autosomal recessive

Albinism, Oculocutaneous, Type I

Clinical Characteristics
Ocular Features: 

Oculocutaneous albinism is a genetically and clinically heterogeneous condition.  It is congenital in origin and the combination of foveal hypoplasia and anomalous decussation of neuronal axons in the chiasm results in a permanent reduction of vision in the range of 20/50-20/200.  Most individuals have nystagmus, photophobia, and strabismus.  The iris usually is light blue and transmits light.  The retina lacks pigmentation as well.  The ocular features are similar in types IA and IB.  The iris may darken with age in type IB (606952 ). 

Systemic Features: 

There are generally no systemic abnormalities in these pigmentation disorders with the exception of sensorineural hearing loss in some, and, of course, complete absence of pigment in skin and hair.  Anomalous decussation of axons in the auditory system has been demonstrated in such cases and otic pigment is lacking in albinos.  The skin contains amelanic melanocytes but these cells contain granules similar to those of normal cells.   Some patients with residual tyrosinase activity (type 1B, 606952 ) develop some pigmentation of hair and skin, especially in cooler areas of the body such as the extremities. 

Genetics

This type of oculocutaneous albinism is caused by mutations in the TYR gene (11q14-q21) and inherited in an autosomal recessive pattern. 

Type IA (OCA1A) has no demonstrable tyrosinase activity while type IB (OCA1B, 606952) has a reduction in enzyme activity.  Yet other patients with mutations in TYR have a variant called 'yellow albinism' in which tyrosinase activity resembles that found in type IB.  To explain the difference in skin color, it has been suggested that an individual's background ethnicity may impact the pigmentation phenotype.

Other types also transmitted as autosomal recessive conditions are OCA2 (203200), OCA3 (203290), AND OCA4 (606574). 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the basic disease but low vision aids may be helpful for some patients.  Dark glasses provide comfort for photophobic individuals.  The skin should be protected against sunburn. 

References
Article Title: 

A new hypothesis of OCA1B

Chiang PW, Drautz JM, Tsai AC, Spector E, Clericuzio CL. A new hypothesis of OCA1B. Am J Med Genet A. 2008 Nov 15;146A(22):2968-70.

PubMed ID: 
18925668

Oculocutaneous albinism

Gronskov K, Ek J, Brondum-Nielsen K. Oculocutaneous albinism. Orphanet J Rare Dis. 2007 Nov 2;2:43. Review.

PubMed ID: 
17980020

Cone-Rod Dystrophies, AD and AR

Clinical Characteristics
Ocular Features: 

Cone-rod dystrophies (CRD) are a group of pigmentary retinopathies that have early and important changes in the macula.  Cone dysfunction occurs first and is often followed by rod photoreceptor degeneration.

Common initial symptoms are decreased visual acuity, dyschromatopsia, and photophobia which are often noted in the first decade of life.  Night blindness occurs later as the disease progresses.  A fine nystagmus is also common. Visual field defects include an initial central scotoma with patchy peripheral defects followed by larger defects in later stages.  The fundus exam can be normal initially, but is followed by pigmentary bone spicule changes, attenuation of retinal vessels, waxy pallor of the optic disc and retinal atrophy.  A ring maculopathy surrounding the fovea is usually evident.  The ERG first reveals photopic defects and later scotopic changes.  Fluorescein angiography and fundus autofluorescence generally reveal atrophic retinopathy.  Many patients eventually become legally blind as the disease progresses and some end up with no light perception.

Cone-rod dystrophies are a group of disorders separate from rod-cone dystrophies where the primary defect is in the rod photoreceptors with typical pigmentary changes in the peripheral retina. The progression of vision loss is generally slower in rod-cone dystrophies. Cone dystrophies comprise another group of disorders with exclusive cone involvement in which the macula often has a normal appearance in association with loss of central acuity.

Systemic Features: 

No systemic disease is associated with simple cone-rod dystrophies.  See below for syndromal disorders with cone-rod dystrophy. 

