ESPE Abstracts

Background: Wolfram syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by non-autoimmune diabetes mellitus and progressive optic atrophy. WS includes other possible disorders, such as diabetes insipidus, sensorineural deafness, genitourinary tract problems, neurological or psychiatric disorders and others.

Case presentation: A 12-years-old boy presented with glicosuria and shortly developed insulin-dependent diabetes mellitus. Autoimmune markes for diabetes were negative, insulin requirement ranged from 0.22 to 0.43 U/kg per day) and HbA1c from 53 to 59 mmol/mol). Family history for autoimmunity was negative. Genetic tests for monogenic diabetes were performed and no mutations for GCK-MODY 2 and HNFA1-MODY 3 were found. At age 16 years metabolic control worsened and optic atrophy was identified during a routinary eye examination and confirmed by MRI. Wolframin (WFS1) gene was analysed and compound heterozygosity for a missense and a frameshift mutations in exon 8 was found: c.(2104G>A)+(2155_2168dup14); p.(Gly702Ser)+(Phe725fs). The missense mutation, paternally inherited, is annotated by Human Gene Mutation Database (HGMD), but no phenotype description is available. The frameshift mutation, also detected in the mother, is a 14 bp duplication, not previously reported. It causes a frameshift which results in a premature stop codon, predicting a truncated protein of 25 amino acids shorter than the wild-type wolframin. No mutation was shared by the twin brother. No signs of central diabetes insipidus or any other diseases associated with WS were found. Our report of a novel inactivating mutation increases the spectrum of WFS1 defects and contributes to establish phenotype-genotype relationship.

Conclusion: WS diagnosis is often delayed and misdiagnosed as autoimmune diabetes. The rarity of the condition and the absence of other diseases at diabetes diagnosis makes extremely challenging the recognition of WS. However the compound heterozygosity for the here reported mutations, even markedly altering the protein structure, seems to confer a mild phenotype among the spectrum of WS manifestations.