Congenital cataracts in two siblings with Wolfram Syndrome

Mets, Rebecca B.; Emery, Sarah B.; Lesperance, Marci M.; Mets, Marilyn B.

doi:10.3109/13816810.2010.516056

Cited by 11 publications

(8 citation statements)

References 8 publications

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“…By contrast, in the present study, DNA was available from the parents of two children (Family 81) with Wolfram syndrome, who are compound heterozygous for p.A684V and p.V415del in WFS1 . The children both have juvenile onset of insulin‐dependent diabetes mellitus, OA, bilateral profound sensorineural hearing loss and congenital cataracts [Mets et al, 2010]. Interestingly, we identified the p.A684V mutation in heterozygous state in the father, who has OA and hearing loss only, while the mother, heterozygous for the p.V415del mutation, had no symptoms.…”

Section: Discussionmentioning

confidence: 72%

Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment

Rendtorff

Lodahl

Boulahbel

et al. 2011

American J of Med Genetics Pt A

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Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1. In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare, and almost exclusively attributed to mutations in the Optic Atrophy-1 gene (OPA1), most commonly the p.R445H mutation.We present eight probands and their families from the US, Sweden, and UK with OA and SNHL, whom we analyzed for mutations in OPA1 and WFS1. Among these families, we found three heterozygous missense mutations in WFS1 segregating with OA and SNHL: p.A684V (six families), and two novel mutations, p.G780S and p.D797Y, all involving evolutionarily conserved amino acids and absent from 298 control chromosomes. Importantly, none of these families harbored the OPA1 p.R445H mutation. No mitochondrial DNA deletions were detected in muscle from one p.A684V patient analyzed. Finally, wolframin p.A684V mutant ectopically expressed in HEK cells showed reduced protein levels compared to wild-type wolframin, strongly indicating that the mutation is disease-causing.Our data support OA and SNHL as a phenotype caused by dominant mutations in WFS1 in these additional eight families. Importantly, our data provide the first evidence that a single, recurrent mutation in WFS1, p.A684V, may be a common cause of ADOA and SNHL, similar to the role played by the p.R445H mutation in OPA1. Our findings suggest that patients who are heterozygous for WFS1 missense mutations should be carefully clinically examined for OA and other manifestations of Wolfram syndrome.

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Section: Discussionmentioning

confidence: 72%

Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment

Rendtorff

Lodahl

Boulahbel

et al. 2011

American J of Med Genetics Pt A

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“…Table 2 summarizes the clinical characteristics for 30 affected members from 19 families with WFS1 mutations. [ 5 – 7 , 34 , 36 – 38 ]…”

Section: Resultsmentioning

confidence: 99%

WFS1 mutation screening in a large series of Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis

et al. 2018

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A heterozygous mutation in the Wolfram syndrome type 1 gene (WFS1) causes autosomal dominant nonsyndromic hereditary hearing loss, DFNA6/14/38, or Wolfram-like syndrome. To date, more than 40 different mutations have been reported to be responsible for DFNA6/14/38. In the present study, WFS1 variants were screened in a large series of Japanese hearing loss (HL) patients to clarify the prevalence and clinical characteristics of DFNA6/14/38 and Wolfram-like syndrome. Massively parallel DNA sequencing of 68 target genes was performed in 2,549 unrelated Japanese HL patients to identify genomic variations responsible for HL. The detailed clinical features in patients with WFS1 variants were collected from medical charts and analyzed. We successfully identified 13 WFS1 variants in 19 probands: eight of the 13 variants were previously reported mutations, including three mutations (p.A684V, p.K836N, and p.E864K) known to cause Wolfram-like syndrome, and five were novel mutations. Variants were detected in 15 probands (2.5%) in 602 families with presumably autosomal dominant or mitochondrial HL, and in four probands (0.7%) in 559 sporadic cases; however, no variants were detected in the other 1,388 probands with autosomal recessive or unknown family history. Among the 30 individuals possessing variants, marked variations were observed in the onset of HL as well as in the presence of progressive HL and tinnitus. Vestibular symptoms, which had been rarely reported, were present in 7 out of 30 (23%) of the affected individuals. The most prevalent audiometric configuration was low-frequency type; however, some individuals had high-frequency HL. Haplotype analysis in three mutations (p.A716T, p.K836T, and p.E864K) suggested that the mutations occurred at these mutation hot spots. The present study provided new insights into the audiovestibular phenotypes in patients with WFS1 mutations.

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“…Plausible explanations for this difference include differences in diagnostic criteria, age of the cohort and variable expression or penetrance of the mutated gene. Adding to reports of early-onset SNHL [ 9 , 11 , 12 , 20 – 23 , 29 – 33 ], 6 of the 30 patients (20%) with SNHL had severe-to-profound hearing loss with onset by 3 years of age.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal hearing loss in Wolfram syndrome

Karzon

Narayanan

Chen

et al. 2018

Orphanet J Rare Dis

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BackgroundWolfram syndrome (WFS) is a rare autosomal recessive disease with clinical manifestations of diabetes mellitus (DM), diabetes insipidus (DI), optic nerve atrophy (OA) and sensorineural hearing loss (SNHL). Although SNHL is a key symptom of WFS, there is limited information on its natural history using standardized measures. Such information is important for clinical care and determining its use as an outcome measure in clinical trials.MethodsStandardized audiologic measures, including pure-tone testing, tympanometry, speech perception, and the unaided Speech Intelligibility Index (SII) were assessed in patients with confirmed WFS annually. Mixed model analyses were used to examine main effects of age, time or interactions for pure tone average (PTA), high frequency average (HFA) and SII.ResultsForty WFS patients were evaluated between 1 and 6 times. Mean age at initial enrollment was 13.5 years (SD = 5.6). Patients were classified as having normal hearing (n = 10), mild-to-severe (n = 24) or profound SNHL (n = 6). Mean age of diagnosis for SNHL was 8.3 years (SD = 5.1) with 75% prevalence. HFA worsened over time for both ears, and SII worsened over time in the worse ear, with greater decline in both measures in younger patients. Average estimated change over 1 year for all measures was in the subclinical range and power analyses suggest that 100 patients would be needed per group (treatment vs. placebo) to detect a 60% reduction in annual change of HFA over 3 years. If trials focused on just those patients with SNHL, power estimates suggest 55 patients per group would be sufficient.ConclusionsMost patients had a slow progressive SNHL emerging in late childhood. Change over time with standard audiologic tests (HFA, SII) was small and would not be detectable for at least 2 years in an individual. Relatively large sample sizes would be necessary to detect significant impact on hearing progression in a clinical trial. Hearing function should be monitored clinically in WFS to provide appropriate intervention. Because SNHL can occur very early in WFS, audiologists and otolaryngologists should be aware of and refer for later emerging symptoms.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0852-0) contains supplementary material, which is available to authorized users.

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Congenital cataracts in two siblings with Wolfram Syndrome

Cited by 11 publications

References 8 publications

Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment

Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment

WFS1 mutation screening in a large series of Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis

Longitudinal hearing loss in Wolfram syndrome

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