rod-cone dystrophy

RAB18 Deficiency

Clinical Characteristics
Ocular Features: 

Microphthalmia with microcornea, lens opacities, small and unresponsive pupils, and optic atrophy are the outstanding ocular features of this syndrome.  The eyes appear deeply set.  Some but not all have ERG evidence of rod and cone dysfunction.  The VEP is usually abnormal.  Short palpebral fissures have been described. 

Systemic Features: 

Patients with the micro syndrome have many somatic and neurologic abnormalities.  Infants usually have feeding problems that is sometimes accompanied by gastroesophageal reflux.  Some degree of psychomotor retardation and developmental delays is common.  Both spasticity and hypotonia have been described.  Some patients have seizures.  Facial hypertrichosis, anteverted ears, and a broad nasal bridge are often noted.   There may be absence of the corpus callosum while diffuse cortical and subcortical atrophy, microgyria, and pachygyria may be evident on MRI imaging.  Hypogenitalism may be a feature in both sexes.  Males may also have cryptorchidism and a micropenis while females can have hypoplasia of the labia minora and clitoris and a small introitus.  Microcephaly is inconsistently present. 

Genetics

This is a clinically and genetically heterogeneous disorder caused by homozygous mutations in at least 4 genes: RAB3GAP1 (WARBM1), RAB3GAP2 (WARBM2), RAB18 (WARBM3), and TBC1D20 (WARBM4).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available.  Vision remains subnormal even after cataracts are removed.  Nutrition may be improved with placement of a gastrostomy tube.

References
Article Title: 

New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish

Morris-Rosendahl DJ, Segel R, Born AP, Conrad C, Loeys B, Brooks SS, M?oller L,Zeschnigk C, Botti C, Rabinowitz R, Uyanik G, Crocq MA, Kraus U, Degen I, Faes F. New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish. Eur J Hum Genet. 2010 Oct;18(10):1100-6.

PubMed ID: 
20512159

Retinitis Pigmentosa, AR

Clinical Characteristics
Ocular Features: 

The term retinitis pigmentosa is applied to a large group of disorders with great clinical and genetic heterogeneity.  The ocular disease is characterized by night blindness, field constriction, and pigmentary changes in the retina.  The latter is sometimes described as having a ‘bone corpuscle’ appearance with a perivascular distribution.  A ring scotoma is usually evident.  Age of onset and rate of progression is highly variable, even within families.  The rods are impacted early but cone deterioration with loss of central vision usually follows.  Some patients complain of dyschromatopsia and photophobia.  The ERG generally documents this progression but the mfERG shows wide variations in central cone functioning.  Legal blindness is common by the 5thdecade of life or later.  The course of clinical and ERG changes is more aggressive in the X-linked form than in the autosomal dominant disease.  The final common denominator for all types is first rod and then cone photoreceptor loss through apoptosis.

As many as 50% of patients develop posterior subcapsular cataracts.  The vitreous often contains cells and particulate debris.   Retinal arterioles are often attenuated and the optic nerve may have a waxy pallor, especially late in the disease.  Occasional patients have cysts in the macula.  Some patients experience continuous photopsia. 

Systemic Features: 

The ‘simple’ or nonsyndromal type of RP described here has no systemic features.  However, the retinopathy is seen in a number of syndromes and, of course, in some infectious diseases as well.  It is more accurate to label the fundus finding as 'pigmentary retinopathy' in such cases.

Genetics

A significant proportion of RP cases occur sporadically, i.e., without a family history.  Mutations in more than 30 genes cause autosomal recessive RP disorders and these account for more than half of all cases of retinitis pigmentosa.  More than 100 mutations have been identified in the RHO gene (3q21-q24) alone.  Mutations in some genes cause RP in both autosomal recessive and autosomal dominant inheritance patterns.  Compound heterozygosity is relatively common in autosomal recessive disease.  See OMIM 268000 for a complete listing of mutations.

Many genes associated with retinitis pigmentosa have also been implicated in other pigmentary retinopathies.  In addition, numerous phenocopies occur, caused by a variety of drugs, trauma, infections and numerous neurological disorders.  To make diagnosis even more difficult, the fundus findings and ERG responses in nonsyndromic RP in most patients are too nonspecific to be useful for classification. Extensive systemic and ocular evaluations are important and should be combined with genotyping in both familial and nonfamilial cases to determine the diagnosis and prognosis. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Photoreceptor transplantation has been tried in without improvement in central vision or interruption in the rate of vision loss.  Longer term results are needed.  Resensitizing photoreceptors with halorhodopsin using archaebacterial vectors shows promise in mice.  High doses of vitamin A palmitate slow the rate of vision loss but plasma levels and liver function need to be checked at least annually.  Oral acetazolamide can be helpful in reducing macular edema.

