Wolfram Syndrome Type 2: A Systematic Review of a Not Easily Identifiable Clinical Spectrum

Background: Wolfram syndrome (WS) is a rare autosomal recessive disorder that is characterized by the presence of diabetes mellitus, optic atrophy and hearing loss, all of which are crucial elements for the diagnosis. WS is variably associated with diabetes insipidus, neurological disorders, urinary tract anomalies, endocrine dysfunctions and many other systemic manifestations. Since Wolfram and Wagener first described WS in 1938, new phenotypic/genotypic variants of the syndrome have been observed and the clinical picture has been significantly enriched. To date, two main subtypes of WS that associated with two different mutations are known: WS type 1 (WS1), caused by the mutation of the wolframine gene (WS1; 606201), and WS type 2 (WS2), caused by the mutation of the CISD2 gene (WS2; 604928). Methods: A systematic review of the literature was describe the phenotypic characteristics of WS2 in order to highlight the key elements that differentiate it from the classic form. Conclusion: WS2 is the rarest and most recently identified subtype of WS; its clinical picture is partially overlapping with that of WS1, from which it traditionally differs by the absence of diabetes insipidus and the presence of greater bleeding tendency and peptic ulcers.

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Wolfram Syndrome: A Case Report and Review of Clinical Manifestations, Genetics Pathophysiology, and Potential Therapies

Case Reports in Endocrinology ◽

10.1155/2018/9412676 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

N. B. Toppings ◽

J. M. McMillan ◽

P. Y. B. Au ◽

O. Suchowersky ◽

L. E. Donovan

Keyword(s):

Diabetes Mellitus ◽

Optic Atrophy ◽

Cell Function ◽

Clinical Manifestations ◽

Autosomal Recessive Disorder ◽

Wolfram Syndrome ◽

Biallelic Mutations ◽

Therapeutic Considerations

Background.Classical Wolfram syndrome (WS) is a rare autosomal recessive disorder caused by mutations inWFS1,a gene implicated in endoplasmic reticulum (ER) and mitochondrial function. WS is characterized by insulin-requiring diabetes mellitus and optic atrophy. A constellation of other features contributes to the acronym DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness). This review seeks to raise awareness of this rare form of diabetes so that individuals with WS are identified and provided with appropriate care.Case.We describe a woman without risk factors for gestational or type 2 diabetes who presented with gestational diabetes (GDM) at the age of 39 years during her first and only pregnancy. Although she had optic atrophy since the age of 10 years, WS was not considered as her diagnosis until she presented with GDM. Biallelic mutations inWFS1were identified, supporting a diagnosis of classical WS.Conclusions.The distinct natural history, complications, and differences in management reinforce the importance of distinguishing WS from other forms of diabetes. Recent advances in the genetics and pathophysiology of WS have led to promising new therapeutic considerations that may preserveβ-cell function and slow progressive neurological decline. Insight into the pathophysiology of WS may also inform strategies forβ-cell preservation for individuals with type 1 and 2 diabetes.

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Case Report: Ophthalmologic Evaluation Over a Long Follow-Up Time in a Patient With Wolfram Syndrome Type 2: Slowly Progressive Optic Neuropathy as a Possible Clinical Finding

Frontiers in Pediatrics ◽

10.3389/fped.2021.661434 ◽

2021 ◽

Vol 9 ◽

Author(s):

Valentina Di Iorio ◽

Enza Mozzillo ◽

Francesco Maria Rosanio ◽

Francesca Di Candia ◽

Rita Genesio ◽

...

Keyword(s):

Optic Neuropathy ◽

Wide Spectrum ◽

Sensorineural Deafness ◽

Wolfram Syndrome ◽

Peptic Ulcers ◽

Gene Encoding ◽

Exon 2 ◽

Increased Risk

Wolfram syndrome (WFS) is a rare autosomal recessive neurodegenerative disease whose diagnosis requires diabetes mellitus and optic atrophy (OA). WFS includes a wide spectrum of other possible complications such as diabetes insipidus, sensorineural deafness, urinary tract problems, neurological and psychiatric disorders. Most WFS patients show type 1 syndrome (WFS1) caused by mutations in the WFS1 gene, encoding Wolframin protein, while few patients are affected by WFS type 2 (WFS2) due to a pathogenetic variants in the CISD2 gene encoding an endoplasmic reticulum intermembrane small protein. WFS2 is considered a phenotypic and genotypic variant of WFS, from which differs only for the increased risk of bleeding and presence of peptic ulcers. OA and diabetes are considered cardinal features of WFS. We hereby report the ophthalmologic evaluation in a patient, previously described, with WFS2 after 8 years of follow-up. A 20-year-old white woman was referred to our retinal center for the first time in 2012 following a diagnosis of a novel intragenic exon 2 CISD2 homozygous deletion, for the suspicion of an associated bilateral OA. Fundus examination, spectral-domain optical coherence tomography, visual field, visual evoked potentials were performed and confirmed the presence of an optic neuropathy that remained stable over 8 years follow up. A slowly progressive optic neuropathy, rather than OA can characterize patients with WFS2 and CISD2 intragenic deletion.

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