Usher Syndrome

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Classification according to ICD-10
Q87.8 Usher Syndrome
H35.5 Hereditary retinal dystrophy
H90.3 Bilateral hearing loss due to sensorineural hearing loss
ICD-10 online (WHO version 2019)

The Usher syndrome is a Hörsehbehinderung which autosomal - recessive inherited.

Approximately 40 syndromes are known to occur in humans which include symptoms of deafness combined with blindness . Usher syndrome is the trigger in every second affected patient; thus it is the most common cause of hereditary blind deafness .

Complaints and symptoms

Usher syndrome is defined by early onset of inner ear hearing loss or deafness from birth and later loss of the field of vision , caused by retinopathia pigmentosa (RP, formerly referred to as "retinitis pigmentosa"). The death of the photoreceptors usually takes place from the periphery to the macula . As is typical for retinopathia pigmentosa, it first leads to night blindness and then to a gradual restriction of the field of vision up to an increasingly narrowing "tunnel vision", which in a later stage usually leads to blindness depending on the Usher subtype . The hearing impairment in Usher syndrome is essentially due to damage to the hair cells in the cochlea of ​​the inner ear . It usually occurs from birth in the form of deafness or moderate to severe hearing loss.

After the clinically heterogeneous course of Usher syndrome had already been described, Usher syndrome was divided into three types according to clinical characteristics. According to this, a patient with Usher type 1 (USH1), the most severe course of this disease, is deaf from birth, and the onset of retinopathia pigmentosa can be diagnosed from the age of 10 . Additionally, many, but not all, patients have an impaired sense of balance . With Usher type 2 (USH2) a constant but profound hearing loss is determined and the onset of retinopathia pigmentosa sets in during puberty . Usher type 3 (USH3) differs from USH1 and USH2 in the later onset of both deafness and retinopathia pigmentosa. The hearing loss begins postlingually and is progressive. Retinopathia pigmentosa does not set in in USH3 patients until the second decade of life. The division into these three types is still used.

In rare cases, Usher syndrome is also associated with epileptic seizures .

history

Probably as early as 1858 Albrecht von Graefe , a pioneer of modern ophthalmology , first described Usher's syndrome. He reported the case of a deaf patient with retinitis pigmentosa who had two brothers who were equally affected.

A short time later, one of Graefe's students, Richard Liebreich , examined the population of Berlin for symptoms of deafness with retinopathia pigmentosa. He already emphasized the recessive nature of this disease, as the cases of blind-deafness combination occurred especially in siblings from blood-related marriages or in families with affected persons in different generations. In addition, his observations provided the first evidence for the coupled inheritance of blindness and deafness, since no cases of isolated blindness or deafness could be found in the family trees.

The clinical picture was finally named after the British ophthalmologist Charles Usher , who in 1914 again worked out the pathology and inheritance of this disease on the basis of 69 cases .

Synonyms are Sjogren-Hallgren syndrome , Hallgren syndrome and von Graefe-Sjogren syndrome . These terms refer to additions made by the Swedish psychiatrist and neurologist Karl Gustav Torsten Sjögren in 1950 and by Bertil Hallgren in 1958.

genetics

Known Usher Syndrome Subtypes (excluding USH1A).
Usher type  Gene locus  gene protein  function 
1AB 11q13.5 MYO7A Myosin VIIA Motor protein
1C 11p15.1-p14 USH1C Harmonin Scaffold protein
1D 10q21-q22 CDH23 Cadherin 23 Cell adhesion
1E 21q21 ? ? ?
1F 10q11.2-q21  PCDH15   Protocadherin 15  Cell adhesion
1G 17q24-q25 USH1G SANS Scaffold protein
2A 1q41 USH2A Usherin ?
2 B 3p23-p24.2 SLC4A7 NBC-3  Co-transporters of ions 
2C 5q14.3-q21.1 VLGR1 VLGR1b Very large GPCR
2D 9q32-q34 WHRN Whirlin Scaffold protein
3A 3q21-q25 USH3A Clarin-1 ?
3B 20q ? ? ?

