Wolfram Syndrome (Diabetes Insipidus, Diabetes, Optic Atrophy, and Deafness)

Abstract

OBJECTIVE —Wolfram syndrome is an autosomal recessive neurodegenerative disorder characterized by diabetes insipidus, diabetes (nonautoimmune), optic atrophy, and deafness (a set of conditions referred to as DIDMOAD). The WFS1 gene is located on the short arm of chromosome 4. Wolfram syndrome prevalence is 1 in 770,000 live births, with a 1 in 354 carrier frequency. RESEARCH DESIGN AND METHODS —We evaluated six Italian children from five unrelated families. Genetic analysis for Wolfram syndrome was performed by PCR amplification and direct sequencing. RESULTS —Mutation screening revealed five distinct variants, one novel mutation (c.1346C>T; p.T449I) and four previously described, all located in exon 8. CONCLUSIONS —Phenotype-genotype correlation is difficult, and the same mutation gives very different phenotypes. Severely inactivating mutations result in a more severe phenotype than mildly inactivating ones. Clinical follow-up showed the progressive syndrome's seriousness.

Stress hypERactivation in the β-cell

“…Mortality occurs in approximately 65% of patients before the age of 35, 59 primarily caused by central respiratory and renal failure, as well as brain stem atrophy. 62 While generally considered a rare disease in most countries, for example in the UK the prevalence is 1/770,000, 59 with a carrier frequency of 1/354, 63 some countries like Japan and Lebanon have higher incidences. 61,64 The nuclear gene responsible for this syndrome which spans 33.4 kb of genomic DNA was identified by two separate groups in 1998 and named WFS1.…”

Identification of Novel Wsf1 Mutations in a Sicilian Child with Wolfram Syndrome

“…To date, over 200 distinct mutations in WFS1 have been identified in WS individuals from different ethnic backgrounds, and these include a variety of missense, nonsense, and frameshift insertion/ deletion mutations [3,5,6,[13][14][15][16][17][18][19][20][21][22].…”

Diabetes mellitus y atrofia óptica: estudio del síndrome de Wolfram

“…Hasta el momento se han descrito más de 200 mutaciones distintas del gen WFS1. 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] .…”

“…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.…”