retinal dystrophy

Leber Congenital Amaurosis with Early-Onset Deafness

Clinical Characteristics
Ocular Features: 

Evidence for retinal disease can be seen within 3 years of age.  Three of 5 patients had no detectable responses on the ERG when tested at birth.  A 34-year-old female was noted to have advanced retinitis pigmentosa with attenuation of retinal vessels, choroidal atrophy, peripheral pigmentary deposits, and macular anomalies.  The posterior fundus may have a salt-and-pepper pigmentation.  Hypermetropia was present in all 5 patients.

Visual acuity varies widely and may be normal even among older patients.

Systemic Features: 

Mild to severe sensorineural hearing loss secondary to cochlear cell loss is usually diagnosed in the first decade.  All patients had normal neuro-psychomotor development.

Genetics

Heterozygous mutations in the TUBB4B gene (9q34.3) have been found in 5 individuals in 4 families with this disorder.  There may be significant mosaicism in blood cells.

See Leber Congenital Amaurosis for additional information on non-syndromal Leber congenital amaurosis and responsible mutations.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for the general condition but refractive correction, low vision aids, and assistive hearing devices may be of benefit.

References
Article Title: 

Mutations in TUBB4B Cause a Distinctive Sensorineural Disease

Luscan R, Mechaussier S, Paul A, Tian G, Gerard X, Defoort-Dellhemmes S, Loundon N, Audo I, Bonnin S, LeGargasson JF, Dumont J, Goudin N, Garfa-Traore M, Bras M, Pouliet A, Bessieres B, Boddaert N, Sahel JA, Lyonnet S, Kaplan J, Cowan NJ, Rozet JM, Marlin S, Perrault I. Mutations in TUBB4B Cause a Distinctive Sensorineural Disease. Am J Hum Genet. 2017 Dec 7;101(6):1006-1012.

PubMed ID: 
29198720

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: 

Retinal Dystrophy With Or Without Extraocular Anomalies

Clinical Characteristics
Ocular Features: 

Progressive deterioration of rod and cone function is characteristic of this condition which is clinically manifest as some variation of pigmentary retinopathy.  Early (second decade) pigmentary changes resemble retinitis pigmentosa but in the fourth and fifth decades they resemble a peripheral pattern-like reticular dystrophy.  Central chorioretinal atrophy has been described in some patients.  The ERG responses are abnormal suggesting loss of the photoreceptors.

Systemic Features: 

Extraocular anomalies are highly variable ranging from a mild intellectual disability in some patients, to thyroid goiter and nodules, and primary ovarian insufficiency.  Sensorineural hearing loss was present in one family and one patient had pulmonary fibrosis.

Genetics

Homozygous missense mutations in the RCBTB1 gene (13q14) seem to be responsible for this condition.  Six families have been reported.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Isolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1, a Gene Implicated in Ubiquitination

Coppieters F, Ascari G, Dannhausen K, Nikopoulos K, Peelman F, Karlstetter M, Xu M, Brachet C, Meunier I, Tsilimbaris MK, Tsika C, Blazaki SV, Vergult S, Farinelli P, Van Laethem T, Bauwens M, De Bruyne M, Chen R, Langmann T, Sui R, Meire F, Rivolta C, Hamel CP, Leroy BP, De Baere E. Isolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1, a Gene Implicated in Ubiquitination. Am J Hum Genet. 2016 Aug 4;99(2):470-80.

PubMed ID: 
27486781

Spastic Paraplegia with Psychomotor Retardation and Seizures

Clinical Characteristics
Ocular Features: 

The eyes are usually deeply set.  Nothing is known regarding visual acuity.  Strabismus is a common feature.  Retinal dystrophy (not further described) has been reported in 4 of 8 patients described.  The ERG in one individual was read as consistent with cone-rod dystrophy.

Systemic Features: 

Newborns are hypotonic and severe psychomotor retardation is evident a few months later.  Truncal ataxia and progressive lower limb spasticity are seen later.  Mobility is significantly impaired and many individuals are confined to bed or a wheelchair and never walk.  Dysarthria is frequently present and some individuals have a neurosensory hearing loss.  Myoclonic seizures may be evident.  Kyphoscoliosis, macrocephaly, and various foot deformities have been described.

CT scans of the brain may show generalized cerebral atrophy and a hypoplastic corpus callosum.  The ventricles may be enlarged and the EEG confirms the occurrence of myoclonic as well as tonic-clonic and focal epilepsy.

Genetics

This is an autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the HACE1 gene (6q16).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported for this condition but physical therapy and assistive devices such as hearing and visual aids may be helpful.

