Julat rujukan bagi jumlah homosisteina dalam plasma di kalangan kanak-kanak di Malaysia

Homosisteinemia merupakan salah satu penyakit kepincangan metabolisme terwaris (IEM) yang menyebabkan peningkatan paras homosisteina. Homosisteina adalah salah satu asid amino mengandungi sulfur yang mempunyai kumpulan thiol yang dibentuk hasil daripada proses demetilasi asid amino methionina. Dalam penyakit kepincangan metabolisme terwaris (inborn errors of metabolism – IEM), terdapat tujuh jenis penyakit berpunca daripada kekurangan enzim yang terlibat dalam metabolisme homosisteina. Paras jumlah homosisteina adalah berbeza mengikut jenis penyakit akibat kekurangan enzim ini. Maka, terdapat keperluan bagi mewujudkan suatu julat rujukan untuk membezakan antara populasi normal dengan populasi berpenyakit. Kajian ini menerangkan penemuan berkenaan julat rujukan bagi jumlah homosisteina di kalangan kanak-kanak di Malaysia. Sebanyak 3 ml darah telah diambil daripada 86 individu normal (52 orang kanak-kanak lelaki dan 34 orang kanak-kanak perempuan) dan seterusnya diproses serta dianalisis menggunakan kaedah kromatografi cecair berprestasi tinggi jenis fasa penukar ion (HPLC-IEC). Hasil kajian mendapati min jumlah homosisteina bagi keseluruhan populasi rujukan ialah sebanyak 8.1 ± 3.89 μM (95% selang keyakinan 7.3-8.9 μM). Julat rujukan sedia ada bagi populasi rujukan adalah sebanyak 2.5 – 16.2 μM dengan had pemutus terendah (lower cut-off) dan had pemutus teratas (upper cut-off) masing-masing adalah 1.0 μM dan 21.0 μM. Julat tersebut didapati agak tinggi berbanding dengan penyelidik luar. Penemuan julat rujukan bagi jumlah homosisteina untuk populasi kanak-kanak di Malaysia yang terbaru ini dapat mengurangkan jumlah kadar positif palsu semasa proses diagnosis penyakit dilakukan

Challenges identified in the management of patients with inherited metabolic disorders – A five year experience from Pakistan

Background: Pakistan is the sixth most populous country in the World. High rates of consanguinity and inter caste marriages have resulted in a substantial burden of inherited metabolic disorders (IMDs). Despite this load, there is a dearth of both medical genetic and clinical metabolic services in Pakistan. There are inadequate numbers of appropriately trained clinicians, ill-equipped laboratories, lack of scientists and technologists equipped with skills to deal with the challenging laboratory investigations involved in IMD and a health care infra-structure unable to support a service. Aim: We present the first five year experience of the first established metabolic unit at a tertiary care hospital in Pakistan and present the case for screening of parents, parents’ siblings and antenatal diagnostic testing in subsequent pregnancies in order that families can make informed choices in preventing recurrence. Subjects and methods: This retrospective observational study comprising of patients’ chart review was conducted in the Department of Paediatrics, AKUH Karachi in Pakistan for patients who presented to the Clinical Genetics unit from January 2008 to December 2012 seeking diagnosis and treatment for the underlying IMD. Results: We evaluated 426 children, of which, 333 (78%) had consanguineous parents. Most patients, 151 (35%). evaluated for IMD were between 1 year and 5 years of age. Developmental delay, seizures, hypotonia, microcephaly, neuroregression, dystonia, ataxia and encephalopathy were the most common reasons for referrals. Only 155 (36%) patients underwent metabolic biochemical testing. Among the investigated group of patients, diagnoses were established for 85 (55%) patients equivalent to only 19.8% of the total. Conclusion: Neonatal screening for IMDs and their treatment in the current situation is an unaffordable practical option in Pakistan. Screening parents, siblings and subsequent pregnancies, however, is likely to provide a cost effective and acceptable alternative in reducing the burden and enabling early, effective detection of affected progeny before the stage when neurometabolic changes become irreversible in developing countries like Pakistan with very limited resources

Inherited metabolic disorders presenting as hypoxic ischaemic encephalopathy: A case series of patients presenting at a tertiary care hospital in Pakistan

In spite of the efforts and interventions by the Government of Pakistan and The World Health Organization, the neonatal mortality in Pakistan has declined by only 0.9% as compared to the global average decline of 2.1% between 2000 and 2010. This has resulted in failure to achieve the global Millennium Development Goal 4. Hypoxic-ischaemic encephalopathy, still birth, sepsis, pneumonia, diarrhoea and birth defects are commonly attributed as leading causes of neonatal mortality in Pakistan. Inherited metabolic disorders often present at the time of birth or the first few days of life. The clinical presentation of the inherited metabolic disorders including hypotonia, seizure and lactic acidosis overlap with clinical features of hypoxic-ischaemic encephalopathy and sepsis. Thus, these disorders are often either missed or wrongly diagnosed as hypoxicischaemic encephalopathy or sepsis unless the physicians actively investigate for the underlying inherited metabolic disorders. We present 4 neonates who had received the diagnosis of hypoxic-ischaemic encephalopathy and eventually were diagnosed to have various inherited metabolic disorders. Neonates with sepsis and hypoxic-ischaemic encephalopathy-like clinical presentation should be evaluated for inherited metabolic disorders

Clinical and Mutational Analysis of the GCDH Gene in Malaysian Patients with Glutaric Aciduria Type 1

Glutaric aciduria type 1 (GA1) is an autosomal recessive metabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase enzyme encoded by the GCDH gene. In this study, we presented the clinical and molecular findings of seven GA1 patients in Malaysia. All the patients were symptomatic from infancy and diagnosed clinically from large excretion of glutaric and 3-hydroxyglutaric acids. Bidirectional sequencing of the GCDH gene revealed ten mutations, three of which were novel (Gln76Pro, Glu131Val, and Gly390Trp). The spectrum of mutations included eight missense mutations, a nonsense mutation, and a splice site mutation. Two mutations (Gln76Pro and Arg386Gln) were homozygous in two patients with parental consanguinity. All mutations were predicted to be disease causing by MutationTaster2. In conclusion, this is the first report of both clinical and molecular aspects of GA1 in Malaysian patients. Despite the lack of genotype and phenotype correlation, early diagnosis and timely treatment remained the most important determinant of patient outcome