Low vision aids and mobility training can be facilitating for many patients.  Cataract surgery may restore several lines of vision, at least temporarily.

Several pharmaceuticals should be avoided, including isotretinoin, sildenafil, and vitamin E. 

References
Article Title: 

Retinitis Pigmentosa, AD

Clinical Characteristics
Ocular Features: 

Retinitis pigmentosa is a large group of disorders with great clinical and genetic heterogeneity.  The ocular disease is characterized by night blindness, field constriction, and pigmentary changes in the retina.  The later may have a 'bone corpuscle' appearance with a perivascular distribution.  A ring scotoma is sometimes evident.  Age of onset and rate of progression is highly variable, even within families.  The rods are impacted early but cone deterioration with loss of central vision usually follows.  Some patients complain of dyschromatopsia and photophobia.  The ERG generally documents this progression but the mfERG shows wide variations in central cone functioning.  Legal blindness is common by the 5thdecade of life or later.  The course of clinical and ERG changes is more aggressive in the X-linked form than in the autosomal dominant RHO disease.  The final common denominator for all types is first rod and then cone photoreceptor loss through apoptosis.

As many as 50% of patients develop posterior subcapsular cataracts.  The vitreous often contains cells and particulate debris.   Retinal arterioles are often attenuated and the optic nerve may have a waxy pallor, especially late in the disease.  Occasional patients have cysts in the macula.  Some patients experience continuous photopsia.  

Systemic Features: 

The 'simple' or nonsyndromal type of RP described here has no systemic features.  However, the retinopathy is seen in a number of syndromes and, of course, in trauma and in some infectious diseases as well. 

Genetics

A significant proportion of RP cases occur sporadically, i.e., without a family history.  Mutations in more than 25 genes cause autosomal dominant RP disorders and these account for about one-third of all cases of retinitis pigmentosa but there are many more specific mutations.  More than 100 have been identified in the RHO gene (3q21-q24) alone, for example.  Mutations in some genes cause RP in both autosomal recessive and autosomal dominant inhritance patterns.  See OMIM 268000 for a complete listing of mutations.

Many genes associated with retinitis pigmentosa have also been implicated in other pigmentary retinopathies.  In addition numerous phenocopies occur, caused by a variety of drugs, trauma, infections and numerous neurological disorders.  To make diagnosis even more difficult, the fundus findings and ERG responses in nonsyndromic RP in most patients are too nonspecific to be useful for classification. Extensive systemic and ocular evaluations are important and should be combined with genotyping in both familial and nonfamilial cases to determine the diagnosis and prognosis. 

For autosomal dominant retinitis pigmentosa resulting from mutations in RP1, see Retinitis Pigmentosa 1 (180100). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Photoreceptor transplantation has been tried in 8 patients without improvement in central vision or interruption in the rate of vision loss.  Longer term results are needed.  Resensitizing photoreceptors with halorhodopsin using archaebacterial vectors shows promise in mice.  High doses of vitamin A palmitate slow the rate of vision loss but plasma levels and liver function need to be checked at least annually.  The use of oral and systemic carbonic anhydrase inhibitors can be helpful in reducing macular edema.

Low vision aids and mobility training can be facilitating for many patients.  Cataract surgery may restore several lines of vision at least temporarily.

Several pharmaceuticals should be avoided, including isotretinoin, sildenafil, and vitamin E. 

References
Article Title: 

Retinitis Pigmentosa 3, X-Linked

Clinical Characteristics
Ocular Features: 

Retinitis pigmentosa is a large group of disorders with great clinical and genetic heterogeneity.  The ocular disease is characterized by night blindness, field constriction, and pigmentary changes in the retina.  The later may have a ‘bone corpuscle’ appearance with a perivascular distribution.  A ring scotoma is sometimes evident.  Age of onset and rate of progression is highly variable, even within families.  In this, an X-linked form of the disease, the first symptoms often appear early in the second decade of life.  The rods are impacted early but cone deterioration with loss of central vision usually follows.  Some patients complain of dyschromatopsia and photophobia.  The ERG generally documents this progression but the mfERG shows wide variations in central cone functioning.  Legal blindness is common by the 4thor 5thdecades of life.  The course of clinical and ERG changes is more aggressive in the X-linked form than in autosomal dominant retinitis pigmentosa disease resulting from RHO mutations.  The final common denominator for all types is first rod and then cone photoreceptor loss through apoptosis.

