Hussein Morfeq, MDKing Abdulaziz University

Jeddah, Saudi Arabia

Usher syndromeBritish ophthalmologist Charles Usher: who in

1914 wrote a paper describing several cases in which the link between congenital deafness and retinitis pigmentosa .

Other names for Usher syndrome include :Hallgren syndromeUsher-Hallgren syndromerp-dysacusis syndrome dystrophia retinae dysacusis syndrome.

Usher syndromeUsher syndrome = progressive recessive retinitis pigmentosa + congenital

moderate-to-severe SN hearing loss .

It is inherited in an autosomal recessive pattern and is estimated to occur in 1-3 in 10,000 people.

The genes also play a role in the development and stability of the retina by influencing the structure and function of both the rod photoreceptor cells and supporting cells called the retinal pigmented epithelium.

Responsible for up to 10% of cases of congenital deafness. and accounts for about 50% of the deaf blind in the United States.

it represents the major cause of syndromic deafness with blindness.

Type I and type III can also include difficulties with balance due to inner ear problems; due to the failure of the hair cells of the inner ear, stereocilia.

Usher syndrome Usher syndrome is divided into three types: I, II and III.

In the United States, types 1 and 2 are the most common types

Children with type I syndrome are born profoundly deaf, and eyesight usually begins degrading after the first decade of life, beginning with night-blindness. They also experience degrading tunnel vision.

Many use Sign language. When vision loss is severe or when one is blind one must use tactile signing.

Problems with balance are present in people with Usher I and sometimes Usher III.

Night vision loss begins first blind spots develop in the side (peripheral) vision doughnut shape tunnel vision Central vision is reduced and blurs

Cataracts may develop in the teenage years or in adulthood.

Type II children are hearing impairment with stable hearing throughout their lives. Changes in sight in type II cases usually begin later, sometimes only becoming noticeable after the second decade of life.

In the type III syndrome, hearing loss as well as retinitis pigmentosa can occur later in life. Hearing loss in Usher III is progressive.

Type 1: 3 to 6 per 100,000 Type 2 (50% most common)

Type 3 (Finland)

Hearing

Profound deafness in both ears from birth

Moderate to severe hearing loss from birth

Normal at birth; progressive loss in childhood or early teens

Vision

Decreased night vision before age 10

Decreased night vision begins in late childhood or teens

Varies in severity; night vision problems often begin in teens

Vestibular function (balance)

Balance problems from birth

NormalNormal to near-normal, chance of later problems

Type 1 Usher syndrome: MY07A, USH1C, CDH23, PCDH15, SANS

Type 2 Usher syndrome: USH2A(Usherin protein), VLGR1, WHRN

Type 3 Usher syndrome: USH3A

symptomsRods involvement:Night Blindness (1st symptoms) .

Difficulty in adapting to bright light or rapidly changing light conditions .

Tunnel Vision: Rods dysfunctioning in the periphery.

Cones involvement:Early: "doughnut vision“.Late: Loss of central acuity: early degeneration of the cone cells in the macula. 50% of individuals develop complete blindness before age 50 years.

Imbalance: Vestibulocerebellar ataxia (stereocilia)

Evaluation: VA: 20/20 to LP Fundus exam: 'bone corpuscle' lumps . VF Goldmann (kinetic) perimetry : most useful measure for ongoing

follow-up care of patients with RP.Midperipheral scotomasring scotomatunnel vision

IVFG: cystoid macular edema Optical coherence tomography (OCT): cystoid macular edema Electroretinography (the most crucial): measures the electrical

responses of various cell types in the retina, including the photoreceptors (rods and cones), inner retinal cells (bipolar and amacrine cells), and the ganglion cells.

Electrooculography: Central macular changes, normal ERG findings, and abnormal EOG findings suggest Best vitelliform macular dystrophy.

Color testing: Mild blue-yellow axis color defects are common Audiometric tests : sensorineural hearing impairment Genetic testing: chromosomal mutations. the most common locus for

syndromic RP

Evaluation: Inherited/syndromic disease lab tests

Refsum disease - Serum phytanic acid in the presence of other neurologic abnormalities

Gyrate atrophy - Ornithine levels

Kearns-Sayre syndrome - ECG to help rule out heart block

Abetalipoproteinemia - Lipid profile with possible protein electrophoresis

Differential diagnosis Alport syndrome: nephropathy, sensorineural hearing loss, myopia,

cataract, retinal detachment

Alstrom syndrome: atypical retinal pigmentary degeneration, sensorineural hearing loss, obesity, diabetes mellitus, nephropathy, acanthosis nigricans

Bardet-Biedl syndrome: retinitis pigmentosa, hypogenitalism, polysyndactyly, mental retardation, obesity, sensorineural deafness

Cockayne syndrome: cachectic dwarfism, pigmenta ry retinal degeneration, optic atrophy, sensorineural hearing loss, characteristic faces, mental retardation

spondyloepiphyseal dysplasia congenita: dwarfism, mild deafness, cleft palate, congenital high myopia with associated retinal degeneration, cataracts, glaucoma

Flynn-Aird syndrome: severe myopia, atypical retinitis pigmentosa, sensorineural hearing loss, shooting pain, joint stiffness, muscular wasting kyphoscoliosis, skin atrophy, baldness, cystic bone changes

Friedreich ataxia: spinocerebellar degeneration, limb incoordination, nerve deafness, retinal degeneration, optic atrophy

Hurler syndrome (MPS-1): coarse facial features, short stature, progressive mental deterioration, corneal clouding, pigmentary retinopathy, optic atrophy

Kearns-Sayre syndrome (CPEO): progressive external ophthalmoplegia, retinitis pigmentosa, heart block, sensorineural hearing loss

Norrie syndrome: bilateral congenital retinal detachment, sensorineural hearing loss, mental retardation.

