pigmentary retinopathy

Neurodevelopmental Disorder, Mitochondrial, with Abnormal Movements and Lactic Acidosis

Clinical Characteristics
Ocular Features: 

Optic atrophy is sometimes present.  Nystagmus, and strabismus are seen in some patients.  A pigmentary retinopathy was found in one individual.

Systemic Features: 

This is a clinically heterogeneous disorder with extensive neurological deficits.  Patients have feeding and swallowing difficulties from the neonatal period.  There is intrauterine growth retardation and postnatally patients usually exhibit psychomotor delays and intellectual disabilities.  Some develop seizures and few achieve normal developmental milestones.  Axial hypotonia is present from early infancy and most patients have muscle weakness and atrophy.  However, there may be spastic quadriplegia which is often associated with dysmetria, tremor, and athetosis.  Ataxia eventually develops in most patients. 

Brain imaging shows cerebral and cerebellar atrophy, enlarged ventricles, white matter defects, and delayed myelination. 

Incomplete metabolic studies suggest there may be abnormalities in mitochondrial oxidative phosphorylation activity in at least some tissues.  Most patients have an elevated serum lactate.

Death in childhood is common.

Genetics

Homozygous and compound heterozygous mutations in the WARS2 gene have been found in several families with this condition.  The considerable variation in the phenotype may at least partially be explained by the fact that an additional variant in the W13G gene is sometimes present which impairs normal localization of the WARS2 gene product within mitochondria.

The transmission pattern in several families is consistent with autosomal recessive inheritance.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported for the general condition.

References
Article Title: 

Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy

Wortmann SB, Timal S, Venselaar H, Wintjes LT, Kopajtich R, Feichtinger RG, Onnekink C, Muhlmeister M, Brandt U, Smeitink JA, Veltman JA, Sperl W, Lefeber D, Pruijn G, Stojanovic V, Freisinger P, V Spronsen F, Derks TG, Veenstra-Knol HE, Mayr JA, Rotig A, Tarnopolsky M, Prokisch H, Rodenburg RJ. Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy. Hum Mutat. 2017 Dec;38(12):1786-1795.

PubMed ID: 
28905505

Retinitis Pigmentosa 80

Clinical Characteristics
Ocular Features: 

Night blindness is an early symptom which may be noted in early childhood.  Vision loss can be documented in early childhood and progressively worsens to hand motions or light perception by the 3rd to 5th generation.  The fundus appearance has been described as normal in 1-year old patients but retinal pigmentary changes and arteriolar changes are evident in some children by the age of 2 years.  Typical bone spicule pigmentary changes have been described in some older patients.  Staring at lights (photophilia) has been noted in children under 1 year of age while eye-rubbing (oculodigital sign) may be seen soon thereafter.  Nystagmus is often present.

ERG responses are greatly diminished or nonrecordable.  Rods are more severely affected than cones.  OCT shows loss of inner and outer segments of photoreceptors.

Systemic Features: 

Systemic signs seem variable but full evaluations have not been done in all patients.  Mild developmental delay has been reported in some individuals and significant childhood onset hearing loss has been documented in at least one person.  Radiography of the hands revealed cone-shaped phalangeal epiphyses in 5 probands and one proband had short fingers in one study.

Genetics

Homozygous or compound heterozygous mutations in the IFT140 gene (16p13.3) segregates with the phenotype as expected for an autosomal recessive disorder.

The same gene is mutated in Short-Rib Thoracic Dysplasia 9 (266920) in which similar digital and retinal changes are seen.  However, renal, hepatic, and additional skeletal disease are also present.  These may be the same conditions pending further elucidation of the phenotypes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported for the general disorder.  However, low vision aids should be offered to young people, especially during school years.

References
Article Title: 

Retinal Dystrophy with or without Macular Staphyloma

Clinical Characteristics
Ocular Features: 

Few patients have had complete eye studies and physical findings are seemingly limited to the eye.  Patients complain of progressively decreasing vision as early as the first decade of life.  Abnormal retinal findings may be present by the second decade and maybe earlier.  The RPE can appear mottled and the retinal vessels are attenuated.  Retinal pigment clumping occurs later.  Night blindness and visual field constriction occur.  Cone and flicker ERGs may be nonrecordable while rod and flash ERGs are reduced consistent with a rod-cone dystrophy.  The retinal lamination has been described as abnormal on OCT in some individuals.

Macular staphylomas have been described in three unrelated offspring of consanguineous parents.

Vision loss is severe with legal blindness by midlife and one patient lost light perception by 40 years of age.  

Systemic Features: 

No consistent systemic abnormalities have been reported.

Genetics

Homozygous or compound heterozygous mutations in the C21orf2 gene (21q22.3) are the cause of this autosomal recessive syndrome.

