Síndrome de Wolfram: da definição às bases moleculares / Wolfram syndrome: from definition to molecular bases / Wolfram syndrome: from definition to molecular bases

A 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 acrônimo 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 proteína 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.

Neurologic involvement in wolfram syndrome

To study 10 patients with Wolfram syndrome sometimes referrd to as DIDMOAD [diabetes insipidus, mellitus, optic atrophy and deafness] from three Jordanian families to assess for neurologic involvement, all of them had diabetes mellitus, nine [90%] patients had optic atrophy [OA], and eight [80%] patients had sensorineural deafness. All patients had standard full clinical neurologic examination. Eight patients were seen by staff psychiatrist for one time interview. Standard non-contrast brain and pituitary magnetic resonance imaging was carried out for all the patients. five patients had full field pattern shift visual evoked response. Eight patients had nerve conduction study of one upper and one lower limb. Six patients had 18 channel electroencephalogram. Five patients had brainstem evoked response study. Apart from defining features of the syndrome [diabetes mellitus, optic atrophy, sensorineural deafness] 3 patients [30%] had abnormal neurologic examination [depressed deep tendon reflexes, stuttering and mild ataxia], two [20%] had mildly abnormal psychiatric findings [temper outburst and depression] three patients [30%] had abnormal brain magnetic resonance imaging, three patients [30%] had abnormal visual evoked response with demylinating pattern in early optic involvement and axonal pattern in late disease. Two patients [20%] had abnormal nerve conduction study [mild sensory motor polyneuropathy with axonal and demyelinating features]. One patient [10%] had abnormal electroencephalogram and all patients tested for brainstem evoked response [100%] had normal brainstem evoked response study. This study shows part of the spectrum of neurologic involvement in Wolfram syndrome. It is consistent with the degenerative nature of this clinical entity. Early demyelination followed by degeneration may be inferred from this study, and this is important to prove or disprove in the light of lacking enough neuropathologic data and understanding of its pathogenesis. Further pathologic and neurophysiologic studies are required