The genetic heterogeneity was first described in the late 20th century, with the increase of scientific methods. By linkage analysis of patients were several independent loci on different chromosomes identified (see table), in which hereditary defects that cause Usher syndrome, were found. With the help of these loci, the disease was divided into different subtypes (USH1A-G, USH2A-C, USH3A-B). By sequencing candidate genes , the affected gene could also be found in most of the loci . In the case of a Usher subtype - namely USH1A on chromosome locus 14q32 - it could be shown that this was incorrectly determined and does not exist. In contrast, another subtype including the affected gene was recently discovered with USH2D.

In the meantime, interaction experiments ( yeast two-hybrid system , immunoprecipitation, etc.) have shown that the identified gene products are linked to one another in a protein complex or in several larger protein complexes from different cell adhesion proteins with a connection to the cytoskeleton . These complexes are localized on the one hand at the synapses and in the stimulus-absorbing compartments ( stereocilia of the hair cells ; outer segment of the photoreceptors ) of the sensory cells concerned . The available data suggest that these Usher protein complexes play a role in the membrane positioning of specific proteins that are presumably involved in signal transmission. If one of the components is missing, this protein complex can no longer fulfill its function in the cell and it is likely to degenerate with the known consequences for the patient.

The scaffold protein harmonin , responsible for Usher subtype 1C, plays a key role here . This is able to interact with almost all Usher proteins known to date via its so-called PDZ domains . This enables harmonine to mediate the protein complex. The protein described as USH2D Whirlin also has PDZ domains and could play a similar role.

distribution

Epidemiological studies on Usher syndrome show a prevalence of three to six affected persons out of 100,000 inhabitants in an originally European population, with Germany at the upper limit. If the age of those affected is also taken into account with these patient numbers, there is an increase in the prevalence up to ten affected persons under 100,000 up to the sixth decade of life. The reasons for this are likely to be difficulties in diagnosing Usher syndrome, especially in young patients with the onset of retinopathia pigmentosa, often only congenital deafness is diagnosed. The effective prevalence for Usher syndrome is therefore likely to be higher.

The further division of the patient numbers into the three types of Usher syndrome is inconsistent. Studies in Europe show a proportion of 25% to 44% USH1 patients and 56% to 75% USH2 patients. The same applies to USH3, which was initially determined with a very small percentage. However, studies in Birmingham (UK) show a share of 20% and in Finland USH3 accounts for 40% of the cases. Regional start-up effects contribute to the wide range, but here too the diagnostic difficulties are likely to distort the results.

Diagnosis and treatment

A diagnosis of Usher's syndrome as early as possible is important in order to reduce the trauma in the patient that arises when this disease is discovered, especially because of the possible consequences of blindness in the case of impaired hearing. Those who are hearing impaired from birth belong to the risk group within the population. Other symptoms that are often only discovered later and should be checked are night blindness , sensitivity to changes in light and a restricted field of vision .

As a diagnostic aid, the electroretinogram is suitable for examining the retinal function , in order to detect the onset of retinopathia pigmentosa at a young age. Still in development are DNA chip and protein chip , which should allow for faster diagnosis of Usher subtype. This can also help with genetic family counseling. At the moment there is only the costly option of analyzing the individual chromosome sections.

There is as yet no treatment for retinopathia pigmentosa . Still in the research are gene therapy approaches in which defective genes could be replaced in the retina, or stem cell therapies in which the degenerated retina to be repaired. So-called retina implants are also being developed , in which microsystem technology is used as a prosthesis to replace the functions of the defective retina. Currently, a subretinal implant with a possible resolution of 1500 diodes should be able to achieve first visual successes again.

The therapy of choice for hearing impairments is provision of a hearing aid or, in the case of severe hearing impairment, a cochlear implant . Like other people with hearing disorders that cannot be compensated for by apparatus or after the decision not to want them, Usher sufferers also interact with deaf people, since communication here takes place on the same level with sign language . However, this type of communication is only possible if there is sufficient light and enough distance to the person opposite so that both hands of the person opposite are visible. Alternatively, lip reading can be used, but this usually works worse. With increasing blindness there is also the possibility to communicate either via Lormen or via the so-called tactile sign language (e.g. Tadoma and Gestuno ) . With the latter, you try to feel the corresponding gestures by taking the other person's hands in your own while communicating.

