TY - JOUR
T1 - Identification of three novel pathogenic mutations in cystathionine beta-synthase gene of Pakistani intellectually disabled patients
AU - Wasim, Muhammad
AU - Khan, Haq N
AU - Ayesha, Hina
AU - Iqbal, Mazhar
AU - Tawab, Abdul
AU - Irfan, Muhammad
AU - Kanhai, Warsha
AU - Goorden, Susanna M I
AU - Stroomer, Lida
AU - Salomons, Gajja
AU - Vaz, Frederic M
AU - Karnebeek, Clara D M van
AU - Awan, Fazli R
N1 - Funding Information: 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). Publisher Copyright: © 2021 Walter de Gruyter GmbH, Berlin/Boston.
PY - 2022/3/28
Y1 - 2022/3/28
N2 - 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. 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. 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. 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.
AB - 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. 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. 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. 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.
KW - Pakistan
KW - RP-HPLC-FLD
KW - aminoacidopathies
KW - classical homocystinuria
KW - inborn errors of metabolism
KW - mutations
UR - http://www.scopus.com/inward/record.url?scp=85121443841&partnerID=8YFLogxK
U2 - https://doi.org/10.1515/jpem-2021-0508
DO - https://doi.org/10.1515/jpem-2021-0508
M3 - Article
C2 - 34905667
SN - 0334-018X
VL - 35
SP - 325
EP - 332
JO - Journal of pediatric endocrinology & metabolism
JF - Journal of pediatric endocrinology & metabolism
IS - 3
ER -