Wolfram syndrome 2: a novel CISD2 mutation identified in Italian siblings.

Abstract

Wolfram syndrome, also referred to as Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness (DIDMOAD), is a rare autosomal recessive neurodegenerative disorder. Affected individuals had childhood insulinrequiring non-autoimmune diabetes mellitus and bilateral progressive optic atrophy, usually occurring during the first and second decade of life, respectively. Neurological clinical features include sensorineural hearing loss (slowly progressive high-frequency deafness), ataxia, dementia and psychiatric disease; olfactory defects are also frequent; central apnoea is a common cause of mortality. Further, neuronal degeneration might be involved in gastrointestinal dysmotility and a number of urinary tract dysfunctions (hydroureter, detrusor-sphincter dyssynergia, detrusor overactivity, urinary tract atony). Additional manifestations include endocrine dysfunctions—such as central diabetes insipidus, hypogonadism and growth retardation— and congenital heart disease consisting of pulmonary stenosis and ventricular septal defect. Wolfram syndrome is caused by mutations of at least two different genes, WFS1 and CISD2, both encoding for transmembrane proteins localizing in the endoplasmic reticulum (ER). They seem to affect cellular calcium homeostasis and are likely to be involved in ER stress both in neurons and beta cells, leading to cellular dysfunction and death [1]. Wolfram syndrome 1 (MIM #222300) has an estimated prevalence of 1:770,000 live births, and it is caused by homozygous or compound heterozygous mutations in WFS1 gene at 4p16.1 encoding wolframin; approximately 256 different loss-of-function mutations have been reported so far. Wolfram syndrome 2 (MIM #604928) was described for the first time in the year 2000 in a large consanguineous Jordanian family [2]. Affected individuals presented with new phenotypic features: peptic ulcer disease, bleeding tendency secondary to a platelet aggregation abnormality and absence of diabetes insipidus [3]. In 2007, a missense mutation was reported in a novel gene, CISD2, mapping in 4q24 [4]. There are no other reports of new cases of Wolfram syndrome 2 after the original description of the Jordanian family and the identification of CISD2 gene. We now report a novel CISD2 mutation, causing Wolfram syndrome 2 in an Italian family. Managed by Massimo Porta.