macular dystrophy

Heimler Syndrome 1

Clinical Characteristics
Ocular Features: 

Some patients have mottling of the retinal pigment and features of macular dystrophy.

Systemic Features: 

Primary dentition seems to be normal but secondary teeth have generalized enamel hypoplasia.  Severe bilateral sensorineural hearing loss has been diagnosed in the first or second year of life.  The toenails have transverse ridges (Beau lines) and the fingernails exhibit leukonychia.

Due to the small number of reported families, there is some uncertainty regarding the specificity of the clinical features among the Heimler 1 and Heimler 2 syndromes.

Genetics

Biallelic mutations in the PEX1 gene (7q21.2) are responsible for this syndrome.

Heimler Syndrome 2 (616617) seems to be a unique disorder of peroxisome biogenesis resulting from biallelic mutations in the PEX6 gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Spectrum of PEX1 and PEX6 variants in Heimler syndrome

Smith CE, Poulter JA, Levin AV, Capasso JE, Price S, Ben-Yosef T, Sharony R, Newman WG, Shore RC, Brookes SJ, Mighell AJ, Inglehearn CF. Spectrum of PEX1 and PEX6 variants in Heimler syndrome. Eur J Hum Genet. 2016 Nov;24(11):1565-1571.

PubMed ID: 
27302843

Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6

Ratbi I, Falkenberg KD, Sommen M, Al-Sheqaih N, Guaoua S, Vandeweyer G, Urquhart JE, Chandler KE, Williams SG, Roberts NA, El Alloussi M, Black GC, Ferdinandusse S, Ramdi H, Heimler A, Fryer A, Lynch SA, Cooper N, Ong KR, Smith CE, Inglehearn CF, Mighell AJ, Elcock C, Poulter JA, Tischkowitz M, Davies SJ, Sefiani A, Mironov AA, Newman WG, Waterham HR, Van Camp G. Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6. Am J Hum Genet. 2015 Oct 1;97(4):535-45.

PubMed ID: 
26387595

Macular dystrophy in Heimler syndrome

Lima LH, Barbazetto IA, Chen R, Yannuzzi LA, Tsang SH, Spaide RF. Macular dystrophy in Heimler syndrome. Ophthalmic Genet. 2011 Jun;32(2):97-100.

PubMed ID: 
21366429

Macular Dystrophy, Patterned 2

Clinical Characteristics
Ocular Features: 

Abnormal pigmentation of yellow, white, or black color accumulates in the central area of the macula.  The deposition of pigment appears in the retinal pigment epithelium (RPE) level in a pattern more or less resembling the wings of a butterfly.  The peripheral retina has diffuse pigment mottling.  Drusen-like structures may be seen at the peripheral borders of the macular pigmentation.  Visual fields are normal usually but there may be some decrease in central sensitivity.

However, this is a generalized retinal disorder as revealed by the abnormal mass response (decreased light/dark ratio) of the electrooculogram (EOG).   Patients may not have visual symptoms until their late 20s or early 30s even though the pigmentation may be evident in the second decade.  Color vision, dark adaptation and the ERG are normal.  Younger patients may have normal vision.

Systemic Features: 

No systemic associations have been reported.

Genetics

This condition results from heterozygous mutations in the CTNNA1 gene (5q31).  For a similar disorder see Macular Dystrophy, Patterned 1 (169150).

As many as 25% of patients with myotonic dystrophy 1 (160900) and myotonic dystrophy 2 (602668) have a patterned pigmentary maculopathy.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no known treatment.

References
Article Title: 

Mutations in CTNNA1 cause butterfly-shaped pigment dystrophy and perturbed retinal pigment epithelium integrity

Saksens NT, Krebs MP, Schoenmaker-Koller FE, Hicks W, Yu M, Shi L, Rowe L, Collin GB, Charette JR, Letteboer SJ, Neveling K, van Moorsel TW, Abu-Ltaif S, DeBaere E, Walraedt S, Banfi S, Simonelli F, Cremers FP, Boon CJ, Roepman R, Leroy BP, Peachey NS, Hoyng CB, Nishina PM, den Hollander AI. Mutations in CTNNA1 cause butterfly-shaped pigment dystrophy and perturbed retinal pigment epithelium integrity. Nat Genet. 2016 Feb;48(2):144-51.

