tunnel vision

Retinitis Pigmentosa 42

Clinical Characteristics
Ocular Features: 

The fundus phenotype of retinitis pigmentosa appears late.  Night vision difficulties are prominent symptoms but the age of onset is unknown. Reduction in visual acuity is variable and is usually not manifest until 50 years of age but it may remain near normal or in that range for another decade or two.  Concentric constriction (within 10-20 central degrees) in peripheral fields can be a presenting symptom and may not appear until age 65 years of age.  Patches of visual field retention can sometimes be demonstrated in the periphery.  Rod and cone full field ERG amplitudes are substantially reduced

Systemic Features: 

None.

Genetics

Heterozygous mutations in KLHL7 (7p15.3) segregate with the clinical phenotype.

Homozygous mutations in the KLHL7 gene cause cold-induced sweating syndrome 3 (CISS3) (617055).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

None known.

References
Article Title: 

Mutations in a BTB-Kelch protein, KLHL7, cause autosomal-dominant retinitis pigmentosa

Friedman JS, Ray JW, Waseem N, Johnson K, Brooks MJ, Hugosson T, Breuer D, Branham KE, Krauth DS, Bowne SJ, Sullivan LS, Ponjavic V, Granse L, Khanna R, Trager EH, Gieser LM, Hughbanks-Wheaton D, Cojocaru RI, Ghiasvand NM, Chakarova CF, Abrahamson M, Goring HH, Webster AR, Birch DG, Abecasis GR, Fann Y, Bhattacharya SS, Daiger SP, Heckenlively JR, Andreasson S, Swaroop A. Mutations in a BTB-Kelch protein, KLHL7, cause autosomal-dominant retinitis pigmentosa. Am J Hum Genet. 2009 Jun;84(6):792-800.

PubMed ID: 
19520207

Retinitis Pigmentosa with Ataxia

Clinical Characteristics
Ocular Features: 

Pigmentary retinopathy has been noted by 6 months of age. Typical symptoms of retinitis pigmentosa are reported by early childhood.  The visual fields are progressively constricted and a ring scotoma can be plotted.  Night blindness and visual acuity loss are evident in the first decade of life and progressively worsen leading to severe handicaps by the third.  Fundus pigmentation in the midperiphery becomes more prominent and in at least some patients the pattern consists of typical bone spicules.  Cellophane maculopathy has been described.

Systemic Features: 

Proprioceptive deficits and areflexia appear in early childhood and ataxia worsens as individuals mature.  Scoliosis and general weakness and wasting become prominent manifestations.  Sensory neuropathy with loss of vibratory and position sense, astereognosia, and agraphesthesia can become apparent in the first decade of life.  Walking is delayed and gait abnormalities are clearly evident by the second decade leading to orthopedic deformities such as scoliosis.  Unassisted walking becomes impossible.  The intrinsic hand and foot muscles also have mild weakness.  Sural nerve biopsy may reveal loss of large myelinated fibers.  Hyperintense signals in the posterior spinal columns can be seen on MRI.  No anatomic changes have been described in the cerebrum or cerebellum.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in FLVCR1 (1q32.2-q41).  This disorder has some clinical similarities to Biemond 1 syndrome but differs in the inheritance pattern and the molecular basis.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No specific treatment is available but physical therapy and low vision aids may improve the quality of life.

References
Article Title: 

Usher Syndrome Type II

Clinical Characteristics
Ocular Features: 

Retinitis pigmentosa is clinically similar to that of nonsyndromal RP and produces symptoms of nightblindness by adolescence.  The ERG is severely reduced and visual fields are constricted.  Rods seem to be more severely affected than cones.  A loss of thickness in the outer nuclear layer in USH2C and USH2A types has been described.  The fundus often contains patches of hyperfluorescence which become larger and often coalesce in older patients.  The retinal disease is progressive but more slowly than in type I.  Eventually by the 4th to 5th decades the visual field is constricted to 5-10 degrees.  It can result in blindness.  Cataracts are common and some patients have cystic changes in the macula.

Systemic Features: 

The hearing deficit in type II can be described as hearing loss rather than deafness as found in type I.  Usually high frequencies are impacted more severely than lower frequencies producing a characteristic 'sloping' audiogram.  The hearing loss is present at birth and progressive, at least in some individuals.  Speech usually develops.  Vestibular dysfunction is not a feature of type II Usher syndrome.  The mental changes observed in type I do not occur in type II.

Genetics

Like other forms of Usher syndrome, type II is inherited in an autosomal recessive pattern.  Like type I, it is genetically heterogeneous and mutations in at least 4 genes seem to be responsible.  Three have been identified: type IIA (USH2A; 276901) results from mutations in the USH2A gene on chromosome 4 (1q41), type IIC (USH2D; 605472) from mutations in GPR98 (5q14), and type IID (USH2D; 611383) is caused by mutations in the DFNB31 gene (9q32-q34).  Type IIB (USH2B) results from mutations in a locus mapped to 3p24.2-p23 but the gene has not been identified.  Clinical features are sufficiently similar so that these are discussed here as a single entity.

This is the most common of the three types of Usher syndrome.  Type I Usher syndrome (276900) results from mutations in at least 7 genes and type III (276902) is caused by a mutations in the CLRN1 gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Hearing aids can be helpful and speech therapy may be highly beneficial for the development of speech.  Cochlear implants have been suggested for older persons who have the more severe hearing loss.  Auditory testing should be done shortly after birth and the hearing loss monitored periodically.

An investigational drug (QRX-411) developed by ProQR has been approved as an orphan drug by the FDA and the EMA for patients with the USH2A mutation. 

References
Article Title: 

Kinetics of visual field loss in Usher syndrome Type II

Iannaccone A, Kritchevsky SB, Ciccarelli ML, Tedesco SA, Macaluso C, Kimberling WJ, Somes GW. Kinetics of visual field loss in Usher syndrome Type II. Invest Ophthalmol Vis Sci. 2004 Mar;45(3):784-92.

PubMed ID: 
14985291

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.

Pedigree: 
Autosomal recessive
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
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