Genetics

Non-syndromic cone-rod dystrophies can be either autosomal dominant, autosomal recessive or X-linked and are caused by defects in at least 17 different genes.  This database entry discusses only the autosomal disorders.  See X-linked cone-rod dystrophies in a separate entry.

Cone-rod dystrophies inherited in an autosomal dominant pattern include:

CORD2 (120970) is caused by mutations in CRX at 19q13.3, a homeobox gene responsible for the development of photoreceptor cells.  These are responsible for 5-10% of autosomal dominant cone-rod dystrophy cases (602225) and can also cause one type (LCA7) of Leber congenital amaurosis (602225) and a late-onset retinitis pigmentosa phenotype.

CORD5 (600977) is caused by mutations in the PITPNM3 gene at 17p13.1. 

CORD6 (601777) is caused by a mutation in GUCY2D in a similar location on chromosome 17. 

CORD7 (603649) is caused by mutations in RIMS1 at 6q12-q13.

Mutations in AIPL1 (604392), located in the same region, usually causes a form of Leber congenital amaurosis (LCA4) as well as retinitis pigmentosa (604393) but has also been reported in a cone-rod pigmentary retinopathy.

CORD11 (610381) is caused by mutations in RAXL1 (19p13.3).

CORD12 (612657) results from mutations in the PROM1 gene (4p15.3).

Mutations in the gene GUCA1A on chromosome 6p21.1 causes CORD14 (602093).

An as yet unclassified autosomal dominant type of cone-rod dystrophy has recently been localized to 10q26.

Cone-rod dystrophies inherited in an autosomal recessive pattern include:

Mutations in ABCA4 at 1p21-p13 is responsible for 30-60% of cases of autosomal recessive CRD (CORD3; 604116) .  ABCA4 is also known to cause autosomal recessive Stargardt disease.

CORD8 (605549) has been found in a single consanguineous family and the mutation localized to 1q12-q24.

ADAM9 (602713) at 8p11 and 8p11.23 contains mutations that have been shown to cause autosomal recessive CORD9 in several consanguineous families.

Mutations in RPGRIP1 (14q11) are responsible for CORD13 (608194).

The CDHR1 gene (10q23.1) contains mutations that cause CORD15 (613660).

Other autosomal CRD disorders are CORD1 (600624) described in a single individual and possibly those due to mutations in HRG4 at 17q11.2 (604011).

Syndromal cone-rod dystrophies:

Cone-rod dystrophy may also be associated with other syndromes, such as Bardet-Biedl syndrome (209900), or spinocerebellar ataxia Type 7 (164500), autosomal recessive amelogenesis imperfecta with cone-rod dystrophy or Jalili syndrome (217080), neurofibromatosis type I (162200), and hypotrichosis with juvenile macular dystrophy and alopecia (601553).  Metabolic disorders associated with cone-rod dystrophy include Refsum disease with phytanic acid abnormality (266500) and Alport syndrome (301050). 

Cone-Rod Dystrophy 19 (615860) has been associated with male infertility as the result of mutations in TTLL5 affecting both photoreceptors and sperm.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for these dystrophies but red-tinted lenses provide comfort and may sometimes improve acuity to some extent.  Low vision aids can be helpful. 

References
Article Title: 

A novel locus for autosomal dominant cone-rod dystrophy maps to chromosome 10q

Kamenarova K, Cherninkova S, Romero Dur?degn M, Prescott D, Vald?(c)s S?degnchez ML, Mitev V, Kremensky I, Kaneva R, Bhattacharya SS, Tournev I, Chakarova C. A novel locus for autosomal dominant cone-rod dystrophy maps to chromosome 10q. Eur J Hum Genet. 2012 Aug 29. doi: 10.1038/ejhg.2012.158. [Epub ahead of print]

PubMed ID: 
22929024

Cone rod dystrophies

Hamel CP. Cone rod dystrophies. Orphanet J Rare Dis. 2007 Feb 1;2:7. Review.

