Diabetes Mellitus and Optic Atrophy: A Study of Wolfram Syndrome in the Lebanese Population

Abstract

Wolfram syndrome (WFS) is a rare hereditary neurodegenerative disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). WFS seems to be a heterogeneous disease that has not yet been fully characterized in terms of clinical features and pathophysiological mechanisms because the number of patients in most series was small. In this study we describe 31 Lebanese WFS patients belonging to 17 families; this, to our knowledge, is the largest number of patients reported in one series so far. Criteria for diagnosis of WFS were the presence of insulin-dependent diabetes mellitus and optic atrophy unexplained by any other disease. Central diabetes insipidus was found in 87% of the patients, and sensorineural deafness confirmed by audiograms was present in 64.5%. Other less frequent features included neurological and psychiatric abnormalities, urodynamic abnormalities, limited joint motility, cardiovascular and gastrointestinal autonomic neuropathy, hypergonadotropic hypogonadism in males, and diabetic microvascular disease. New features, not reported in previous descriptions, such as heart malformations and anterior pituitary dysfunction, were recognized in some of the patients and participated in the morbidity and mortality of the disease. Genetic analysis revealed WFS1 gene mutations in three families (23.5%), whereas no abnormalities were detected in mitochondrial DNA. In conclusion, WFS is a devastating disease for the patients and their families. More information about WFS will lead to a better understanding of this disease and hopefully to improvement in means of its prevention and treatment.

A novel ALMS1 splice mutation in a non-obese juvenile-onset insulin-dependent syndromic diabetic patient

“…Detailed clinical and biological examinations were done at age 19, as described. 4 DNA from 180 Lebanese subjects was used as population controls. 5 …”

“…The combination of juvenile-onset insulin-dependent diabetes and optic atrophy led to the likely diagnosis of WFS, and at age 19 the patient participated in a comprehensive clinical study of WFS and underwent a series of clinical and biological tests. 4 Clinical and imaging studies. Ophthalmic examination confirmed blindness, with no light perception.…”

Stress hypERactivation in the β-cell

“…There is also preliminary evidence that WFS1 regulates a key transcription factor of the UPR, ATF6, through the ubiquitin-proteasome pathway. Higher expression of WFS1 in b-cells, prevents hyperactivation of ER stress signaling with urinary tract abnormalities and neuropsychiatric impairment, 61 while powdered cataract and retinopathy can also be seen in a fraction of these patients 60,61 (Fig. 3).…”

“…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. 65,66 To date, there are over 130 distinct mutations in WFS1 identified in patients.…”

Síndrome de Wolfram: da definição às bases moleculares

“…Recentemente, disfunção de hipófise anterior foi reportada na SW. Medlej e col. verificaram secreção anormal de um ou mais hormônios hipofisários em 75% dos pacientes, sendo a deficiência de GH a alteração mais freqüentemente documentada (30). Interessante é que o hipopituitarismo nesses pacientes não provocou sintomas clínicos, explicando a ausência de investigação de alterações da hipófise anterior em muito estudos prévios.…”