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BACKGROUND: Aromatic L-amino acid decarboxylase deficiency is a rare neurometabolic disease due to impaired decarboxylation of neurotransmitter precursors to its active form. CASE: We retrospectively reviewed 8 cases from 2008 to 2019 with cerebrospinal fluid neurotransmitter analysis performed at our centre. All cases had an elevated urine vanillactic acid and, in most cases, with N-acetylvanilalanine detected. Cerebrospinal fluid analysis showed low downstream metabolites vanillylmandelic acid, homovanillic acid but high 3-O-methyl-L-DOPA, 5-hydroxytryptophan. Cerebrospinal fluid pterins were normal. Genotyping in DDC confirms the diagnosis. Urine organic acid analysis provided the first clue to diagnosis in four of the cases, which then triggered cerebrospinal fluid neurotransmitter and genetic analysis. We also developed a diagnostic decision support system to assist the interpretation of the mass spectrometry data from urine organic acids. CONCLUSIONS: Urine organic acid could be essential in guiding subsequent investigations for the diagnosis of aromatic L-amino acid decarboxylase deficiency. We propose to screen suspected cases first with urine organic acids, specifically looking for vanillactic acid and N-acetylvanilalanine. Suggestive findings should be followed with target analysis for c.714 + 4A > T in ethnically Chinese patients. The assistive tool allowed expedite interpretation of profile data generated from urine organic acids analysis. It may also reduce interpreter's bias when peaks of interest are minor peaks in the spectrum.
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Errores Innatos del Metabolismo de los Aminoácidos , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/epidemiología , Errores Innatos del Metabolismo de los Aminoácidos/genética , Descarboxilasas de Aminoácido-L-Aromático/deficiencia , Descarboxilasas de Aminoácido-L-Aromático/genética , Humanos , Prevalencia , Estudios RetrospectivosAsunto(s)
Variación Genética/genética , Trastornos del Movimiento/enzimología , Trastornos del Movimiento/genética , Fenotipo , Tiamina Pirofosfoquinasa/deficiencia , Tiamina Pirofosfoquinasa/genética , Adulto , Estimulación Encefálica Profunda/métodos , Familia , Femenino , Humanos , Trastornos del Movimiento/terapiaRESUMEN
FLNC-related myofibrillar myopathy could manifest as autosomal dominant late-onset slowly progressive proximal muscle weakness; involvements of cardiac and/or respiratory functions are common. We describe 34 patients in nine families of FLNC-related myofibrillar myopathy in Hong Kong ethnic Chinese diagnosed over the last 12 years, in whom the same pathogenic variant c.8129G>A (p.Trp2710*) was detected. Twenty-six patients were symptomatic when diagnosed; four patients died of pneumonia and/or respiratory failure. Abnormal amorphous material or granulofilamentous masses were detected in half of the cases, with mitochondrial abnormalities noted in two-thirds. We also show by haplotype analysis the founder effect associated with this Hong Kong variant, which might have occurred 42 to 71 generations ago or around Tang and Song dynasties, and underlain a higher incidence of myofibrillar myopathy among Hong Kong Chinese. The late-onset nature and slowly progressive course of the highly penetrant condition could have significant impact on the family members, and an early diagnosis could benefit the whole family. Considering another neighboring founder variant in FLNC in German patients, we advocate development of specific therapies such as chaperone-based or antisense oligonucleotide strategies for this particular type of myopathy.
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Filaminas/genética , Músculo Esquelético/patología , Miopatías Estructurales Congénitas/genética , Adulto , Anciano , Pueblo Asiatico , Electromiografía , Femenino , Efecto Fundador , Hong Kong/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Debilidad Muscular/diagnóstico por imagen , Debilidad Muscular/genética , Debilidad Muscular/patología , Músculo Esquelético/diagnóstico por imagen , Mutación/genética , Miopatías Estructurales Congénitas/epidemiología , Miopatías Estructurales Congénitas/patología , Linaje , FenotipoRESUMEN
Objective·To detect the effects of propofol on rat hippocampal astrocytes and clarify its mechanism.Methods·According to the time after propofol injection,twenty-four SD rats were randomly divided into three groups,i.e.0 min,45 min and 90 min group.Rats were administrated intraperitoneally with propofol (10 mg/mL,100 mg/kg body weight).The levels of glial fibrillary acidic protein (GFAP) and S100β mRNA in rat hippocampus were evaluated by realtime PCR.And cell viabilities and levels of GFAP mRNA were examined in primary cultured hippocampal astrocytes induced by 10 μmol/L propofol with or without 10 μmol/L extracellular signal-regulated kinase (ERK) inhibitor PD98059 pretreatment.Results·The mRNA levels of GFAP in the hippocampal tissue were (1.32±0.12) times (P=0.000) and (1.12±0.09) times (P=0.012) that in 0 min group,respectively,45 min and 90 min after injection of propofol.The mRNA levels of S100β in the hippocampal tissue were (1.14±0.11) times (P=0.005) and (1.05±0.10)times (P=0.284) that in 0 min group,respectively,45 min and 90 min after injection of propofol.The mRNA levels of GFAP and S100β were timedependently altered,first increasing,and then decreasing.In vitro,the cell viabilities (P=0.041) and levels of GFAP mRNA (P=0.026) in primary cultured hippocampal astrocytes were significantly elevated after propofol treatment,and these effects of propofol were reversed by ERK inhibitor PD98059.Conclusion·Propofol time-dependently upregulated the expression of GFAP and S100β via ERK signaling pathway in rat hippocampal astrocytes,so as to activate astrocytes.