PubMed ID: 
17270046

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: 

GM1 Gangliosidosis

Clinical Characteristics
Ocular Features: 

Based on clinical manifestations, three types have been described: type I or infantile form, type II or late-infantile/juvenile form, and type III or adult/chronic form but all are due to mutations in the same gene.  Only the infantile form has the typical cherry red spot in the macula but is present in only about 50% of infants.  The corneal clouding is due to intracellular accumulations of mucopolysaccharides in corneal epithelium and keratan sulfate in keratocytes.  Retinal ganglion cells also have accumulations of gangliosides.  Decreased acuity, nystagmus, strabismus and retinal hemorrhages have been described. 

Systemic Features: 

Infants with type I disease are usually hypotonic from birth but develop spasticity, psychomotor retardation, and hyperreflexia within 6 months.  Early death from cardiopulmonary disease or infection is common.  Hepatomegaly, coarse facial features, brachydactyly, and cardiomyopathy with valvular dysfunction are common.  Dermal melanocytosis has also been described in infants in a pattern some have called Mongolian spots.  Skeletal dysplasia is a feature and often leads to vertebral deformities and scoliosis.  The ears are often large and low-set, the nasal bridge is depressed, the tongue is enlarged and frontal bossing is often striking.  Hirsutism, coarse skin, short digits, and inguinal hernias are common.

The juvenile form, type II, has a later onset with psychomotor deterioration, seizures and skeletal changes apparent between 7 and 36 months and death in childhood.  Visceral involvement and cherry-red spots are usually not present. 

Type III, or adult form, is manifest later in the first decade or even sometime by the 4th decade.  Symptoms and signs are more localized.  Neurological signs are evident as dystonia or speech and gait difficulties.  Dementia, parkinsonian signs, and extrapyramidal disease are late features.  No hepatosplenomegaly, facial dysmorphism, or cherry red spots are present in most individuals. Lifespan may be normal in this type. 

Genetics

This is an autosomal recessive lysosomal storage disease secondary to a mutations in GLB1 (3p21.33).  It is allelic to Morquio B disease (MPS IVB) (253010).  The mutations in the beta-galactosidase-1 gene result in intracellular accumulation of GM1 ganglioside, keratan sulfate, and oligosaccharides.  The production of the enzyme varies among different mutations likely accounting for the clinical heterogeneity. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment that effectively alters the disease course. 

References
Article Title: 

Stargardt Disease

Clinical Characteristics
Ocular Features: 

Stargardt disease or fundus flavimaculatus is a progressive form of juvenile macular degeneration with considerable clinical and genetic heterogeneity.  It may be considered a syndromal cone-rod dystrophy because of overlapping clinical features such as loss of color vision and photophobia in some patients.  Adding to the confusion is the fact that mutations in at least 4 genes are responsible for similar clinical characteristics.  Due to the lack of diagnostic distinctions and the wide range of nonspecific clinical manifestations, Stargardt disease and fundus flavimaculatus are discussed here as a single entity.

Onset of vision loss is often noted late in the first decade of life usually with rapid progression.  However, some patients are asymptomatic until much later, even into the fifth decade.  There is evidence that patients with an early onset have a worse prognosis compared to those with a later onset.  Nevertheless, large series of patients contain at least 23% with 20/40 or better acuity, about 20% with 20/50 -20/100, 55% have 20/200-20/400, and a small number have vision less than 20/400. 

Some color discrimination is lost and photophobia may be a complaint.  Dark adaptation is prolonged but nightblindness does not usually occur and peripheral visual fields are normal.  The posterior pole characteristically has yellowish pisciform, round, and linear subretinal lipofuscin deposits which often extend to the equator.  These may be present before clinical symptoms are present.  Histopathology reveals accumulations of this material in RPE cells.  Atrophy of the RPE in the same region is often visible as well but these changes may be subtle initially.  Some patients have peripheral pigment clumping which may resemble the bone spicule configuration seen in retinitis pigmentosa.  However, retinal vessel caliber is normal in Stargardt disease.  Extensive macular disease can be associated with temporal pallor of the optic nerve.  The ERG shows reduced photopic responses with normal or near normal scotopic tracings.  Fluorescein angiography often reveals more extensive disease than seen on fundoscopy.  Window defects are common in the macula where the RPE is atrophied.  The flecks may be hypo- or hyperfluorescent.  Over 50% of patients have patches of angiographically dark choroid in the posterior pole which is thought to be secondary to transmission blockage by lipofuscin accumulations in the RPE. 

