Phenotypic Variability of Alström’s Syndrome in Bedouin Sibs

Farah, Solange Bento; Shubaili, A.F.; Khuraibit, A.; Sabry, M.A.; Fårag, T I

doi:10.1159/000157393

Cited by 3 publications

(4 citation statements)

References 4 publications

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“…However, by comparing the 8 subjects from kindred 1 to the 4 presumably unrelated subjects, the variability in ancillary characteristics, and the variability of onset and severity of the major abnormalities appear to be age-related rather than resulting from genetic heterogeneity. Similar phenotypic variability was demonstrated previously in affected sibs with AS [Pfeiffer and Pusch, 1978;Farah et al, 1996;Michaud et al, 1996].…”

Section: Discussionsupporting

confidence: 88%

“…Hepatic and renal abnormalities. Previous reports have cited 9 AS patients with associated liver disease [Awazu et al, 1995[Awazu et al, , 1997Connolly et al, 1991;Farah et al, 1996;Horiuchi et al, 1976;Ikeda et al, 1974;Lista et al, 1972;Puech et al, 1982;Sebag et al, 1984]. Ten of the 12 individuals in our cohort exhibit elevation of AST, ALT, or LDH, providing some evidence for hepatic damage (Table II).…”

Section: Endocrine Abnormalitiessupporting

confidence: 50%

“…Non-insulin dependent diabetes mellitus (NIDDM) develops in early adulthood. In the final stages of the disease, affected individuals exhibit progressive chronic nephropathy with eventual renal failure, which is the most frequent cause of death [Goldstein and Fialkow, 1973;Farah et al, 1996;Winsor, 1973]. Hepatic dysfunction [Lista et al, 1972;Ikeda et al, 1974;Awazu et al, 1995Awazu et al, , 1997], atherosclerotic disease, or congestive heart failure secondary to dilated cardiomyopathy [Warren et al, 1987] have also been documented.…”

Section: Introductionmentioning

confidence: 99%

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Genealogy, natural history, and phenotype of Alström syndrome in a large Acadian kindred and three additional families

et al. 1997

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We describe a large Acadian kindred including 8 Alstrom Syndrome (AS) patients, with an age range of 4 to 26 at the time of clinical assessment. The affected subjects come from 5 nuclear families within this kindred. The phenotype includes early childhood retinopathy, progressive sensorineural hearing loss, truncal obesity, and acanthosis nigricans. In addition, hyperinsulinemia and hypertriglyceridemia with normal cholesterol levels were observed in most affected individuals tested. Non-insulin dependent diabetes mellitus and growth retardation appear to be age-related manifestations that occur post-adolescence. Younger affected children are not overtly hyperglycemic and are normal or above average height for age. Although the AS patients in kindred 1 presumably carry the same mutation, many manifestations of the disease are variable. For example, of the 8 children in the Acadian kindred, 4 have scoliosis, 2 have had infantile cardiomyopathy, 2 are hypothyroid, 1 has had hepatic dysfunction and is hypertensive, and 4 have developed asthma. Seven subjects described in this kindred exhibit developmental delay. One additional manifestation not described widely in the literature, advanced bone age, was observed in all subjects tested. The clinical data from this large Acadian kindred, together with information obtained from 4 additional AS patients in 3 unrelated kindreds, confirm and extend clinical observations previously described. In addition, the Acadian kindred with multiple affected individuals, probably arising from a common founder, should allow for identification of the chromosomal localization of a gene causing AS.

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Section: Discussionsupporting

confidence: 88%

Section: Endocrine Abnormalitiessupporting

confidence: 50%

Section: Introductionmentioning

confidence: 99%

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Genealogy, natural history, and phenotype of Alström syndrome in a large Acadian kindred and three additional families

et al. 1997

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“…The high incidence of phenotypic variability in sets of siblings is well documented [Anzai et al, 1985;Farah et al, 1996;Marshall et al, 1997Marshall et al, , 2005Paisey et al, 2000;Hung et al, 2001;Hoffman et al, 2005]. Additionally, differences in cardiac and hepatic manifestations observed in unrelated kindreds sharing identical mutations provides further evidence suggesting genetic background and/or environmental factors may lead to the wide variations in age of onset and severity of the Alström syndrome phenotypic spectrum [Collin et al, 2002].…”

Section: Discussionmentioning

confidence: 95%

Spectrum ofALMS1variants and evaluation of genotype-phenotype correlations in Alström syndrome

et al. 2007

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Alström syndrome is a monogenic recessive disorder featuring an array of clinical manifestations, with systemic fibrosis and multiple organ involvement, including retinal degeneration, hearing loss, childhood obesity, diabetes mellitus, dilated cardiomyopathy (DCM), urological dysfunction, and pulmonary, hepatic, and renal failure. We evaluated a large cohort of patients with Alström syndrome for mutations in the ALMS1 gene. In total, 79 disease-causing variants were identified, of which 55 are novel mutations. The variants are primarily clustered in exons 8, 10, and 16, although we also identified novel mutations in exons 12 and 18. Most alleles were identified only once (45/79), but several were found recurrently. Founder effects are likely in families of English and Turkish descent. We also identified 66 SNPs and assessed the functional significance of these variants based on the conserved identity of the protein and the severity of the resulting amino acid substitution. A genotype-phenotype association study examining 18 phenotypic parameters in a subset of 58 patients found suggestive associations between disease-causing variants in exon 16 and the onset of retinal degeneration before the age of 1 year (P = 0.02), the occurrence of urological dysfunction (P = 0.02), of DCM (P = 0.03), and of diabetes (P = 0.03). A significant association was found between alterations in exon 8 and absent, mild, or delayed renal disease (P = 0.0007). This data may have implications for the understanding of the molecular mechanisms of ALMS1 and provides the basis for further investigation of how alternative splicing of ALMS1 contributes to the severity of the disease.

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Doppler Tissue, Strain, and Strain Rate Imaging in Pediatric Patients with Alström Syndrome: Are There Regional Functional Abnormalities?

Toulany

Shea

Warren

2006

Journal of the American Society of Echocardiography

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Phenotypic Variability of Alström’s Syndrome in Bedouin Sibs

Cited by 3 publications

References 4 publications

Genealogy, natural history, and phenotype of Alström syndrome in a large Acadian kindred and three additional families

Genealogy, natural history, and phenotype of Alström syndrome in a large Acadian kindred and three additional families

Spectrum ofALMS1variants and evaluation of genotype-phenotype correlations in Alström syndrome

Doppler Tissue, Strain, and Strain Rate Imaging in Pediatric Patients with Alström Syndrome: Are There Regional Functional Abnormalities?

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