Genetic basis of channelopathies and cardiomyopathies in Hong Kong Chinese patients: a 10-year regional laboratory experience.

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_198056.2:c.429del and c.2024-11T>A), two in MYBPC3 (NM_000256.3:c.906-22G>A and c.2105_2106del), and two in LMNA (NM_170707.3:c.73C>A and c.1209_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.

Expanded newborn metabolic screening programme in Hong Kong: a three-year journey.

INTRODUCTION: No universal expanded newborn screening service for inborn errors of metabolism is available in Hong Kong despite its long history in developed western countries and rapid development in neighbouring Asian countries. To increase the local awareness and preparedness, the Centre of Inborn Errors of Metabolism of the Chinese University of Hong Kong started a private inborn errors of metabolism screening programme in July 2013. This study aimed to describe the results and implementation of this screening programme. METHODS: We retrieved the demographics of the screened newborns and the screening results from July 2013 to July 2016. These data were used to calculate quality metrics such as call-back rate and false-positive rate. Clinical details of true-positive and false-negative cases and their outcomes were described. Finally, the call-back logistics for newborns with positive screening results were reviewed. RESULTS: During the study period, 30 448 newborns referred from 13 private and public units were screened. Of the samples, 98.3% were collected within 7 days of life. The overall call-back rate was 0.128% (39/30 448) and the false-positive rate was 0.105% (32/30 448). Six neonates were confirmed to have inborn errors of metabolism, including two cases of medium-chain acyl-coenzyme A dehydrogenase deficiency, one case of carnitine-acylcarnitine translocase deficiency, and three milder conditions. One case of maternal carnitine uptake defect was diagnosed. All patients remained asymptomatic at their last follow-up. CONCLUSION: The Centre of Inborn Errors of Metabolism has established a comprehensive expanded newborn screening programme for selected inborn errors of metabolism. It sets a standard against which the performance of other private newborn screening tests can be compared. Our experience can also serve as a reference for policymakers when they contemplate establishing a government-funded universal expanded newborn screening programme in the future.

Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome: a treatable genetic liver disease warranting urgent diagnosis.

Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is an autosomal recessive disorder caused by a defect in ornithine translocase. This condition leads to variable clinical presentations, including episodic hyperammonaemia, hepatic derangement, and chronic neurological manifestations. Fewer than 100 affected patients have been reported worldwide. Here we report the first two cases in Hong Kong Chinese, who were compound heterozygous siblings for c.535C>T (p.Arg179*) and c.815C>T (p.Thr272Ile) in the SLC25A15 gene. When the mother refused prenatal diagnosis for the second pregnancy, urgent genetic testing provided the definitive diagnosis within 24 hours to enable specific treatment. Optimal management of these two patients relied on the concerted efforts of a multidisciplinary team and illustrates the importance of an expanded newborn screening service for early detection and treatment of inherited metabolic diseases.

The first case report of McLeod syndrome in a Chinese patient.

We report the first case of McLeod syndrome (MLS) in a 47-year-old Chinese man who presented with progressive limb weakness, chorea of feet, red blood cell acanthocytosis, absence of Kx red blood cell antigen and weak expression of Kell antigens. The diagnosis of MLS was confirmed by genetic testing showing a hemizygous mutation of XK gene. We review literature on neuroacanthocytosis in the Chinese population.

A patient with congenital hyperlactataemia and Leigh syndrome: an uncommon mitochondrial variant.

We report an uncommon mitochondrial variant in a baby girl with congenital hyperlactataemia and Leigh syndrome. The patient presented with a single episode of generalised clonic convulsion at day 19, and was found to have isolated and persistent hyperlactataemia ranging from 3.34 to 9.26 mmol/L. She had elevated serum lactate-to-pyruvate ratios of up to 35 and high plasma alanine concentration, indicative of a respiratory chain defect. At the age of 8 months, she developed evolving neurological and imaging features compatible with Leigh syndrome. Genetic testing for common mitochondrial DNA mutations, large mitochondrial DNA deletions, and selected nuclear genes was negative. Further analysis of lymphocyte mitochondrial DNA by sequencing revealed an uncommon heteroplasmic variant, NC_012920.1(MT-ND5):m.13094T>C (p.Val253Ala), which was previously shown to reduce complex I activity. In patients in whom there was a high suspicion of mitochondrial disorder, entire mitochondrial DNA analysis may be warranted if initial screening of common mitochondrial DNA mutations is negative.

