Wolfram Syndrome 1: A Pediatrician’s and Pediatric Endocrinologist’s Perspective

Abstract

Wolfram syndrome 1 (WS1) is a rare autosomal recessive neurodegenerative disease caused by mutations in WFS1 and WFS2 genes that produce wolframin, a protein involved in endoplasmic reticulum calcium homeostasis and cellular apoptosis. Its main clinical features are diabetes insipidus (DI), early-onset non-autoimmune insulin-dependent diabetes mellitus (DM), gradual loss of vision due to optic atrophy (OA) and deafness (D), hence the acronym DIDMOAD. Several other features from different systems have been reported such as urinary tract, neurological, and psychiatric abnormalities. In addition, endocrine disorders that can appear during childhood and adolescence include primary gonadal atrophy and hypergonadotropic hypogonadism in males and menstrual cycle abnormalities in females. Further, anterior pituitary dysfunction with deficient GH and/or ACTH production have been described. Despite the lack of specific treatment for the disease and its poor life expectancy, early diagnosis and supportive care is important for timely identifying and adequately managing its progressive symptoms. The current narrative review focuses on the pathophysiology and the clinical features of the disease, with a special emphasis on its endocrine abnormalities that appear during childhood and adolescence. Further, therapeutic interventions that have been proven to be effective in the management of WS1 endocrine complications are discussed.

Moody Only Monogenic? A Narrative Review of the Rare and Low-Penetrant Genetic Variants

“…Several studies have documented a relevant association of WFS1 and type 2 diabetes mellitus, suggesting a possible contribution of WFS1 gene in T2DM pathogenesis. (33,34,35,36,37,38) Moreover, a missense alteration of WFS1 (Arg456His) has been also described in one case of T1DM, which could be interpreted as a potential genetic risk factor for type 1 diabetes . (39) WFS1 mutations are also responsible for diabetes development in the setting of Wolfram Syndrome 1 (WS1), a rare neurodegenerative disorder with other classical features comprising central diabetes insipidus, optic atrophy and neurosensorial deafness.…”

“…(39) WFS1 mutations are also responsible for diabetes development in the setting of Wolfram Syndrome 1 (WS1), a rare neurodegenerative disorder with other classical features comprising central diabetes insipidus, optic atrophy and neurosensorial deafness. (33) WS1 diabetes presents MODY-like features. (12,40) In particular, it is early-onset and non auto-immune insulin-dependent.…”

“…In comparison with type 1 diabetes mellitus, WS1 patients are usually characterized by inferior values of HbA1c, lower doses of insulin requirement, less cases of ketoacidosis at diagnosis and a longer remission period. (33)…”