Among other things, choroideremia is to be distinguished .

Web links

Individual evidence

  1. ↑ A. von Graefe: Exceptional behavior of the visual field with pigment degeneration of the retina. In: Archives for Ophthalmology. 1858; 4, pp. 250-253.
  2. ↑ R. Liebreich: Descent from marriages among blood relatives as the reason for retinitis pigmentosa. In: Dtsch. Klin. 1861; 13, p. 53.
  3. ^ Charles Usher: On the inheritance of retinitis pigmentosa with notes of cases. In: The Royal London Ophthalmic Hospital Reports 1914; 19, pp. 130-236.
  4. ^ B. Leiber: The clinical syndromes. Syndromes, sequences and symptom complexes. Edited by G. Burg, J. Kunze, D. Pongratz, PG Scheurlen, A. Schinzel, J. Spranger, 7th edition. Urban & Schwarzenberg, 1990, ISBN 3-541-01727-9 .
  5. ↑ T. Sjogren: Hereditary congenital spinicerebellar ataxia accompanied by congenital cataract and oligophrenia. In: Confinia Neurologica . Basel 1950, Volume 10, pp. 293-308.
  6. ^ Bertil Hallgren: Retinitis pigmentosa in combination with congenital deafness and vestibulo-cerebellar ataxia; with psychiatric abnormality in some cases. A clinical and genetic study. In: Acta genetica et statistica medica. Basel 1958, Volume 8, pp. 97-104.
  7. ↑ Who named it
  8. ↑ C. Petit: Usher syndrome: from genetics to pathogenesis. In: Annu. Rev. Genomics Hum. Genet. 2001 (2), pp. 271-297 PMID 11701652 .
  9. ↑ a b J. Reiners u. a .: Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease. In: Exp. Eye Res. 2006; 83 (1), pp. 97-119 PMID 16545802
  10. ↑ S. Gerber et al. a .: USH1A: Chronicle of a Slow Death. In: Am J Hum Genet. 2006; 78 (2), pp. 357-359. PMID 16400615
  11. ↑ I. Ebermann et al. a .: A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss. In: Hum Genet. 2006 Dec 15; PMID 17171570 .
  12. ↑ J. Reiners et al. a .: Scaffold protein harmonine (USH1C) provides molecular links between Usher syndrome type 1 and type 2. In: Hum Mol Genet . 2005 Dec 15; 14 (24), pp. 3933-3943. PMID 16301216 .
  13. ↑ B. Boëda et al. a .: Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle. In: EMBO J . 2002 Dec 16; 21 (24), pp. 6689-6699. PMID 12485990
  14. ↑ A. Adato et al. a .: Interactions in the network of Usher syndrome type 1 proteins. In: Hum Mol Genet. 2005 Feb 1; 14 (3), pp. 347-356. PMID 15590703
  15. ↑ P. Goodwin: Hereditary retinal disease. In: Curr Opin Ophthalmol. 2008 May; 19 (3), pp. 255-262. PMID 18408503
  16. ^ I. Mooney I, J. LaMotte: A review of the potential to restore vision with stem cells. In: Clin Exp Optom. 2008 Jan; 91 (1), pp. 78-84. PMID 18045253
  17. ↑ N. Alteheld u. a .: Towards the bionic eye - the retina implant: surgical, opthalmological and histopathological perspectives. In: Acta Neurochirurgica Suppl. 2007; 97 (Pt 2), pp. 487-493. PMID 17691339 .
  18. ↑ Pilot study successful: Chip enables blind people to get their bearings. BioPro 2007 Archived copy ( Memento of the original from July 21, 2015 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. @1@ 2Template: Webachiv / IABot / www.bio-pro.de