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Objective·To detect the effects of propofol sedation on cognitive function in rats and its mechanism. Methods?·?Forty-eight SD rats were randomly divided into three groups, i.e. control group, 100?mg/kg group and 300?mg/kg group. Rats were administrated intraperitoneally with propofol (10?mg/mL, 100?mg/kg or 300?mg/kg). The mRNA levels of brain derived neurotropic factor (BDNF)-TrkB/p75 signal molecules in rat hippocampus were evaluated by realtime PCR 45 min after propofol treatment. Learning and memory ability was examined by inhibitory avoidance (IA) test after propofol treatment. Results?·?The mRNA levels of BDNF in the hippocampal tissue were (1.20±0.13) fold (P=0.002) and (88±12) % (P=0.044) of that in control group, respectively, in 100?mg/kg group and 300?mg/kg group after injection of propofol. The mRNA levels of TrkB were (1.01±0.11) fold ( P=0.982) and (86±11) % (P=0.018) of that in control group, respectively, in 100?mg/kg group and 300?mg/kg group. The mRNA levels of p75 were (1.02±0.10) fold (P=0.778) and (1.59±0.18) fold (P=0.000) of that in control group, respectively, in 100?mg/kg group and 300?mg/kg group. There was no significant difference of the 24 h IA memory retention latency between 100?mg/kg group and control group. The 24 h IA memory retention latency in 300?mg/kg group was significantly decreased compared with control group (P=0.028) and 100?mg/kg group (P=0.020). Conclusion?·?Propofol dose-dependently regulates the expression of BDNF-TrkB/p75 signal molecules, and high dose propofol may reduce cognitive function via BDNF-TrkB/p75 signal.
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BACKGROUND: Beta-ureidopropionase deficiency is a rare inborn error of metabolism (IEM) affecting pyrimidine metabolism. To-date, about 30 genetically confirmed cases had been reported. The clinical phenotypes of this condition are variable; some patients were asymptomatic while some may present with developmental delay or autistic features. In severe cases, patients may present with profound neurological deficit including hypotonia, seizures and mental retardation. Using NMR-based urinalysis, this condition can be rapidly diagnosed within 15 min. CASE: An 11-month-old Chinese boy had dual molecular diagnoses, ß-ureidopropionase deficiency and Dravet syndrome. He presented with intractable and recurrent convulsions, global developmental delay and microcephaly. Urine organic acid analysis using GC-MS and NMR-based urinalysis showed excessive amount of ß-ureidopropionic acid and ß-ureidoisobutyric acid, the two disease-specific markers for ß-ureidopropionase deficiency. Genetic analysis confirmed homozygous known disease-causing mutation UPB1 NM_016327.2: c.977G>A; NP_057411.1:p.R326Q. In addition, genetic analysis for Dravet syndrome showed the presence of heterozygous disease-causing mutation SCN1A NM_001165963.1:c.4494delC; NP_001159435.1:p.F1499Lfs*2. CONCLUSIONS: The differentiation between Dravet syndrome and ß-ureidopropionase deficiency is clinically challenging since both conditions share overlapping clinical features. The detection of urine ß-ureidoisobutyric and ß-ureidopropionic acids using NMR or GC-MS is helpful in laboratory diagnosis of ß-ureidopropionase deficiency. The disease-causing mutation, c.977G>A of ß-ureidopropionase deficiency, is highly prevalent in Chinese population (allele frequency=1.7%); ß-ureidopropionase deficiency screening test should be performed for any patients with unexplained neurological deficit, developmental delay or autism.
