autosomal dominant

Perrault Syndrome

Clinical Characteristics
Ocular Features: 

Nystagmus and limited extraocular movements are usually present in PRLTS1.  Optic atrophy and poor visual acuity have been reported. Ptosis may be present.  The clinical manifestations are variable among and within the types.  Rod dysfunction and ‘retinal atrophy’ were reported in one patient.  The majority of patients have had only limited ocular evaluations.

Systemic Features: 

This is a sex-influenced condition in which both sexes have a sensorineural hearing deficit and neurodegenerative disease (both central and peripheral) but only the females have gonadal dysgenesis.  Motor development is often delayed and ataxia along with a peripheral sensory neuropathy and a variable degree of limb weakness can be present.  Learning difficulties, cognitive decline, and frank mental retardation are frequently described.  The cerebellum may be atrophic.

There is considerable variability in the clinical signs.

Genetics

The combination of hearing loss in males and females, ovarian dysgenesis in females, and variable neurologic signs including external ophthalmoplegia and sometimes optic atrophy is known as Perrault syndrome.  The ocular movement abnormalities are seen primarily in PRLTS1. 

At least 5 unique mutations have been found accounting for types PRLTS1-5.  PRLTS1 (233400) results from mutations in HSD17B4 (5q23.1), type PRLTS2 (614926) is caused by mutations in the HARS2 gene, PPRLTS3 (614129) by mutations in the CLPP gene, PRLTS4 (615300) by mutations in the LARS2 gene, and PRLTS5 (616138) by mutations in C10orf2 (listed in this database as External Ophthalmoplegia, C10orf2, and mtDNA mutations,.

The inheritance pattern among different types may be autosomal recessive or autosomal dominant.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is known.

References
Article Title: 

Perrault syndrome: further evidence for genetic heterogeneity

Jenkinson EM, Clayton-Smith J, Mehta S, Bennett C, Reardon W, Green A, Pearce SH, De Michele G, Conway GS, Cilliers D, Moreton N, Davis JR, Trump D, Newman WG. Perrault syndrome: further evidence for genetic heterogeneity. J Neurol. 2012 May;259(5):974-6.

PubMed ID: 
22037954

Perrault syndrome in sisters

McCarthy DJ, Opitz JM. Perrault syndrome in sisters. Am J Med Genet. 1985 Nov;22(3):629-31.

PubMed ID: 
4061497

Macular Dystrophy, Vitelliform 5

Clinical Characteristics
Ocular Features: 

This is a late onset form of vitelliform macular dystrophy with symptoms noted by the 5th decade or later.  Only central vision seems to be impacted and a central scotoma may be demonstrable.  The ERG, EOG and color vision responses may be normal.  Mild autofluorescence has been reported.  The vitelliform lesions are small and may be multiple.  No drusen-like lesions have been seen.  Visual acuity is variable, ranging from normal to a mild decrease. 

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This form of vitelliform dystrophy results from heterozygous mutations in the IMPG2 gene (3q12).  Patients with homozygous mutations have also been reported.

Genotyping has identified at least 5 forms of vitelliform macular dystrophy.  In addition to the iconic Best disease (VMD2, 153700) apparently first described by Friedreich Best in 1905 and now attributed to mutations in the Best1 gene, we know of at least 4 more and specific mutations have been identified in three.  No mutation or locus has yet been identified in VMD1 (153840) but it is likely a unique condition since mutations in other genes known to cause vitelliform dystrophy have been ruled out.  Other forms are VMD3 (608161) due to mutations in the PRPH2 gene, VMD4 (616151) resulting from mutations in the IMPG1 gene, and VMD5 described here.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known for the macular dystrophy.  Low vision devices might be helpful for selected individuals.

