L. K. Law

Genetic and environmental risk factors for Parkinson’s disease in a Chinese population

An epidemiological study of the environmental and genetic factors as well as the possible interplay between them was conducted among 215 patients with Parkinson’s disease and 313 controls in a Chinese population in Hong Kong. In univariate analysis, a regular tea drinking habit was found to be a protective factor, which had not been reported before. Smoking (a protective factor), family history, duration of pesticide exposure (in years) in farming and pesticide exposure during farming in women (both risk factors) have been reported previously. In multivariate analysis, current smoking reached borderline significance at the 5% level and the variables, years exposed to pesticides and family history were significant at the 10% level. By contrast with the common occurrence of polymorphism of the CYP2D6 gene (a gene involved with xenobiotic metabolism) in white people, it is very rare in China and is not thought to be a significant factor contributing to Parkinson’s disease in Chinese people.

Randomized trial of the effect of supplementation on the cognitive function of older people with subnormal cobalamin levels

Background. Low serum cobalamin levels are often found in apparently normal older subjects. A major worry of leaving cobalamin deficiency untreated is that it may lead to subtle deterioration in cognitive function.

The dopamine transporter gene and Parkinson's disease in a Chinese population

We studied a variable number tandem repeat polymorphism within the dopamine transporter gene (DAT) for an association with Parkinsons disease in a Chinese population. Five alleles were detected, consisting of 6, 8, 9, 10, and 11 copies of the 40 base pair repeat sequence. The 10-copy allele was most common, accounting for 90% of alleles. There were no significant differences between the patients and the control subjects in the distribution frequencies of the alleles or genotypes. Therefore, this polymorphism is not associated with Parkinsons disease in Chinese populations.

Novel mutations in ETFDH gene in Chinese patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency.

BACKGROUNDnMultiple acyl-CoA dehydrogenase deficiency (MADD, OMIM 231680) or glutaric aciduria type II (GAII) is an inherited autosomal recessive disease affecting fatty acid, amino acid and choline metabolism, due to mutations in one of three genes namely, electron transfer flavoprotein alpha-subunit, ETFA (OMIM 608053), electron transfer flavoprotein beta-subunit, ETFB (OMIM 130410) and electron transfer flavoprotein dehydrogenase, ETFDH (OMIM 231675). Some MADD patients are responsive to riboflavin treatment with an excellent prognosis. Recently, mutations in ETFDH were found to be responsible for all riboflavin-responsive MADD patients. In this study, we present the clinical features and molecular studies of 2 Chinese families with riboflavin-responsive MADD.nnnMETHODSnGenomic DNA was extracted from peripheral blood samples or skin fibroblast cultures from the patients and normal controls. The thirteen exons of ETFDH were amplified by PCR. PCR products were sequenced in both forward and reverse directions. To rule out mutations in other genes, phenotype segregation was studied in the families by microsatellite markers in the proximity of the 3 genes, ETFA, ETFB and ETFDH.nnnRESULTSnFour novel mutations in ETFDH were detected in the 2 families. In family 1, a frame shift mutation, c.1355delG which introduced a premature-termination codon (PTC), I454X in exon 11 of ETFDH was found. Another mutation was a c.250G>A transition in exon 3 of ETFDH, A84T. In family 2, two novel missense mutations were identified, P137S, in exon 4 and G467R in exon 11. No carrier of these four mutations was identified from about 150 alleles of healthy Chinese control subjects.nnnCONCLUSIONSnFour novel mutations (3 missenses and 1 deletion) in ETFDH were found in Chinese families that presented with riboflavin-responsive MADD, which further expands the list of mutations found in patients with riboflavin-responsive MADD. Furthermore, we illustrated the utility of phenotype-genotype segregation in MADD families to prioritize genes for sequencing or to rule out the presence of disease causing mutation in other genes in MADD and other diseases caused by multiple genes.