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Anomalías Múltiples/orina , Amidohidrolasas/deficiencia , Encefalopatías/orina , Epilepsias Mioclónicas/genética , Epilepsias Mioclónicas/orina , Espectroscopía de Resonancia Magnética/métodos , Trastornos del Movimiento/orina , Errores Innatos del Metabolismo de la Purina-Pirimidina/orina , Urinálisis/métodos , Amidohidrolasas/genética , Amidohidrolasas/orina , Epilepsias Mioclónicas/complicaciones , Cromatografía de Gases y Espectrometría de Masas/métodos , Homocigoto , Humanos , Lactante , Masculino , Canal de Sodio Activado por Voltaje NAV1.1/genética , Urea/análogos & derivados , Urea/orina , beta-Alanina/análogos & derivados , beta-Alanina/orinaRESUMEN
BACKGROUND: Although commercially available nerve conduits are an accepted tool for overcoming short gaps in peripheral nerve repair, unexplained inconsistencies in clinical outcomes are not uncommon. Although exceeding the critical gap size and nerve caliber are most frequently cited as the source of these failures, oversizing of the nerve conduit in relation to the nerve diameter may be a previously unrecognized factor as well. METHODS: Sixty female Sprague-Dawley rats underwent excision of a 10-mm section midway between the sciatic notch and the sciatic nerve division of one hindlimb. The defect was immediately repaired by reversing the resected nerve section and suturing it back in place (reverse autograft) (group A, n = 13) or it was repaired with a 14-mm nerve tube of 3 mm in diameter (group B, n = 12), 2 mm in diameter (group C, n = 15), or 1.5 mm in diameter (group D, n = 15). At twelve weeks, the rodents underwent muscle strength testing before harvest of muscle and nerve (including the conduit) for histomorphologic assessment. RESULTS: Most conduits from group B were collapsed at final inspection and demonstrated diminished nerve regenerate. Muscle atrophy was most pronounced in groups B and C (p < 0.05), although normalized muscle contraction force was weakest in group B (p < 0.05), indicating inferior reinnervation. The axon counts, axon diameter, and G-ratios at the midpart of the conduit or graft demonstrated more axons and lower G-ratios in the autologous graft group. Among the conduit groups, the axon counts were lowest in group B (p < 0.05) followed by group C (p < 0.05). The G-ratio was highest in group B (p < 0.05), although the axon diameter was highest in group B (p < 0.05) as well. CONCLUSIONS: Repair of a 10-mm gap in a rodent nerve with an oversized, poorly fitted nerve conduit resulted in tube collapse, poor nerve regenerate, and decreased muscle reinnervation compared with the findings in the animals treated with more accurately fitted nerve conduits. CLINICAL RELEVANCE: Accurate sizing of nerve conduits to the nerve-stump diameter improves nerve recovery.
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Anastomosis Quirúrgica/métodos , Regeneración Nerviosa/fisiología , Procedimientos Neuroquirúrgicos/métodos , Nervios Periféricos/trasplante , Nervio Ciático/cirugía , Anastomosis Quirúrgica/efectos adversos , Animales , Modelos Animales de Enfermedad , Femenino , Miembro Posterior/inervación , Miembro Posterior/cirugía , Fuerza Muscular/fisiología , Músculo Esquelético/inervación , Músculo Esquelético/cirugía , Conducción Nerviosa/fisiología , Procedimientos Neuroquirúrgicos/efectos adversos , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Recuperación de la Función , Factores de Riesgo , Trasplante AutólogoRESUMEN
2,4-Dinitrophenol (2,4-DNP), a yellowish compound, has historically been used in the manufacture of dyes, explosives, and fungicides. As it uncouples mitochondrial oxidative phosphorylation, the compound was also used as an antiobesity agent early in the past century. The compound was subsequently banned by the United States Food and Drug Administration in 1938 due to its potentially fatal adverse effects, including hyperthermia, cataract, agranulocytosis, hepatoxicity, nephrotoxicity, and cardiotoxicity. However, the popularity of 2,4-DNP as a slimming aid has appeared to increase again in recent years. The Hong Kong Hospital Authority Toxicology Reference Laboratory recently confirmed two cases of self-administered 2,4-DNP with different clinical presentations to hospitals in the area. Here we describe those two cases, in an attempt to underscore the potential of misuse of this substance by body-conscious groups among the Chinese population.
