Wolfram syndrome, a rare neurodegenerative disease: from pathogenesis to future treatment perspectives

J Transl Med. 2019 Jul 23;17(1):238. doi: 10.1186/s12967-019-1993-1.


Background: Wolfram syndrome (WS), a rare genetic disorder, is considered the best prototype of endoplasmic reticulum (ER) diseases. Classical WS features are childhood-onset diabetes mellitus, optic atrophy, deafness, diabetes insipidus, neurological signs, and other abnormalities. Two causative genes (WFS1 and WFS2) have been identified. The transmission of the disease takes place in an autosomal recessive mode but autosomal dominant mutations responsible for WS-related disorders have been described. Prognosis is poor, death occurs at the median age of 39 years with a major cause represented by respiratory failure as a consequence of brain stem atrophy and neurodegeneration. The aim of this narrative review is to focus on etiology, pathogenesis and natural history of WS for an adequate patient management and for the discussion of future therapeutic interventions.

Main body: WS requires a multidisciplinary approach in order to be successfully treated. A prompt diagnosis decreases morbidity and mortality through prevention and treatment of complications. Being a monogenic pathology, WS represents a perfect model to study the mechanisms of ER stress and how this condition leads to cell death, in comparison with other prevalent diseases in which multiple factors interact to produce the disease manifestations. WS is also an important disease prototype to identify drugs and molecules associated with ER homeostasis. Evidence indicates that specific metabolic diseases (type 1 and type 2 diabetes), neurodegenerative diseases, atherosclerosis, inflammatory pathologies and also cancer are closely related to ER dysfunction.

Conclusions: Therapeutic strategies in WS are based on drug repurposing (i.e., investigation of approved drugs for novel therapeutic indications) with the aim to stop the progression of the disease by reducing the endoplasmic reticulum stress. An extensive understanding of WS from pathophysiology to therapy is fundamental and more studies are necessary to better manage this devastating disease and guarantee the patients a better quality of life and longer life expectancy.

Keywords: Deafness; Diabetes insipidus; Optic atrophy; Type 1 diabetes; WFS1; WFS2; Wolfram syndrome.

Publication types

  • Review

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Clinical Trials as Topic
  • Diabetes Mellitus, Type 1 / complications
  • Diabetes Mellitus, Type 1 / diagnosis
  • Diabetes Mellitus, Type 1 / etiology
  • Diabetes Mellitus, Type 1 / therapy
  • Disease Progression
  • Drug Development
  • Drug Repositioning
  • Endoplasmic Reticulum / metabolism
  • Female
  • Genes, Recessive
  • Humans
  • Infant
  • Interdisciplinary Communication
  • Male
  • Membrane Proteins / genetics
  • Neurodegenerative Diseases / complications
  • Neurodegenerative Diseases / diagnosis*
  • Neurodegenerative Diseases / etiology
  • Neurodegenerative Diseases / therapy*
  • Prognosis
  • Quality of Life
  • Wolfram Syndrome / complications
  • Wolfram Syndrome / diagnosis*
  • Wolfram Syndrome / etiology
  • Wolfram Syndrome / therapy*
  • Young Adult


  • Membrane Proteins
  • wolframin protein