Single mitochondrial DNA deletions in chronic progressive external ophthalmoplegia (CPEO) and Kearns-Sayre syndrome (KSS) patients from a multiethnic Asian population

Mitochondrial DNA (mtDNA) deletions are a major cause of chronic progressive external ophthalmoplegia (CPEO) and Kearns-Sayre syndrome (KSS). We analyzed single mtDNA deletions in 11 CPEO and one KSS patients by means of Southern blot and long polymerase chain reaction (PCR) assays. The deletion sizes ranged from 3.4 kb to 6.9 kb whereas the heteroplasmy level varied from 18.8% to 85.5%. Two unique deletions sized 4320 bp and 4717 bp were found. This study represents the first genetic screen of mtDNA disorders in Malaysia, and it follows the data seen in other published reports on CPEO and KSS genetic aetiology.

Biochemical profiling of inborn errors of purine and pyrimidine metabolism by high-performance liquid chromatography - a strategy to improve childhood mortality and morbidity in Malaysian children

The epidemiology of inborn errors of purine and pyrimidine [PnP] metabolism in developing countries is unknown. Facilities for the analysis of PnP metabolites in Malaysia are currently lacking owing to limited resources and expertise in this field. To achieve the correct diagnosis for these disorders is a time-consuming and costly process. The tests are not readily available for our seriously ill patients.. The primary aim of this study was to establish a simple and cost-effective method using rapid-resolution high-performance liquid chromatography [RR-HPLC] for the diagnosis of inborn errors of PnP metabolism among Malaysian children who are suspected to have disorders of PnP metabolism. The secondary aim was to study the epidemiology and biochemical phenotype in our patients. The analytical method was developed using a reversed-phase high-performance liquid chromatography [RP-HPLC] with C[18] column coupled to a diode array detector for simultaneous determination of the PnP metabolites. A total of 1499 patients were studied. 556 healthy children and adults were recruited as normal controls to establish age-related reference ranges and urinary uric acid - creatinine ratios. The method established was able to separate up to 18 PnP metabolites in a single analytical run time of 28 minutes. Good precision [coefficient variation of < 2%] and a linearity range up to 2000 micro mol/l [r2 > 0.9993] was also observed. Recoveries were 99.8-108.4fi for the tested metabolites. The detection limit of 2.18-12.5 micro mol/l was adequate to detect patients with slightly increased concentration of these metabolites. Age-related reference ranges among our population were established and were used for diagnostic interpretation related to this group of disorders. Twelve patients [0.8%] were diagnosed, including four with combined molybdenum cofactor deficiency, three with isolated sulphite oxidase deficiency, two with thymidine phosphorylase deficiency, one with adenylosuccinate lyase deficiency and two with dihydropyrimidine dehydrogenase deficiency. Four cases of urea cycle defects were also detected. The method that we developed was proven to be efficient, reliable and sensitive enough to be applied in our clinical laboratory for the diagnosis of inborn errors of PnP metabolism disorders among Malaysian children. Early recognition and correct diagnosis allowed prompt treatment, better outcome and genetic counselling

Exercise induced cramps and myoglobinuria in dystrophinopathy – a report of three Malaysian patients

Dystrophinopathies commonly present as Duchenne or Becker muscular dystrophy but rare, unusual phenotypes have also been described. We have identifi ed three Malaysian boys with an unusual form of dystrophinopathy, presenting with exercise-induced cramps and myoglobinuria, but with no apparent muscle weakness. Immunohistochemistry for dystrophin and genetic analysis confi rmed the diagnosis. The frequency of this phenotype is unknown but there have been several case reports. Consistent with these reports, we also found that two of our patients had deletions in the rod domain of dystrophin, which has been suggested to be associated with this unusual manifestation

Spectrum of inherited metabolic disorders in Malaysia

Issues pertaining to the diagnosis and management of inborn errors of metabolism (IEM) in Malaysia included low awareness of atypical and variable presentations in IEMs leading to delayed diagnosis or treatment, absence of reliable population data on IEMs and involvement of multiple siblings in the same family due to consanguinity. The importance of careful family history taking and genetic counselling are emphasised. Selected testing of ill infants and children for IEM yielded a positive 2% (264/13,500) results for IEMs in Malaysia. Out of the 264 patients, the spectrum of IEMs in Malaysia included organic acidurias (98), aminoacidopathies (78), urea cycle defects (54), neurotransmitter conditions (12) and lysosomal disorders, mainly mucopolysaccharidosis (14). Confirmatory studies of IEMs are an important aspect of management of IEMs. There is a need for more metabolic specialists and funding for diagnosis and treatment of IEMs in Malaysia. Long-term care issues and cost-effectiveness of IEM therapy, supportive and preventive aspects will need further studies in Malaysia.