The monoamine oxidase B gene GT repeat polymorphism and Parkinson's disease in a Chinese population

Abstract Monoamine oxidase B (MAOB) metabolises dopamine and activates neurotoxins known to induce parkinsonism in humans and primates. Therefore the MAOB gene (MAOB; Xp15.21–4) is a candidate gene for Parkinson’s disease (PD). Longer length dinucleotide repeat sequences in a highly polymorphic GT repeat region of intron 2 of this gene showed an association with PD in an Australian cohort. We repeated this allele-association study in a population of 176 Chinese PD patients ¶(90 men, 86 women) and 203 age-matched controls (99 men, 104 women). Genomic DNA was extracted from venous blood and the polymerase chain reaction was used to amplify the appropriate regions of the MAOB gene. The length of each (GT) repeat sequence was determined by 5% polyacrylamide denaturing gel electrophoresis. There was no significant difference in allele frequencies of the (GT) repeat allelic variation between patients and controls (χ2 = 2.48; df = 5, P < 0.75). Therefore the longer length GT repeat alleles are not associated with PD in this Chinese population. Possible reasons for the discrepancy between Chinese and Australian populations include a different interaction between this genetic factor and environmental factors in the two populations and the possibility that the long length GT repeat alleles may represent a marker mutation, genetically linked to another susceptibility allele in whites but not in Chinese. Methodological differences in the ascertainment of cases and controls in this cohort could also explain the observed differences. Further study is required to determine whether the longer length GT repeat alleles are true susceptibility alleles in PD.

Recurrent and Novel Mutations of GCDH Gene in Chinese Glutaric Acidemia Type I Families

Glutaric acidemia type I is caused by mutations of the glutaryl‐CoA dehydrogenase (GCDH) gene resulting in loss of GCDH enzyme activity. Patients present with progressive dystonia and lesions in basal ganglia. Dietary treatment, when instituted from the early neonatal period, markedly reduces dystonia and morbidity. Early diagnosis and prenatal diagnosis will be facilitated by knowledge of locally prevalent GCDH mutations. Several common GCDH mutations have been found in different ethnic groups. GCDH mutations were studied in 5 Chinese glutaric acidemia type I families. We detected two novel recurrent mutations (A219T and IVS10‐2A>C) which were found in two unrelated families. An asymptomatic carrier of IVS10‐2A>C was also found on screening of 120 individuals. Other mutations were identified, including two other novel (R386G & IVS3+1G>A) and two known mutations (G178R & R355H). Fibroblasts from patients carrying the novel mutations were confirmed to be deficient for GCDH activity. This is the first report of GCDH mutations describing recurrent mutations in Chinese patients. The carrier rate of IVS10‐2A>C may be particularly high in Chinese.

Classical galactosaemia in Chinese: A case report and review of disease incidence

Abstract: We report a case of galactose‐1‐phosphate uridyl transferase (GALT) deficiency in a full‐term Chinese neonate, who presented with atypical biochemical features of hyperammonaemia in addition to the classical presenting features of jaundice and lethargy after feeding. Red cell GALT activity was virtually absent in the patient while 50% of normal activity was found in parents and a sibling. Mutation screening excluded both Q188R and N314D as the causative mutation in GALT gene, which suggested a possible genetic segregation among ethnic groups. Data from a Taiwan screening program suggested that the incidence of the disease was approximately 1 in 400 000 in the Chinese population which was a sixth of that in Caucasian populations.

Overview of common inherited metabolic diseases in a Southern Chinese population of Hong Kong

BACKGROUNDnThe Joint metabolic clinic at the Prince of Wales Hospital was established in January 1997 to provide a comprehensive multi-disciplinary care to patients with inherited metabolic diseases (IMDs). Patients are referred from both within and outside our hospital. Until July, 2000, more than 40 patients and families with 20 different biochemical diagnoses attend the clinic for regular follow up. A pattern of more common IMDs among Hong Kong Chinese emerged from our case registry. In order to advance the understanding of Chinese metabolic diseases, we examined the molecular basis of those diseases with unique features in Chinese or were locally prevalent. Mutations were found in patients with primary carnitine deficiency, ornithine transcarbamylase deficiency, X-linked adrenoleukodystrophy, glutaric aciduria type I, and galactosemia. We also analyzed the mutations in multiple carboxylase deficiency and Niemann-pick type C on four families.nnnCONCLUSIONSnAlthough IMDs are a significant cause of mortality and morbidity among pediatric patients, with a better understanding of the molecular genetics of these diseases, prenatal diagnosis of these common IMDs will be facilitated, which is currently the most effective way of controlling IMDs.