Differential diagnosis

Differential diagnosisOsteopetrosis (Albers-Schonberg disease): marble bone

and spontaneous fractures, macrocephaly, optic atrophy, heptosplenomegaly, anemia, retinal degeneration, conductive hearing loss

Refsum's disease (phytanic acid storage disease):dystopia canthorum, large root of nose, confluent eyebrows, heterochromia irides, sensorineural hearing loss, poliosis, pigment disturbance of RPE normal to subnormal ERG

Zellweger syndrome (cerebro-hepato-renal syndrome): neonatal hypotonia, severe neurodevelopmental delay, hepatomegaly, renal cysts, sensorineural deafness, retinal dysfunction (abnormal ERG), facial dysmorphism

Treatment Vitamin A/beta-carotene Docosahexaenoic acid (DHA) Acetazolamide Calcium channel blockers Lutein/zeaxanthin Medications with potential adverse effects in RP:

Isotretinoin (Accutane)- Sildenafil (Viagra)- Vitamin E Surgery:

- cataract extraction: Bastek et al studied 30 patients with RP; 83% of them improved by 2 lines on the Snellen visual acuity chart with cataract surgery. Perioperative use of corticosteroids is recommended to prevent postoperative cystoid macular edema.- Ciliary neurotrophic factor (CNTF) has been shown to slow retinal degeneration in a number of animal models.- RPE cell transplants - retinal prosthesis or phototransducing chip - Gene therapy to replace the defective protein by using DNA vector

the ophthalmologist may act as the consultant to an internist. Audiology consultation Annual patient examinations usually are sufficient to measure Goldmann visual field and visual

acuity. If medical treatment is initiated, more frequent visits and laboratory blood work may be indicated. Patients with systemic conditions that are associated with retinitis pigmentosa (RP) may require closer

follow-up care.

Treatment: genetic counseling and early diagnosis. 10% of congenitally deaf children may have Usher syndrome Currently, there is no cure for Usher syndrome. The best treatment involves early identification so that educational programs can begin as soon as possible. Typically, treatment will include hearing aids, assistive listening devices, cochlear implants, or other

communication methods such as American Sign Language; orientation and mobility training; and communication services and independent-living training that may include Braille instruction, low-vision services, or auditory training.

Some ophthalmologists believe that a high dose of vitamin A palmitate may slow, but not halt, the progression of retinitis pigmentosa.

This belief stems from the results of a long-term clinical trial supported by the National Eye Institute and the Foundation for Fighting Blindness. Based on these findings, the researchers recommend that most adult patients with the common forms of RP take a daily supplement of 15,000 IU (international units) of vitamin A in the palmitate form under the supervision of their eye care professional.

(Because people with type 1 Usher syndrome did not take part in the study, high-dose vitamin A is not recommended for these patients.) People who are considering taking vitamin A should discuss this treatment option with their health care provider before proceeding.

using gene therapy to replace the missing gene, researchers have succeeded in reversing one form of the disease in knockout mice

Recent studies of mouse models have shown that one form of the disease — that associated with a mutation in myosin VIIa — can be alleviated by replacing the mutant gene using a lentivirus.

Another study on Ush2a mouse showed Cell transplantation prevented functional deterioration for at least 10 weeks and reversed the mislocalization of cone pigment.

Other guidelines regarding this treatment option include: Do not substitute vitamin A palmitate with a beta-carotene supplement.

Do not take vitamin A supplements greater than the recommended dose of 15,000 IU or modify your diet to select foods with high levels of vitamin A.

Women who are considering pregnancy should stop taking the high-dose supplement of vitamin A three months before trying to conceive due to the increased risk of birth defects.

Women who are pregnant should stop taking the high-dose supplement of vitamin A due to the increased risk of birth defects.

In addition, according to the same study, people with RP should avoid using supplements of more than 400 IU of vitamin E per day.

NIDCD researchers, along with collaborators from universities in New York and Israel, pinpointed a mutation, named R245X, of the PCDH15 gene that accounts for a large percentage of type 1 Usher syndrome in today’s Ashkenazi Jewish population.