References
Article Title: 

DDD study. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families

Akawi N, McRae J, Ansari M, Balasubramanian M, Blyth M, Brady AF, Clayton S, Cole T, Deshpande C, Fitzgerald TW, Foulds N, Francis R, Gabriel G, Gerety SS, Goodship J, Hobson E, Jones WD, Joss S, King D, Klena N, Kumar A, Lees M, Lelliott C, Lord J, McMullan D, O'Regan M, Osio D, Piombo V, Prigmore E, Rajan D, Rosser E, Sifrim A, Smith A, Swaminathan GJ, Turnpenny P, Whitworth J, Wright CF, Firth HV, Barrett JC, Lo CW, FitzPatrick DR, Hurles ME; DDD study. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families. Nat Genet. 2015 Nov;47(11):1363-9.

PubMed ID: 
26437029

HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome

Hollstein R, Parry DA, Nalbach L, Logan CV, Strom TM, Hartill VL, Carr IM, Korenke GC, Uppal S, Ahmed M, Wieland T, Markham AF, Bennett CP, Gillessen-Kaesbach G, Sheridan EG, Kaiser FJ, Bonthron DT. HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome. J Med Genet. 2015 Dec;52(12):797-803.

PubMed ID: 
26424145

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

Retinal Dystrophy, Newfoundland Type

Clinical Characteristics
Ocular Features: 

There is considerable clinical heterogeneity, mostly age-dependent.  Night blindness can occur in early childhood but usually later even though scotopic responses can be undetectable in the first decade of life while photopic responses are reduced on the ERG at all ages.  Both rod and cone responses may be extinguished in later life.  Visual acuity can be decreased beginning in early childhood and legal blindness usually occurs by the second or third decade of life.  However, the loss of vision continues to progress and severe vision loss to finger-counting may be present in older individuals.  A scallop-bordered lacunar atrophy may be seen in the midperiphery.  The macula is only mildly involved by clinical examination although central retinal thinning is seen in all cases.  Dyschromatopsia is mild early and usually becomes more severe.  The visual fields are moderately to severely constricted although in younger individuals a typical ring scotoma is present.  The peripheral retina contains ‘white dots’ and often resembles the retinal changes seen in retinitis punctate albescens.

Systemic Features: 

None reported.

Genetics

Homozygous mutations in the RLBP1 gene (15q26.1) are responsible for this disorder.  Homozygous mutations in RLBP1 have also been found among patients with fundus albipunctatus (136880), retinitis punctata albescens, and in Bothnia type retinal dystrophy (607475),

NFRCD clinically resembles Bothnia type retinal dystrophy (607475) which likewise results from mutations in the RLBP1 gene but the maculae appear normal or have only a mild ‘beaten-bronze’ atrophy.

See Flecked Retina entry for somewhat similar conditions.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Microphthalmia, Syndromic 5

Clinical Characteristics
Ocular Features: 

One or both eyes may be small, sometimes resembling clinical anophthalmia. Other ocular anomalies such as coloboma, microcornea, cataracts, and hypoplasia or agenesis of the optic nerve have been reported.

A pigmentary retinopathy has been described.  The retinal vessels are often attenuated and sometimes sparse.  The optic nerves and chiasm are frequently absent or hypoplastic as seen on the MRI.  ERG and VEP responses are inconsistent but are generally abnormal indicating photoreceptor malfunction.  

Systemic Features: 

Patients have a variety of systemic abnormalities including pituitary dysfunction, joint laxity, hypotonia, agenesis of the corpus callosum, and seizures.  Hypothyroidism and deficiencies of growth hormone, gonadotropins, and cortisol are present in some patients.  Developmental delay and cognitive impairment are frequently present but mental functioning is normal in some patients.  The genitalia of males are often underdeveloped.  Patients are often short in stature.

Genetics

This is an autosomal dominant condition secondary to heterozygous mutations in the OTX2 gene (14q22.3).  A variety of point mutations as well as microdeletions involving the OTX2 gene have been reported.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the syndrome but surgical and/or endocrinological treatment may be used to correct individual features.  Special education and low vision aids may be helpful in selected patients.

References
Article Title: 

Heterozygous mutations of OTX2 cause severe ocular malformations

Ragge NK, Brown AG, Poloschek CM, Lorenz B, Henderson RA, Clarke MP, Russell-Eggitt I, Fielder A, Gerrelli D, Martinez-Barbera JP, Ruddle P, Hurst J, Collin JR, Salt A, Cooper ST, Thompson PJ, Sisodiya SM, Williamson KA, Fitzpatrick DR, van Heyningen V, Hanson IM. Heterozygous mutations of OTX2 cause severe ocular malformations. Am J Hum Genet. 2005 Jun;76(6):1008-22. Apr 21. Erratum in: Am J Hum Genet. 2005 Aug;77(2):334..

PubMed ID: 
15846561

Retinal Cone Dystrophy 3B

Clinical Characteristics
Ocular Features: 

This is a degenerative disorder in which patients have a progressive deterioration of visual acuity and color vision.  Most patients have significant myopia.  Visual difficulties begin in early childhood with acuity of 20/100 or worse by the second decade of life.  Color vision deficits can be detected in the second decade but nyctalopia occurs later in young adults.  Photophobia is a prominent symptom.  The ERG shows reduced and delayed cone responses.  Rod responses to low intensity flashes are undetectable but increased stimulus intensity leads to an abrupt increase in amplitude, often exceeding the upper limits of normal.

