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Usher Syndrome

USH

Usher syndrome is a congenital disorder seen in children primarily manifesting as bilateral sensorineural deafness, retinitis pigmentosa, and vestibular areflexia.


Presentation

Usher syndrome exists in three types with type 1 patients being the most severely affected, whilst type 2 and 3 represent moderate and mild entities of this syndrome, respectively. Affected heterozygotic children are usually asymptomatic while homozygotes displaying a wide array of features present most often since birth.

A moderate to profound sensorineural hearing loss in both ears is seen at birth in homozygotic type 1 and type 2 patients. They may also concurrently develop speech deficits. Type 3 patients present with normal hearing at birth.

The sensorineural deafness is often diagnosed in isolation until the features of retinitis pigmentosa become apparent. Retinitis pigmentosa is initially marked by symmetrical and bilateral degeneration of the peripheral regions of the retina and later spreading to the more central regions [1]. Frequently, the initial symptoms noticed by the individual or his/her parents or teachers include night blindness and tunnel vision, with the constriction of visual fields continuing well into adulthood [2]. These features occur much earlier in type 1 patients than in the other types. Complete blindness may develop in these individuals.

Another important feature exclusive only to type 1 Usher syndrome patients is vestibular areflexia due to which walking milestones are achieved at a later date than usual (18 months to 2 years). Other children may appear clumsy whilst walking with frequent injuries being reported in these patients.

Turkish
  • Three cases of Usher syndrome associated with a variant of Dandy-Walker malformation in three siblings from consanguineous Turkish parents are described. The siblings had retinitis pigmentosa and hearing loss.[ncbi.nlm.nih.gov]
  • After hearing her story and having it touch his heart, the general manager of Turkish Airlines made the Myers family an offer they couldn’t refuse: free, round-trip tickets to any location in the world.[medicaldaily.com]
Hepatomegaly
  • The firstborn son of unrelated parents, who both had sensorineural deafness and RP diagnosed as USH, presented with sensorineural deafness, RP, dysmorphism, developmental delay, hepatomegaly, and hypsarrhythmia and died at age 17 mo.[ncbi.nlm.nih.gov]
Hearing Impairment
  • One individual (IV:1) is profoundly hearing impaired and has normal vestibular function and retinitis punctata albescens (RPA).[ncbi.nlm.nih.gov]
  • Consequently, the disruption of Ush2a in zebrafish led to a hearing impairment, like that in mammals.[bioportfolio.com]
Psychiatric Symptoms
  • Furthermore, the authors compare their psychiatric symptoms with other reports and the possible etiologies of psychotic symptoms are discussed.[ncbi.nlm.nih.gov]
  • PubMed Central View Article PubMed Google Scholar Rijavec N, Grubic VN: Usher syndrome and psychiatric symptoms: a challenge in psychiatric management. Psychiatr Danub. 2009, 21: 68-71.[behavioralandbrainfunctions.biomedcentral.com]
Distractibility
  • Common findings of Usher syndrome, including night blindness, impaired vision, visual field defects, and retinal changes may distract the clinician from considering the diagnosis of glaucoma.[ncbi.nlm.nih.gov]
  • Remove sources of background distraction and glare. Employ a copy signer in a busy classroom with signing students . Employ tracking and/or tactile techniques when needed.[asha.org]
Vertigo
  • She did not complain of vertigo. The family history was unremarkable. Physical examination revealed no obvious abnormalities of the external ear or tympanic membrane.[e-ceo.org]
  • Case 3 The patient was a 43-year-old female with a history of hypertension, hypothyroidism, sarcoidosis, gastritis, uveitis, and vertigo who presented with 2-year history of progressively worsening lower back pain radiating to both lower extremities.[cyberleninka.org]
  • 吉村 豪兼; 矢野 卓也; 内藤 武彦; 宮川 麻衣子; 茂木 英明; 西尾 信哉; 宇佐美 真一; めまいを主訴とした多発性硬化症の1例 Equilibrium research,70(4):245-249 2011(Aug. 01) Author:吉村 豪兼; 坂口 正範; 福岡 久邦; 塚田 景大; 宇佐美 真一; Abstract:A 27-year-old woman who was referred to our hospital 5 days after an episode of vertigo[soar-rd.shinshu-u.ac.jp]

Workup

The diagnosis of Usher syndrome is primarily clinical and should be suspected in individuals who present with the clinical features as listed above amidst otherwise normal physical examination. These include sensorineural deafness, vestibular areflexia, and retinitis pigmentosa. A thorough assessment to detect the presence and severity of these conditions needs to be made via appropriate audiological, vestibular, and ophthalmologic evaluation. In addition, the presence of a family history of autosomal recessive diseases raises the likelihood of the presence of Usher syndrome in these individuals.

When the clinical features are inconclusive, molecular genetic testing techniques may be employed to reach a proper diagnosis. These may include serial single gene testing, multi-gene panels, or other extensive genomic tests to look for pathogenic variants of the related genes.

Single gene testing may involve the testing of genes such as the MY07A, USH1C, and CDH23 genes for type 1 patients. Testing for the USH2A, ADGRV1, and WHRN (DFNB31) genes may be required for type 2 patients [3] [4] [5]. Multi-gene panels may also be utilized to look for biallelic pathologic variants of the associated genes [6] [7] [8]. Other molecular techniques assessing the deletions and/or duplications of the genes may also be employed.

If the diagnosis is still uncertain, more comprehensive genomic tests (exome and full genome sequencing) may be carried out which may reveal mutations and diseases not included in the differential diagnosis previously.