References
Article Title: 

Mutations in IMPG2, encoding interphotoreceptor matrix proteoglycan 2, cause autosomal-recessive retinitis pigmentosa

Bandah-Rozenfeld D, Collin RW, Banin E, van den Born LI, Coene KL, Siemiatkowska AM, Zelinger L, Khan MI, Lefeber DJ, Erdinest I, Testa F, Simonelli F, Voesenek K, Blokland EA, Strom TM, Klaver CC, Qamar R, Banfi S, Cremers FP, Sharon D, den Hollander AI. Mutations in IMPG2, encoding interphotoreceptor matrix proteoglycan 2, cause autosomal-recessive retinitis pigmentosa. Am J Hum Genet. 2010 Aug 13;87(2):199-208.

PubMed ID: 
20673862

Macular Dystrophy, Vitelliform 4

Clinical Characteristics
Ocular Features: 

This is a late onset form of vitelliform dystrophy in which symptoms are usually noted between the ages of 20 to 45 years.  The vitelliform lesions usually occur singly and are often small.  Some individuals have small drusen-like macular lesions adjacent to the vitelliform lesions, at the periphery of the macula, or even outside the macula.  The lesions contain lipofuscin which can be seen on autofluorescence photographs.  Visual acuity can remain near normal for many years.  The EOG ratio and ERG responses are usually normal or near normal.  Choroidal neovascularization has not been described. 

Systemic Features: 

There are no systemic manifestations.

Genetics

This form of vitelliform dystrophy (VMD4) is caused by heterozygous mutations in the IMPG1 gene (6q14.1).  However, rare families have been reported in which compound heterozygous or homozygous mutations have been found.  Some of the heterozygous parents of children with two mutations were found to have minor fundus changes such as tiny extramacular vitelliform spots in spite of being asymptomatic. This suggests that the transmission pattern of fundus changes may be both autosomal recessive and autosomal dominant. 

Genotyping has identified at least 5 forms of vitelliform macular dystrophy.  In addition to the iconic Best disease (VMD2, 153700) apparently first described by Friedreich Best in 1905 and now attributed to mutations in the Best1 gene, we know of at least 4 more and specific mutations have been identified in three.  No mutation or locus has yet been identified in VMD1 (153840) but it is likely a unique condition since mutations in other genes known to cause vitelliform dystrophy have been ruled out.  Other forms are VMD3 (608161) due to mutations in the PRPH2 gene, VMD4 described here, and VMD5 (616152) caused by mutations in the IMPG2 gene.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the vitelliform disease but low vision devices can be helpful in some patients for selected tasks.

References
Article Title: 

Mutations in IMPG1 cause vitelliform macular dystrophies

Manes G, Meunier I, Avila-Fernandez A, Banfi S, Le Meur G, Zanlonghi X, Corton M, Simonelli F, Brabet P, Labesse G, Audo I, Mohand-Said S, Zeitz C, Sahel JA, Weber M, Dollfus H, Dhaenens CM, Allorge D, De Baere E, Koenekoop RK, Kohl S, Cremers FP, Hollyfield JG, Senechal A, Hebrard M, Bocquet B, Ayuso Garcia C, Hamel CP. Mutations in IMPG1 cause vitelliform macular dystrophies. Am J Hum Genet. 2013 Sep 5;93(3):571-8.

PubMed ID: 
23993198

Macular Dystrophy, Vitelliform 3

Clinical Characteristics
Ocular Features: 

Patients generally become symptomatic (reduced vision and metamorphopsia) in the fourth and fifth decades.  Vision loss is mild as in vitelliform 1 disease and only slowly progressive in most patients.  One or sometimes more small, oval, and slightly elevated yellow lesions resembling an egg yolk may be seen in the fovea along with paracentral drusen and mild RPE changes.  The fundus changes can appear any time in adult life but little is known about their nature history.  The EOG light/dark ratio may be normal or slightly decreased and the ERG likewise can be normal or, in some cases, reveals rod and cone system abnormalities.  Optical coherence tomography shows yellowish deposits between the neurosensory retina and the RPE with foveal thinning.  Color vision has been described as normal. The visual field may show peripheral constriction or central scotomas.  Choroidal neovascularization occurs rarely.

