retinitis pigmentosa

Retinitis Pigmentosa 47

Clinical Characteristics
Ocular Features: 

Onset of night blindness and field constriction symptoms occur during the 4th and 5th decades of life.  Pigmentary abnormalities of the retina are the hallmark of this condition.  Retinal thinning, bone spicule pigmentation, vascular attenuation, optic disc pallor, and pigmentary atrophy have all been noted.

In patients with the autosomal dominant form of this disease, rod function is severely impaired or absent as evidenced by ERG studies.  Cone responses are often reduced on an age-related basis and in the range of 85-95% below normal.  As expected, dark-adapted visual thresholds are elevated and visual fields are restricted peripherally.  Loss of vision is age-related but some individuals can retain acuities of 20/35 to 20/40 into their sixth decade.  It is more common for acuities to be in the range of 20/200 to 20/400 later in life.

Systemic Features: 

No systemic disease is associated with this disorder.

Genetics

Mutations in the SAG gene (2q37) are responsible for this form of RP.  Both autosomal recessive and autosomal dominant modes of inheritance have been reported.

In one family with homozygous mutations a sib had features of Oguchi disease which also results from homozygous mutations in SAG.

Among Hispanic families in the southwestern US, heterozygous mutations in SAG are a common cause of autosomal dominant retinitis pigmentosa.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported for this disorder.

References
Article Title: 

A Novel Dominant Mutation in SAG, the Arrestin-1 Gene, Is a Common Cause of Retinitis Pigmentosa in Hispanic Families in the Southwestern United States

Sullivan LS, Bowne SJ, Koboldt DC, Cadena EL, Heckenlively JR, Branham KE, Wheaton DH, Jones KD, Ruiz RS, Pennesi ME, Yang P, Davis-Boozer D, Northrup H, Gurevich VV, Chen R, Xu M, Li Y, Birch DG, Daiger SP. A Novel Dominant Mutation in SAG, the Arrestin-1 Gene, Is a Common Cause of Retinitis Pigmentosa in Hispanic Families in the Southwestern United States. Invest Ophthalmol Vis Sci. 2017 May 1;58(5):2774-2784.

PubMed ID: 
28549094

Retinitis Pigmentosa With or Without Skeletal Anomalies

Clinical Characteristics
Ocular Features: 

Downward slanting lid fissures may be detectable at birth as part of the general craniofacial dysmorphism.  Some degree of night blindness causes symptoms by the second decade of life and constricted visual fields with pigmented retinopathy and vessel narrowing can be detected.  The ERG shows reduced or absent responses.  The retinal phenotype is progressive.   

Systemic Features: 

Most but not all patients have skeletal anomalies.  Nonspecific craniofacial dysmorphology features are frequently present including frontal bossing, macrocephaly, low-set ears, large columella, hypoplastic nares, and malar hypoplasia.  A short neck, brachydactyly, and overall shortness of stature are often present.  Some individuals have nail dysplasia.  The proximal femoral metaphyses sometimes show chondrodysplasia.

There is often some degree of intellectual disability and there may be delays in speech, feeding, and walking.

Genetics

This disorder results from homozygous or compound heterozygous mutations in the CWC27 gene (5q12.3).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No general treatment has been reported.  Low vision aids and night vision devices may be helpful, especially for educational activities.

References
Article Title: 

Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies

Xu M, Xie YA, Abouzeid H, Gordon CT, Fiorentino A, Sun Z, Lehman A, Osman IS, Dharmat R, Riveiro-Alvarez R, Bapst-Wicht L, Babino D, Arno G, Busetto V, Zhao L, Li H, Lopez-Martinez MA, Azevedo LF, Hubert L, Pontikos N, Eblimit A, Lorda-Sanchez I, Kheir V, Plagnol V, Oufadem M, Soens ZT, Yang L, Bole-Feysot C, Pfundt R, Allaman-Pillet N, Nitschke P, Cheetham ME, Lyonnet S, Agrawal SA, Li H, Pinton G, Michaelides M, Besmond C, Li Y, Yuan Z, von Lintig J, Webster AR, Le Hir H, Stoilov P; UK Inherited Retinal Dystrophy Consortium., Amiel J, Hardcastle AJ, Ayuso C, Sui R, Chen R, Allikmets R, Schorderet DF. Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies. Am J Hum Genet. 2017 Apr 6;100(4):592-604.

