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Wolfram syndrome(DIDMOAD)

MedGen UID:
21923
Concept ID:
C0043207
Disease or Syndrome
Synonyms: Diabetes mellitus AND insipidus with optic atrophy AND deafness; DIDMOAD syndrome
SNOMED CT: Marquardt-Loriaux syndrome (70694009); DIDMOAD syndrome (70694009); Wolfram syndrome (70694009); DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, deafness) syndrome (70694009)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Related genes: CISD2, WFS1
 
Monarch Initiative: MONDO:0018105
OMIM®: 222300
Orphanet: ORPHA3463

Definition

WFS1 Wolfram syndrome spectrum disorder (WFS1-WSSD) is a progressive neurodegenerative disorder characterized by onset of diabetes mellitus (DM) and optic atrophy (OA) before age 16 years, and typically associated with other endocrine abnormalities, sensorineural hearing loss, and progressive neurologic abnormalities (cerebellar ataxia, peripheral neuropathy, dementia, psychiatric illness, and urinary tract atony). Although DM is mostly insulin-dependent, overall the course is milder (with lower prevalence of microvascular disease) than that seen in isolated DM. OA typically results in significantly reduced visual acuity in the first decade. Sensorineural hearing impairment ranges from congenital deafness to milder, sometimes progressive, hearing impairment. [from GeneReviews]

Additional descriptions

From OMIM
Wolfram syndrome-1 (WFS1) is a rare and severe autosomal recessive neurodegenerative disease characterized by diabetes mellitus, optic atrophy, diabetes insipidus, and deafness (DIDMOAD). Additional clinical features may include renal abnormalities, ataxia, dementia or impaired intellectual development, and diverse psychiatric illnesses. The minimal diagnostic criteria for Wolfram syndrome are optic atrophy and diabetes mellitus of juvenile onset. Hearing impairment in Wolfram syndrome is typically progressive and mainly affects the higher frequencies, but a small fraction of affected individuals have congenital deafness (summary by Rendtorff et al., 2011). Autosomal dominant mutations in the WFS1 gene have been found to cause low-frequency nonsyndromic deafness (600965) as well as a Wolfram syndrome-like phenotype (614296) in which affected individuals have hearing impairment with diabetes mellitus and/or optic atrophy. Genetic Heterogeneity of Wolfram Syndrome Wolfram syndrome-2 (WFS2; 604928) is caused by mutation in the CISD2 gene (611507) on chromosome 4q24.  http://www.omim.org/entry/222300
From MedlinePlus Genetics
Wolfram syndrome is a condition that affects many of the body's systems. The hallmark features of Wolfram syndrome are high blood sugar (glucose) levels resulting from a shortage of the hormone insulin (a condition called diabetes mellitus) and progressive vision loss due to degeneration of the nerves that carry information from the eyes to the brain (a condition called optic atrophy). People with Wolfram syndrome often also have pituitary gland dysfunction that results in excess urine production (a condition called diabetes insipidus), hearing loss caused by changes in the inner ear (sensorineural deafness), urinary tract problems, reduced amounts of the sex hormone testosterone in males (hypogonadism), or neurological or psychiatric disorders.

Diabetes mellitus is typically the first symptom of Wolfram syndrome, usually diagnosed around age 6. Nearly everyone with Wolfram syndrome who develops diabetes mellitus requires insulin replacement therapy. Optic atrophy is often the next symptom to appear, usually around age 11. The first signs of optic atrophy are loss of color vision and side (peripheral) vision. Over time, the vision problems get worse, and people with optic atrophy are usually blind within approximately 8 years after signs of optic atrophy first begin.

In diabetes insipidus, the pituitary gland, which is located at the base of the brain, does not function normally. This abnormality disrupts the release of a hormone called vasopressin, which helps control the body's water balance and urine production. Approximately 70 percent of people with Wolfram syndrome have diabetes insipidus. Pituitary gland dysfunction can also cause hypogonadism in males. The lack of testosterone that occurs with hypogonadism affects growth and sexual development. About 65 percent of people with Wolfram syndrome have sensorineural deafness that can range in severity from deafness beginning at birth to mild hearing loss beginning in adolescence that worsens over time. Sixty to 90 percent of people with Wolfram syndrome have a urinary tract problem. Urinary tract problems include obstruction of the ducts between the kidneys and bladder (ureters), a large bladder that cannot empty normally (high-capacity atonal bladder), disrupted urination (bladder sphincter dyssynergia), and difficulty controlling the flow of urine (incontinence).

About 60 percent of people with Wolfram syndrome develop a neurological or psychiatric disorder, most commonly problems with balance and coordination (ataxia), typically beginning in early adulthood. 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), seizures, reduced sensation in the lower extremities (peripheral neuropathy), and intellectual impairment. Psychiatric disorders associated with Wolfram syndrome include psychosis, episodes of severe depression, and impulsive and aggressive behavior.

