of newborn screening for early diagnosis. Our patient was asymptomatic before metabolic decompensation. However, once metabolic decompensation occurred, rapid deterioration and death followed, which obviated the opportunity to diagnose and treat. The only way to save these patients' lives and improve their outcome is early diagnosis and appropriate treatment. Therefore, we strongly urge the implementation of newborn screening using tandem mass spectrometry for VLCAD deficiency and other highly treatable inborn errors of metabolism in Hong Kong.

Background: Neonatal diabetes mellitus (NDM) is a rare but important condition affecting approximately 1 in 100,000 newborns. Permanent form requires life-long treatment with difficulties in long-term compliance and metabolic complications. Exact genetic diagnosis can enable improved outcome and patient satisfaction by switching insulin injection to oral sulfonylureas. Successful cases have been reported with most experience on the KCNJ11-mutated permanent form. Here we report a successful experience in an ABCC8-mutated infant with permanent NDM., Patient and Methods: A 4-month-old Chinese girl was incidentally found to have hyperglycemia with baseline C-peptide of 0.05 nmol/L requiring insulin injection of 0.2 IU/kg/d. Genetic analysis of KCNJ11 and ABCC8 was performed by polymerase chain reaction and direct DNA sequencing at the age of 3 years. Sulfonylurea transition was conducted after the ABCC8 mutation detection., Results: A novel homozygous ABCC8 NM&#95;000352.3: c.3068 A>G; NP&#95;000343.2: p.H1023R mutation was detected. C-peptide level increased to 0.14 nmol/L and HbA1c was normalized to 5.8% from 8.0% after 8 months of oral glibenclamide treatment with a maintenance dosage of 0.65 mg/kg/d., Conclusions: In this patient with ABCC8-mutated permanent NDM, oral sulfonylurea is also effective in achieving satisfactory diabetic control. Our study adds information to the personalized medicine practice of ABCC8-mutated permanent NDM.

Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant disease characterized by the occurrences of parathyroid tumors and ossifying fibroma of maxilla/mandible. It is caused by mutations in CDC73 gene and mutation carriers are at increased risk of parathyroid carcinoma. Hyperparathyroidism could be the sole manifestation. We reported two Chinese patients having parathyroid neoplasm with equivocal malignant potential and parathyroid carcinoma respectively with both germline and somatic CDC73 mutations detected. Both of them presented with severe hypercalcemia and primary hyperparathyroidism with no other HPT-JT associated tumors and negative family history. We identified one novel germline mutation CDC73 NM&#95;024529.4: c.1475G > A; NP&#95;078805.3: p.Trp492X and one novel somatic mutation CDC73 NM&#95;024529.4: c.142G > T; NP&#95;078805.3: p.Glu48X. The other germline mutation CDC73 NM&#95;024529.4: c.226C > T; NP&#95;078805.3: p.Arg76X and somatic mutation CDC73 NM&#95;024529.4: c.85delG; NP&#95;078805.3: p.Glu29SerfsX8 were previously reported. This is the first report of CDC73 mutations in the Chinese population. Genetic analysis is reliable to confirm the underlying hereditary basis of hyperparathyroidism. By identification of mutations, the patient and the family members could benefit from regular surveillance for early detection of tumors.

Epilepsy is a clinically and genetically heterogeneous group of disorders. The advent of molecular genetics brings unprecedented advancement in diagnostic molecular pathology and reduces over-reliance on traditional clinical classification. Severe myoclonic epilepsy of infancy or Dravet syndrome is a catastrophic infantile-onset epilepsy. We report two unrelated Hong Kong Chinese patients with this condition presenting with febrile seizures, epilepsy with different semiologies, psychomotor retardation, and recurrent status epilepticus. Two different mutations were characterised, viz NM&#95;001165963.1: c.680T>G; NP&#95;001159435.1: p.I227S and NM&#95;001165963.1: c.3953T>G; NP&#95;001159435.1: p.L1318R (novel). Genetic characterisation conveys a definitive diagnosis and is important from the perspective of selecting anti-epileptic drug therapy and genetic counselling.