The fundus appears normal in some patients but foveal or parafoveal atrophy, a macular bull’s eye, hyperfluorescence anomalies, and a generalized fine pigmentary retinopathy have been reported.  There may be some temporal pallor in the optic nerves.  Nystagmus and strabismus may be present.

Systemic Features: 

No systemic disease has been reported.

Genetics

This is an autosomal recessive disorder resulting from homozygous or compound heterozygous mutations in the KCNV2 gene (9p24.2).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available for this dystrophy.  Low vision aids and tinted lenses may be helpful.

References
Article Title: 

Microphthalmia, Syndromic 6

Clinical Characteristics
Ocular Features: 

Ultrasound evaluation reveals globe size to vary widely from extremely small (6 mm) to normal axial length. Clinical anophthalmia is often diagnosed.  Both anophthalmia and microphthalmia may exist in the same individual. True anophthalmia has been confirmed in some patients in which no ocular tissue was detectable with ultrasound examination.  In such cases the optic nerves and chiasm are often missing as well.  Iris colobomas are common and these may extend posteriorly.  Myopia is sometimes present.

The ERG reveals generalized rod and cone dysfunction in some eyes, but may be normal in others. In many eyes the ERG is nonrecordable. Cataracts are frequently present.

Systemic Features: 

Digital and hand anomalies are common.  The hands are often described as broad and the thumbs may be low-placed.  The nails can appear dysplastic and postaxial polydactyly is often present.  Mild webbing of the fingers has been reported as well.  Microcephaly and the cranium can be misshapen. A high arched palate is often present and clefting has also been noted.  Micrognathia may be present. Some evidence of physical growth retardation is often evident.

Pituitary hypoplasia is not uncommon and may be associated with hypothyroidism and cryptorchidism with hypospadias, and a small or bifid scrotum.

The brain anomalies vary considerably.  Many patients have mild to moderate developmental delays with some learning difficulties. Sensorineural hearing loss is often present. Hypoplasia of the vermis, thinning of the corpus callosum, widening of the lateral ventricles, and occasional generalized cortical atrophy, at least in older individuals, have been described.

Genetics

This is an autosomal dominant condition caused by a point mutation in BMP4 (bone morphogenetic protein-4) (14q22-q23).  A number of chromosomal deletions involving this gene have also been identified in individuals who have this syndrome but since contiguous genes such as OTX2 and SIX6 may also be involved, the phenotype is more likely to be associated with other anomalies including genital hypoplasia, pituitary hypoplasia, absence of the optic nerves and/or chiasm, developmental delay, digital malformations, and cerebellar dysplasia.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Cataracts can be removed in selected individuals with potential visual function.  Socket prostheses should be considered in anophthalmia and extreme microphthalmia.  Low vision devices, Braille, and mobility training should be initiated early when appropriate.  Hearing evaluations should be done as soon as practical.

Learning specialists and special education facilities should be available for selected patients.  Polydactyly, syndactyly, skull, and cleft palate repairs may be indicated.

References
Article Title: 

Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways

Bakrania P, Efthymiou M, Klein JC, Salt A, Bunyan DJ, Wyatt A, Ponting CP, Martin A, Williams S, Lindley V, Gilmore J, Restori M, Robson AG, Neveu MM, Holder GE, Collin JR, Robinson DO, Farndon P, Johansen-Berg H, Gerrelli D, Ragge NK. Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways. Am J Hum Genet. 2008 Feb;82(2):304-19.

PubMed ID: 
18252212

Gurrieri Syndrome

Clinical Characteristics
Ocular Features: 

Tapetoretinal degeneration has been described in several patients.  Some patients have keratoconus with lens and corneal opacities.  Visual acuities have not been reported.  The full ocular phenotype must be considered unknown since most patients have not had full ophthalmic evaluations.

Systemic Features: 

Features of an osteodysplasia are among the most striking in this syndrome.  Short stature, brachydactyly, delayed bone age, osteoporosis, and hypoplasia of the acetabulae and iliac alae are usually present.  Birth weight is often low.  Joints may be hyperflexible as part of the generalized hypotonia. The eyes are deep-set, the nasal bridge is prominent, the midface is flat, and the supraorbital ridges are prominent giving the face a rather coarse look.  Prognathism with a prominent lower lip and dental malocclusion reinforce this appearance.  Seizures beginning in early childhood may be difficult to control.  Most patients have severe psychomotor retardation and never acquire speech.

Genetics

The genetics of this familial disorder remain unknown.  No locus or mutation has been identified but one patient had an absent maternal allele of the proximal 15q region as found in Angelman syndrome.

Orofaciodigital syndrome IX (258865) is another autosomal recessive syndrome sometimes called Gurrieri syndrome.  In Gurrieri’s original description of two brothers, chorioretinal lacunae, similar to those seen in Aicardi syndrome (304050), were present.  The systemic features are dissimilar, however.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

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