There are two types of Wolfram syndrome with many overlapping features. The two types are differentiated by their genetic cause. In addition to the usual features of Wolfram syndrome type 1 (described above), individuals with Wolfram syndrome type 2 have stomach or intestinal ulcers and excessive bleeding after an injury. The tendency to bleed excessively combined with the ulcers typically leads to abnormal bleeding in the gastrointestinal system. People with Wolfram syndrome type 2 do not develop diabetes insipidus.

Historically, Wolfram syndrome was fatal by mid-adulthood due to complications from the many features of the condition, such as health problems related to diabetes mellitus or neurological problems. However, with better diagnosis and management, life expectancy has risen.  https://medlineplus.gov/genetics/condition/wolfram-syndrome

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Wolfram syndrome in Orphanet.

Professional guidelines

PubMed

Iafusco D, Zanfardino A, Piscopo A, Curto S, Troncone A, Chianese A, Rollato AS, Testa V, Iafusco F, Maione G, Pennarella A, Boccabella L, Ozen G, Palma PL, Mazzaccara C, Tinto N, Miraglia Del Giudice E
Int J Environ Res Public Health 2022 Feb 27;19(5) doi: 10.3390/ijerph19052755. PMID: 35270448Free PMC Article
Pallotta MT, Tascini G, Crispoldi R, Orabona C, Mondanelli G, Grohmann U, Esposito S
J Transl Med 2019 Jul 23;17(1):238. doi: 10.1186/s12967-019-1993-1. PMID: 31337416Free PMC Article
Urano F
Curr Diab Rep 2016 Jan;16(1):6. doi: 10.1007/s11892-015-0702-6. PMID: 26742931Free PMC Article

Recent clinical studies

Etiology

Ferreras C, Gorito V, Pedro J, Ferreira S, Costa C, Santos Silva R, Castro Correia C
Endokrynol Pol 2021;72(4):353-356. Epub 2021 May 19 doi: 10.5603/EP.a2021.0038. PMID: 34010437
Alfaro R, Doty T, Narayanan A, Lugar H, Hershey T, Pepino MY
Orphanet J Rare Dis 2020 Feb 22;15(1):57. doi: 10.1186/s13023-020-1335-7. PMID: 32087739Free PMC Article
Licis A, Davis G, Eisenstein SA, Lugar HM, Hershey T
Orphanet J Rare Dis 2019 Aug 2;14(1):188. doi: 10.1186/s13023-019-1160-z. PMID: 31375124Free PMC Article
Karaa A, Goldstein A
Pediatr Diabetes 2015 Feb;16(1):1-9. Epub 2014 Oct 20 doi: 10.1111/pedi.12223. PMID: 25330715
Zmyslowska A, Borowiec M, Antosik K, Szalecki M, Stefanski A, Iwaniszewska B, Jedrzejczyk M, Pietrzak I, Mlynarski W
Clin Endocrinol (Oxf) 2011 Nov;75(5):636-41. doi: 10.1111/j.1365-2265.2011.04102.x. PMID: 21564155

Diagnosis

de Muijnck C, Brink JBT, Bergen AA, Boon CJF, van Genderen MM
Surv Ophthalmol 2023 Jul-Aug;68(4):641-654. Epub 2023 Feb 9 doi: 10.1016/j.survophthal.2023.01.012. PMID: 36764396
Rigoli L, Caruso V, Salzano G, Lombardo F
Int J Environ Res Public Health 2022 Mar 9;19(6) doi: 10.3390/ijerph19063225. PMID: 35328914Free PMC Article
Zhang H, Colclough K, Gloyn AL, Pollin TI
J Clin Invest 2021 Feb 1;131(3) doi: 10.1172/JCI142244. PMID: 33529164Free PMC Article
Urano F
Curr Diab Rep 2016 Jan;16(1):6. doi: 10.1007/s11892-015-0702-6. PMID: 26742931Free PMC Article
Karaa A, Goldstein A
Pediatr Diabetes 2015 Feb;16(1):1-9. Epub 2014 Oct 20 doi: 10.1111/pedi.12223. PMID: 25330715

Therapy

Gorgogietas V, Rajaei B, Heeyoung C, Santacreu BJ, Marín-Cañas S, Salpea P, Sawatani T, Musuaya A, Arroyo MN, Moreno-Castro C, Benabdallah K, Demarez C, Toivonen S, Cosentino C, Pachera N, Lytrivi M, Cai Y, Carnel L, Brown C, Urano F, Marchetti P, Gilon P, Eizirik DL, Cnop M, Igoillo-Esteve M
Diabetologia 2023 Jul;66(7):1306-1321. Epub 2023 Mar 30 doi: 10.1007/s00125-023-05905-8. PMID: 36995380Free PMC Article
Leslie M
Science 2021 Feb 12;371(6530):663-665. doi: 10.1126/science.371.6530.663. PMID: 33574194
Zhang H, Colclough K, Gloyn AL, Pollin TI
J Clin Invest 2021 Feb 1;131(3) doi: 10.1172/JCI142244. PMID: 33529164Free PMC Article
Abreu D, Urano F
Trends Pharmacol Sci 2019 Oct;40(10):711-714. Epub 2019 Aug 13 doi: 10.1016/j.tips.2019.07.011. PMID: 31420094Free PMC Article
Pallotta MT, Tascini G, Crispoldi R, Orabona C, Mondanelli G, Grohmann U, Esposito S
J Transl Med 2019 Jul 23;17(1):238. doi: 10.1186/s12967-019-1993-1. PMID: 31337416Free PMC Article