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2,4-Dinitrofenol/efectos adversos , Fármacos Antiobesidad/efectos adversos , Adulto , Femenino , Hong Kong , Humanos , MasculinoRESUMEN
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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Mutación/genética , Receptores de Glicina/genética , Síndrome de la Persona Rígida/genética , Adolescente , Pueblo Asiatico , Humanos , MasculinoRESUMEN
Inborn errors of metabolism (IEM) are a phenotypically and genetically heterogeneous group of disorders caused by a defect in a metabolic pathway, leading to malfunctioning metabolism and/or the accumulation of toxic intermediate metabolites. To date, more than 1000 different IEM have been identified. While individually rare, the cumulative incidence has been shown to be upwards of 1 in 800. Clinical presentations are protean, complicating diagnostic pathways. IEM are present in all ethnic groups and across every age. Some IEM are amenable to treatment, with promising outcomes. However, high clinical suspicion alone is not sufficient to reduce morbidities and mortalities. In the last decade, due to the advent of tandem mass spectrometry, expanded newborn screening (NBS) has become a mandatory public health strategy in most developed and developing countries. The technology allows inexpensive simultaneous detection of more than 30 different metabolic disorders in one single blood spot specimen at a cost of about USD 10 per baby, with commendable analytical accuracy and precision. The sensitivity and specificity of this method can be up to 99% and 99.995%, respectively, for most amino acid disorders, organic acidemias, and fatty acid oxidation defects. Cost-effectiveness studies have confirmed that the savings achieved through the use of expanded NBS programs are significantly greater than the costs of implementation. The adverse effects of false positive results are negligible in view of the economic health benefits generated by expanded NBS and these could be minimized through increased education, better communication, and improved technologies. Local screening agencies should be given the autonomy to develop their screening programs in order to keep pace with international advancements. The development of biochemical genetics is closely linked with expanded NBS. With ongoing advancements in nanotechnology and molecular genomics, the field of biochemical genetics is still expanding rapidly. The potential of tandem mass spectrometry is extending to cover more disorders. Indeed, the use of genetic markers in T-cell receptor excision circles for severe combined immunodeficiency is one promising example. NBS represents the highest volume of genetic testing. It is more than a test and it warrants systematic healthcare service delivery across the pre-analytical, analytical, and post-analytical phases. There should be a comprehensive reporting system entailing genetic counselling as well as short-term and long-term follow-up. It is essential to integrate existing clinical IEM services with the expanded NBS program to enable close communication between the laboratory, clinicians, and allied health parties. In this review, we will discuss the history of IEM, its clinical presentations in children and adult patients, and its incidence among different ethnicities; the history and recent expansion of NBS, its cost-effectiveness, associated pros and cons, and the ethical issues that can arise; the analytical aspects of tandem mass spectrometry and post-analytical perspectives regarding result interpretation.
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Errores Innatos del Metabolismo/diagnóstico , Tamizaje Neonatal/métodos , Salud Global , Humanos , Incidencia , Recién Nacido , Legislación Médica , Errores Innatos del Metabolismo/epidemiología , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/fisiopatología , Tamizaje Neonatal/legislación & jurisprudencia , Tamizaje Neonatal/tendencias , Consentimiento Paterno/legislación & jurisprudenciaRESUMEN
A liquid chromatography-tandem mass spectrometry method for simultaneous detection of 22 toxic plant alkaloids, including aconitum alkaloids and their hydrolyzed products (aconitine, hypaconitine, mesaconitine, yunaconitine, crassicauline A, benzoylaconine, benzoylmesaconine, benzoylhypaconine, deacetylyunaconitine, deacetylcrassicauline A), solanaceous tropane alkaloids (atropine, anisodamine, scopolamine, anisodine), sophora alkaloids (matrine, sophoridine, oxymatrine, cytisine, N-methylcytisine), strychnos alkaloids (brucine, strychnine) and colchicine, in herbal and urine samples was developed and validated. Following sample preparation by liquid-liquid extraction, chromatographic separation was achieved on Eclipse XDB C8 column. Identification was based on two multiple reaction monitoring transitions and the relative ion intensity. Method selectivity was demonstrated. The limits of detection were 5ng/mL for all analytes, except 50ng/mL for cytisine. The herbal matrix effects ranged from 89% to 118%, whereas the urine matrix effects were between 91% and 109% for all analytes except cytisine (57%) and N-methylcytisine (67%). The urine extraction recovery ranged from 74% to 110% for all analytes, except cytisine (15%) and oxymatrine (30%). With the good extraction efficiency of the other major sophora alkaloids, the relatively low extraction recovery of the minor sophora alkaloids cytisine and oxymatrine did not affect identification of sophora alkaloids as a group. Carry-over was minimal at less than 0.1%. The method was successfully applied in analysis of 170 cases of suspected herbal poisoning, with aconitum alkaloids, sophora alkaloids, solanaceous tropane alkaloids, and strychnos alkaloids being detected in 53, 42, 18, and 6 cases, respectively.