Systemic Features: 

None.

Genetics

This group of disorders may be caused by mutations in at least 4 genes.  These are: STGD1 (248200) caused by mutations in the ABCA4 gene located at 1p22.1, or in CNGB3 (262300) (8q21-q22) which also is mutant in achromatopsia 3 (ACHM3), STGD3 (605512) caused by mutations in the ELOVL4 gene at 6q14, and STGD4 (603786) caused by a mutation in PROM1 on chromosome 4p.  STGD4 and STGD3 disease have been found in pedigrees consistent with autosomal dominant inheritance but STGD1 disease seems to be inherited in an autosomal recessive pattern.

Genotyping is necessary for accurate diagnostic determinations.  In particular, a few patients clinically found to have typical areolar macular dystrophy, retinitis pigmentosa, juvenile macular degeneration, and cone dystrophies have been reported in association with several of these mutations and reports have also associated Stargardt disease with mutations in RDS.

A single family with a brother and sister with Stargardt disease and neurological malformations has been reported (612948).  Both had developmental delays associated with absence or hypoplasia of the corpus callosum, upslanted lid fissures, 'flared eyebrows', a broad nasal tip, a broad face with a pointed chin, and sensorineural hearing loss along with mild digital malformations.  Evidence of macular degeneration was seen at age 7 years and vision in both individuals was in the 20/100-20/200 range. No associated locus or mutation has been identified.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for this disorder but low vision aids can be helpful especially in the early stages of the disease.

Isotretinoin has been shown to slow the accumulation of lipofuscin pigments in mice but its role in human Stargardt disease has not been reported.  Trials using stem cells are underway with encouraging early results.

References
Article Title: 

Comprehensive analysis of patients with Stargardt macular dystrophy reveals new genotype-phenotype correlations and unexpected diagnostic revisions

Zaneveld J, Siddiqui S, Li H, Wang X, Wang H, Wang K, Li H, Ren H, Lopez I, Dorfman A, Khan A, Wang F, Salvo J, Gelowani V, Li Y, Sui R, Koenekoop R, Chen R. Comprehensive analysis of patients with Stargardt macular dystrophy reveals new genotype-phenotype correlations and unexpected diagnostic revisions. Genet Med. 2014 Dec 4.  [Epub ahead of print].

PubMed ID: 
25474345

Colorblindness-Achromatopsia 5

Clinical Characteristics
Ocular Features: 

Poor visual acuity and congenital nystagmus are characteristic of ACHM5 and may be seen in infancy.  Vision loss can be progressive for those who have a milder form of colorblindness or incomplete achromatopsia.  Such patients have a somewhat later onset and may not have nystagmus or photophobia.  Cone responses are usually absent in the ERG whereas rod responses are often normal.  However, in the incomplete form there may be reduced but measureable cone responses.  There may be some reduction in rod responses with disease progression.  Myopia has been found in some patients.  Atrophy of the RPE in the posterior pole characteristic of progressive cone dystrophies may be seen. 

Systemic Features: 

No systemic abnormalities are found in this disorder. 

Genetics

This is an autosomal recessive disorder resulting from mutations in the PDE6C gene located at 10q24.  This condition is sometimes called cone dystrophy 4.

Other forms of achromatopsia are ACHM3 caused by mutations in CNGB3 (262300), ACHM2 caused by mutations in CNGA3 (216900), and ACHM4 by mutations in GNAT2 (139340).

 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the cone dystrophy but dark glasses and red colored contact lenses are helpful in reducing the photophobia and can improve acuity to some extent.  Low vision aids can also be helpful. 

References
Article Title: 

A Nonsense Mutation in PDE6H Causes Autosomal-Recessive Incomplete Achromatopsia

Kohl S, Coppieters F, Meire F, Schaich S, Roosing S, Brennenstuhl C, Bolz S, van Genderen MM, Riemslag FC; the European Retinal Disease Consortium, Lukowski R, den Hollander AI, Cremers FP, De Baere E, Hoyng CB, Wissinger B. A Nonsense Mutation in PDE6H Causes Autosomal-Recessive Incomplete Achromatopsia. Am J Hum Genet. 2012 Sep 7; 91(3) :527-32.

