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.

Lathosterolosis: a disorder of cholesterol biosynthesis resembling smith-lemli-opitz syndrome.

Lathosterolosis is an inborn error of cholesterol biosynthesis due to deficiency of the enzyme 3-beta-hydroxysteroid-delta-5-desaturase (or sterol-C5-desaturase or SC5D). This leads to a block in conversion of lathosterol into 7-dehydrocholesterol. Only three patients with lathosterolosis have been reported in literature, of which one survived. We report a patient with dysmorphism, multiple congenital anomalies, and developmental delay, initially suspected to have Smith-Lemli-Opitz syndrome, who was later found to have elevated levels of lathosterol in both plasma and fibroblasts. Genetic study confirmed a compound heterozygous mutation in the sterol-C5-desaturase-like (SC5DL) gene on chromosome 11q23. Simvastatin was started as a treatment therapy and it resulted in normalization of blood lathosterol level and improvement in the neurodevelopmental profile. However, additional patients are needed for better delineation of the clinical spectrum, genotype-phenotype correlation, and potential efficacy of simvastatin treatment in this rare disorder. If the presence of distinctive facial features and limb anomalies raise the suspicion of a cholesterol biosynthesis defect, testing of full sterol profile is warranted as normal cholesterol or 7-dehydrocholesterol levels cannot rule out the diagnosis of cholesterol synthesis defect like lathosterolosis.

Diagnosis of dihydropyrimidinase deficiency in a Chinese boy with dihydropyrimidinuria.

Dihydropyrimidinase deficiency is an autosomal recessive inborn error of metabolism characterised by the presence of dihydropyrimidinuria. Its clinical presentation is variable and has also been reported in asymptomatic subjects. We report the first case of dihydropyrimidinase deficiency in Hong Kong, which is also the first reported in a Chinese subject. The patient was a 32-month-old boy who presented with language development delay. Biochemical analysis confirmed markedly increased urinary excretion of dihydrouracil and dihydrothymine, whilst DNA testing confirmed that the patient was compound heterozygous for two missense mutations, one known (p.R302Q) and the other was novel (p.N16K).

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.

Complete recovery from acute encephalopathy of late-onset ornithine transcarbamylase deficiency in a 3-year-old boy.

Ornithine transcarbamylase deficiency is the commonest urea cycle disorder which is transmitted in X-linked inheritance. It is mainly characterized in males by acute encephalopathy and hyperammonaemia with fatal outcomes in both classical neonatal and late-onset types. We report a 3-year-old healthy Hong Kong Chinese boy who presented with acute encephalopathy and coma after three days of gastroenteritis. He had no focal neurological deficit and brain CT imaging was normal. His plasma ammonia (54 micromol/L) and glutamine (747 micromol/L) concentrations were normal. The only biochemical abnormalities detected were marked orotic aciduria (700 micromol/mmol creatinine) and elevated urinary uracil. He regained consciousness spontaneously after three days under intensive care with parenteral fluid therapy. He recovered completely without any neurological deficits. Five months after discharge, urinary uracil concentration remained elevated despite normalized orotic acid concentration. Finally, ornithine transcarbamylase deficiency was diagnosed by DNA analysis. A missense mutation of arginine-to-glutamine substitution on amino acid 277 (p.R277Q) was revealed to be a late-onset mutant. Our case strengthens the argument that in any child with coma or acute encephalopathy of undetermined cause, genetic analysis of the OTC gene and the measurement of urinary uracil concentration remain the most reliable indicators of late-onset OTCD during acute and even quiescent phases. Existing neonatal screening programmes for inheritable metabolic disorders fail to detect late-onset variants. Therefore, a high clinical suspicion is a key to correct and timely diagnosis, especially in those patients with atypical presentations.

Combined effect of isoflurane and esmolol on sympathetic responses to tracheal intubation.

