Clinical and molecular findings of 13 families from Saudi Arabia and a family from Sudan with homocystinuria

Zaidi, Syed Hassan Ejaz; Faiyaz-Ul-Haque, Muhammad; Shuaib, Taghreed; Balobaid, Ameera; Rahbeeni, Zuhair; Abalkhail, Hala; Al-Abdullatif, A; Al‐Hassnan, Zuhair N.; Peltekova, Iskra; Al‐Owain, Mohammed

doi:10.1111/j.1399-0004.2011.01690.x

Cited by 17 publications

(10 citation statements)

References 16 publications

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“…In general, the genotypes were consistently associated with pyridoxine responsiveness (presence or absence) within families and also agreed with previous findings worldwide (Janosik et al., ; Kraus, ; Zaidi et al., ). However, it is important to highlight that no clear genotype–phenotype correlation is established for most CBS mutations.…”

Section: Discussionsupporting

confidence: 91%

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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

Sperb‐Ludwig

Borsatto

et al. 2018

Molec Gen & Gen Med

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BackgroundClassical 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.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.ResultsParental 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.ConclusionsMost 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.

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Section: Discussionsupporting

confidence: 91%

“…The p.Trp323Ter (c.969G>A) mutation was also detected with an allele frequency of 11.3%. This mutation is highly prevalent in Saudi Arabia (10 of 13 families assessed) and is associated with severe phenotypes (Zaidi et al., ). In our study, all patients with this mutation were homozygous and pyridoxine nonresponsive.…”

Section: Discussionmentioning

confidence: 99%

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

Poloni

Sperb‐Ludwig

Borsatto

et al. 2018

Molec Gen & Gen Med

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“…The severe end of the spectrum, with multi-system disease, was described in early reports (Carson et al 1965; Schimke et al 1965). Subsequently, connective tissue, neuro-psychiatric and vascular presentations have been recognised (Kelly et al 2003; Linnebank et al 2003; Magner et al 2011; Zaidi et al 2012; Karaca et al 2014). …”

Section: Recommendationsmentioning

confidence: 99%

Guidelines for the diagnosis and management of cystathionine beta‐synthase deficiency

Morris

Kožich

Santra

et al. 2016

J of Inher Metab Disea

247

309

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Cystathionine beta-synthase (CBS) deficiency is a rare inherited disorder in the methionine catabolic pathway, in which the impaired synthesis of cystathionine leads to accumulation of homocysteine. Patients can present to many different specialists and diagnosis is often delayed. Severely affected patients usually present in childhood with ectopia lentis, learning difficulties and skeletal abnormalities. These patients generally require treatment with a low-methionine diet and/or betaine. In contrast, mildly affected patients are likely to present as adults with thromboembolism and to respond to treatment with pyridoxine. In this article, we present recommendations for the diagnosis and management of CBS deficiency, based on a systematic review of the literature. Unfortunately, the quality of the evidence is poor, as it often is for rare diseases. We strongly recommend measuring the plasma total homocysteine concentrations in any patient whose clinical features suggest the diagnosis. Our recommendations may help to standardise testing for pyridoxine responsiveness. Current evidence suggests that patients are unlikely to develop complications if the plasma total homocysteine concentration is maintained below 120 μmol/L. Nevertheless, we recommend keeping the concentration below 100 μmol/L because levels fluctuate and the complications associated with high levels are so serious.

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“…High incidence of consanguineous marriage in the Middle Eastern and North African people causes homozygosity of rare and possibly novel alleles [Al‐Owain et al, ]. Studies of these populations provide a better understanding of genotype‐phenotype correlation in rare diseases [Zaidi et al, ]. While many mutations have been described in COL11A1in patients with Stickler syndrome and Marshall syndrome, the range of clinical presentations and the spectrum of COL11A1 mutations in the Arabian ethnic group has largely remained underreported.…”

Section: Introductionmentioning

confidence: 99%

Marshall syndrome: Further evidence of a distinct phenotypic entity and report of new findings

Khalifa

Imtiaz

Ramzan

et al. 2014

American J of Med Genetics Pt A

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Marshall syndrome and type II Stickler syndrome are caused by mutations in COL11A1, which codes for the proα1chain of collagen XI. Collagen XI is a minor fibrillar collagen co-expressed with collagen II in cartilage and the vitreous of the eye. Characteristic features of Marshall syndrome include midfacial hypoplasia, high myopia, and sensorineural-hearing deficit. Deletions, insertions, splice site, and missense mutations in COL11A1 have been identified in Stickler syndrome and Marshall syndrome patients. In this study, we describe the clinical presentations of seven patients with Marshall syndrome from three unrelated Saudi families, inherited as autosomal dominant (two families) and autosomal recessive (one family). Cardinal clinical features of Marshall syndrome are manifested in all patients. One patient had ectodermal abnormalities. Mutations (c.2702G > A in exon 34,IVS50 + 1G > A, and IVS50 + lG > C) were identified in COL11A1 in affected members. Interestingly, the first report of autosomal recessive Marshall syndrome was from Saudi Arabia caused by the same mutation (c.2702G > A, p.Gly901Glu) as in one of our families. This study depicts detailed phenotypic and genetic description of dominant and recessive forms of Marshall syndrome due to COL11A1 mutations.

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Clinical and molecular findings of 13 families from Saudi Arabia and a family from Sudan with homocystinuria

Cited by 17 publications

References 16 publications

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

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

Guidelines for the diagnosis and management of cystathionine beta‐synthase deficiency

Marshall syndrome: Further evidence of a distinct phenotypic entity and report of new findings

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