Up to 50% of adults develop cataracts beginning in the posterior subcapsular area.  The vitreous often contains cells and some patients have cystoid macular edema.  A waxy pallor of the optic nerve is sometimes present especially in the later stages of the disease.

Female carriers generally are asymptomatic but may also have severe RP.  Occasionally they have an unusual tapetal reflex consisting of a ‘beaten metal’ appearance or sometimes scintillating, golden patches. 

Systemic Features: 

There is no systemic disease in ‘simple’ or non-syndromic retinitis pigmentosa but pigmentary retinopathy is associated with a number of syndromes (syndromal RP) e.g.,  Usher syndromes, Waardenburg syndrome, Alport syndrome, Refsum disease, Kerns-Sayre syndrome, abetalipoproteinemia, neuronal ceroid lipofuscinosis, mucopolysaccharidoses types I, II, III, and Bardet-Biedl syndromes. 

The RPGR gene is important to the normal function of cilia throughout the body.  For this reason disorders resulting from RPGR mutations such as CORDX1 (304020) and this one are sometimes classified as primary ciliary dyskinesias or ciliopathies.  The gene products of the RPGR gene, for example, are localized to connecting cilia of the outer segments of rods and cones and in motile cilia in the airway epithelia.  A subset of families with RP3 have chronic and recurrent upper respiratory infections including sinusitis, bronchitis, pulmonary atelectasis, and otitis media (300455) similar to that seen in the immotile cilia syndrome (244400).  Female carriers in these families have few retinal changes but may suffer recurrent and severe upper respiratory infections similar to hemizygous males.  Severe hearing loss also occurs in both sexes with the RPGR mutations and there is some evidence that this may be a primary sensorineural problem, perhaps in addition to conductive loss from recurrent otitis media.

Genetics

Mutations in more than 100 genes may be responsible for retinitis pigmentosa but sporadic disease occurs as well.  Between 5 and 10% of individuals have X-linked disease.  Perhaps 70% of X-linked RP is caused by mutations in RPGR (Xp11.4) as in this condition.  The same gene is mutant in one form of X-linked cone-rod dystrophy (CORDX1; 304020). These  disorders are sometimes considered examples of X-linked ocular disease resulting from a primary ciliary dyskinesia (244400).

Another form of X-linked RP (RP2) with more choroidal involvement is caused by mutations in the RP2 gene (312600 ; Xp11.23). 

Many genes associated with retinitis pigmentosa have also been implicated in other pigmentary retinopathies.  In addition numerous phenocopies occur, caused by a variety of drugs, trauma, infections and numerous neurological disorders.  To make diagnosis even more difficult, the fundus findings and ERG responses in nonsyndromic RP in most patients are too nonspecific to be useful for classification. Extensive systemic and ocular evaluations are important and should be combined with genotyping in both familial and nonfamilial cases to determine the diagnosis and prognosis. 

Treatment
Treatment Options: 

Photoreceptor transplantation has been tried in 8 patients without improvement in central vision or interruption in the rate of vision loss.  Longer term results are needed.  Resensitizing photoreceptors with halorhodopsin using archaebacterial vectors shows promise in mice.  High doses of vitamin A palmitate slow the rate of vision loss but plasma levels and liver function need to be checked at least annually.  Oral acetazolamide can be helpful in reducing macular edema.

Low vision aids and mobility training can be facilitating for many patients.  Cataract surgery may restore several lines of vision at least temporarily.

Several pharmaceuticals should be avoided, including isotretinoin, sildenafil, and vitamin E. 

References
Article Title: 

Bardet-Biedl Syndromes

Clinical Characteristics
Ocular Features: 

The term Bardet-Biedl is applied to a clinically and genetically diverse group of disorders, of which at least 21 entities (BBS1-BBS21) are recognized.  This discussion is generically relevant to all of the phenotypes since the retinal dystrophy is common to all.