PubMed ID: 
22901948

Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders

Thiadens AA, den Hollander AI, Roosing S, Nabuurs SB, Zekveld-Vroon RC, Collin RW, De Baere E, Koenekoop RK, van Schooneveld MJ, Strom TM, van Lith-Verhoeven JJ, Lotery AJ, van Moll-Ramirez N, Leroy BP, van den Born LI, Hoyng CB, Cremers FP, Klaver CC. Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders. Am J Hum Genet. 2009 Aug;85(2):240-7.

PubMed ID: 
19615668

Colorblindness-Achromatopsia 4

Clinical Characteristics
Ocular Features: 

The ocular phenotype in ACHM4 is similar to that of other forms of achromatopsia.  Nystagmus, poor visual acuity, photophobia, and defects in color vision are usually present.  Some subjects, however, retain some color discrimination, a condition referred to as incomplete achromatopsia.  The ERG documents the absence of cone function but normal rod responses.  The retina appears normal clinically.

Few families have been reported and the complete phenotype remains undocumented.  For example, it has been reported that visual acuity weakens with age in some patients although it is uncertain if this is true of all cases. 

Systemic Features: 

No systemic abnormalities are associated. 

Genetics

This is an autosomal recessive disorder caused by mutations in GNAT2 located at 1p13.  These mutations account for less than 2% of achromatopsia cases.  The majority are caused by mutations in CNGA3 (25%), responsible for ACHM2 (216900) and CNGB3 (50%), causing ACHM3 (262300).  Mutations in PDE6C (613093 ) causing ACHM5 are responsible for less than 2%. No doubt others will be found as many cases do not have mutations in these genes. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this disorder but tinted lenses and low vision aids can be helpful.  Red contact lenses can reduce the photophobia and may improve vision. 

References
Article Title: 

Colorblindness-Achromatopsia 2

Clinical Characteristics
Ocular Features: 

Patients with this congenital, nonprogressive condition often have nystagmus as infants which may improve later. Eccentric fixation secondary to a small central scotoma is often present.  Visual acuity is 20/200 or worse.  Hyperopia is common.  Photophobia is extreme and vision under daylight conditions improves in dim light.  Patients are unable to distinguish any colors.  However, there is considerable variability in symptoms and some individuals retain some color perception and have better visual acuity (sometimes 20/80) than others suggesting some residual cone function.  The term ‘incomplete achromatopsia’ is sometimes applied to such cases but the molecular basis for this variation is unknown.  Optical coherence tomography reveals the central retina to be thinner than in normal controls.  The fundus appearance is normal, however.

ERG responses indicate an absence of cone function with no photopic responses. 

Systemic Features: 

There are no associated systemic abnormalities. 

Genetics

Mutations in CNGA3 account for approximately 25% of cases of achromatopsia.  ACHM2 is an autosomal recessive disorder caused by mutations in CNGA3 (2q11).  Mutations in this gene also have been found in rare patients with progressive cone dystrophies.  A clinically similar but genetically distinct disorder, ACHM3, results from mutations in CNGB3 (262300).  Mutations in GNAT2 (ACHM4; 139340) and PDE6C (ACHM5; 613093) also cause achromatopsia. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the underlying condition but darkly tinted lenses can help in bright light.  Red contact lenses can alleviate photophobia and improve vision as well.  Low vision aids and vocational training can be of great benefit.  In spite of the poor vision, some patients may find that correction of the hyperopia enables them to see better. 

References
Article Title: 

Colorblindness-Achromatopsia 3

Clinical Characteristics
Ocular Features: 

Achromatopsia 3 is a congenital, nonprogressive form of blindness.  It is sometimes referred to as a rod monochromacy or stationary cone dystrophy.  Symptoms are usually present at birth or shortly thereafter.  Patients have pendular nystagmus, progressive lens opacities, severe photophobia, 'day' blindness, and, of course, color blindness.  High myopia is a feature in some populations.  Vision in daylight is often 20/200 or less but vision in dim light is somewhat better. The central scotoma often leads to eccentric fixation. 