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Alcaloides/análisis , Alcaloides/química , Alcaloides/orina , Extractos Vegetales/química , Extractos Vegetales/envenenamiento , Cromatografía Liquida/métodos , Humanos , Límite de Detección , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodosRESUMEN
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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Errores Innatos del Metabolismo/diagnóstico , Tamizaje Neonatal/métodos , Análisis Costo-Beneficio , Electrónica , Humanos , Recién Nacido , Errores Innatos del Metabolismo/economía , Tamizaje Neonatal/economía , Servicio de Patología en Hospital , Derivación y Consulta , Espectrometría de Masas en TándemRESUMEN
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_000018.2:c.277+2T>G; NC_000017.10:g.7123997T>G and a known disease-causing mutation ACADVL NM_000018.2:c.388_390del; NP_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.
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Acil-CoA Deshidrogenasa de Cadena Larga/genética , Errores Innatos del Metabolismo Lipídico/diagnóstico , Enfermedades Mitocondriales/diagnóstico , Enfermedades Musculares/diagnóstico , Tamizaje Neonatal , Acil-CoA Deshidrogenasa de Cadena Larga/sangre , Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Síndromes Congénitos de Insuficiencia de la Médula Ósea , Resultado Fatal , Heterocigoto , Hong Kong , Humanos , Lactante , Recién Nacido , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/prevención & control , Masculino , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/prevención & control , Enfermedades Musculares/genética , Enfermedades Musculares/prevención & control , Mutación , Empalme del ARN/genética , Análisis de Secuencia de ADN , Hermanos , Espectrometría de Masas en TándemRESUMEN
BACKGROUND: Aconite poisoning is a severe, life-threatening poisoning related to the use of traditional Chinese medicine (TCM). Despite current legislation, repeated poisoning cases are steadily encountered. OBJECTIVE: The aim of the study was to summarize the clinical features and to elucidate the causative and contributory factors leading to aconite poisoning. METHODS: This study was conducted within the Hospital Authority Toxicology Reference Laboratory, which is the sole tertiary referral clinical toxicology laboratory in Hong Kong. This retrospective study reviewed all confirmed aconite poisoning cases handled by a clinical toxicology laboratory between April 2004 and July 2009. The diagnosis in all cases was confirmed biochemically by detecting aconitum alkaloids in urine specimens. Additionally, herbal specimens were morphologically identified and herbal formulae were studied and transcribed. The cause of poisoning for each case was determined whenever possible. RESULTS: Fifty-two cases were examined in this aconite poisoning case series. Neurological, cardiovascular and gastrointestinal toxicities were encountered in 49 (94.2%), 46 (88.5%) and 31 (59.6%) patients, respectively. The poisoning was severe in 6 (11.5%) patients, moderate in 17 (32.7%) patients and mild in 29 (55.8%) patients. Amongst 44 patients (84.6%) in whom the underlying reasons of poisoning could be determined, four major causes were found. These included overdose - prescription of a higher than recommended dosage of aconite herbs in 17 (32.7%) cases; 'hidden' poisoning (the aconite herb was not prescribed but dispensed inadvertently) in 17 (32.7%) cases; usage of inadequately processed herbs in 7 (13.5%) cases; and dispensary error in 2 (3.9%) cases. No case fatality was recorded. CONCLUSION: In the majority of cases in this series, the causes of poisoning can be traced to poor-quality herbs, poor quality of prescription practice, or dispensary errors. The quality issues of TCM practice should be critically addressed to minimize this poisoning threat.
