Wolfram Syndrome in the Japanese Population; Molecular Analysis of WFS1 Gene and Characterization of Clinical Features

Abstract

BackgroundWolfram syndrome (WFS) is a recessive neurologic and endocrinologic degenerative disorder, and is also known as DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus, progressive Optic Atrophy and Deafness) syndrome. Most affected individuals carry recessive mutations in the Wolfram syndrome 1 gene (WFS1). However, the phenotypic pleiomorphism, rarity and molecular complexity of this disease complicate our efforts to understand WFS. To address this limitation, we aimed to describe complications and to elucidate the contributions of WFS1 mutations to clinical manifestations in Japanese patients with WFS.MethodologyThe minimal ascertainment criterion for diagnosing WFS was having both early onset diabetes mellitus and bilateral optic atrophy. Genetic analysis for WFS1 was performed by direct sequencing.Principal FindingsSixty-seven patients were identified nationally for a prevalence of one per 710,000, with 33 patients (49%) having all 4 components of DIDMOAD. In 40 subjects who agreed to participate in this investigation from 30 unrelated families, the earliest manifestation was DM at a median age of 8.7 years, followed by OA at a median age of 15.8 years. However, either OA or DI was the first diagnosed feature in 6 subjects. In 10, features other than DM predated OA. Twenty-seven patients (67.5%) had a broad spectrum of recessive mutations in WFS1. Two patients had mutations in only one allele. Eleven patients (27.5%) had intact WFS1 alleles. Ages at onset of both DM and OA in patients with recessive WFS1 mutations were indistinguishable from those in patients without WFS1 mutations. In the patients with predicted complete loss-of-function mutations, ages at the onsets of both DM and OA were significantly earlier than those in patients with predicted partial-loss-of function mutations.Conclusion/SignificanceThis study emphasizes the clinical and genetic heterogeneity in patients with WFS. Genotype-phenotype correlations may exist in patients with WFS1 mutations, as demonstrated by the disease onset.

Diabetes mellitus y atrofia óptica: estudio del síndrome de Wolfram

“…La mayoría de las mutaciones son únicas para un individuo o una familia, por lo que su naturaleza privada hace muy difícil el delinear una clara relación genotipo-fenotipo 32,56,57 . Las mutaciones se distribuyen aleatoriamente en toda la secuencia codificante del gen, pero hasta el 80% de las mutaciones reportadas hasta la fecha se encuentran en el exón 8 25,26,30,31,37,[56][57][58][59] . En este estudio, el 60% de los pacientes (n = 3) cuentan con diagnóstico molecular y se trata de tres hermanos (los tres hombres del estudio) que presentan dos mutaciones en estado heterocigoto: la primera, heredada del padre, es una transición de guanina por citocina en el codón 177 que cambia una arginina por una prolina en el exón 5, y la segunda es una deleción de herencia materna de 16 pb (P451fsX515) en el exón 8 que cambia el marco de lectura y genera un codón de terminación prematura en la secuencia normal de la proteína.…”

“…La prevalencia del SW se estima en 1 por 770,000 personas en el Reino Unido, con una prevalencia de portador de 1 en 354 24 , de 1 en 710,000 en la población japonesa 25 y de 1 en 805,000 en la India 26 . Se han descrito prevalencias más altas, como 1 en 68,000 personas en Líbano 27 , parcialmente atribuible a las altas tasas de consanguinidad en esta región.…”

Bipolar Disorder Type 1 in a 17-Year-Old Girl with Wolfram Syndrome

“…However, detailed data on the psychiatric phenotype are still rare. Several authors reported psychotic symptoms, attempted suicide, violent behavior, and affective disorders (e.g., mixed mood swings), in WS homozygous patients (Swift and Swift 2000;Matsunaga et al 2014;Ramli et al 2014).…”

A p.(Glu809Lys) Mutation in the WFS1 Gene Associated with Wolfram-like Syndrome: A Case Report

“…1:710.000 (1). The disease is also known as the DIDMOAD syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, deafness).…”

“…The disease is also known as the DIDMOAD syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, deafness). Most of the individuals afflicted with this disease have the recessive mutation in the WFS gene 1 (WFS1, 4p16.3) (1,2) and rarely in the WFS gene 2 (WFS2) (3). A dominant mutation in the WFS1 gene was also described in connection with sensorineural hearing loss, deafness, and optic atrophy [Wolfram-like syndrome (WFSL)] (4).…”