Influenza-associated encephalopathy (IAE) is a potentially fatal neurological complication of influenza infection usually in the presence of high and persistent fever. Thermolabile carnitine palmitoyltransferase II enzyme (CPT-II) predisposes IAE, so far only described in Japanese. As the genetic origins of Japanese and Chinese are alike, similar genetic risk factors in CPT-II are expected. We report the first two unrelated Chinese patients of thermolabile CPT-II variants that underlain the persistent high fever-triggered viral infection-associated encephalopathy, multi-organ failure and death. Elevated (C16:0+C18:1)/C2 acylcarnitines ratio and the CPT2 susceptibility variant allele [p.Phe352Cys; p.Val368Ile] were detected. The asymptomatic family members of one patient also had abnormal long-chain acylcarnitines. In our experience of biochemical genetics, the elevated (C16:0+C18:1)/C2 acylcarnitines ratio is unusual and specific for thermolabile CPT-II variants. Allele frequency of [p.Phe352Cys; p.Val368Ile] among Hong Kong Chinese was 0.104, similar to Japanese data, and [p.Phe352Cys] has not been reported in Caucasians. This may explain the Asian-specific phenomenon of thermolabile CPT-II-associated IAE. We successfully demonstrated the thermolabile CPT-II variants in patients with viral infection-associated encephalopathy in another Asian population outside Japanese. The condition is likely under-recognized. With our first cases, it is envisaged that more cases will be diagnosed in subsequent years. The exact pathogenic mechanism of how other factors interplay with thermolabile CPT-II variants and high fever leading to IAE, is yet to be elucidated. Fasting and decreased intake during illness may aggravate the disease. Further studies including high risk and neonatal screening are warranted to investigate its expressivity, penetrance and temperature-dependent behaviors in thermolabile CPT-II carriers. This may lead to discovery of the therapeutic golden window by aggressive antipyretics and L-carnitine administration in avoiding the high mortality and morbidity of IAE.

Hyperphenylalaninemia is one of the commonest inborn errors of metabolism affecting approximately 1 in 15,000 livebirths. Among Chinese, BH4 deficiency leading to hyperphenylalaninemia is much commoner than in Caucasians. Exact diagnosis is important for the treatment and genetic counseling. In 2000, newborn screening for phenylketonuria is mandatory by law in China throughout the whole country. However, it is not yet included in the newborn screening program of the Hong Kong Special Administrative Region, China. Published data on hyperphenylalaninemia among HongKong Chinese are largely lacking. We report a 1-year-old Hong Kong Chinese girl with severe 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency. The patient presented with infantile hypotonia and was misdiagnosed as cerebral palsy. She had very mild hyperphenylalaninemia (95 μmol/L), significantly high phenylalnine-to-tyrosine ratio (3.1), and elevated prolactin of 1109 mIU/L. Genetic analysis confirmed a homozygous known disease-causing mutation PTS NM&#95;000317.1:c.259C>T; NP&#95;000308.1: p.P87S in the proband. In our local experience, while the estimated prevalence of hyperphenylalaninemia due to PTPS deficiency was reported to be 1 in 29,542 live births, not a single case of phenylalanine hydroxylase deficiency has been reported. Furthermore, there is a general lack of awareness of inherited metabolic diseases in the community as well as among the medical professionals. Very often, a low index of clinical suspicion will lead to delay in diagnosis, multiple unnecessary and costly investigations, prolonged morbidity and anxiety to the family affected. We strongly recommend that expanded newborn screening for hyperphenylalaninemia should be implemented for every baby born in the Hong Kong Special Administrative Region, China.

Background: Data of classical inborn errors of metabolism (IEM) of amino acids, organic acids and fatty acid oxidation are largely lacking in Hong Kong, where mass spectrometry-based expanded newborn screening for IEM has not been initiated. The current study aimed to evaluate the approximate incidence, spectrum and other characteristics of classical IEM in Hong Kong, which would be important in developing an expanded newborn screening program for the local area., Methods: The laboratory records of plasma amino acids, plasma acylcarnitines and urine organic acids analyses from year 2005 to 2009 inclusive in three regional chemical pathology laboratories providing biochemical and genetic diagnostic services for IEM were retrospectively reviewed., Results: Among the cohort, 43 patients were diagnosed of IEM, including 30 cases (69%) of amino acidemias (predominantly citrin deficiency, hyperphenylalaninemia due to 6-pyruvoyl-tetrahydropterin synthase deficiency and tyrosinemia type I), 5 cases (12%) of organic acidemias (predominantly holocarboxylase synthetase deficiency) and 8 cases (19%) of fatty acid oxidation defects (predominantly carnitine-acylcarnitine translocase deficiency). The incidence of classical IEM in Hong Kong was roughly estimated to be at least 1 case per 4122 lives births, or 0.243 cases per 1000 live births. This incidence is similar to those reported worldwide, including the mainland of China. The estimated incidence of hyperphenylalaninemia was 1 in 29 542 live births., Conclusions: Our data indicate that it is indisputable for the introduction of expanded newborn screening program in Hong Kong. Since Hong Kong is a metropolitan city, a comprehensive expanded newborn screening program and referral system should be available to serve the neonates born in the area.

