Wolfram syndrome: Hereditary diabetes mellitus with brainstem and optic atrophy

Abstract

Wolfram syndrome was originally described as a combination of familial juvenile-onset diabetes mellitus and optic atrophy. Other neurological features subsequently emerged, and "DIDMOAD" (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) became a commonly accepted acronym. Here, we describe 4 further cases from 2 families, in whom there occurred previously unrecognized neurological features, central apnea and neurogenic upper airway collapse, together precipitating primary respiratory failure (fatal in 1 case), startle myoclonus (in 2 unrelated cases), axial rigidity, and Parinaud's syndrome. Magnetic resonance images revealed striking brainstem atrophy affecting, in particular, the pons and midbrain. The mitochondrial DNA from 3 cases (and relatives) showed no evidence of any of the previously reported abnormalities. These neurological and neuroradiological features, in conjunction with (1) analyses showing the neurodegenerative origin of optic atrophy, deafness, diabetes insipidus, and incontinence, (2) other previously reported neurological complications (including anosmia, ataxia, epilepsy, and neuropsychiatric and cognitive abnormalities), and (3) the very small number of published postmortem studies, indicate that Wolfram syndrome should be reemphasized as a unique hereditary neurodegenerative disorder with prominent optic atrophy and diabetes mellitus.

Hereditary optic neuropathies

“…[137][138][139][140][141][142][143][144] Most cases have been classified as sporadic or recessively inherited. The hallmark of all these cases is the association of juvenile diabetes mellitus and progressive visual loss with optic atrophy, almost always associated with diabetes insipidus, neurosensory hearing loss, or both (hence, the eponym DIDMOAD for diabetes insipidus, diabetes mellitus, optic atrophy, and deafness).…”

“…138,139 Other systemic and neurologic abnormalities include ataxia, axial rigidity, seizures, startle myoclonus, tremor, gastrointestinal dysmotility, vestibular malfunction, central apnea, neurogenic upper airway collapse, ptosis, cataracts, pigmentary retinopathy, iritis, lacrimal hyposecretion, tonic pupil, ophthalmoplegia, convergence insufficiency, vertical gaze palsy, mental retardation, psychiatric abnormalities, nystagmus, short stature, primary gonadal atrophy, other endocrine abnormalities, anosmia, megaloblastic and sideroblastic anaemia, abnormal electroretinography, and elevated cerebrospinal fluid protein. 137,139,140,[143][144][145] Psychiatric disorders are also seen at an increased frequency among heterozygous carriers. 146 Pathology and neuroimaging in some patients reveal widespread atrophic changes and suggest a diffuse neurodegenerative disorder, with particular involvement of the midbrain and pons.…”

“…146 Pathology and neuroimaging in some patients reveal widespread atrophic changes and suggest a diffuse neurodegenerative disorder, with particular involvement of the midbrain and pons. 140,144,147 Median age at death is 30 years, most commonly due to central respiratory failure with brain-stem atrophy. 139,148 When the syndrome is accompanied by anaemia, treatment with thiamine may ameliorate the anaemia and decrease the insulin requirement.…”

Wfs1 gene deletion causes growth retardation in mice and interferes with the growth hormone pathway

“…In addition to these diagnostic syndromes, most WS patients have highly variable clinical symptoms including several neurological abnormalities such as nystagmus, mental retardation, and seizures (1). Moreover, several studies have shown diffuse and widespread atrophy in the brain (19,22). Central respiratory failure due to brainstem atrophy has described as a common cause of death, indicating the significance of neurodegeneration in WS (1,22).…”

Síndrome de Wolfram: da definição às bases moleculares

“…Os achados ao exame de ressonância magnética do cérebro são ausência de sinal de alta intensidade da neuro-hipófise, atrofia da região hipotalâmica, cerebelo, tronco e córtex cerebral, além de atrofia do nervo e quiasma óptico (17,(25)(26)(27). Dados de autópsia mostram uma perda de neurônios com distrofia e edema axonal, freqüentemente associados com gliose e áreas de desmielinização sem sinais de inflamação (28,29).…”