Usher Syndrome Type I

Clinical Characteristics
Ocular Features: 

The fundus dystrophy of retinitis pigmentosa in Usher syndrome is indistinguishable from isolated retinitis pigmentosa.   Night blindness begins by about 10 years of age and the ERG by that time is often markedly diminished or absent.  Patches of hyperfluorescence are seen in younger individuals and these enlarge and coalesce with age.  Tunnel vision occurs early as the peripheral visual field is constricted to 5-10 degrees by midlife.  The retinal disease is progressive and blindness may be the final result.

Systemic Features: 

Type I Usher syndrome is characterized by profound hearing impairment beginning at birth, vestibular dysfunction, and unintelligible speech in addition to retinitis pigmentosa.  Vestibular areflexia is virtually complete and constitutes a defining feature.  Ataxic gait disturbances are common secondary to labyrinthine dysfunction and many children do not walk until 18-24 months of age.  Sitting alone may also be delayed.  Sperm motility is abnormal which is likely the basis for reduced fertility in male patients.  An abnormal exoneme morphology from ciliated progenitors is likely the common basis for these clinical findings.  MRI imaging has found a significant decrease in intracranial volume and brain size.  About 1 in 4 children have behavioral problems or psychosocial difficulties.

Genetics

Type I Usher syndrome is an autosomal recessive genetically heterogeneous disorder as mutations in at least 8 genes produce a similar disease.  These are: MYO7A (276900) at 11q13.5 causing USH1B (USH1A is now considered to be the same), USH1C at 11p15.1 causing USH1C (276904), CDH23 at 10q21-q22, causing USH1D (601067), PCDH15 at 10q21.1 causing USH1F (602083), and USH1G at 17q24-25 causing USH1G (606943).  Mutations in as yet unnamed genes in loci at 21q21 (USH1E; 602097), 10p11.21-q21.1 (USH1K), and 15q22-q23 (USH1H; 612632) may also cause this type I phenotype. They are discussed here as a single entity designated type I since the clinical features of each are indistinguishable.'

A varant of USH1C resulting from homozygous deletions in 11p15-p14, known as homozygous 11p15-p14 deletion syndrome, has the additional feature of severe hyperinsulinemia due to the involvement of ABCC8 and KCNJ11 genes (606528).

Clinical differences have led to the categorization of three types of Usher syndrome:  type I described here, type II (276901) caused by mutations in at least 4 genes, and type III (276902) caused by mutations in CLRN1.

Treatment
Treatment Options: 

At-risk infants should have hearing evaluations as soon as possible after birth.  Assistive hearing devices are of little benefit.  Unless cochlear implants are placed in young children, speech may not develop.  Extra precautions during physical activities such as swimming, bicycling, and night-time driving are highly recommended. Speech therapy and low vision aids can be beneficial.

References
Article Title: 

Targeted exon sequencing in Usher syndrome type I

Bujakowska KM, Consugar MB, Place E, Harper S, Lena J, Taub DG, White J, Navarro-Gomez D, Weigel-DiFranco C, Farkas MH, Gai X, Berson EL, Pierce EA. Targeted exon sequencing in Usher syndrome type I. Invest Ophthalmol Vis Sci. 2014 Dec 2.  [Epub ahead of print].

PubMed ID: 
25468891

Heterogeneity in Phenotype of Usher-Congenital Hyperinsulinism Syndrome: Hearing Loss, Retinitis Pigmentosa, and Hyperinsulinemic Hypoglycemia Ranging from Severe to Mild with Conversion to Diabetes

Al Mutair AN, Brusgaard K, Bin-Abbas B, Hussain K, Felimban N, Al Shaikh A, Christesen HT. Heterogeneity in Phenotype of Usher-Congenital Hyperinsulinism Syndrome: Hearing Loss, Retinitis Pigmentosa, and Hyperinsulinemic Hypoglycemia Ranging from Severe to Mild with Conversion to Diabetes. Diabetes Care. 2012 Nov 12. [Epub ahead of print].

PubMed ID: 
23150283

References

Bujakowska KM, Consugar MB, Place E, Harper S, Lena J, Taub DG, White J, Navarro-Gomez D, Weigel-DiFranco C, Farkas MH, Gai X, Berson EL, Pierce EA. Targeted exon sequencing in Usher syndrome type I. Invest Ophthalmol Vis Sci. 2014 Dec 2.  [Epub ahead of print].

PubMedID: 25468891

Blanco-Kelly F, Jaijo T, Aller E, Avila-Fernandez A, Lopez-Molina MI, Gimenez A, Garcia-Sandoval B, Millan JM, Ayuso C. Clinical Aspects of Usher Syndrome and the USH2A Gene in a Cohort of 433 Patients. JAMA Ophthalmol. 2014 Nov 6. [Epub ahead of print].

PubMedID: 25375654

Al Mutair AN, Brusgaard K, Bin-Abbas B, Hussain K, Felimban N, Al Shaikh A, Christesen HT. Heterogeneity in Phenotype of Usher-Congenital Hyperinsulinism Syndrome: Hearing Loss, Retinitis Pigmentosa, and Hyperinsulinemic Hypoglycemia Ranging from Severe to Mild with Conversion to Diabetes. Diabetes Care. 2012 Nov 12. [Epub ahead of print].

PubMedID: 23150283

Jaworek TJ, Bhatti R, Latief N, Khan SN, Riazuddin S, Ahmed ZM. USH1K, a novel locus for type I Usher syndrome, maps to chromosome 10p11.21-q21.1. J Hum Genet. 2012 Jun 21. doi: 10.1038/jhg.2012.79. [Epub ahead of print].

PubMedID: 22718019

Ahmed ZM, Riazuddin S, Riazuddin S, Wilcox ER. The molecular genetics of Usher syndrome. Clin Genet. 2003 Jun;63(6):431-44. Review.

PubMedID: 12786748

Smith RJ, Berlin CI, Hejtmancik JF, Keats BJ, Kimberling WJ, Lewis RA, Moller CG, Pelias MZ, Tranebjaerg L. Clinical diagnosis of the Usher syndromes. Usher Syndrome Consortium. Am J Med Genet. 1994 Mar 1;50(1):32-8.

PubMedID: 8160750