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].

• Fatigue

  Digestive disorders: including constipation and diarrhoea Chronic fatigue Depression Causes of Wolfram syndrome Wolfram syndrome is caused by a mutation in the WFS1 gene. [diabetes.co.uk]

  Chronic fatigue: People with Wolfram Syndrome have a progressively declining levels of physical stamina. As this condition progresses they will need increasingly greater amounts of sleep. [diabetes.org.uk]

• Weight Gain

  The problems an individual DIABETES MELLITUS may have can include: Frequent thirst and urination Slow healing Weight loss or lack of weight gain or growth with children Itching Constant hunger Dryness of skin The management of DIABETES MELLITUS in WS [syndrome.org]

  The complaints a person with DM may have may include: slow healing, frequent thirst and urination, weight loss, ( or lack of weight gain or growth in children) constant hunger, itching and/or dryness of the skin. [didmoad.org]

  gain Elevated blood sugar levels >126 Elevated HbA1c > 6.5 Other differentials Wolfram syndrome must be differentiated from other similar conditions which lead to multiple endocrine disorders such as autoimmune polyendocrine syndrome, POEMS syndrome, [wikidoc.org]

• Polydipsia

  Although the Wolfram syndrome is rare, it should be considered in diabetic patients with unexplained optic atrophy and hearing loss or with polyuria and polydipsia in the presence of adequate blood sugar control. [ncbi.nlm.nih.gov]

  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 [symptoma.com]

  Causes of polydipsia Increased thirst is often the reaction to fluid loss during exercise, or to eating salty or spicy foods. [diabetes.co.uk]

• Hearing Impairment

  The subgroup of Dutch women, which was excluded from the calculations of the average hearing thresholds, showed a higher degree of hearing impairment. [ncbi.nlm.nih.gov]

  Wolfram Syndrome Type 2 is characterized by juvenile-onset diabetes mellitus, optic atrophy, high-frequency sensorineural hearing impairment, urinary tract dilatation, impaired renal function, hypogonadism, and severe gastrointestinal ulcer and bleeding [preventiongenetics.com]

  In contrast, DFNA6/14 hearing impairment appears to be composed of a large proportion of hereditary LFSNHL. [jamanetwork.com]

• Polyuria

  Although the Wolfram syndrome is rare, it should be considered in diabetic patients with unexplained optic atrophy and hearing loss or with polyuria and polydipsia in the presence of adequate blood sugar control. [ncbi.nlm.nih.gov]

  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 [symptoma.com]

• Urinary Urgency

  Due to maintaining nocturnal enuresis and exacerbation of urinary urgency and incontinence, he was started on oxybutynin (up to 5mg twice a day) for suspected neurogenic bladder. [elsevier.es]

• Overflow Incontinence

  However, severe depression, psychosis, impulsivity, and verbal and physical aggression can result.[4][31] Genitourinary symptoms vary widely; bladder instability or atony can cause urge or overflow incontinence, respectively. [eyewiki.aao.org]

• Headache

  If she sits even for half an hour at a stretch, her legs and hands swell, and she starts getting splitting headaches. [timesofindia.indiatimes.com]

  Raquel struggles with severe diabetes, bladder issues and unbearable headaches, apart from blindness and hearing loss. This disease is slowly stripping my child of her independence and her ability to enjoy life like most children her age. [thesnowfoundation.org]

  There was no history of fever, headache, convulsions, trauma, or any other contributing factors. Neither did we record a history of polyuria, visual deficit nor hearing loss. [cjhr.org]

  However, our WFS sample had similar scores to children with Moyamoya disease (characterized by loss of neurological function, stroke, seizures, and headaches, [ 30 ]), children with visual impairments due to hereditary retinal disorders [ 31 ], and children [content.iospress.com]

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].

• Hyponatremia

  Hyponatremia is commonly seen in WFS1, and is thought to partly be due to partial central DI. [eyewiki.aao.org]

Urano’s efforts, treatments for WS are within our grasp. For more information please see Dr. Urano's blog and clinical trials. A treatment is in clinical trial now and other treatments are being evaluated for clinical trial in the near future. [unravelwolframsyndrome.com]

[citation needed] Treatment[edit] There is no known direct treatment. [en.wikipedia.org]

In this article, we describe natural history and etiology, provide recommendations for diagnosis and clinical management, and introduce new treatments for Wolfram syndrome. [ncbi.nlm.nih.gov]

New treatment for rare disease The technology The University of Birmingham has a candidate drug for Wolfram Syndrome, a rare (1 in 700,000), life-limiting disease that currently has no treatment. [birmingham.ac.uk]

Prognosis of the cardinal clinical signs is such that optic atrophy, though usually quite rapid in the beginning, generally does not lead to complete blindness. [ncbi.nlm.nih.gov]

Diagnosis and Prognosis: The diagnosis can be made by multiple specialists because of the multisystem nature of this disorder. The prognosis is poor as most features are progressive and death by the age of 30 years is not uncommon. [disorders.eyes.arizona.edu]

CISD2 expression is a novel marker correlating with pelvic lymph node metastasis and prognosis in patients with early-stage cervical cancer. Liu L, Xia M, Wang J, Zhang W, Zhang Y, He M. Liu L, et al. [pubmed.ncbi.nlm.nih.gov]

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 [symptoma.com]

We discuss the etiology of our patient's postoperative events, and conclude that kidney transplantation may expose dormant manifestations-or aggravate existing manifestations-of Wolfram syndrome. [ncbi.nlm.nih.gov]

Etiology 2 causative genes have been identified: WFS1 (4p16.1) which codes for Wolframin, a protein localized to the endoplasmic reticulum (ER) and which plays a role in calcium homeostasis and unfolded protein response. [orpha.net]

Three patients originated from the studied regions with complete epidemiological data on paediatric diabetes. The total number of patients with diagnosed diabetes in the study equalled 2,568 cases. [ncbi.nlm.nih.gov]

The goal of our study is to highlight the epidemiological, clinical and genetic features of this syndrome among children. [chu-fes.ma]

Summary Epidemiology The prevalence is estimated to be 1/770,000 in UK. Clinical description Onset of WS1 lies in the first decade and it is characterized with DM (91% of cases), OA (87%). [orpha.net]

Epidemiology of WS1 WS1 is a very rare neurodegenerative disease. [encyclopedia.pub]

These researches provide interesting insight into the relation of neurodegenerative diseases, mitochondrial disorders, and autophagy and are useful for the pathophysiological understanding of both Wolfram syndrome and mitochondrial-mediated premature [ncbi.nlm.nih.gov]

Pathophysiology Caused by a mutation in the gene encoding wolframin (WFS1) on chromosome 4p16.1. Another locus for the disorder has been mapped to 4q (WFS2). [accessanesthesiology.mhmedical.com]

We hope that these findings open new horizons to future molecular investigations which may help to prevent and treat this devastating disease. [ncbi.nlm.nih.gov]

It is important for early diagnosis and treatment to evaluate type 1 diabetes patients in terms of Wolfram syndrome components, this may prevent complications. [endocrine-abstracts.org]

Dantrolene blocks that enzyme and also prevents brain cell death in animal and cell models of the disorder. [medicalxpress.com]

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.