Ophthalmic diseases associated with hearing loss:

Cataracts - Congenital rubellaColoboma - Coloboma of iris, heart deformities,

choanal atresia, retarded growth, genital and ear deformities (CHARGE) association

Dystopia canthorum - Waardenburg syndrome (WS)Heterochromia irides - WSKeratitis - Cogan syndromeOcular palsy - Duane syndromeRetinal atrophy - Cockayne syndromeRetinitis pigmentosum - Usher syndromeRetinal degeneration - Alström syndromeCongenital blindness, pseudotumor retinae - Norrie

syndrome

references EARLY DIAGNOSIS OF USHER SYNDROME IN CHILDREN

BY Marilyn B. Mets, MD, Nancy M. Young, MD (BY INVITATION), Arlene Pass, BS (BY INVITATION), AND Janice B. Lasky,MD (BY INVITATION)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1298229/pdf/taos00001-0240.pdf

Novel USH2A compound heterozygous mutations cause RP/USH2 in a Chinese familyXiaowen Liu,1,2 Zhaohui Tang,2 Chang Li,2 Kangjuan Yang,3 Guanqi Gan,2 Zibo Zhang,3 Jingyu Liu,2 Fagang Jiang,1 Qing Wang,2 and Mugen Liu2

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2842093/

Cottet S, Schorderet DF. Mechanisms of apoptosis in retinitis pigmentosa. Curr Mol Med. Apr 2009;9(3):375-83. [Medline].

Emedicine: Author: David G Telander, MD, PhD, Assistant Professor, Department of Ophthalmology and Vision Science, Division of Vitreo-Retinal Diseases and Surgery, University of California Davis School of MedicineCoauthor(s): Anthony de Beus, MD, PhD, Consulting Staff, Southwest Eye Centers; Kent W Small, MD, Director/President, Macular and Retinal Disease Center; President, Molecular Insight LLC; Consulting Surgeon, Glendale Eye Medical Group

Usher Syndrome(National Institute on Deafness and Other Communication Disorders)

Usher Syndrome(National Eye Institute, National Institute on Deafness and Other Communication Disorders)

retina-international.org

nidcd.nih.gov

RPgroup of inherited disorders characterized by

progressive peripheral vision loss and night vision difficulties (nyctalopia) that can lead to central vision loss.

RP is a misnomer, as the word retinitis implies an inflammatory response, which has not been found to be a predominant feature of this condition.

RP can be passed on by all types of inheritance: 20-25% is autosomal dominant, 15-20% is autosomal recessive, and 5-10% is X linked, while the remaining 45-50% is found in patients without any known affected relatives.

RP is most commonly found in isolation, but it can be associated with systemic disease.

The most common systemic association is hearing loss (up to 30% of patients). Many of these patients are diagnosed with Usher syndrome.

Pathophysiology RP is typically thought of as a rod-cone dystrophy in which the

genetic defects cause cell death (apoptosis), predominantly in the rod photoreceptors; less commonly, the genetic defects affect the RPE and cone photoreceptors.

RP has significant phenotypic variation, as there are many different genes that lead to a diagnosis of RP, and patients with the same genetic mutation can present with very different retinal findings.

The first histologic change found in the photoreceptors is shortening of the rod outer segments. The outer segments progressively shorten, followed by loss of the rod photoreceptor. This occurs most significantly in the mid periphery of the retina. These regions of the retina reflect the cell apoptosis by having decreased nuclei in the outer nuclear layer.

In many cases, the degeneration tends to be worse in the inferior retina, thereby suggesting a role for light exposure.

Cone photoreceptor death occurs in a similar manner to rod apoptosis with shortening of the outer segments followed by cell loss. This can occur early or late in the various forms of RP.

FrequencyThe prevalence of typical RP is reported to be

approximately 1 in 4000 in the United States. The carrier state is believed to be

approximately 1 in 100.Worldwide prevalence of RP is approximately 1

in 5000.because of these X-linked varieties, men may

be affected slightly more than women.The age of onset can vary. RP usually is

diagnosed in young adulthood, although it can present anywhere from infancy to the mid 30s to 50s.

Sytmptoms:Nyctalopia: First symptoms and the hall markLoss of vision: Painless, slowly progressive.

Peripheral then tunnel vision.Photopsia+ve family historyDrug history is essential to rule out

phenothiazine/thioridazine toxicity.

PhysicalVA: vary from 20/20 to light perception, but

usually preserved until late of the disease.

Pupil: Normal +/- RAPD

Anterior segment: 50% of RP patient will develop posterior subcapsular cataract.

PhsyicalFundus: The retina can appear unaffected early in the

disease.

Typical key findings include the following: Bone spicules - Midperipheral retinal hyperpigmentation

in a characteristic pattern Optic nerve waxy pallor Atrophy of the RPE in the mid periphery of the retina Retinal arteriolar attenuation

The presence of vitreous cells is common. Patients can have a loss of the foveolar reflex an abnormal vitreoretinal interface. A subset of patients with RP develops cystoid macular

edema with an associated more rapid and potentially reversible loss of vision.

Retinitis punctata albescens, a variant of RP, presents with yellow deposits deep in the retina rather the normal increased pigmentation of the peripheral retina.

Fundus:

Cone-rod retinal degenerations present with central macular pigmentary changes (bull's eye maculopathy).

Choroideremia and gyrate atrophy typically present with large scalloped areas of peripheral retinal atrophy.