Variability in the clinical features often leads to misdiagnosis in individual patients who are sometimes considered to have age-related macular degeneration, retinitis pigmentosa, fundus flavimaculatus, dominant drusen, butterfly macular dystrophy, and pattern dystrophy.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This is an autosomal dominant condition resulting from heterozygous mutations in the RDS (PRPH2) gene (6p21.1). 

The gene product of PRPH2 is active in the retina. It is important to the integrity and stability of the structures that contain light-sensitive pigments (e.g., photoreceptors).  More than 100 mutations have been identified. The resultant phenotype can be highly variable, even within members of the same family but most affected individuals have some degree of pigmentary retinopathy within the macula or throughout the posterior pole.  The altered gene product resulting from mutations in PRPH2 often leads to symptoms beginning in midlife as a result of the slow degeneration of photoreceptors.  This database contains at least 11 disorders in which PRPH2 mutations have been found.

Genotyping has identified at least 5 forms of vitelliform macular dystrophy.  In addition to the iconic Best disease (VMD2, 153700) apparently first described by Friedreich Best in 1905 and now attributed to mutations in the Best1 gene, we know of at least 4 more and specific mutations have been identified in three.  No mutation or locus has yet been identified in VMD1 (153840) but it is likely a unique condition since mutations in other genes known to cause vitelliform dystrophy have been ruled out.  Other forms are VMD3 described here, VMD4 (616151) resulting from mutations in the IMPG1 gene, and VMD5 (616152) caused by mutations in the IMPG2 gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known for this disorder.  Anti-VEGF and ablation therapy may be helpful in selected individuals with choroidal neovascularization.  Low vision aids may also be beneficial.

References
Article Title: 

Macular Dystrophy, Vitelliform 1

Clinical Characteristics
Ocular Features: 

This is an uncommon form of vitelliform macular dystrophy and may not be a unique disorder.  Onset of disease is usually later than in the classic Best disease due to mutations in the Best1 gene.  Only slight to moderate vision impairment is present. Small drusen-like lesions may be seen in the foveal areas along with macular or extramacular punctate yellow lesions.  Importantly, the EOG light/dark Arden ratio is often normal or only slightly impacted even when severe loss of vision is present.  It has been claimed that fundus fluorescein angiography is diagnostically more reliable than the EOG.  Patchy RPE depigmentation is often present in the central and the peripheral retina as well as in the peripapillary area.

The clinical features resemble vitelliform macular dystrophy resulting from mutations in the IMPG1 and IMPG2 genes. 

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

No mutation or locus has been found to segregate with VMD1 disease.  However, it is probably a unique condition since other VMD-causing mutations such as those in Best1, PRPH2, IMPG1, and IMPG2 have been ruled out in a number of families.

The transmission pattern is consistent with autosomal dominant inheritance.

Genotyping has identified at least 5 forms of vitelliform macular dystrophy.  In addition to the iconic Best disease (VMD2, 153700) apparently first described by Friedreich Best in 1905 and now attributed to mutations in the Best1 gene, we know of at least 4 more and specific mutations have been identified in three.  Other forms are VMD3 (608161) due to mutations in the PRPH2 gene, VMD4 (616151) resulting from mutations in the IMPG1 gene, and VMD5 (616152) caused by mutations in the IMPG2 gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for this disease but low vision devices may be helpful.

References
Article Title: 

Macular Degeneration, Early-Onset

Clinical Characteristics
Ocular Features: 

Onset of distorted vision has been reported as early as the fourth decade of life with clinical evidence of pigmentary changes in the macula noted in the fifth decade.  Large areas of central RPE atrophy can be seen.  In the single family reported (a father and his 4 sons), there is considerable clinical heterogeneity in the RPE changes in the fundus.  Acuity is variable depending upon the stage of disease.

Systemic Features: 

No systemic disease has been reported.

Genetics

Heterozygous mutations in the FBN2 gene, encoding Fibrillin 2, a component protein of the extracellular matrix that segregates with this presumably autosomal dominant macular disease have been reported. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment beyond anti-VEGF therapy is available.  Low vision devices may be helpful.

References
Article Title: 

Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration.

