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Wolfram Syndrome

DIDMOAD

Wolfram syndrome is a very rare autosomal recessive genetic disease comprising of diabetes insipidus, diabetes mellitus, atrophy of the optic nerve, deafness, and progressive neurological deterioration. Most patients develop symptoms in the first two decades of life, and the majority suffer from numerous complications that end in premature death at some point in adulthood, mainly due to neurological disability and respiratory insufficiency. A thorough clinical workup and genetic studies are vital in order to make the diagnosis.


Presentation

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].

Camping
  • ER stress and mutant WFS1 inhibit complex formation and activation of AC8, reducing cAMP synthesis and insulin secretion.[ncbi.nlm.nih.gov]
  • NAF-1 repression in INS-1 cells decreased insulin content and glucose-stimulated insulin secretion, while maintaining the response to cAMP, and enhanced the accumulation of labile iron and reactive oxygen species in mitochondria.[ncbi.nlm.nih.gov]
  • Cryns K, Sivakumaran TA, Van den Ouweland JM, Pennings RJ, Cremers CW, Flothmann K, Young TL, Smith RJ, Lesperance MM, Van Camp G.[ghr.nlm.nih.gov]
  • The WFS1 gene also plays a key role in intracellular calcium homeostasis and cAMP mediated signaling. Recent studies have suggested that WFS1 deficiency may also lead to impaired acidification of insulin secretory granules [ 9, 10 ].[hoajonline.com]
Goiter
  • In addition, two had goiter, two delayed puberty, one seizure and one mental retardation with depression attacks. Urinary tract dilatation was recorded in five patients. Four patients developed typical complications of DM.[ncbi.nlm.nih.gov]
Polydipsia
  • This syndrome should be considered in young diabetic patients with unexplained visual loss or with polyuria and polydipsia in the presence of adequate blood sugar control.[ncbi.nlm.nih.gov]
  • 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]
  • DESIGN AND METHODS: Sequencing of AVP and WFS1 genes was performed in nine children with CDI, aged between 9 and 68 months, and negative family history for polyuria and polydipsia.[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]
  • He has presented with polyuria, polydipsia, bedwetting, visual impairment, hearing loss, and quick emotional upset/agitation. His height was 139 cm and weight was 30.4 kg.[japi.org]
Hepatomegaly
  • We report possible additional clinical and laboratory findings that have not been pre-viously reported, such as asymptomatic hypoparathyroidism, osteomalacia, growth hormone (GH) deficiency and hepatomegaly.[ncbi.nlm.nih.gov]
Babinski Sign
  • These correlated with anosmia, loss of vision, loss of hearing, cerebellar symptoms and signs, Babinski sign, and clonus, respectively, clinically observed in this patient.[ncbi.nlm.nih.gov]
Clonus
  • These correlated with anosmia, loss of vision, loss of hearing, cerebellar symptoms and signs, Babinski sign, and clonus, respectively, clinically observed in this patient.[ncbi.nlm.nih.gov]
Sleep Disturbance
  • Standardized self- and parent-report questionnaires on psychiatric symptoms and sleep disturbances were acquired from all groups and an unstructured psychiatric interview was performed within only the WFS group.[ncbi.nlm.nih.gov]
Polyuria
  • This syndrome should be considered in young diabetic patients with unexplained visual loss or with polyuria and polydipsia in the presence of adequate blood sugar control.[ncbi.nlm.nih.gov]
  • 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]
  • DESIGN AND METHODS: Sequencing of AVP and WFS1 genes was performed in nine children with CDI, aged between 9 and 68 months, and negative family history for polyuria and polydipsia.[ncbi.nlm.nih.gov]
  • Persistent hypernatremia, iposmolar polyuria and high plasma osmolality suggested DI, confirmed by a normal urine concentration after vasopressin test. Treatment with vasopressin allowed a normalization of sodium levels and urine output.[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]

Workup

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].

HLA-DR2
  • Two of three patients with Wolfram syndrome had the HLA-DR2 antigen. Combining our cases with those described in the literature, 7 of 11 patients have the HLA-DR2 antigen.[ncbi.nlm.nih.gov]
  • In conclusion, whereas HLA may increase susceptibility to the WS, as shown by the existence of an HLA-DR2 association, the major genetic influence on the inheritance of the WS must be at another locus.[ncbi.nlm.nih.gov]
  • Both patients were HLA DR2 positive. At 16 years old, her creatinine clearance was 16 ml/min/1.73 m2. Her brother's creatinine clearance was 25 ml/min/1.73 m2 at 13 years old.[ncbi.nlm.nih.gov]

Treatment

  • Treatment with GLP-1-RA and/or iron chelation improves mitochondrial function and restores β-cell function.[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]
  • 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]
  • The two possible treatments are: A- Sodium Valproate treatment This treatment is for 3 years, until final assessments to see if it works. These are tablets. B- Placebo treatment This is also for 3 years.[wolframsyndrome.dom.wustl.edu]
  • 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]

Prognosis

  • 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]
  • The prognosis of this syndrome is currently poor, and many patients die prematurely with severe neurological disabilities, raising the urgency for developing novel treatments for Wolfram syndrome.[ncbi.nlm.nih.gov]
  • It illustrates the wide variety of neurologic signs in this syndrome and the necessity of rapid therapeutic coverage to improve the prognosis. Copyright 2010 American Neurological Association.[ncbi.nlm.nih.gov]
  • LEVEL OF EVIDENCE: Level II (National cohort study of prognosis). Crown Copyright 2017. Published by Elsevier Inc. All rights reserved.[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]

Etiology

  • 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.[ncbi.nlm.nih.gov]
  • The etiology involves a single gene mutation of the wolframin protein inducing endoplasmic reticulum stress and apoptosis in selected cell types with resultant diabetes insipidus, diabetes mellitus, optic atrophy, and sensory-neural deafness.[ncbi.nlm.nih.gov]
  • The aim of this study was to identify the molecular etiology of WS and to perform a possible genotype-phenotype correlation in Iranian kindred. An Iranian family with two patients was clinically studied and WS was suspected.[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]

Epidemiology

  • 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]
  • BACKGROUND: Since the original description, there have been only few epidemiological studies of Wolfram syndrome (WS).[ncbi.nlm.nih.gov]
  • 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]
Sex distribution
Age distribution

Pathophysiology

  • The ophthalmologic, urologic, otologic, psychiatric and endocrine findings of the syndrome are discussed as well as their pathophysiology. Two recent reports with features atypical of the Wolfram syndrome are discussed.[ncbi.nlm.nih.gov]
  • By contrast, pathophysiological deletion mutants of WFS1 lacking the degron, such as W648X, Y660X, and Q667X, are resistant to degradation by Smurf1. Depletion of Smurf1 by RNA interference results in increased WFS1 and decreased ATF6α levels.[ncbi.nlm.nih.gov]
  • 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]
  • These measures may provide objective indices of Wolfram syndrome pathophysiology that will be useful in unraveling the underlying mechanisms and in testing the impact of treatments on the brain.[ncbi.nlm.nih.gov]

Prevention

  • An early diagnosis is important to prevent unnecessary diagnostic investigations.[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]
  • The benefits of continuous subcutaneous insulin infusion and that of tight metabolic control in prevention of abortions and fetal malformations in diabetes associated with pregnancy are well documented.[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]

References

Article

  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.

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Last updated: 2019-07-11 21:42