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

  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]

• Male Hypogonadism

  Pituitary gland dysfunction can also cause hypogonadism in males. The lack of testosterone that occurs with hypogonadism affects growth and sexual development. [ghr.nlm.nih.gov]

  Delayed sexual maturation and male hypogonadism due to primary gonadal failure have been reported in 6% of male patients. Our patient had unilateral undescended testes. This feature has not been reported previously. [ijpmonline.org]

  hypogonadism Decreased function of male gonad 0000026 Myopathy Muscle tissue disease 0003198 Ophthalmoplegia Eye muscle paralysis 0000602 Peripheral neuropathy 0009830 Respiratory insufficiency Respiratory impairment 0002093 Sleep disturbance Difficulty [rarediseases.info.nih.gov]

• 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]

• Anosmia

  Moreover, some peculiar signs occurred such as anosmia, ophthalmoplegia interna, and central nystagmus. [ncbi.nlm.nih.gov]

  Diagnosis A combination of juvenile-onset diabetes mellitus and optic nerve atrophy plus one or more of the following: anosmia, brain stem signs (gaze palsies, nystagmus, dysarthria, dysphagia, primary respiratory failure), deafness, seizures or myoclonus [accessanesthesiology.mhmedical.com]

  Other neurological problems experienced by people with Wolfram syndrome include irregular breathing caused by the brain's inability to control breathing (central apnea), loss of the sense of smell (anosmia), loss of the gag reflex, muscle spasms (myoclonus [medlineplus.gov]

• Respiratory Insufficiency

  insufficiency have all been documented. [symptoma.com]

  insufficiency Respiratory impairment 0002093 Sleep disturbance Difficulty sleeping Trouble sleeping [ more ] 0002360 Percent of people who have these symptoms is not available through HPO Abnormal bleeding Bleeding tendency 0001892 Abnormality of the [rarediseases.info.nih.gov]

• 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]

  […] curid=18421017 Primary polydipsia Psychogenic Polyuria Polydipsia Nocturia Dry mucus membrane History of psychiatric disorders Gestational diabetes insipidus Polyuria Polydipsia Nocturia Pregnancy Dry mucus membranes Pregnancy Diabetes mellitus Polyuria [wikidoc.org]

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

• Hypertension

  A girl and her younger brother had insulin-dependent diabetes mellitus at 11 years old with early onset of renal impairment, proteinuria and hypertension. Urinary tract dilatation was demonstrated in both patients. [ncbi.nlm.nih.gov]

  Patient was on testosterone and anti hypertensives. He was diagnosed of hypocontractile bladder and congenital bilateral megaureter with vesico-ureteric reflux 2 years back. History of hemiparesis 2 years back. [ijpmonline.org]

  […] committee, Ohio State Named to the Castle Connolly list of “Regional Top Doctors,” 2014–2019 Procedures and Conditions I Treat WAGR Syndrome Optic Nerve Injuries Eye Tumors Eye Abnormalities Conjunctival Diseases Eye Hemorrhage Eye Manifestations Ocular Hypertension [wexnermedical.osu.edu]

• Visual Impairment

  Optic atrophy: Caused by death of the optic nerve leading to visual impairment and sometimes grey vision. Deafness : Difficulty hearing high pitched sounds or within crowded rooms. [diabetes.co.uk]

  Initially, all of these patients were treated as having type 1 diabetes with progressive visual impairment despite good metabolic control (mean HbA1c 7.5±1.3%). [ncbi.nlm.nih.gov]

  The second case is a 55-year-old man with a past medical history of learning difficulties since childhood, and visual impairment since adolescence. [elsevier.es]

  Visual impairment, starting with wearing glasses, but rapidly increasing. You find yourself holding books of all kinds very close to your face. Color blindness. Socks never match the outfit. The lawn has many patches of missed grass, after cutting. [wolframsyndrome.org]

• Visual Impairment

  Optic atrophy: Caused by death of the optic nerve leading to visual impairment and sometimes grey vision. Deafness : Difficulty hearing high pitched sounds or within crowded rooms. [diabetes.co.uk]

  Initially, all of these patients were treated as having type 1 diabetes with progressive visual impairment despite good metabolic control (mean HbA1c 7.5±1.3%). [ncbi.nlm.nih.gov]

  The second case is a 55-year-old man with a past medical history of learning difficulties since childhood, and visual impairment since adolescence. [elsevier.es]

  Visual impairment, starting with wearing glasses, but rapidly increasing. You find yourself holding books of all kinds very close to your face. Color blindness. Socks never match the outfit. The lawn has many patches of missed grass, after cutting. [wolframsyndrome.org]

• 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]

  impairment and impaired glucose regulation caused by a missense mutation in the WFS1 gene. 53 62 Eiberg H...Tranebjaerg L 16648378 2006 25 Genetics of hearing loss: Allelism and modifier genes produce a phenotypic continuum. 53 62 McHugh RK...Friedman [malacards.org]

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

  Neurol India 2016;64:1312-3 The authors report the case of a 27-year-old male patient who presented with progressive visual diminution, bilateral sensorineural hearing impairment, and history of juvenile-onset diabetes mellitus; however, cranial magnetic [neurologyindia.com]

• Polyuria

  […] curid=18421017 Primary polydipsia Psychogenic Polyuria Polydipsia Nocturia Dry mucus membrane History of psychiatric disorders Gestational diabetes insipidus Polyuria Polydipsia Nocturia Pregnancy Dry mucus membranes Pregnancy Diabetes mellitus Polyuria [wikidoc.org]

  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]

• Kidney Failure

  You also don’t tend to get microvascular complications like retinopathy (which can cause blindness) or nephropathy (which can cause kidney failure). [diabetes.org.uk]

