Wolfram Syndrome

Wolfram syndrome, initially described in the first half of the 20th century, is a very rare genetic disorder that includes several clinical entities - juvenile-onset diabetes mellitus, diabetes insipidus, optic atrophy, and deafness, which is why the term DIDMOAD is sometimes used in the literature [1] [2] [3] [4] [5] [6] [7]. The onset of symptoms in Wolfram syndrome almost universally occurs in childhood and early adolescence [1] [3] [5]. Diabetes mellitus, with its typical symptoms of polyuria, polydipsia, weight loss, etc., is the first one to develop around 6 years of age, followed by atrophy of the optic nerve that presents with severe deficits in peripheral and color vision around 11 years of age [1] [2] [5]. Diabetes insipidus appears soon after, whereas a variable degree of sensorineural hearing deficit (from total hearing loss from birth to a delayed presentation of a milder impairment in adolescence that progressively worsens) has been observed [1] [2] [3]. Abnormalities of the urinary tract, such as atony of the bladder, ductal obstruction, and difficulties urinating affect up to 90% of patients and cause significant impairment in the quality of life [1] [2]. However, the main reason for a poor overall prognosis is the eventual occurrence of neurological deficits that presumably appear as a result of underlying genetic mutations - ataxia, myoclonus, dysphagia, poor autonomic system regulation (diarrhea, sweating, inability to control sphincters, etc.) reduced senses, psychiatric symptoms (mainly mood disorders), and atrophy of the brainstem that leads to respiratory insufficiency have all been documented [1] [2] [3]. Unfortunately, most patients die suffering from Wolfram syndrome at a median age of 30 years [1] [2] [3].

The diagnosis of Wolfram syndrome might be difficult to attain given the rare occurrence of this genetic disease, as studies estimate a prevalence rate of 1 in 160,000 to 770,000 individuals [1] [2]. For this reason, physicians must perform a detailed clinical examination and obtain a thorough patient history [1]. Because the autosomal recessive pattern of inheritance is established as the mode of transmission, a detailed family history might be of crucial importance for identifying similar symptoms in parents or other close relatives. Some authors claim that in all children under 16 years of age who present with diabetes mellitus and visual deficits, Wolfram syndrome must be included in the differential diagnosis [1] [5]. During the physical examination, which should include a comprehensive neurological assessment, as well as vision and hearing testing, key pieces of the clinical presentation can be revealed. To confirm the diagnosis, however, genetic testing for Wolfram syndrome 1 (WFS1) gene, located on chromosome 4, must be carried out [1] [3] [4]. The exact pathogenesis model remains unknown, but WFS1 is assumed to play a key role in the functioning of cells of both endocrine and neuronal origin [5]. In addition to WFS1 mutations, some studies have identified additional mutations that have shown autosomal dominant properties [4].

1. Urano F. Wolfram Syndrome: Diagnosis, Management, and Treatment. Curr Diab Rep. 2016;16:6.
2. Barrett TG, Bundey SE, Macleod AF. Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet. 1995;346(8988):1458–1463.
3. Barrett TG, Bundey SE. Wolfram (DIDMOAD) syndrome. J Med Genet. 1997;34(10):838–841.
4. Hansen L, Eiberg H, Barrett T, et al. Mutation analysis of the WFS1 gene in seven Danish Wolfram syndrome families; four new mutations identified. Eur J Hum Genet. 2005;13(12):1275–84.
5. Naderian G, Ashtari F, Nouri-Mahdavi K, Sajjadi V. A Case of Wolfram Syndrome. J Ophthalmic Vis Res. 2010;5(1):53-56.
6. Medlej R, Wasson J, Baz P, et al. Diabetes mellitus and optic atrophy: a study of Wolfram syndrome in the Lebanese population. J Clin Endocrinol Metab. 2004;89(4):1656-1661.
7. Rohayem J, Ehlers C, Wiedemann B, et al. Diabetes and Neurodegeneration in Wolfram Syndrome: A multicenter study of phenotype and genotype. Diabetes Care. 2011;34(7):1503-1510.