Abstract
PurposeTo study the genetic basis and clinical manifestations of Wolfram syndrome in a multi-affected family.MethodsComplete clinical examinations including urological, ophthalmic, neurological, and endocrinologic assessment were performed for three affected family members. Genomic DNA was extracted from peripheral blood leukocytes with salting out method and all WFS1 exons and their flanking regions were sequenced. Candidate variation was screened for segregation in the pedigree by Sanger sequencing.ResultsA known pathogenic missense mutation in WFS1 gene (c.1885CT which leads to p.Arg629Trp in the encoded protein) was identified in all affected individuals. Both clinical and genetic investigations confirmed Wolfram syndrome diagnosis with variable phenotypic featuresConclusion Identical mutations in the Wolfram syndrome causative gene can lead to variable manifestations of the syndrome even in the same family. Although the medical findings and clinical examination are imperative for the diagnosis of Wolfram syndrome, genetic testing is useful to confirm the diagnosis, especially in cases with possible reduced penetrance of the characteristic signs.
Highlights
Wolfram syndrome (WFS) called DIDMOAD is a progressive neurodegenerative disease affecting multiorgan systems.[1]
WFS is a rare progressive neurodegenerative disorder characterized by optic atrophy (OA) and diabetes mellitus (DM) at childhood which is inherited in an autosomal recessive pattern.[6]
Most of these mutations result in loss of function protein expression which is responsible for Wolframin protein inactivation and consequent disease manifestations; the exact genotype–phenotype correlation in WFS-affected patients is not well understood.[9, 10]
Summary
Wolfram syndrome (WFS) called DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, deafness) is a progressive neurodegenerative disease affecting multiorgan systems.[1] Wolfram and Wagener first described this entity in four siblings in 1938.[2] It’s a kind of rare genetic disorder with a prevalence of approximately 1 per 770,000 in the United Kingdom and 1 per 100,000 in North America.[1] WFS is inherited in an autosomal recessive pattern; it should be more prevalent in populations with high rates of consanguineous marriages. Juvenile-onset diabetes mellitus (DM) and optic atrophy (OA) are two characteristic features for clinical diagnosis of the syndrome that are typically exhibited at the mean age of 6 and 11 years, respectively. Other common clinical manifestations include diabetes insipidus (DI), sensorineural deafness, urinary tract involvement, and neuropsychiatric disorders.[1]
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