Homozygous or heterozygous mutations in the same gene are responsible for axial spondylometaphyseal dysplasia (602271).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

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

Aniridia 2

Clinical Characteristics
Ocular Features: 

A 17-year-old male with this condition was diagnosed at the age of two years with bilateral iris hypoplasia.  Cataracts were seen at the age of 17 years.  There was no foveal depression.

In a 5 generation Chinese family there were additional signs including optic atrophy, ectopia lentis, pigmentary retinopathy, and 'dysplasia' of the trabecular meshwork in 5 members.

Systemic Features: 

No systemic abnormalities have been reported.  A single extensively studied patient, who had no developmental problems, was normal by renal ultrasound, audiometric studies, and neurologic evaluations.

Genetics

Autosomal dominant aniridia is the result of PAX6 (a transcription regulator gene) dysfunction.  In the majority of cases there are mutations in the PAX6 gene itself as in AN1.  There are reports, however, of familial aniridia in which direct PAX6 mutations have been excluded.  Two additional forms of aniridia in which there are alterations in genes that modulate the expression of PAX6 have been reported.  AN2 described here with mutations in ELP4, a nucleotide variant within an intron of the ELP4 gene (11p13) located distal to the 3-prime end of the PAX6 gene, plus AN3 (617142) with mutations in TRIM44.  Both ELP4 and TRIM44 are regulators of the PAX6 transcription gene.

Aniridia 2 has been reported in one patient with a nucleotide variant within an intron of the ELP4 gene (11p13) located distal to the 3-prime end of the PAX6 gene.  The gene product is a cis-regulatory enhancer.  

Other evidence for aniridia resulting from regulatory modification of PAX6 gene function comes from families in which there are structural alterations such as deletions in chromosome 11, downstream of the PAX6 gene location.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment has not been reported.

References
Article Title: 

A deletion 3' to the PAX6 gene in familial aniridia cases

D'Elia AV, Pellizzari L, Fabbro D, Pianta A, Divizia MT, Rinaldi R, Grammatico B, Grammatico P, Arduino C, Damante G. A deletion 3' to the PAX6 gene in familial aniridia cases. Mol Vis. 2007 Jul 23;13:1245-50.
 

PubMed ID: 
17679951

Retinitis Pigmentosa 76

Clinical Characteristics
Ocular Features: 

Onset of night blindness occurs early in the second decade of life.  Vision is in the range of 20/40 to 20/100 in the first decades worsens slowly but there is a wide range.  Some older individuals may have hand motion vision in at least one eye but some retain 20/40.  All patients have peripheral field restrictions and some have pallor of the optic disc.  Retinal vessels are attenuated.  Fundus pigmentation is usually abnormal with some combination of bone spicule and diffuse salt and pepper pigmentation.  The macula is usually involved with a flat fovea, cystoid macular edema, and chorioretinal atrophy.

Retinal thinning is seen on OCT.  The ERG can be flat but in some individuals the rod responses are primarily reduced.

Systemic Features: 

No systemic abnormalities have been associated.

Genetics

Homozygous or compound heterozygous mutations in the POMGNT1 gene (1p34) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treeatment is available.

References
Article Title: 

Mutations in POMGNT1 cause non-syndromic retinitis pigmentosa

Xu M, Yamada T, Sun Z, Eblimit A, Lopez I, Wang F, Manya H, Xu S, Zhao L, Li Y, Kimchi A, Sharon D, Sui R, Endo T, Koenekoop RK, Chen R. Mutations in POMGNT1 cause non-syndromic retinitis pigmentosa. Hum Mol Genet. 2016 Apr 15;25(8):1479-88.

PubMed ID: 
26908613

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

Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome 3

Clinical Characteristics
Ocular Features: 

Patients have been described as having variable oculofacial features including epicanthal folds, hypertelorism, strabismus, and 'tapetoretinal degeneration'.    

Systemic Features: 

The full phenotype is variable and unknown based on the 5 reported patients from 4 families of whom 3 were consanguineous.  Recurrent infections (especially respiratory and otitis media) seem to be among the most consistent features.  Others include intrauterine growth retardation, developmental delay including psychomotor delays, a flat midface with various anomalies, low-set ears, renal dysgenesis, polydactyly, severe agammaglobulinemia, hypospadias, and cryptorchidism.  Normal T-cell function and normal B cells are present.  Conductive hearing loss, polydactyly, and scoliosis may be features as well.  Two of the 5 reported patients with ICF3 were reported to have mental retardation.  One patient died at the age of 26 years.

Genetics

Homozygosity of CDCA7 (2q31.1) mutations with centromeric instability and hypomethylation of selected juxtacentromeric heterochromatin regions is responsible for this (ICF3) autosomal recessive condition.  There is genetic heterogeneity in ICF (ICF1, ICF2, ICF3, and ICF4 [see 242860).   