In search of the diagnosis, and the patient: transient galactosemia demystified after 14 years.

Infantile galactosemia can be caused by inborn errors of galactose metabolism or other rare causes like Fanconi-Bickel syndrome, congenital porto-systemic shunting and multiple hepatic arterio-venous malformations. All these disease entities are however not commonly seen. We report a case of transient infantile galactosemia who first presented in the 1990s, for which no underlying pathology could be identified despite extensive investigations. The diagnosis had not been apparent until after more than a decade, at that time the patient was lost to contact. Considering the potential diagnosis an important and significant one, efforts were made by the case pathologists and clinicians to search for the patient. Ethical dilemmas were encountered during the search of the patient, which involved issues of patient confidentiality and autonomy, and the doctors' duty-to-care. Modern biochemical and molecular testing confirmed the diagnosis after the patient was finally found. The case illustrates the power of molecular testing to retrospectively diagnose an inherited metabolic disease when biochemical abnormalities have subsided, the value of an accurate and precise diagnosis, and the importance of appropriate genetic counselling in an apparently asymptomatic patient in the era of personalized medicine.

Phaeochromocytoma in the Hong Kong Chinese population.

OBJECTIVE: To review the clinical manifestations of phaeochromocytoma in a Hong Kong Chinese population. DESIGN: Retrospective review. SETTING. Five public hospitals in Hong Kong. PATIENTS: Seventeen patients with operated phaeochromocytoma between 1994 and 2003 were reviewed retrospectively. RESULTS: Six patients (35%) were men, 11 (65%) were women. The mean age at presentation was 47 (range, 17-72) years. The diagnosis post-presentation was delayed by 1 to 132 months. Over 70% of the patients had hypertension. The most frequent symptoms were headache (53%), palpitations (53%), and sweating (41%); all these symptoms were present in 24% of the patients. Four (24%) had hereditary phaeochromocytoma/paraganglioma syndrome. The sensitivity of 24-hour urinary catecholamine measurements was 82%. Mean urinary adrenaline and noradrenaline concentrations were respectively 7- and 8-fold greater than the upper reference limits. Computed tomography and metaiodobenzylguanidine scintigraphy were the most widely used means for tumour localisation (sensitivity, 100% and 87% respectively). Approximately 65% of the patients had intra-adrenal tumours; 53% were on right side, 18% were bilateral. All the patients were prescribed phenoxybenzamine (dosage range, 20-120 mg/day) preoperatively. Two thirds of the patients had improved blood pressure 1 year after the operation. No malignancy was reported after a mean follow-up period of 7 years. CONCLUSION: Our series of patients with phaeochromocytomas commonly had a high frequency of normotension and extra-adrenal tumours. A high index of clinical suspicion and appropriate biochemical investigations are necessary to make the diagnosis, especially for patients manifesting adrenal incidentaloma and extra-adrenal lesion.

A novel duplication at the putative DNA polymerase alpha arrest site and a founder mutation in Chinese in the IVD gene underlie isovaleric acidaemia.

Isovaleric acidaemia is a rare inherited organic acidaemia associated with a characteristic odour in affected patients. Fewer than 40 causative mutations have been reported to date. We report a case in a Hong Kong Chinese neonate who presented with respiratory distress and acute encephalopathy requiring aggressive resuscitation and treatment. Residual gross motor developmental delay was still observed at the age of 16 months. The child was subsequently found to harbour a known missense mutation (c.A1199G [p.Y371C]) and a novel 4-bp duplication (c.1148_1151dupGCTA [p.Y355X]) in the IVD gene. We suggest that the former is a founder mutation in the Chinese population and propose an explanation for the duplication event. Strategies that may achieve early diagnosis and prompt treatment include raising awareness of this condition, implementation of a tandem mass spectrometry neonatal screening programme, and local acquisition of appropriate medications for these metabolic diseases.