Background: Von Hippel-Lindau (VHL) syndrome is an autosomal dominant familial cancer syndrome predisposing the affected individuals to multiple tumours in various organs. The genetic basis of VHL in Southern Chinese is largely unknown. In this study, we characterized the mutation spectrum of VHL in nine unrelated Southern Chinese families., Methods: Nine probands with clinical features of VHL, two symptomatic and eight asymptomatic family members were included in this study. Prenatal diagnosis was performed twice for one proband. Two probands had only isolated bilateral phaeochromocytoma. The VHL gene was screened for mutations by polymerase chain reaction, direct sequencing and multiplex ligation-dependent probe amplification (MLPA)., Results: The nine probands and the two symptomatic family members carried heterozygous germline mutations. Eight different VHL mutations were identified in the nine probands. One splicing mutation, NM&#95;000551.2: c.463+1G > T, was novel. The other seven VHL mutations, c.233A > G [p.Asn78Ser], c.239G > T [p.Ser80Ile], c.319C > G [p.Arg107Gly], c.481C > T [p.Arg161X], c.482G > A [p.Arg161Gln], c.499C > T [p.Arg167Trp] and an exon 2 deletion, had been previously reported. Three asymptomatic family members were positive for the mutation and the other five tested negative. In prenatal diagnosis, the fetuses were positive for the mutation., Conclusions: Genetic analysis could accurately confirm VHL syndrome in patients with isolated tumours such as sporadic phaeochromocytoma or epididymal papillary cystadenoma. Mutation detection in asymptomatic family members allows regular tumour surveillance and early intervention to improve their prognosis. DNA-based diagnosis can have an important impact on clinical management for VHL families.

Introduction: Leigh Syndrome is an uncommon cause of infantile apnea., Case Summary: We report a 5-month-old girl with sudden respiratory arrest followed by episodic hyper- and hypo-ventilation, encephalopathy, and persistent lactic acidosis. Computed tomography of the brain revealed symmetric low densities over the basal ganglia, internal capsule, thalami, and midbrain. Cardiac echocardiogram was suggestive of hypertrophic cardiomyopathy., Discussion: Diagnosis of Leigh syndrome due to T8993G mutation was confirmed with polymerase chain reaction and direct DNA sequencing of mitochondrial genome. To our knowledge, this is the first report of proven maternally inherited Leigh syndrome in Hong Kong.

Tyrosine hydroxylase deficiency is a rare neurotransmitter disorder affecting the rate-limiting step in catecholamine biosynthesis. There are about 40 cases reported worldwide. Here, we report the biochemical and molecular findings of eight unrelated Chinese patients with tyrosine hydroxylase deficiency. We have identified eight novel mutations with 5 missense, 2 nonsense and 1 splicing mutations in the TH gene, namely p.R153X, p.R169X, p.G294R, p.G315S, p.A385V, p.I394T, p.G408R, and c.1163+5G>C. The mutations of the TH gene in Chinese are heterogeneous., (Copyright 2009 Elsevier Inc. All rights reserved.)

By combining surprising new results from a full polarization analysis of nodal angle-resolved photoemission data from pristine and modulation-free Bi(2)Sr(2)CaCu(2)O(8+delta) with structural information from LEED and ab initio one-step photoemission simulations, we prove that the shadow Fermi surface in these systems is of structural origin, being due to orthorhombic distortions from tetragonal symmetry present both in surface and bulk. Consequently, one of the longest standing open issues in the investigation of the Fermi surface of these widely studied systems finally meets its resolution.