Ratnapriya R, Zhan X, Fariss RN, Branham KE, Zipprer D, Chakarova CF, Sergeev YV, Campos MM, Othman M, Friedman JS, Maminishkis A, Waseem NH, Brooks M, Rajasimha HK, Edwards AO, Lotery A, Klein BE, Truitt BJ, Li B, Schaumberg DA, Morgan DJ, Morrison MA, Souied E, Tsironi EE, Grassmann F, Fishman GA, Silvestri G, Scholl HP, Kim IK, Ramke J, Tuo J, Merriam JE, Merriam JC, Park KH, Olson LM, Farrer LA, Johnson MP, Peachey NS, Lathrop M, Baron RV, Igo RP Jr, Klein R, Hagstrom SA, Kamatani Y, Martin TM, Jiang Y, Conley Y, Sahel JA, Zack DJ, Chan CC, Pericak-Vance MA, Jacobson SG, Gorin MB, Klein ML, Allikmets R, Iyengar SK, Weber BH, Haines JL, Leveillard T, Deangelis MM, Stambolian D, Weeks DE, Bhattacharya SS, Chew EY, Heckenlively JR, Abecasis GR, Swaroop A. Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration. Hum Mol Genet. 2014 Nov 1;23(21):5827-37.

PubMed ID: 
24899048

Familial Exudative Vitreoretinopathy, EVR3

Clinical Characteristics
Ocular Features: 

Abnormal retinal angiogenesis with retinal ischemia is the development defect that leads to the clinical features of the familial exudative vitreoretinopathies.  It is usually bilateral.  There is considerable clinical heterogeneity in the appearance of both the retina and the vitreous but common to all is the presence of peripheral areas of avascularity in the retina that may be seen in newborns.  This may only be visible using fluorescein angiography in mild cases.  The vessels may be hyperpermeable resulting in patchy exudates in the retina.  Neovascularization often develops with retinal and vitreous bleeding and eventually retinal traction resulting in retinal folds and detachments. Severe disease with early onset may result in blindness in infants but milder disease may be asymptomatic even as adults.  Cataracts may result.

The ocular disease may be confused with retinal dysplasia (as seen in pseudogliomas and Norrie disease [310600]) or retinopathy of prematurity.

Systemic Features: 

 No systemic features have been reported in EVR3.

Genetics

This is likely an autosomal dominant disorder based on pedigree evidence but no specific mutation has been found.  A disease locus at 11p13-p12 has been identified by linkage studies, located near the FZD4 gene containing the mutation responsible for EVR1.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Appropriate vitreoretinal surgery to release vitreous traction and to repair retinal detachments should be considered.  Cataract removal may be beneficial.  Low vision aids could be helpful in milder cases with residual vision.

References
Article Title: 

Familial Exudative Vitreoretinopathy, EVR5

Clinical Characteristics
Ocular Features: 

The clinical picture is highly heterogeneous.  Abnormal peripheral vascularization of the retina is generally evident and most individuals have retinal exudates.  The amount of exudation is dependent to some extent upon age.  Fluorescein angiography may demonstrate incomplete vascularization of the peripheral retina.  The ocular phenotype can resemble retinal dysplasia.  Occasional infants can have severe retinal disease and may be considered blind but many individuals have minimal disease and retain good vision into adulthood.  Unfortunately, traction retinal detachments may develop at any time and are responsible for blindness in some patients. 

Cataracts are sometimes present. Ectopic pupils, lack of well-defined pupillary collarettes, remnants of the fetal vascular stalk, and shallowing of the anterior chamber have been noted in several patients.  Microphthalmia and corneal opacities may also be present.  Horizontal nystagmus can be seen in severely affected babies before one month of age.

Systemic Features: 

No systemic features have been reported.

Genetics

This disorder can be inherited in an autosomal dominant pattern as the result of heterozygous mutations in the TSPAN12 gene (7q31.31).  However, individuals with more severe disease may have homozygous mutations in this gene. 

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

This disorder can be inherited in an autosomal dominant pattern as the result of heterozygous mutations in the TSPAN12 gene (7q31.31).  However, individuals with more severe disease may have homozygous or compound heterozygous mutations in this gene. 

