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Published on: June 15, 2011
Identification of three novel pathogenic mutations in cystathionine beta-synthase gene of Pakistani intellectually
Muhammad Wasim1,2, Haq N Khan1,2,3, Hina Ayesha4
1Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
Insights
Classical homocystinuria (HCU), a metabolic disorder causing intellectual disability, was screened in 429 Pakistani patients. Seven families with HCU were identified, and personalized treatment led to significant symptom improvement.
Area of Science:
- Biochemistry
- Genetics
- Metabolic Disorders
Background:
- Classical homocystinuria (HCU) is an autosomal recessive metabolic disorder caused by cystathionine-β-synthase (CBS) deficiency.
- Symptoms include intellectual disability, ectopia lentis, and elevated plasma methionine and homocysteine.
Purpose of the Study:
- To screen for classical homocystinuria (HCU) in intellectually disabled patients in Punjab, Pakistan.
- To identify causative mutations in the cystathionine-β-synthase (CBS) gene.
Main Methods:
- Biochemical and genetic analyses were performed on 429 patients with intellectual disability.
- Targeted exonic analysis of the CBS gene was conducted.
Main Results:
- Nine patients from seven families were diagnosed with HCU, exhibiting elevated plasma methionine and homocysteine.
- Seven causative homozygous mutations in the CBS gene were identified, including three novel missense mutations.
- Treatment with pyridoxine, folic acid, cobalamin, betaine, and dietary protein restriction resulted in behavioral and physical improvements.
Conclusions:
- Early diagnosis and personalized treatment, including cofactor therapy and dietary management, can significantly improve health outcomes for HCU patients.
- This pioneering screening initiative in Pakistan aims to reduce the burden of treatable inborn errors of metabolism in intellectually disabled individuals.
Background:
Classical homocystinuria (HCU) is an autosomal recessive inborn error of metabolism, which is caused by the cystathionine-β-synthase (CBS: encoded by CBS) deficiency. Symptoms of untreated classical HCU patients include intellectual disability (ID), ectopia lentis and long limbs, along with elevated plasma methionine, and homocysteine.
Methods:
A total of 429 ID patients (age range: 1.6-23 years) were sampled from Northern areas of Punjab, Pakistan. Biochemical and genetic analyses were performed to find classical HCU disease in ID patients.
Results:
Biochemically, nine patients from seven unrelated families were identified with high levels of plasma methionine and homocysteine. Targeted exonic analysis of CBS confirmed seven causative homozygous mutations; of which three were novel missense mutations (c.451G>T; p.Gly151Trp, c.975G>C; p.Lys325Asn and c.1039 + 1G>T splicing), and four were recurrent variants (c.451 + 1G>A; IVS4 + 1 splicing, c.770C>T; p.Thr257Met, c.808_810del GAG; p.Glu270del and c.752T>C; p.Leu251Pro). Treatment of patients was initiated without further delay with pyridoxine, folic acid, cobalamin, and betaine as well as dietary protein restriction. The immediate impact was noticed in behavioral improvement, decreased irritability, improved black hair color, and socialization. Overall, health outcomes in this disorder depend on the age and symptomatology at the time of treatment initiation.
Conclusions:
With personalized treatment and care, such patients can reach their full potential of living as healthy a life as possible. This screening study is one of the pioneering initiatives in Pakistan which would help to minimize the burden of such treatable inborn errors of metabolism in the intellectually disabled patients.
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