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome

Thijssen PE, Ito Y, Grillo G, Wang J, Velasco G, Nitta H, Unoki M, Yoshihara M, Suyama M, Sun Y, Lemmers RJ, de Greef JC, Gennery A, Picco P, Kloeckener-Gruissem B, Gungor T, Reisli I, Picard C, Kebaili K, Roquelaure B, Iwai T, Kondo I, Kubota T, van Ostaijen-Ten Dam MM, van Tol MJ, Weemaes C, Francastel C, van der Maarel SM, Sasaki H. Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome. Nat Commun. 2015 Jul 28;6:7870.

PubMed ID: 
26216346

Spondylometaphyseal Dysplasia, Axial

Clinical Characteristics
Ocular Features: 

Due to the small number of individuals reported, the ocular phenotype is variable and likely incompletely described.  Optic atrophy and pigmentary retinopathy are the most consistent findings.  The most completely studied individual had evidence of slight bilateral optic nerve atrophy on cerebral MRI imaging as well.  There may be extensive RPE atrophy but the fundus pigmentation is usually described as resembling retinitis pigmentosa.  The ERG in several patients during the second decade of life already shows severe dysfunction of the photoreceptors, with cones the most severely impacted.  In spite of this Goldmann visual fields have been reported to be normal.  The macula and OCT have been reported as normal.  Telecanthus, nystagmus, hypertelorism, proptosis, and photophobia have been reported.  Early onset and progressive visual impairment are characteristic.

Systemic Features: 

Only 5 patients with this condition have been reported most of whom were short in stature.  There may be frontal bossing and the chest is narrow and flattened.  Moderate platyspondyly has been described with enlarged but shortened ribs and an irregular iliac crest.  Rhizomelic shortening of the limbs is common.  The femoral metaphyses are abnormal with their necks shortened and enlarged.  The ribs are enlarged but shortened as well and are flared at the ends.  Mental development and function are normal.

Genetics

This is an autosomal recessive condition due to homozygous or compound heterozygous mutations in C21orf2.

Treatment
Treatment Options: 

No effective treatment is known.

References
Article Title: 

Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations

Wang Z, Iida A, Miyake N, Nishiguchi KM, Fujita K, Nakazawa T, Alswaid A, Albalwi MA, Kim OH, Cho TJ, Lim GY, Isidor B, David A, Rustad CF, Merckoll E, Westvik J, Stattin EL, Grigelioniene G, Kou I, Nakajima M, Ohashi H, Smithson S, Matsumoto N, Nishimura G, Ikegawa S. Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations. PLoS One. 2016 Mar 14;11(13).

PubMed ID: 
26974433

Axial spondylometaphysealdysplasia

Ehara S, Kim OH, Maisawa S, Takasago Y, Nishimura G. Axial spondylometaphysealdysplasia. Eur J Pediatr. 1997 Aug;156(8):627-30.

PubMed ID: 
9266195

Macular Dystrophy, Patterned 3

Clinical Characteristics
Ocular Features: 

This condition has been found in an extended pedigree among peoples originating in the West Indies.  Vision loss is noted after the age of 50 years but clinical evidence can be seen in the fourth or fifth decades. The findings are primarily in the retinal pigment epithelium but Bruch's membrane is also involved.  Choroidal neovascularization and macular scarring may be present. The fundus pigmentary pattern has been described as resembling "dried-out soil" or crocodile skin.  In late stages the fundus picture resembles retinitis pigmentosa with loss of the RPE and photoreceptors.  The loss of photoreceptors continues throughout life. An 85 year old woman with light perception only has been described. 

In early stages the full-field ERG can be nomal but later rod and cone responses are severely reduced.  The OCT may show scalloped elevation at the borders of the scalloped patches corresponding to the irregular thickness of the RPE and Bruch membrance.

Knockout mice have both thickened and thinned areas of the Bruch membrane.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This autosomal dominant condition results from heterozygous mutations in MAPKAPK3 (3p21.3), a mitogene-activated kinase of the p38 signaling pathway.  It is highly expressed in the RPE.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

A dominant mutation in MAPKAPK3, an actor of p38 signaling pathway, causes a new retinal dystrophy involving Bruch's membrane and retinal pigment epithelium

Meunier I, Lenaers G, Bocquet B, Baudoin C, Piro-Megy C, Cubizolle A, Quiles M, Jean-Charles A, Cohen SY, Merle H, Gaudric A, Labesse G, Manes G, Pequignot M, Cazevieille C, Dhaenens CM, Fichard A, Ronkina N, Arthur SJ, Gaestel M, Hamel CP. A dominant mutation in MAPKAPK3, an actor of p38 signaling pathway, causes a new retinal dystrophy involving Bruch's membrane and retinal pigment epithelium. Hum Mol Genet. 2016 Mar 1;25(5):916-26.

PubMed ID: 
26744326

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