PubMed ID: 
28285769

Retinitis Pigmentosa, RDH11 Syndrome

Clinical Characteristics
Ocular Features: 

Night vision problems and cataracts may be noted late in the first decade of life.  The fundus has changes typical of retinitis pigmentosa such as a salt-and-pepper retinopathy and narrowing of the arterioles with relative sparing of the fovea.  Confluent bone-spicule pigmentation is present in the periphery.  The optic nerve may have a pinkish waxy appearance.  Best-corrected visual acuity early is in the 20/25-20/30 range early in life with progressive deterioration.  Full field ERGs and visual fields are consistent with retinitis pigmentosa with the scotopic system more severely affected than the photopic.

Systemic Features: 

Developmental delays and cognitive deficits are apparent in early childhood.  Diastema and malocclusion may be present.  Short stature (5th percentile) is characteristic along with facial dysmorphology consisting of hypoplasia of the alae nasae, malar hypoplasia and slight up slanting of the palpebral fissures.

Genetics

A single family with three affected sibs (2 boys and one girl) has been reported.  The parents were phenotypically normal consistent with autosomal recessive inheritance.  Two variants in the RDH11 (14q24.1) gene were identified in the (compound heterozygous) siblings as responsible for a truncated, inactive enzyme.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment information is available.  Patients may benefit from special education, low vision aids, and physical therapy.Cataract surgery may be indicated.

References
Article Title: 

Pseudoxanthoma Elasticum-Like Disease

Clinical Characteristics
Ocular Features: 

Retinitis pigmentosa has been diagnosed clinically and confirmed by ERG studies in some patients. The fundi in a few individuals have the typical angioid streaks and/or peau d’orange changes. The impact on visual acuity and its prognosis has not been systematically studied.

Systemic Features: 

The skin changes resulting from fragmentation and aberrant mineralization of connective tissue, particularly elastic fibers, resemble those seem in classic pseudoxanthoma elasticum. These include the presence of yellowish papules or leathery plaques with dot-like depressions (‘chicken skin’). However, the skin changes are more widespread and involve trunk as well as limbs and flexural areas. Ultrastructurally the elastic fibers are more severely fragmented than those in classic PXE.

Many patients in addition have deficiencies in vitamin K-dependent clotting factors such as II, VII, IX, and X. Epistaxis, spontaneous gingival bleeding and severe vaginal hemorrhages may occur. Cerebral aneurysms, vascular occlusions, and atherosclerotic plaques in the lower extremities have been reported in a few patients.

Genetics

Classic pseudoxanthoma elasticum is due to homozygous mutations in the ABCC6 (ATP-binding cassette subfamily C member 6) gene. However, in the PXE-like condition described here homozygous or compound heterozygous mutations in the GGCX (gamma-glutamyl carboxylase) gene (2p11.2) are responsible. Some heterozygous GGCX individuals in families with this genotype who are also heterozygous for ABCC6 mutations (doubly heterozygous) may have similar skin features. Thus the condition described here may also be a digenic disorder in some individuals.

Pseudoxanthoma elasticum-like disease is an autosomal recessive disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the connective tissue defect but individual problems such as subretinal neovascularization, hemorrhages, and vascular occlusions may respond to appropriate therapy.

References
Article Title: 

Retinitis Pigmentosa 25

Clinical Characteristics
Ocular Features: 

There is considerable clinical heterogeneity with a wide range in age of onset and progression.  Night blindness, sometimes with photophobia, has its onset in the second or third decade of life and central acuity can be impacted by age 30 years.  Other patients have no symptoms until the fifth decade.  Some patients lose the ability to perceive light by the sixth decade.  The visual fields are usually constricted although one patient had a central scotoma.  The ERG is usually nonrecordable but other patients may have a variable rod-cone pattern of attenuation.  The retinal vessels are also attenuated and some patients have mild optic atrophy.  The pigmentary retinopathy is also variable with sometimes central lesions and in other patients more peripheral.  One patient had posterior subcapsular cataracts.