Hypsarrhythmia
  • The firstborn son of unrelated parents, who both had sensorineural deafness and RP diagnosed as USH, presented with sensorineural deafness, RP, dysmorphism, developmental delay, hepatomegaly, and hypsarrhythmia and died at age 17 mo.[ncbi.nlm.nih.gov]

Treatment

  • Using the results of this successful basic research, the Usher treatment team in Mainz headed by Dr Kerstin Nagel-Wolfrum has now evaluated potential ocular treatment options.[sciencedaily.com]
  • While there are currently no universally agreed upon treatments for Usher syndrome, there are a number of treatments nearing clinical trial that could potentially help people with Usher syndrome.[usher-registry.org]
  • No treatments exist for Usher syndrome, which affects as many as 50,000 people in the United States and Europe.[ohsu.edu]
  • Back to top What treatments are available? While there are no treatments for Usher syndrome, intensive research is underway to discover the causes of and treatments for all types of the disease.[blindness.org]

Prognosis

  • Because of the poor visual prognosis, the patient refused surgery in that eye. Tractional retinal detachment should be added to the differential diagnoses of visual loss in patients with retinitis pigmentosa.[ncbi.nlm.nih.gov]
  • Diagnosis and Prognosis: Auditory testing can detect deafness at birth but this is often missed in the absence of a family history.[disorders.eyes.arizona.edu]

Etiology

  • Furthermore, the authors compare their psychiatric symptoms with other reports and the possible etiologies of psychotic symptoms are discussed.[ncbi.nlm.nih.gov]
  • Study of the etiology of deafness in an institutionalized population in Colombia. Am J Med Genet. 1992;44:405-8. 5. Tamayo ML, Bernal JE, Tamayo GE, Frias JL, Alvira G, Vergara O, et al. Usher syndrome: Results of a screening program in Colombia.[revistabiomedica.org]

Epidemiology

  • These results suggest that our panel is an effective approach for the genetic diagnosis of Usher syndrome leading to: 1) an accurate molecular diagnosis, 2) better genetic counselling, 3) more precise molecular epidemiology data fundamental for future[ncbi.nlm.nih.gov]
  • Epidemiology The incidence is about 1 in 25,000. About 3-6% of hearing impaired children have the condition. Types 1 and 2 are more common than type 3 and together account for 90-95% of Usher's syndrome and about 10% of all children born deaf.[patient.info]
  • This was possibly thanks to the epidemiological surveillance practiced in communities to control vector transmission, allied with the National Program for Chagas Disease Control and rural socioeconomic factors.[htct.com.br]
  • Targeted exon sequencing successfully discovers rare causative genes and clarifies the molecular epidemiology of Japanese deafness patients. PLoS ONE 8, e71381 (2013). 3. Shearer, A. E., Black-Ziegelbein, E. A., Hildebrand, M. S., Eppsteiner, R.[nature.com]
Sex distribution
Age distribution

Pathophysiology

  • The identification of pathogenic mutations is of great significance for elucidating the underlying pathophysiology of USH.[ncbi.nlm.nih.gov]
  • […] deposits at the dermoepidermal junction For a thorough description and introduction to the possible causes of pemphigus, see the article " Pemphigus: An Acronym for a Disease with Multiple Causes ", published by the International Pemphigus Society. [2] Pathophysiology[emedicine.medscape.com]
  • Burnett MG, Zager EL: Pathophysiology of peripheral nerve injury: a brief review. Neurosurg Focus 16:E1, 2004 5. Cheatham SW, Kolber MJ, Salamh PA: Meralgia paresthetica: a review of the literature. Int J Sports Phys Ther 8:883-893, 2013 6.[cyberleninka.org]

Prevention

  • BF844 effectively attenuated progressive hearing loss and prevented deafness in this model. Because the CLRN1(N48K) mutation causes both hearing and vision loss, BF844 could in principle prevent both sensory deficiencies in patients with USH3.[ncbi.nlm.nih.gov]
  • However, early diagnosis is important in order to attenuate the far-reaching consequences of this condition and to take preventative measures.[hear.com]
  • Prevention There are no current guidelines to prevent Usher syndrome. References: Dammeyer J. Children with Usher syndrome: Mental and behavioral disorders. Behav Brain Funct. 2012;8:16. Lopes VS, Williams DS.[cancercarewny.com]
  • So far, there has been little research on Usher-Syndrome itself and unfortunately there is currently no prevention or treatment for this illness available.[ushernet.org]

References

Article

  1. Gregory-Evans K, Bhattacharya SS. Genetic blindness: current concepts in the pathogenesis of human outer retinal dystrophies. Trends Genet. 1998;14(3):103-108.
  2. Pennings RJE, Huygen PLM, Orten DJ, et al. Evaluation of visual impairment in Usher syndrome 1b and Usher syndrome 2a. Acta Ophthalmol Scand. 2004;82(2):131-139.
  3. Bonnet C, Grati M ’Hamed, Marlin S, et al. Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis. Orphanet J Rare Dis. 2011;6:21.
  4. Le Quesne Stabej P, Saihan Z, Rangesh N, et al. Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study. J Med Genet. 2012;49(1):27-36.
  5. García-García G, Besnard T, Baux D, et al. The contribution of GPR98 and DFNB31 genes to a Spanish Usher syndrome type 2 cohort. Mol Vis. 2013;19:367-373.
  6. Hilgert N, Kahrizi K, Dieltjens N, et al. A large deletion in GPR98 causes type IIC Usher syndrome in male and female members of an Iranian family. J Med Genet. 2009;46(4):272-276.
  7. Besnard T, Vaché C, Baux D, et al. Non-USH2A mutations in USH2 patients. Hum Mutat. 2012;33(3):504-510.
  8. Aparisi MJ, Aller E, Fuster-García C, et al. Targeted next generation sequencing for molecular diagnosis of Usher syndrome. Orphanet J Rare Dis. 2014;9:168.

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Last updated: 2019-07-11 22:00