PubMed ID: 
26691986

Macular Dystrophy with Central Cone Involvement

Clinical Characteristics
Ocular Features: 

This is primarily a cone dystrophy but there is evidence of some rod damage in older patients.  A mild decrease in central acuity is noted by individuals in the third to sixth decades.  Slight pigmentary changes and color vision abnormalities can be documented with the onset of these symptoms and a bull's eye maculopathy and severe atrophy of the central fovea may be present. An enlarging central scotoma with normal periphery can sometimes be identified.  Other patients have an atrophic appearance to the peripapillary area with a pale optic disc.  ERG responses to full-field testing are normal but multifocal studies reveal severely reduced central responses.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

Compound heterozygosity for a missense mutation and a nonsense mutation in the MFSD8 gene (4q28.2) has been found among members of a Dutch sibship suggesting autosomal recessive inheritance.       

The same mutant gene has been identified in some patients with late infantile or early juvenile onset lysosomal storage disease known as neuronal ceroid lipofuscinoses (610951) in which there may be optic atrophy, attenuated retinal vessels, a pigmentary retinopathy, and severe vision loss.   However, it is of note that no members of the Dutch family with the macular cone dystrophy described here had extraocular manifestations.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

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

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

Cranial Dysinnervation Disorders with Strabismus and Arthrogryposis

Clinical Characteristics
Ocular Features: 

Strabismus and/or ophthalmoplegia are important features of a group of conditions known as cranial dysinnervation disorders.  Ptosis, Duane syndrome, V pattern exotropia and various degrees of ophthalmoplegia may be seen.  There may be considerable asymmetry in the manifestations in the two eyes.  Epicanthal folds, blepharophimosis, and hypermetropia are sometimes present.  Some patients have corneal leukomas, keratoglobus, high corneal astigmatism, and dysplastic optic disks. 

A pigmentary retinopathy and folds in the macula with an abnormal ERG has been reported.  Subnormal vision has been reported in some patients.

Systemic Features: 

Patients are often short in stature with pectus excavatum, spine stiffness, highly arched palate, and club feet.  Limited forearm rotation and wrist extension may be present.  The fingers appear long and often have contractures while the palmar and phalangeal creases may be absent.  Camptodactyly and clinodactyly are common.  Deep tendon reflexes are often hyporeactive and decreased muscle mass has been noted.  The muscles seem "firm" to palpation.  Restrictive lung disease has been reported.  Hearing loss is experienced by some individuals.

Genetics

Distal arthrogryposis type 5D is caused by homozygous or compound heterozygous mutations in the ECEL1 gene located at 2q36.  However, a similar phenotype (albeit with more severe ocular manifestations) results from heterozygous mutations in PIEZO2 (18p11).  Heterozygous mutations in the PIEZO2 gene have also been reported to cause distal arthrogryposis type 3 (Gordon syndrome [114300]) and Marden-Walker syndrome (248700) and all of these may be simply phenotypical variations of the same disorder.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for this condition.  Patients with subnormal vision may benefit from low vision aids and selective surgery may be helpful in reducing the physical restrictions from physical deformities.

References
Article Title: 

Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5

McMillin MJ, Beck AE, Chong JX, Shively KM, Buckingham KJ, Gildersleeve HI, Aracena MI, Aylsworth AS, Bitoun P, Carey JC, Clericuzio CL, Crow YJ, Curry CJ, Devriendt K, Everman DB, Fryer A, Gibson K, Giovannucci Uzielli ML, Graham JM Jr, Hall JG, Hecht JT, Heidenreich RA, Hurst JA, Irani S, Krapels IP, Leroy JG, Mowat D, Plant GT, Robertson SP, Schorry EK, Scott RH, Seaver LH, Sherr E, Splitt M, Stewart H, Stumpel C, Temel SG, Weaver DD, Whiteford M, Williams MS, Tabor HK, Smith JD, Shendure J, Nickerson DA; University of Washington Center for Mendelian Genomics, Bamshad MJ. Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5. Am J Hum Genet. 2014 May 1;94(5):734-44.

PubMed ID: 
24726473

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