Identification of three novel pathogenic mutations in cystathionine beta-synthase gene of Pakistani intellectually disabled patients

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.

Association of selected genetic variants in CBS and MTHFR genes in a cohort of children with homocystinuria in Sri Lanka

“…In 2021, Wasim M. et al conducted a mutation analysis on 429 patients with an intellectual disability from northern areas of Punjab, Pakistan. Only nine patients were identified with homocystinuria, and none had c.833T>C mutation [ 22 ]. A study on three patients in a Pakistani consanguineous family with symptoms in 2021 confirmed homocystinuria was not detected with c.833T>C mutation [ 23 ].…”

Need and Challenges in Establishing Newborn Screening Programs for Inherited Metabolic Disorders in Developing Countries

“…Several nations are screening different IEMs according to their prevalence in that population [83,84] as presented in Table 3 with three most prevalent groups of disorders. In our country (Pakistan), there is no newborn screening program yet available for the screening of inherited metabolic disorders, hence we are making efforts to establish NBS in our country, [9,42,45,62,[85][86][87][88][89] although scarce data are available on such disorders in Pakistan. [9,62,[85][86][87][88][90][91][92][93][94] On the other hand, reports from Pakistan show that burden of inherited disorders is quite high due to consanguinity, hence there is a dire need to develop a NBS program, which can help to minimize the burden of such disorders from the society especially focus on aminoacidopathies, organic acidemias, and fatty acid oxidation disorders.…”

Current and Novel Therapeutical Approaches of Classical Homocystinuria in Childhood With Special Focus on Enzyme Replacement Therapy, Liver-Directed Therapy and Gene Therapy

“…There are different treatment modalities and ongoing research studies concentrating on new treatment options (Table 1) [21,28,37,39,47,[52][53][54][55][56][57][58][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79]. One of the most important facts in treatment are to hold plasma homocysteine as close as to the normal range [1-8, 21, 23, 24, 26].…”

“…Pyridoxine in its active form PLP is a cofactor of numerous enzymes which play an important role in amino acid, fat and carbohydrate metabolism, among others. The recommended treatment of non-responsive patients is methionine-restrict- Liver transplantation Small population surgically treated with liver transplantation to date; danger of postoperative side effects; one adult patient with primary underlying cancer disease and domino liver Tx [39,[54][55][56] Gene therapy Mutation repair Gene therapy is still in childhood shoes, studies focus on adenovirus-associated gene transfer or mini circle DNA vector in mice are confidential [67][68][69][70]; one-time approach would be desirable [37,[56][57][58]61].…”

“…Gene therapy could play an important role in the future to treat HCU in a curable aspect. But at all, gene therapeutical aspects are still in childhood shoes and should urgently further evaluated in detail [ 37 , 57 , 58 ]. Moreover, mutation repair, could play an important role to cure the disease ( Table 1 ) [ 21 , 28 , 37 , 39 , 47 , 52 - 58 , 61 - 79 ].…”