Association between apolipoprotein E genotypes and Parkinson's disease.

Previous studies on the association between apolipoprotein E (APOE) alleles and Parkinson's disease (PD) have shown contradictory results. A recent study showed that APOE is involved in a molecular pathway of α-synuclein-induced neurodegeneration. We therefore conducted the first Thai study on APOE genotypes in patients with PD. We analysed the frequencies of APOE genotypes in our case-control study of 155 patients with sporadic PD and 158 control participants. We identified a higher frequency of the APOE-ε2 allele among patients with PD than among controls (odds ratio=2.309, 95% confidence interval=1.111-4.799). Genetic association is a powerful tool for detecting disease susceptibility alleles, but there are many pitfalls to consider before claiming any association. The discrepancy among the results of the genetic association studies of APOE genotypes as a risk of susceptibility to PD emphasises that this association merits clarification by the study of a single large homogeneous population.

Mutation and haplotype analysis of oculopharyngeal muscular dystrophy in Thai patients.

Oculopharyngeal muscular dystrophy (OPMD) is an inherited neuromuscular disease associated with a short trinucleotide repeat expansion in Exon 1 of the PABPN1 gene. OPMD is uncommon in East Asian populations, and there have been no previous reports of Thai patients. We studied clinical and molecular genetic features of six unrelated Thai patients with autosomal dominant OPMD. All patients had expansions of the guanine-cytosine-guanine (GCG) repeat ranging from three to seven additional repeats in the PABPN1 gene. Haplotype analysis showed that these mutations might have originated independently. Analysis of the size of the GCG repeat in the PABPN1 gene in 200 Thai control patients showed that 0.5% of the control subjects possessed (GCG)(7), thereby suggesting that the prevalence of autosomal recessive OPMD in the Thai population was approximately 1 in 160,000. In conclusion, our data suggest that OPMD in Thailand may be more common than previously thought.

CTG repeat lengths of the DMPK gene in myotonic dystrophy patients compared to healthy controls in Thailand.

Myotonic dystrophy (DM) is frequently associated with large expansions of the cytosine-thymine-guanine (CTG) repeat in the myotonic dystrophy protein kinase gene (DMPK). The frequency of distribution of the CTG repeat length in normal alleles of several populations is well correlated with the prevalence of DM. Therefore, we studied the CTG repeat length of the DMPK gene in DM patients and controls in Thailand. Only seven typical patients with DM from six unrelated families were identified, all with large pathological CTG repeat expansions (> 400 repeats) in the DMPK gene. Only 2.75% of controls had normal CTG repeat alleles > 18 repeats. The frequency distribution of the CTG-repeat alleles in the normal Thai population is similar to that of the Taiwanese population (χ² with Yates correction = 1.393; p = 0.2379). These data suggest that the incidence of DM might be rare in Thailand, where the risk of developing DM is possibly similar to that in Taiwan.

Levodopa induced motor complications in Thai Parkinson's disease patients.

BACKGROUND: Long-term levodopa usage in Parkinson's disease (PD) patients is known to cause several motor complications. It may be related to several factors such as levodopa dosage, duration of treatment and severity of disease. OBJECTIVE: To study the prevalence of levodopa motor complications and associated factors in Thai Parkinson's disease patients. MATERIAL AND METHOD: The authors prospectively collected baseline characteristics of PD patients, details of treatment and complications from 3 hospitals in various parts of Thailand. These patients were diagnosed by UK PD Brain Bank criteria. RESULTS: A total of 154 patients aged 68.1 +/- 9.5 years were recruited. Age of onset was 61.2 +/- 9.8 years. Most patients were in Hoehn-Yahr stage 1-3. The common clinical features were bradykinesia, rigidity and resting tremor Treatments were levodopa (98.1 per cent), anticholinergic (29.9 per cent), dopamine agonists (26 per cent) and COMT inhibitor (9.1 per cent). Eighty-five per cent of the patients had excellent response to levodopa. However, 25 per cent of patients developed motor complications, which were wearing off (79 per cent), on-off fluctuation (45 per cent), freezing (42 per cent), morning dyskinesia (10.5 per cent) and permanent dyskinesia (23.7 per cent). Twelve patients developed severe levodopa induced chorea. Factors associated with levodopa side effects were earlier age of onset, long duration of disease, advanced stage, higher levodopa dosage and long duration of levodopa treatment. In the present study, age of onset was inversely correlated with H-Y stage, while dosage of levodopa was positively correlated with H-Y stage but inversely correlated with lower ADL score, which may be due to advanced disease state. CONCLUSION: Levodopa motor complications are common in Thai PD patients. Wearing off on-off fluctuation and freezing are common forms of motor complications.