A progressive rod-cone dystrophy is a cardinal feature of all forms of Bardet-Biedl syndrome.  However, a subset of patients have primary cone degeneration.  In at least some forms of this syndrome, the cause seems to be a defect in the cilia that impairs the intraciliary protein transport between the inner and outer segments of the photoreceptors.  Vision loss has an early onset and usually progresses rapidly with severe loss of central and peripheral vision by the second or third decade of life.  Night blindness may be evident by 7 or 8 years of age.  The ERG is not recordable even in early childhood.  Pigmentary changes in the retina are often labeled retinitis pigmentosa but they are atypical for the usual disease.  Early changes are more characteristic of atrophy with a paucity of pigment but later the bone spicule pattern of hyperpigmentation appears.  The macula can appear atrophic and sometimes has a bull's eye pattern.  Optic atrophy and retinal arteriole narrowing may be seen.  Bardet-Biedl syndrome is clinically similar to Biemond syndrome (210350) except for iris colobomas that occur in the latter disorder.

Systemic Features: 

Obesity, mental retardation, renal disease, and hepatic fibrosis with syndactyly, brachydactyly, and post-axial polydactyly are characteristic.  The degree of mental handicap varies widely.  Diabetes mellitus is present in about one-third of patients.  Structural deformities of genitalia as well as hypogonadism and menstrual irregularities often occur as in some other disorders but the association of severe vision loss and characteristic retinal changes are diagnostically helpful.  Kidney failure secondary to cystic nephronophthisis or other renal malformations is common. Hypercholesterolemia is found in many patients.  Many patients have motor difficulties, appearing clumsy and unsteady.  Emotional lability and inappropriate outbursts can be part of these syndromes as well.

Genetics

The syndromes of Bardet-Biedl are inherited in an autosomal recessive pattern.  At least 21 mutations have been identified.  Not all cases are caused by homozygosity of the same mutation since compound heterozygosity at two loci may also cause similar phenotypes.

Laurence-Moon syndrome (245800) is considered part of the Bardet-Biedl group of diseases in this database. 

Mutations in PNPLA6 have been found in some individuals with a form of Bardet-Biedl syndrome as well as in Boucher-Neuhauser Syndrome (215470) also known as Chorioretinopathy, Ataxia, Hypogonadism Syndrome, and Trichomegaly Plus Syndrome (275400), in this database.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment exists for these syndromes but organ specific therapy may be helpful.

Studies in a mice model suggest that the neural retina may at least partially recover in type 1 following subretinal injection of viral vectors containing the wild-type bbs1 gene.

 

References
Article Title: 

Bardet-Biedl Syndrome

Suspitsin EN, Imyanitov EN. Bardet-Biedl Syndrome. Mol Syndromol. 2016 May;7(2):62-71.

PubMed ID: 
27385362

Predominantly cone-system dysfunction as rare form of retinal degeneration in patients with molecularly confirmed Bardet-Biedl Syndrome

Scheidecker S, Hull S, Perdomo Y, Studer F, Pelletier V, Muller J, Stoetzel C, Schaefer E, Defoort-Dhellemmes S, Drumare I, Holder Graham E, Hamel Christian P, Webster Andrew R, Moore Anthony T, Puech B, Dollfus Helene J. Predominantly cone-system dysfunction as rare form of retinal degeneration in patients with molecularly confirmed Bardet-Biedl Syndrome. Am J Ophthalmol. 2015 May 14. [Epub ahead of print]. 

PubMed ID: 
25982971

Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes

Hufnagel RB, Arno G, Hein ND, Hersheson J, Prasad M, Anderson Y, Krueger LA, Gregory LC, Stoetzel C, Jaworek TJ, Hull S, Li A, Plagnol V, Willen CM, Morgan TM, Prows CA, Hegde RS, Riazuddin S, Grabowski GA, Richardson RJ, Dieterich K, Huang T, Revesz T, Martinez-Barbera JP, Sisk RA, Jefferies C, Houlden H, Dattani MT, Fink JK, Dollfus H, Moore AT, Ahmed ZM. Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes. J Med Genet. 2015 Feb;52(2):85-94.

PubMed ID: 
25480986

Mutations in IFT172 Cause Isolated Retinal Degeneration and Bardet-Biedl Syndrome

Bujakowska KM, Zhang Q, Siemiatkowska AM, Liu Q, Place E, Falk MJ, Consugar M, Lancelot ME, Antonio A, Lonjou C, Carpentier W, Mohand-Sayid S, den Hollander AI, Cremers FP, Leroy BP, Gai X, Sahel JA, van den Born LI, Collin RW, Zeitz C, Audo I, Pierce EA. Mutations in IFT172 Cause Isolated Retinal Degeneration and Bardet-Biedl Syndrome. Hum Mol Genet. 2014 Aug 28.  [Epub ahead of print].

PubMed ID: 
25168386

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