Prognosis

Rigoli L, Caruso V, Salzano G, Lombardo F
Int J Environ Res Public Health 2022 Mar 9;19(6) doi: 10.3390/ijerph19063225. PMID: 35328914Free PMC Article
Iafusco D, Zanfardino A, Piscopo A, Curto S, Troncone A, Chianese A, Rollato AS, Testa V, Iafusco F, Maione G, Pennarella A, Boccabella L, Ozen G, Palma PL, Mazzaccara C, Tinto N, Miraglia Del Giudice E
Int J Environ Res Public Health 2022 Feb 27;19(5) doi: 10.3390/ijerph19052755. PMID: 35270448Free PMC Article
Delprat B, Maurice T, Delettre C
Cell Death Dis 2018 Mar 6;9(3):364. doi: 10.1038/s41419-018-0406-3. PMID: 29511163Free PMC Article
Astuti D, Sabir A, Fulton P, Zatyka M, Williams D, Hardy C, Milan G, Favaretto F, Yu-Wai-Man P, Rohayem J, López de Heredia M, Hershey T, Tranebjaerg L, Chen JH, Chaussenot A, Nunes V, Marshall B, McAfferty S, Tillmann V, Maffei P, Paquis-Flucklinger V, Geberhiwot T, Mlynarski W, Parkinson K, Picard V, Bueno GE, Dias R, Arnold A, Richens C, Paisey R, Urano F, Semple R, Sinnott R, Barrett TG
Hum Mutat 2017 Jul;38(7):764-777. Epub 2017 Jun 1 doi: 10.1002/humu.23233. PMID: 28432734Free PMC Article
Urano F
Curr Diab Rep 2016 Jan;16(1):6. doi: 10.1007/s11892-015-0702-6. PMID: 26742931Free PMC Article

Clinical prediction guides

Rosanio FM, Di Candia F, Occhiati L, Fedi L, Malvone FP, Foschini DF, Franzese A, Mozzillo E
Int J Environ Res Public Health 2022 Jan 12;19(2) doi: 10.3390/ijerph19020835. PMID: 35055657Free PMC Article
Delvecchio M, Iacoviello M, Pantaleo A, Resta N
Int J Environ Res Public Health 2021 Apr 30;18(9) doi: 10.3390/ijerph18094796. PMID: 33946243Free PMC Article
Alfaro R, Doty T, Narayanan A, Lugar H, Hershey T, Pepino MY
Orphanet J Rare Dis 2020 Feb 22;15(1):57. doi: 10.1186/s13023-020-1335-7. PMID: 32087739Free PMC Article
Rutishauser J, Beuret N, Prescianotto-Baschong C, Spiess M
Exp Suppl 2019;111:299-315. doi: 10.1007/978-3-030-25905-1_14. PMID: 31588537
Astuti D, Sabir A, Fulton P, Zatyka M, Williams D, Hardy C, Milan G, Favaretto F, Yu-Wai-Man P, Rohayem J, López de Heredia M, Hershey T, Tranebjaerg L, Chen JH, Chaussenot A, Nunes V, Marshall B, McAfferty S, Tillmann V, Maffei P, Paquis-Flucklinger V, Geberhiwot T, Mlynarski W, Parkinson K, Picard V, Bueno GE, Dias R, Arnold A, Richens C, Paisey R, Urano F, Semple R, Sinnott R, Barrett TG
Hum Mutat 2017 Jul;38(7):764-777. Epub 2017 Jun 1 doi: 10.1002/humu.23233. PMID: 28432734Free PMC Article

Recent systematic reviews

Lim HD, Lee SM, Yun YJ, Lee DH, Lee JH, Oh SH, Lee SY
BMC Med Genomics 2023 Apr 11;16(1):79. doi: 10.1186/s12920-023-01506-x. PMID: 37041640Free PMC Article
de Muijnck C, Brink JBT, Bergen AA, Boon CJF, van Genderen MM
Surv Ophthalmol 2023 Jul-Aug;68(4):641-654. Epub 2023 Feb 9 doi: 10.1016/j.survophthal.2023.01.012. PMID: 36764396
Rosanio FM, Di Candia F, Occhiati L, Fedi L, Malvone FP, Foschini DF, Franzese A, Mozzillo E
Int J Environ Res Public Health 2022 Jan 12;19(2) doi: 10.3390/ijerph19020835. PMID: 35055657Free PMC Article
Yu G, Yu ML, Wang JF, Gao CR, Chen ZJ
Endocrine 2010 Oct;38(2):147-52. Epub 2010 Oct 23 doi: 10.1007/s12020-010-9350-4. PMID: 20972738

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