New phenotypic diversity associated with the mitochondrial tRNA(SerUCN) gene mutation.

We performed detailed clinical, histopathological, biochemical, in vitro translation and molecular genetic analysis in patients from two unrelated families harbouring the tRNA(SerUCN) 7472C-insertion mutation. Proband 1 developed a progressive neurodegenerative phenotype characterised by myoclonus, epilepsy, cerebellar ataxia and progressive hearing loss. Proband 2 had a comparatively benign phenotype characterised by isolated myopathy with exercise intolerance. Both patients had the 7472C-insertion mutation in identical proportions and they exhibited a similar muscle biochemical and histopathological phenotype. However, proband 2 also had a previously unreported homoplasmic A to C transition at nucleotide position 7472 in the tRNA(SerUCN) gene. This change lengthens further the homopolymeric C run already expanded by the 7472C-insertion. These data extend the phenotypic range associated with the 7472C-insertion to include isolated skeletal myopathy, as well as a MERRF-like phenotype.

Human mitochondrial DNA diseases.

The mitochondrial encephalomyopathies are a genetically heterogeneous group of disorders associated with impaired oxidative phosphorylation. Patients may exhibit a wide range of clinical symptoms and experience significant morbidity and mortality. There is currently no curative treatment. At present the majority of genetically defined mitochondrial encephalomyopathies are caused by mutations in mitochondrial DNA. The underlying molecular mechanisms and the complex relationship between genotype and phenotype in these mitochondrial DNA diseases remain only partially understood. We describe the key features of mitochondrial DNA genetics and outline some of the common disease phenotypes associated with mtDNA defects. A classification of pathogenic mitochondrial DNA point mutations which may have therapeutic implications is outlined.

A novel mutation in the mitochondrial tRNA(TYr) gene associated with exercise intolerance.

The authors report a novel A5874G mutation in the mitochondrial tRNA tyrosine (tRNA(TYr)) gene associated with exercise intolerance, limb weakness, and complex III deficiency. The mutation was absent in blood from the patient and all maternal family members, indicating that it may be a spontaneous somatic mutation in muscle. This is the first point mutation in the tRNA(TYr) gene associated with human disease and is further evidence that exercise intolerance associated with complex III deficiency is genetically heterogeneous.

Increased risk of stroke in patients with the A12308G polymorphism in mitochondria.

Factors which increase the risk of stroke in patients with the A3243G (mitochondrial encephalomyopathy, lactic acidosis, and stroke [MELAS]) mutation in human mitochondrial DNA are unclear. Previous work on lung-cancer cells with an A3243G mutation showed that a mutation in the mitochondrial transfer gene for leucine tRNA(Leu(CUN)) was able to ameliorate the A3243G-induced biochemical phenotype. We analysed the tRNA(Leu(CUN)) gene in 48 unrelated A3243G cases. We showed that a polymorphism, A12308G, in tRNA(Leu(CUN)) increases the risk of developing stroke in patients with the A3243G mutation (relative risk=2.17). This may have implications for genetic counselling.

The mitochondrial DNA G13513A transition in ND5 is associated with a LHON/MELAS overlap syndrome and may be a frequent cause of MELAS.

We report on 4 male patients with clinical, radiological, and muscle biopsy findings typical of the mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) phenotype. Skeletal muscle mitochondrial DNA (mtDNA) analysis showed that all patients harbored a heteroplasmic G13513A mutation in the ND5 subunit gene. One of these cases (Patient 1) presented with symptoms characteristic of Leber's hereditary optic neuropathy (LHON) 2 years before the first stroke-like episode. Quantitative analysis in several postmortem tissue sections showed that the relative proportions of mutant mtDNA were generally lower than those reported with other pathogenic mtDNA mutations. Single-fiber polymerase chain reaction studies demonstrated significantly higher amounts of mutant mtDNA in ragged red fibers (RRFs) compared with non-RRFs. This study indicates that the G13513A transition is likely to be pathogenic, that it can cause an LHON/MELAS overlap syndrome, and that it may be a more frequent cause of MELAS than previously recognized.