  […] urine being produced Dehydration Loss of body fluids from the bloodstream into the tissues due to: burns or severe infections (sepsis) or heart, liver, or kidney failure Psychogenic polydipsia – compulsive water drinking associated with mental/psychiatric [diabetes.co.uk]

• Ataxia

  Additional clinical findings may include renal abnormalities, ataxia, dementia, intellectual disability, and psychiatric illness. The minimal criteria for diagnosing Wolfram syndrome are juvenile onset diabetes mellitus and optic atrophy. [dnatesting.uchicago.edu]

  Spinocerebellar ataxia type 1 with multiple system degeneration and glial cytoplasmic inclusions. Ann Neurol 1996;39:241–55 ↵ Bürk K, Abele M, Fetter M, et al. [ajnr.org]

  Neurological complications such as ataxia, autonomic nervous system dysfunction, mental retardation and brainstem atrophy occur in 3rd to 4th decade. [diapedia.org]

• Nystagmus

  Subjects were also examined for presence or absence of afferent pupillary defects, cataracts, nystagmus, and strabismus. [ncbi.nlm.nih.gov]

  Clinical aspects Diabetes mellitus, diabetes insipidus, optic nerve atrophy, sensorineural hearing loss, autonomic dysfunction, cardiomyopathy, mental retardation, seizures, nystagmus, hydronephrosis, megaloblastic ... [accessanesthesiology.mhmedical.com]

• Peripheral Neuropathy

  Several other features are observed in patients including deafness, ataxia, and peripheral neuropathy. A gene called WFS1 is identified on chromosome 4p, responsible for Wolfram syndrome. [ncbi.nlm.nih.gov]

  In addition to these diagnostic syndromes, most WS patients have several neurological and neuropathological features such as ataxia, peripheral neuropathies, seizures and diffuse and widespread atrophy in the brain. [jnss.org]

  neuropathy), and intellectual impairment. [ghr.nlm.nih.gov]

  WFS can manifest with various other neurological findings (e.g., peripheral neuropathy, ataxia, and cognitive impairment)[1][2][3] or other systemic findings (e.g., renal tract abnormalities, gonadal atrophy, and psychiatric disturbances).[1][4] Classically [eyewiki.aao.org]

• Cerebellar Ataxia

  Autosomal dominant cerebellar ataxia type I: clinical features and MRI in families with SCA1, SCA2 and SCA3. Brain 1996;119:1497–505 ↵ Giuffrida S, Saponara R, Restivo DA, et al. [ajnr.org]

  Most of the brain dysfunctions include cerebellar ataxia, cognitive impairment, nystagmus, dysphagia, and central sleep apneas. [istem.eu]

  Many patients develop cerebellar ataxia resulting in gait and balance issues10. Other issues include peripheral neuropathy, loss of gag reflex, myoclonus, mental retardation, seizures, and dementia1. [morancore.utah.edu]

• Neurologic Manifestation

  Additional neurologic manifestations include truncal ataxia, myoclonus, epilepsy, nystagmus, and hyposmia.(1,2.) [ncbi.nlm.nih.gov]

  Manifestations Sensation Disorders Vision Disorders Blindness Deaf-Blind Disorders Hearing Disorders Hearing Loss Deafness Deaf-Blind Disorders Neurodegenerative Diseases Heredodegenerative Disorders, Nervous System Optic Atrophies, Hereditary Diseases [hon.ch]

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].

• Hyperglycemia

  Typically, WFS necessitates insulin treatment similar to type 1 diabetes (T1D), but the mechanism of beta cell mass reduction leading to hyperglycemia is different. [ncbi.nlm.nih.gov]

  This is an intriguing finding because hyperglycemia occurs on top of tissue ER stress in Wolfram syndrome. [care.diabetesjournals.org]

  […] bloodstream into the tissues due to: burns or severe infections (sepsis) or heart, liver, or kidney failure Psychogenic polydipsia – compulsive water drinking associated with mental/psychiatric disorders Excessive thirst can be caused by high blood sugar (hyperglycemia [diabetes.co.uk]

  The underlying depression begets worsened glycemic control, leading to decreased beta cell function and even worse hyperglycemia. [hoajonline.com]

Consequently, novel treatments designed for WS may have broader implications for more common medical conditions related to ER stress and dysfunction. [wsresearchalliance.org]

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]

CRISPR CAS 9 Understanding the Treatment Plan Although Wolfram syndrome is a rare disorder, novel treatments for WS can also treat patients suffering from diabetes, neurodegenerative diseases, and retinal degeneration. [unravelwolframsyndrome.com]

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]

Treatment for Wolfram syndrome involves treating each of the individual symptoms. Diabetes insipidus: Controlled by taking the hormone vasopressin either by nasal spray, tablets or by injection. [diabetes.co.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]

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]

In this article, we describe natural history and etiology, provide recommendations for diagnosis and clinical management, and introduce new treatments for Wolfram syndrome. Leggi l'articolo completo (in inglese): leggi online scarica pdf [regione.lazio.it]

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]

The Power of Wolfram syndrome Although Wolfram syndrome is an ultra-rare genetic disorder, its constituent medical components (e.g. diabetes mellitus, deafness, and retinal degeneration) and underlying ER pathophysiology are individually present in many [wsresearchalliance.org]

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]

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]

Recent research also suggests it can prevent the destruction of insulin-secreting beta cells in animal models of Wolfram syndrome. Researchers at Washington University School of Medicine in St. [medicalxpress.com]

The cell death is preceded by a reduction in p21 protein, which is a target for preventing Wolfram Syndrome (WS)-related neurodegeneration. [birmingham.ac.uk]

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.