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CBS mutations are good predictors for B6-responsiveness: A study based on the analysis of 35 Brazilian Classical Homocystinuria patients.

ABSTRACT: BACKGROUND:Classical homocystinuria (HCU) is a monogenic disease caused by the deficient activity of cystathionine ?-synthase (C?S). The objective of this study was to identify the CBS mutations in Brazilian patients with HCU. METHODS:gDNA samples were obtained for 35 patients (30 families) with biochemically confirmed diagnosis of HCU. All exons and exon-intron boundaries of CBS gene were sequenced. Gene expression analysis by qRT-PCR was performed in six patients. Novel missense point mutations were expressed in E. coli by site-directed mutagenesis. RESULTS:Parental consanguinity was reported in 16 families, and pyridoxine responsiveness in five (15%) patients. Among individuals from the same family, all presented the same phenotype. Both pathogenic mutations were identified in 29/30 patients. Twenty-one different mutations were detected in nine exons and three introns; being six common mutations. Most prevalent were p.Ile278Thr (18.2%), p.Trp323Ter (11.3%), p.Thr191Met (11.3%), and c.828+1G>A (11.3%). Eight novel mutations were found [c.2T>C, c.209+1delG, c.284T>C, c.329A>T, c.444delG, c.864_868delGAG c.989_991delAGG, and c.1223+5G>T]. Enzyme activity in E. coli-expressed mutations was 1.5% for c.329A>T and 17.5% for c.284T>C. qRT-PCR analysis revealed reduced gene expression in all evaluated genotypes: [c.209+1delG; c.572C>T]; [c.2T>C; c.828+1G>A]; [c.828+1G>A; c.1126G>A]; [c.833T>C; c.989_991delAGG]; [c.1058C>T; c.146C>T]; and [c.444delG; c.444delG]. The expected phenotype according to the genotype (pyridoxine responsiveness) matched in all cases. CONCLUSIONS:Most patients studied were pyridoxine nonresponsive and presented early manifestations, suggesting severe phenotypes. Many private mutations were observed, but the four most prevalent mutations together accounted for over 50% of mutated alleles. A good genotype-phenotype relationship was observed within families and for the four most common mutations.

SUBMITTER: Poloni S

PROVIDER: S-EPMC5902399 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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CBS mutations are good predictors for B6-responsiveness: A study based on the analysis of 35 Brazilian Classical Homocystinuria patients.

Poloni Soraia S Sperb-Ludwig Fernanda F Borsatto Taciane T Weber Hoss Giovana G Doriqui Maria Juliana R MJR Embiruçu Emília K EK Boa-Sorte Ney N Marques Charles C Kim Chong A CA Fischinger Moura de Souza Carolina C Rocha Helio H Ribeiro Marcia M Steiner Carlos E CE Moreno Carolina A CA Bernardi Pricila P Valadares Eugenia E Artigalas Osvaldo O Carvalho Gerson G Wanderley Hector Y C HYC Kugele Johanna J Walter Melanie M Gallego-Villar Lorena L Blom Henk J HJ Schwartz Ida Vanessa D IVD

Molecular genetics & genomic medicine 20180120 2

<h4>Background</h4>Classical homocystinuria (HCU) is a monogenic disease caused by the deficient activity of cystathionine β-synthase (CβS). The objective of this study was to identify the CBS mutations in Brazilian patients with HCU.<h4>Methods</h4>gDNA samples were obtained for 35 patients (30 families) with biochemically confirmed diagnosis of HCU. All exons and exon-intron boundaries of CBS gene were sequenced. Gene expression analysis by qRT-PCR was performed in six patients. Novel missense ...[more]

PMID: 29352562

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Project description:BACKGROUND:Classical homocystinuria due to cystathionine β-synthase (CBS) deficiency (OMIM 236200) is a recessively inherited condition caused by mutations in the CBS gene. The founder mutation p.R336C accounts for almost all CBS deficiency in Qatar, affecting approximately 1 in 1,800 births, making it the most prevalent monogenic disease among the Qatari population. Untreated patients can have severe intellectual disability (ID), devastating multisystem complications and premature death. Current treatment is based on pharmacology therapy and life-long methionine-restricted diet, which is difficult to maintain particularly in late diagnosed individuals. Data on the neurodevelopmental and psychological impact of the disease on outcomes among Qatari patients are generally lacking and have not been studied. OBJECTIVES:To examine the cognitive, educational and psychological outcomes of classical homocystinuria on Qatari patients. SUBJECTS AND METHODS:Thirty-two cases with classical homocystinuria and 25 sibling controls were recruited to evaluate the neurodevelopmental and cognitive outcomes. We reviewed the subjects' medical record and collected pertinent clinical and educational data from parents. Stanford-Binet Intelligence Test (Arabic translation - 4th ed.) was used for cognitive (IQ) testing. RESULTS:The mean age for the subjects was 11.2 years (range 0.6-29) with 56% males. The majority of cases (93%) carried the mutation (p.R336C), and parental consanguinity was 84%. There were no differences between the two groups in the fine motor, expressive language, behavioural and visual skills. However, cases have much lower total IQ particularly in the domains of short memory, quantitative reasoning and visual-spatial domains. A significant number of adolescents and adult cases had medical co-morbidities as well as behavioural and emotional problems. CONCLUSION:Individuals with classical homocystinuria have many developmental and cognitive difficulties with significant number of cases having learning disability and lower IQs (cf. sibling controls) with adolescents and adults more affected. Those diagnosed by newborn screening have better developmental and cognitive outcomes compared to late diagnosed cases. Psychological and psychiatric referrals should be part of the standard of care for those cases.

Dataset Information

CBS mutations are good predictors for B6-responsiveness: A study based on the analysis of 35 Brazilian Classical Homocystinuria patients.

Publications

CBS mutations are good predictors for B6-responsiveness: A study based on the analysis of 35 Brazilian Classical Homocystinuria patients.

Similar Datasets

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