Systemic Features: 

No systemic disease has been reported.

Genetics

This is an autosomal recessive form of retinitis pigmentosa resulting from homozygosity or compound heterozygosity in the EYS gene (6q12).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Retinitis Pigmentosa and Mental Retardation

Clinical Characteristics
Ocular Features: 

The lenses may have pleomorphic white axial opacities but in other patients can be totally opacified.  Optic atrophy is present and vision may be reduced to light perception but nystagmus is absent.  Evidence suggests that vision loss is progressive.  Some patients have extensive posterior synechiae while others have been noted to have sluggish pupils.  High myopia is a feature. The retinal pigmentation has a typical retinitis pigmentosa picture with attenuated retinal vessels and equatorial bone spicule pigmentation located in the midperiphery while the macula can have a bull’s eye appearance.   

Systemic Features: 

Early development may seem normal but developmental milestones are usually delayed.  Postnatal microcephaly and growth deficiency with mental retardation and early hypotonia are typical features.  The mental retardation may be severe.  Scoliosis and arachnodactyly have been noted and hypogonadism has been reported.  Speech may not develop and mobility is sometimes limited.

Genetics

The family pattern suggests autosomal recessive inheritance.  Homozygosity mapping has identified in a region of chromosome 8 (8q21.2-22.1) that overlaps the region for Cohen syndrome () but no specific mutated gene has been identified.      

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

None.

References
Article Title: 

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: 

Nanophthalmos with Retinitis Pigmentosa

Clinical Characteristics
Ocular Features: 

Poor vision is present beginning in childhood and may progress to hand motion or even loss of light perception when retinal detachments occur.  Nystagmus has been seen in one patient.  Corneal diameters were 11 mm, the angles were open, and axial lengths were shortened to about 17 mm.  Alternating areas of hypo- and hyperfluorescence are seen with fluorescein angiography corresponding to areas with pigment clumping seen throughout the fundi.  The fundus pigmentation is atypical for retinitis pigmentosa, however, in spite of the title given by the authors.  No scotopic or photopic responses are seen on the ERG.  Drusen were present in the optic nerves. 

Systemic Features: 

No systemic disease is associated. 

Genetics

A single family with affected male and female sibs has been reported and a homozygous nonsense mutation in exon 5 of the CRB1 gene (1q31-32.1) was present in both. 

Another recessive form of microphthalmia with retinitis pigmentosa plus has been reported (611040) without nanophthalmos features and having a mutation in the MFRP gene. True nanophthalmos with retinopathy (267760) has some features similar to the disorder described here but with macular cysts.  No responsible mutation has been identified in this disorder however. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Low vision aids might be helpful in early stages of the disease. 

References
Article Title: 

Microphthalmia with Retinitis Pigmentosa

Clinical Characteristics
Ocular Features: 

A decrease in visual acuity with night blindness begins in the third decade of life.  The axial length is decreased resulting in high hyperopia.  There is diffuse scleral thickening, macular schisis of the outer retinal layers, and drusen may be present in the optic nerve.  The retinal pigment epithelium is abnormal with both pigment clumping and bone-spicule formation.  Areas of hypo- and hyperfluorescence are seen on fluorescein angiograms.  The cornea is normal-sized with shallow anterior chambers but narrow angles were not reported.  Intraocular pressures were normal.  On ERG recordings rod responses are missing while cone tracings are severely diminished. 

Systemic Features: 

No systemic disease is associated. 

Genetics

Based on consanguinity in the parents of the single family reported, this seems to be an autosomal recessive disorder.  Molecular studies confirm that the four affected sibs are homozygous for mutations in the MFRP gene (11q23) while the parents are both heterozygous.

Another disorder of small eyes but with classical findings of nanophthalmos and retinitis pigmentosa has also been described (267760) (nanophthalmos with retinopathy) and may be the same disorder especially since no molecular mutation has been identified.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Low vision aids may be helpful, at least in early stages of the disease. 

References
Article Title: 

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.  The mutation (8993T-G) occurs in a subunit 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

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