retinitis pigmentosa

Neuropathy, Ataxia, and Retinitis Pigmentosa

Clinical Characteristics
Ocular Features: 

Night blindness and visual field restriction are early symptoms usually in the second decade of life.  The retina may first show a salt-and-pepper pigmentary pattern which later resembles the classic bone-spicule pattern of retinitis pigmentosa with vascular attenuation.  The optic nerve becomes pale and eventually marked optic atrophy develops.  Severe vision loss is evident in young adults and some patients become blind. 

Systemic Features: 

The onset of systemic symptoms such as unsteadiness occurs some time in the second decade of life.  Irritability, delayed development, and psychomotor retardation may be evident in children whereas older individuals can have frank dementia.  The MRI may reveal cerebral and cerebellar atrophy.  Seizures may have their onset by the third decade.  Numbness, tingling and pain in the extremities are common.  EMG and nerve conduction studies can demonstrate a peripheral neuropathy.  Neurogenic muscle weakness can be marked and muscle biopsy may show partial denervation. Some patients have hearing loss.  A few patients have cardiac conduction defects. 

Genetics

This is a mitochondrial disorder with pedigrees showing maternal transmission.  Mutations (8993T-G) have been found in subunits of mitochondrial H(+)-ATPase or MTATP6.  The amount of heteroplasmy is variable and likely responsible for the clinical heterogeneity in this disorder.  Individuals with more than 90% mutated chromosomes are considered to have a subtype of Leigh syndrome (MILS) with earlier onset (3-12 months of age).  NARP patients usually have 70-80% or less of mutated mitochondria.  The amount of heteroplasmy may vary among tissues. 

Treatment
Treatment Options: 

No treatment is available for this disease but low vision aids can be helpful in early stages of disease.  Recently it has been demonstrated that alpha-ketoglutarate/aspartate application to fibroblast cell cultures can provide some protection from cell death in NARP suggesting a potential therapeutic option. 

References
Article Title: 

Retinopathy of NARP syndrome

Kerrison JB, Biousse V, Newman NJ. Retinopathy of NARP syndrome. Arch Ophthalmol. 2000 Feb;118(2):298-9.

PubMed ID: 
10676807

Usher Syndrome Type III

Clinical Characteristics
Ocular Features: 

Retinitis pigmentosa is a cardinal feature with onset of severe symptoms of nightblindness and tunnel vision by the second decade of life.  The ERG shows depressed responses.  Central vision may also be lost in young adults.  Hypermetropic astigmatism has been reported as the most typical refractive error for type III in the presence of nightblindness and hearing loss, at least in Finnish patients.

Systemic Features: 

Hearing loss is progressive but later in onset than in type I and type II.  Infants are usually born with normal hearing and often experience some loss of hearing by the end of the first decade of life.  Speech can develop normally because of the late onset of the hearing deficit.  Hearing loss is progressive early with older patients having a profound and eventually more stable hearing deficit.  The amount of vestibular dysfunction is variable but usually is severe enough to cause significant unsteadiness.  The mental changes associated with type I are absent.

Genetics

Usher syndrome is a clinically and genetically heterogeneous condition.   Type IIIA is caused by a mutation in the CLRN1 gene (3q21-q25).  It is inherited in an autosomal recessive pattern.  Type IIIB (614505) is the result of homozygous mutations in HARS (5q31.3).

There is also a disorder resembling Usher that results from homozygous mutations in ABHD12 (20p11.21) that also causes PHARC (612674) (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and early onset cataract).

This is the least common type of Usher syndrome.  Three additional types of Usher syndrome are recognized:  type I (276900) results from mutations in at least 7 different genes, type II (276901) from mutations in 4 genes, and Type IV resulting from mutations in the ARSG gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Hearing aids might be helpful early but cochlear implants may be needed in older patients with severe deafness.  Low vision aids are often helpful.

References
Article Title: 

Targeted next-generation sequencing identifies a homozygous nonsense mutation in ABHD12, the gene underlying PHARC, in a family clinically diagnosed with Usher syndrome type 3

Eisenberger T, Slim R, Mansour A, Nauck M, N?ornberg G, N?ornberg P, Decker C, Dafinger C, Ebermann I, Bergmann C, Bolz HJ. Targeted next-generation sequencing identifies a homozygous nonsense mutation in ABHD12, the gene underlying PHARC, in a family clinically diagnosed with Usher syndrome type 3. Orphanet J Rare Dis. 2012 Sep 2;7(1):59. [Epub ahead of print]

PubMed ID: 
22938382

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

Abetalipoproteinemia

Clinical Characteristics
Ocular Features: 

The major ocular manifestations of abetalipoproteinemia are in the retina which develops diffuse and sometimes patchy pigmentary changes often called atypical retinitis pigmentosa.  In other cases the picture resembles retinitis punctata albescens with perivascular white spots in the peripheral retina.  Night blindness is an early and prominent symptom with abnormal dark adaptation thresholds evident before fundus pigment changes are seen.  The ERG shows loss of rod function before that of cone function.  The macula may or may not be affected while peripheral fields are often severely constricted.  Loss of photoreceptors occurs throughout life and visual fields show progressive constriction, sometimes with central sparing.  A single case of bilateral disc swelling in a 9 year-old girl has been reported.

Systemic Features: 

Celiac disease and steatorrhea due to a deficiency of circulating chylomicra underlie the malabsorption of vitamins A and E which is probably responsible for the majority of systemic manifestations.  Red blood cells have a peculiar burr-like morphology that has led to the designation 'acanthocytes'.  Liver failure and cirrhosis sometimes occur.  Plasma lipids are generally low including cholesterol, triglycerides, and beta lipoproteins.  Central and peripheral nerve demyelination occurs leading to a progressive ataxia and other neurological symptoms.

Genetics

This autosomal recessive disease seems to result from an inability to synthesize the apoB peptide that is a part of the LDL and VLDL.   A mutation in the MTP gene (4q22-q24) is responsible.  The gene is sometimes called MTTP as it codes for micosomal triglyceride transfer protein.

Acanthocytosis is also a feature in the autosomal recessive condition known as chorea-acanthocytosis (200150), a progressive degenerative movement disorder primarily affecting the limbs resulting from mutations in the VPS13A gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment with vitamins A and E may be beneficial.  Cone function improves before rod function with massive doses of vitamin A but usually only after months of treatment.  It has been reported that Vitamin A alone without vitamin E is insufficient to arrest the retinal disease.

References
Article Title: 

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