Biochemical and molecular characterization of tyrosine hydroxylase deficiency in Hong Kong Chinese.

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.

Pantothenate kinase-associated neurodegeneration in two Chinese children: identification of a novel PANK2 gene mutation.

Pantothenate kinase-associated neurodegeneration (formerly Hallervorden-Spatz syndrome), the most prevalent form of neurodegeneration with brain iron accumulation, is a rare degenerative brain disease characterised by predominantly extrapyramidal dysfunction resulting from mutations in the PANK2 (pantothenate kinase 2) gene. Using DNA mutation analysis, the authors identified a novel missense mutation (P354L) in exon 4 of the PANK2 gene in an adolescent with classic pantothenate kinase-associated neurodegeneration. DNA-based diagnosis of pantothenate kinase-associated neurodegeneration plays a key role in determination, and can make the diagnosis more simply, directly, and economically because it obviates the need for unnecessary biochemical tests. Once pantothenate kinase-associated neurodegeneration-like symptoms are identified, mutation analysis and target screening for the family of the proband can provide efficient and accurate evidence of pantothenate kinase-associated neurodegeneration inheritance.

Adulteration of over-the-counter slimming products with pharmaceutical analogue--an emerging threat.

OBJECTIVES: To review pharmaceutical analogue adulteration of non-prescription slimming products. DESIGN: Retrospective study. SETTING: Tertiary referral centre for toxicology analysis, Hong Kong. PATIENTS: All patients known to have been hospitalised after taking slimming products adulterated with pharmaceutical analogues from September 2004 to December 2006. MAIN OUTCOME MEASURES: Age, reasons for hospital admission, major biochemical findings, and toxicology analysis results of the offending slimming products. RESULTS: N-nitrosofenfluramine, an analogue of fenfluramine with hepatotoxic effect, was found in two slimming products. Three patients were hospitalised after taking these slimming products, one of whom developed liver failure treated by liver transplantation. Another slimming product was found to contain N-desmethyl-sibutramine, an analogue of sibutramine. A patient with an unremarkable medical history developed acute psychosis after taking the latter product for 1 week. CONCLUSIONS: Analogues, created by modifying the chemical structures of pharmaceuticals, are used as adulterants in non-prescription slimming products, in an attempt to evade regulatory inspection. The imperceptible use of these analogues is very dangerous because they have not been tested formally for efficacy and safety. In view of the potential harm to the public, more effective and proactive measures are required to guard against the illicit use of pharmaceutical analogues. There is also a need for increased awareness among the public and the medical professionals about this emerging threat.

Carnitine-acylcarnitine translocase deficiency in three neonates presenting with rapid deterioration and cardiac arrest.

We report on three Chinese neonates with carnitine-acylcarnitine translocase deficiency. They presented within the first 48 hours of life. Two neonates were found in cardiac arrest; one of them survived after resuscitation. The third neonate suddenly developed cardiorespiratory insufficiency and succumbed eventually. The clustering of three cases in 5 years suggests that carnitine-acylcarnitine translocase deficiency is not rare in our Chinese population. We advocate that investigation for metabolic diseases including carnitine-acylcarnitine translocase deficiency should be performed in cases of sudden infant death and unexplained abrupt clinical deterioration in the early neonatal period. Non-ketotic hypoglycaemia is an early clue. The mainstay of initial treatment is glucose infusion at a rate greater than 7 mg/kg/minute, which inhibits beta-oxidation of fatty acids (the defective enzymatic steps in carnitine-acylcarnitine translocase deficiency) and thus prevents the accumulation of toxic long-chain acylcarnitines.