References
Article Title: 

Retinal Dystrophy with Inner Retinal Abnormalities

Clinical Characteristics
Ocular Features: 

Otherwise healthy individuals note onset of light sensitivity between 25 and 40 years of age.  Central vision is progressively lost with average vision levels of 20/50.  In some patients vision is 20/400 but peripheral vision remains normal on visual field testing.  Small central and centrocecal scotomas can be demonstrated.  There is general hyper-reflectivity of the ganglion cell and nerve fiber layers with the latter decreased in thickness especially in the foveal area of all patients.  The optic nerve is often pale.  The ERG recordings are consistent with inner retinal dysfunction with an absent b-wave and a normal a-wave response.  Older patients have additional photopic response abnormalities and delayed implicit times.  Color vision in younger individuals was reported to be normal but older persons had mild deuteranopia.

Systemic Features: 

No systemic disease was noted in the single reported family.  Specifically, no dementia was present in affected individuals (vida infra).

Genetics

This condition has been identified in a single large 3-generation family.  A missense heterozygous mutation in the ITM2B gene (13q14.2) is responsible.  The gene product localizes to the inner nuclear and ganglion cell layers in the eye and co-localizes with the amyloid beta precursor protein of Alzheimer disease in cerebral tissue.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment for the retinal disease is available but photosensitive individuals may benefit from tinted lenses.  Low vision aid can be useful for near vision.

References
Article Title: 

The familial dementia gene revisited: a missense mutation revealed by whole-exome sequencing identifies ITM2B as a candidate gene underlying a novel autosomal dominant retinal dystrophy in a large family

Audo I, Bujakowska K, Orhan E, El Shamieh S, Sennlaub F, Guillonneau X, Antonio A, Michiels C, Lancelot ME, Letexier M, Saraiva JP, Nguyen H, Luu TD, Leveillard T, Poch O, Dollfus H, Paques M, Goureau O, Mohand-Said S, Bhattacharya SS, Sahel JA, Zeitz C. The familial dementia gene revisited: a missense mutation revealed by whole-exome sequencing identifies ITM2B as a candidate gene underlying a novel autosomal dominant retinal dystrophy in a large family. Hum Mol Genet. 2014 Jan 15;23(2):491-501..

PubMed ID: 
24026677

Spinocerebellar Ataxia 38

Clinical Characteristics
Ocular Features: 

Gaze-evoked nystagmus is present with the onset of ataxia.  Some patients report diplopia.  Saccadic movements are described as slow.  Visual acuities and the appearance of the retina and optic nerve have not been reported.

Systemic Features: 

Truncal and gait ataxia are generally evident by age 40 years and progressively worsen.  Mobility requires assistance usually by age 50.  Mild sensory complaints are present in the majority of individuals.  Dysarthria is often a feature.

MRI reveals cerebellar atrophy with no evidence of brainstem involvement.

Genetics

Heterozygous mutations in the ELOVL5 gene (6p12.1) are responsible for this autosomal dominant disorder.  The gene is a member of family that encodes elongases that synthesize long chain fatty acids in the endoplasmic reticulum.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

None known.

References
Article Title: 

ELOVL5 mutations cause spinocerebellar ataxia 38

Di Gregorio E, Borroni B, Giorgio E, Lacerenza D, Ferrero M, Lo Buono N, Ragusa N, Mancini C, Gaussen M, Calcia A, Mitro N, Hoxha E, Mura I, Coviello DA, Moon YA, Tesson C, Vaula G, Couarch P, Orsi L, Duregon E, Papotti MG, Deleuze JF, Imbert J, Costanzi C, Padovani A, Giunti P, Maillet-Vioud M, Durr A, Brice A, Tempia F, Funaro A, Boccone L, Caruso D, Stevanin G, Brusco A. ELOVL5 mutations cause spinocerebellar ataxia 38. Am J Hum Genet. 2014 Aug 7;95(2):209-17.

PubMed ID: 
25065913

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