BACKGROUND: Influences of isoflurane and esmolol on endotracheal intubation induced sympathetic changes could be different. The effect of isoflurane and its combination with esmolol on catecholamine, blood pressure and pulse during endotracheal intubation were investigated. METHODS: Thirty patients were anesthetized with 3.0% isoflurane and tracheal intubation was carried out at the 5th min following the exposure to isoflurane. Half of them received intravenous saline and the other half received esmolol 2 mg/kg at the 4th min. Cardiovascular parameters were recorded and venous blood samples were taken for measurement of catecholamines every min. RESULTS: One min after administration of isoflurane, there was increase of heart rate (P < 0.05), while at the same time the epinephrine level fell (P < 0.05) and norepinephrine level remained unaltered. Both catecholamines raised after intubation (P < 0.05). The sympathetic responses to and the beta-antagonistic effect of esmolol on intubation were not significantly changed in the presence of isoflurane. CONCLUSIONS: Isoflurane increased heart rate while paradoxically decreased epinephrine. Norepinephrine was more specifically related to endotracheal intubation, for its serum level had little change before the event. Based on catecholamine findings, the mechanism of isoflurane effect on the sympathetic system is probably different from that of endotracheal intubation.

The variability of the hepatitis B virus genome: statistical analysis and biological implications.

A statistical analysis of the nucleotide sequence variability in 14 published hepatitis B virus (HBV) genomes was carried out using parametric and nonparametric methods. A parametric statistical model revealed that the different regions of the genome differed significantly in their variability. The conclusion was supported by a nonparametric kernel-density model of the HBV genome. Genes S, C, and P, region X, the precore region, and the pre-S2/pre-S1 regions were ranked in order of increasing variability. In many instances, conserved regions of the genome identified with sequences of known function in HBV biology. However, other characterized regions (such as pre-S) showed much variability despite the involvement of their encoded peptides in specific functions. Point mutations that may result in the formation of stop codons and amino acid changes may affect the clinical picture of HBV infection and may be reflected in atypical serological patterns.

Quantitation of homoharringtonine in plasma by high-performance liquid chromatography with amperometric detection.

A high-performance liquid chromatographic procedure was developed for the quantitation of homoharringtonine in plasma. Harringtonine was used as an internal standard, and 1 ml of sample was required. The single-step extraction with dichloromethane resulted in almost 100% recovery for homoharringtonine and harringtonine. Analysis was performed on a reversed-phase CN column with amperometric detection. Chromatography was completed in 12 min. At an oxidation potential of +1.0 V, the detection limit was 1 ng/ml at a signal-to-noise ratio of 2. The mean analytical recovery for homoharringtonine was 99.5%. The within-run precision and between-run precision were both less than 11%. The method is equally applicable for plasma or serum, and it has been demonstrated to be applicable for study of the pharmacokinetics of homoharringtonine in patients suffering from acute non-lymphocytic leukaemia.

Simultaneous quantitation of catecholamines and O-methylated metabolites in urine by isocratic ion-pairing high-performance liquid chromatography with amperometric detection.

A simple high-performance liquid chromatographic procedure was developed for the simultaneous determination of catecholamines and metanephrines in urine. One-step sample preparation was achieved with Bio-Rex 70 ion-exchange resin. The extract was assayed on a C18 reversed-phase column. Dihydroxybenzylamine was used as an internal standard. The eluent was monitored by an electrochemical detector with an oxidation potential of +0.85 V. The use of 1-heptanesulphonic acid in the mobile phase permitted the separation of norepinephrine, epinephrine, dopamine, normetanephrine and metanephrine in a single chromatogram. The corresponding detection limits were 5, 9, 14, 10 and 30 nmol/l, respectively. For the between-day precision, the coefficients of variation at physiological and pathological concentrations were less than 11%. Compounds with similar chemical structures and drugs commonly prescribed for the treatment of hypertension were assayed and found not to cause interferences in the chromatogram. The assay is reliable and is suitable for the analysis of clinical specimens. Reference values were established for normotensive Chinese patients with no neurological or endocrine disorders and also for patients suffering from essential hypertension.