Deficiency of the carnitine transporter (OCTN2) with partial N-acetylglutamate synthase (NAGS) deficiency

SummaryA patient with recurrent episodes of hyperammonaemia (highest ammonia level recorded 229 xa0μmol/L, normal 9–33) leading to altered levels of consciousness was diagnosed with partial N-acetylglutamate synthase (NAGS) deficiency (9% residual activity) at age 5 years and was treated with ammonia-conjugating agents (Ucephan 250xa0 mg/kg per day and later sodium phenylbutyrate 200–250xa0 mg/kg per day) for 15 years. A chronically low serum carnitine level (pretreatment plasma free carnitine 4xa0 nmol/L, normal 37u2009±8 nmol/L; total carnitine 8xa0 nmol/L, normal 46u2009±10) was assumed to be secondary and was treated with supplemental carnitine (30–50 mg/kg per day). Hypoglycaemia (blood sugar 35 xa0mg/dl, normal 70–100), cardiomegaly, and fatty liver were also noted at diagnosis. The patient died unexpectedly at age 20 years. In retrospect, it was learned that the patient had stopped his carnitine without medical consultation several weeks prior to his death. Additional molecular investigations identified two mutations (R254X and IVS3 + 1G > A) in the patient’s OCTN2 (SLC22A5) gene, consistent with a diagnosis of primary carnitine deficiency due to carnitine transporter defect. R245X is a founder mutation in Southern Chinese populations. It is unknown whether the original NAGS deficiency was primary or secondary, but molecular analysis of the NAGS gene failed to identify mutations. Urea cycle enzyme expression may be affected by fatty acid suppression of an AP-1 binding site in the promoter enhancer region of the urea cycle gene. Regardless, it is clear that the NAGS abnormality has led to delay of recognition of the OCTN2 defect, and modified the clinical course in this patient.

A genomic approach to mutation analysis of holocarboxylase synthetase gene in three Chinese patients with late-onset holocarboxylase synthetase deficiency

OBJECTIVEnMultiple carboxylase deficiency (MCD, MIM:253270) is a common organic aciduria and caused by deficiency of either biotinidase or holocarboxylase synthetase (HLCS; EC 6.3.4.10). Patients commonly present during early infancy with acute metabolic derangements and severe metabolic acidosis. Recently, a late onset form of HLCS deficiency was also described. The different phenotypes (early and late presenting) may be related to a spectrum of mutations in HLCS gene. Applications of mutation analysis in HLCS had been limited previously by the requirement of cDNA from living tissue for study. We described here a genomic approach for molecular diagnosis of HLCS deficiency which we have used to detect mutations in Chinese patients who had the late-onset form of HLCS deficiency. In addition, a fibroblast cell line with MCD from Coriell Cell repositories was also studied.nnnDESIGN AND METHODSnThree Chinese patients with late onset HLCS deficiency were studied. The genomic sequence of HLCS was retrieved and newly designed primers were used to cover all coding sequences of the gene. PCR products were analyzed by direct sequencing. Population allelic frequencies of mutations detected were determined by genotyping of control samples by restriction fragment length polymorphism.nnnRESULTSnWe found a recurrent mutation, R508W, in the three unrelated Chinese patients. Two were homozygous for this mutation. The other patient was a compound heterozygote of R508W and a novel mutation, D634N. The results suggest that R508W may be an important and relatively prevalent disease-causing mutation in Chinese MCD patients. A fibroblast cell-line from an African patient revealed an additional novel mutation, R565X and a known mutation, V550M.nnnCONCLUSIONnR508W is a recurrent mutation in Chinese MCD patients which is associated with the late onset phenotype. This new genomic approach for mutation analysis of HLCS gene provides new opportunities in studies of MCD.