ESPE Abstracts (2015) 84 FC3.4


Wolfram Syndrome: Natural History and Genotype–Phenotype Correlation Based on EURO-WABB Registry Show Gender Differences in Disease Severity

Renuka Diasa,b, Caitlin Richensa, Dewi Astutib, Peter Nightingalec, Ségolène Ayméd, Miguel Lopez de Herediae,f, Virginia Nunese,f, Pietro Maffeig, Susan McCaffertyh, Wojciech Młynarskii, Kay Parkinsonj, Véronique Paquis-Flucklingerk, Julia Rohayeml, Richard Sinnottm, Vallo Tillmannn, Lisbeth Tranebjærgo,p & Timothy Barretta,b


aBirmingham Children’s Hospital, Birmingham, UK; bUniversity of Birmingham, Birmingham, UK; cUniversity Hospitals Birmingham NHS Trust, Birmingham, UK; dINSERM - SC11, Paris, France; eIDIBELL, Hospital Duran i Reynals, Barcelona, Spain; fHospital Duran i Reynals, Barcelona, Spain; gUniversità degli studi di Padova, Padua, Italy; hNational eScience Centre, Glasgow, UK; iMedical University of Lodz, Lodz, Poland; jAlstrom Syndrome UK, Devon, UK; kUniversite Nice Sophia-Antipolis, Nice, France; lUniversitätsklinikum Münster, Munster, Germany; mUniversity of Melbourne, Melbourne, Australia; nTartu University Children’s Hospital, Tartu, Estonia; oH:S Bispebjerg Hospital, Copenhagen, Denmark; pUniversity of Copenhagen, Copenhagen, Denmark

Background: Wolfram syndrome (WS) is a rare autosomal recessive disorder, characterised by early-onset diabetes and optic atrophy. It is caused by mutations in WFS1.

Objective and hypotheses: This study aimed to comprehensively review the natural history of WS in a large cohort of patients from the EURO-WABB registry.

Method: Data from EURO-WABB patients with WS was analysed in conjunction with the Leiden Open Variation Database (LOVD) for genotype–phenotype correlation.

Results: 174 WS patients (90M:84F) had standardised data available. Mean age of diagnosis was 8.39 years (S.D. 4.39). Most patients followed a classical sequence of clinical manifestations (deafness – median age of onset 1 (range 0–9 years); insulin-dependent diabetes – 5 (1–32 years); optic atrophy – 8 (0–32 years); diabetes insipidus – median age – 13 (3–34 years); urological abnormalities – median age 16 (12–20 years) and neurological abnormalities – median age 25.5 (7–40 years)). 11 patients (6.3%) had hypergonadotrophic hypogonadism. A proportion of patients had abnormalities not usually associated with WS: retinal dystrophy (4.6%, n=8), chronic renal failure (5.7%; n=10) and cardiomyopathy (2.8%, n=5). 91 patients had mutations found in both alleles. 16 patients had only one mutation identified. 56 patients had no mutation in either allele identified. 80.8% of all mutations were located within exon 8. Most mutations were nonsense with predicted effects of reduced or truncated WFS1 protein. There was no significant genotype-phenotype correlation for age of onset of diabetes or optic atrophy (nonsense vs missense mutations). There was a gender difference in disease severity with earlier age of onset of insulin dependent diabetes (M=4 years; F=5 years; P=0.04) and incidence of mental health disorders with males being more frequently affected (26M:15F) although this was not significant.

Conclusion: Analysis of the core data from EURO-WABB, the largest standardised patient cohort to date, shows a sequence of clinical manifestations similar to published literature. The phenotypic spectrum of WS is much wider than previously reported. Of note, is the male preponderance with mental health problems including depression and psychosis.