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Aconitum/envenenamiento , Medicamentos Herbarios Chinos/envenenamiento , Medicina Tradicional China/efectos adversos , Relación Dosis-Respuesta a Droga , Hong Kong , Humanos , Errores de Medicación/estadística & datos numéricos , Estudios RetrospectivosRESUMEN
Proopiomelanocortin (POMC) is the polypeptide precursor of several biologically active melanocortin peptides that have important roles in the regulation of food intake and energy homeostasis, adrenal steroidogenesis, melanocyte stimulation, and immune modulation. Mutation of the POMC gene has been associated with adrenal insufficiency, early-onset obesity, and red hair pigmentation. We describe an Indian boy with secondary hypocortisolism, hyperphagia, early-onset obesity, and skin pigmentation problem. Genetics analysis revealed a novel homozygous mutation in the POMC gene (p.Arg86Term). The boy also had central hypothyroidism in addition to the secondary hypocortisolism. Genetics analysis for the POMC gene should be considered in patients with secondary hypocortisolism, early-onset obesity, and pigmentary problems.
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Hormona Adrenocorticotrópica/deficiencia , Mutación , Obesidad/genética , Trastornos de la Pigmentación/genética , Proopiomelanocortina/genética , Pigmentación de la Piel/genética , Peso al Nacer , Preescolar , Humanos , Hipotiroidismo/etiología , Hipotiroidismo/genética , Masculino , Obesidad/etiología , Trastornos de la Pigmentación/etiologíaRESUMEN
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_000352.3: c.3068 A>G; NP_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.
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Transportadoras de Casetes de Unión a ATP/genética , Diabetes Mellitus/tratamiento farmacológico , Gliburida/uso terapéutico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Mutación , Canales de Potasio de Rectificación Interna/genética , Receptores de Droga/genética , Adulto , Diabetes Mellitus/congénito , Diabetes Mellitus/genética , Sustitución de Medicamentos , Femenino , Humanos , Lactante , Masculino , Medicina de Precisión/métodos , Receptores de Sulfonilureas , Resultado del TratamientoRESUMEN
BACKGROUND: The diagnosis of aromatic L-amino acid decarboxylase (AADC) deficiency, one of the pediatric neurotransmitter disorders, is classically made with plasma enzyme level or cerebrospinal fluid (CSF) neurotransmitter profile, while both are technically demanding and the latter requires the invasive lumbar puncture. So far less than 100 cases have been reported worldwide with 20% from Taiwan. It was postulated that the condition might have been under-diagnosed among Chinese populations and a non-invasive screening tool should be developed in areas with high prevalence. METHODS: Urine metabolic profiles performed by gas chromatography-mass spectrometry (GC-MS) in a 31-month period were retrospectively reviewed: those with vanilmandelic acid concentration lower than one percentile plus the presence of 3-o-methyldopa were defined as positive and the patients were further evaluated. RESULTS: Among 1046 metabolic profiles (from 845 patients) reviewed, 3 profiles from 2 patients were screened positive: both cases had compatible CSF neurotransmitter profiles and the diagnosis was further confirmed by genetic analysis of DDC gene. 13 negative urinary metabolic profiles from 7 patients who had CSF neurotransmitters analyzed were identified as controls: all 7 CSF neurotransmitter profiles were not compatible for AADC deficiency. CONCLUSIONS: The GC-MS-based urine metabolic profiling was shown to be a satisfactory screening tool for AADC deficiency. Further confirmation can be performed by mutation analysis in the DDC gene, thus avoiding risks of lumbar puncture. We advocate all ethnic Chinese patients presenting with dystonia have their urine organic acids analyzed before proceeding to CSF neurotransmitters analysis.
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Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/orina , Descarboxilasas de Aminoácido-L-Aromático/deficiencia , Descarboxilasas de Aminoácido-L-Aromático/orina , Cromatografía de Gases y Espectrometría de Masas , Hong Kong/epidemiología , Humanos , Lactante , Masculino , Proyectos Piloto , PrevalenciaRESUMEN
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_000317.1:c.259C>T; NP_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.
Asunto(s)
Fenilcetonurias/diagnóstico , Pueblo Asiatico , China , Femenino , Hong Kong , Humanos , Lactante , Tamizaje MasivoRESUMEN
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_024529.4: c.1475G > A; NP_078805.3: p.Trp492X and one novel somatic mutation CDC73 NM_024529.4: c.142G > T; NP_078805.3: p.Glu48X. The other germline mutation CDC73 NM_024529.4: c.226C > T; NP_078805.3: p.Arg76X and somatic mutation CDC73 NM_024529.4: c.85delG; NP_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.
Asunto(s)
Hiperparatiroidismo/genética , Neoplasias de las Paratiroides/genética , Proteínas Supresoras de Tumor/genética , Adolescente , China , Codón sin Sentido , Genes Supresores de Tumor , Mutación de Línea Germinal , Humanos , Pérdida de Heterocigocidad , Masculino , Persona de Mediana EdadRESUMEN
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.