Abstract
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.
Funding source: International Centre for Genetic Engineering and Biotechnology
Award Identifier / Grant number: CRP/14/012
Award Identifier / Grant number: CRP/PAK14-02
Funding source: Amsterdam University Medical Center
Funding source: High Education Commission
Award Identifier / Grant number: Haq Nawaz Khan (HEC-IRSIP 37 BMS 34)
Award Identifier / Grant number: Muhammad Wasim (HEC-IRSIP 37 BMS 34)
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Research funding: This work was supported by a research project, “Diagnosis of treatable inborn metabolic disorders of intellectual disability” (Project No. CRP/PAK14-02; Contract No. CRP/14/012) funded by the International Centre for Genetic Engineering and Biotechnology (ICGEB), Italy. The doctoral students (MW and HNK) were funded for their research in the Amsterdam University Medical Center (AUMC), by the High Education Commission (HEC) (No. HEC-IRSIP 37 BMS 34), Islamabad, Pakistan specifically the International Research Support Initiative Program (IRSIP).
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Author contributions: CvK and FRA conceptualized and designed the study. MW and HNK collected samples of affected families. MW, AT and MI have optimized the RP-HPLC-FLD assay. MW and HNK wrote initial drafts. LS, SG, FMV and CvK confirmed disease in the affected families by Amino Acid Analyzer, and edited the manuscript. HA and MI provided all the clinical information of the patients. Mutational analysis was performed by GS and KW. All authors have read and approved the manuscript for submission.
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Competing interest: All the authors have no conflict of interest regarding this article.
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Informed consent: Informed written consent was obtained for all the studied participants from their parents/head of special education centers.
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Ethical approval: “All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.”
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