Síndrome de Wolfram: da definição às bases moleculares

Abstract

RESUMOA síndrome de Wolfram (SW) é uma condição neurodegenerativa progressiva de herança autossômica recessiva caracterizada pela presença de diabetes mellitus e atrofia óptica. Freqüentemente também estão presentes o diabetes insipidus e disacusia neurossensorial, explicando o acrô-nimo DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, deafness) pelo qual a síndrome é também conhecida. Além desses, outros comemorativos tais como bexiga neurogênica, ataxia, nistagmo e predisposição a doenças psiquiátricas podem também estar presentes. Em 1994 identificou-se no cromossomo 4p16.1 um dos genes responsáveis pela SW, que foi denominado WFS1 ou wolframina. Esse gene codifica uma proteí-na de 890 aminoácidos de localização no retículo endoplasmático. A função da proteína wolframina ainda não está completamente definida, porém sua localização no retículo endoplasmático sugere um papel na regulação da homeostase do cálcio, transporte de membrana ou processamento protéico. O entendimento de como alterações na função da wolframina resultam em diabetes e neurodegeneração é essencial para o desenvolvimento de terapias para prevenir ou atenuar as conseqüências da SW. Wolfram syndrome (WS) is an autosomal recessive progressive neurodegenerative disorder characterized by diabetes mellitus and optic atrophy. Diabetes insipidus and sensorineural deafness are also noted frequently, explaining the acronym DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and deafness) by which the syndrome is also referred. Additional manifestations such as atonic bladder, ataxia, nystagmus and predisposition for psychiatric illness may be present. The Wolfram syndrome gene, WFS1, was mapped to chromosome 4p16.1 by positional cloning. It encodes an 890-amino-acid polypeptide named wolframin. Although the wolframin function is still not completely known, its localization to the endoplasmic reticulum suggests it can play a role in calcium homeostasis, membrane trafficking and protein processing. Knowing the cellular function of wolframin is necessary for understanding the pathophysiology of Wolfram syndrome. This knowledge may lead to development of therapies to prevent or reduce the outcomes of WS.

Wolfram syndrome: important implications for pediatricians and pediatric endocrinologists

“…Suicidal behavior has also been linked to a specific type of genetic mutation of WFS1 gene by certain authors (78). The high incidence of suicidal behavior reported in patients with this syndrome makes a psychiatric consultation and follow-up an essential part of the treatment (77,79,80).…”

Ophthalmologic Manifestations of Wolfram Syndrome: Report of 14 Cases

“…Rarely, it can be associated with the autosomal recessive form of WFS2 gene (chr 4q22-q24) and is classically associated with peptic ulcer disease and bleeding tendencies without diabetes DI. Rare mutations are related to mitochondrial DNA [1-3, 6, 7, 8]. Wolframin protein plays an important role in regulating endoplasmic reticulum mitochondria homoeostasis and cellular membrane integrity in pancreatic cells and the central nervous system [3].…”

Wolfram Syndrome: A Genetic Analysis of 2 Brothers

“…Wolfram syndrome (WS) or DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness) is progressive, neurodegenerative disease with an autosomal recessive mode of inheritance, and its estimated incidence is 1 our of 770,000 live births (1,2).…”

“…DM without autoimmunity is the first manifestation of WS, and although there is selective, progressive loss of beta cell function, the cells that produce glucagon and somatostatin are preserved. WS has lower prevalence of chronic complications than classical autoimmune type 1 DM, and ketoacidosis occurs only infrequently during WS evolution (1,(3)(4)(5). Bilateral optic nerve atrophy is progressive affecting mainly the peripheral vision, but a recent histopathologic study of retinal and optic nerves demonstrated both central and peripheral involvement.…”

“…DI is usually the central type, which is confirmed by a neuroradiologic absence of T1 hyperintensity of the posterior pituitary lobe on magnetic resonance imaging (MRI), along with gliosis and atrophy of the paraventricular and supraoptic nuclei of the hypothalamus (5). The diagnosis of WS may be delayed because its symptoms are confounded with those of poorly controlled autoimmune type 1 DM (1,5,8,9). Approximately twothirds of patients experience some degree of neurosensory auditory loss, initially of high frequencies and progressing to lower frequencies (1)(2)(3).…”