The ERG shows a complete absence of cone function.  Optical coherence tomography has demonstrated a reduction in macular volume and thickness of the central retina, most marked in the foveolar region, presumably due in some way to the absence or dysfunction of cone photoreceptors.  Few histologic studies of adequately preserved retina have been reported but those available suggest dysmorphism of cones in the central macula.  The clinical appearance of the retina is usually normal. 

Systemic Features: 

There are no associated systemic abnormalities. 

Genetics

This is an autosomal recessive form of color blindness caused by mutations in CNGB3 (8q21-q22).  This mutation is found in nearly half of patients with achromatopsia.  It is especially common among Pingelapese islanders of the Pacific Caroline Islands where consanguinity occurs frequently due to the founder effect resulting from a 1775 typhoon.  A progressive cone dystrophy has been found in a few patients with mutations in this gene.

Other achromatopsia mutations are in CNGA3 causing ACHM2 (216900), GNAT2 causing ACHM4 (139340), and PDE6C causing ACHM5 (613093).   

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available but darkly tinted lenses can alleviate much of the photophobia.  Low vision aids and vocational training should be offered.  Refractive errors should, of course, be corrected and periodic examinations are especially important in children. 

References
Article Title: 

The cone dysfunction syndromes

Michaelides M, Hunt DM, Moore AT. The cone dysfunction syndromes. Br J Ophthalmol. 2004 Feb;88(2):291-7. Review.

PubMed ID: 
14736794

Leber Congenital Amaurosis

Clinical Characteristics
Ocular Features: 

Leber congenital amaurosis is a collective term applied to multiple recessively inherited conditions with early-onset retinal dystrophy causing infantile or early childhood blindness.  There are no established diagnostic criteria.  First signs are usually noted before the age of 6 months.  These consist of a severe reduction in vision accompanied by nystagmus, abnormal pupillary responses, and photophobia.  Ametropia in the form of hyperopia is common.  Keratoconus (and keratoglobus) is frequently found in older children but it is uncertain if this is a primary abnormality or secondary to eye rubbing as the latter is commonly observed.  Repeated pressure on the eye may also be responsible for the relative enophthalmos often seen in these patients.  The ERG is reduced or absent early and permanently.  Final visual acuity is seldom better than 20/400 and perhaps one-third of affected individuals have no light perception.  Some individuals experience a period of vision improvement.

The retina usually has pigmentary changes but these are not diagnostic.  Retinal vessels are generally attenuated.  The RPE may have a finely granulated appearance or, in some cases, whitish dots, and even 'bone spicules'.

Systemic Features: 

A variety of metabolic and physical abnormalities have been reported with LCA but many publications are from the pre-genomic era and the significance of such associations remains uncertain.  Most extraocular signs result from delays in mental development but it is uncertain what role, if any, that visual deprivation plays.  Perhaps 20% of patients are mentally retarded or have significant cognitive deficits.

Genetics

Leber congenital amaurosis is genetically heterogeneous with at least 18 known gene mutations associated with the phenotype.  It is also clinically heterogeneous both within and among families and this is the major obstacle to the delineation of individual clinicogenetic entities.  As more patients are genotyped, it is likely that more precise genotype-phenotype correlations will emerge.  At the present time, however, it is not possible to use clinical findings alone to distinguish individual conditions.

Below are links to the genotypic and phenotypic features of the 19 known types of LCA.  All cause disease in the homozygous or compound heterozygous state. 

LCA type               OMIM#                 Locus              Gene Symbol   

LCA 1                    204000                 7p13.1                 GUCY2D

LCA 2                    204100                 1p31                    RPE65**

LCA 3                    604232                 14q31.3               SPATA7

LCA 4                    604393                 17p13.1               AIPL1

LCA 5                    604537                 6q14.1                 LCA5

LCA 6                    613826                 14q11                  RPGRIP1

LCA 7                    613829                19q13.1                CRX*

LCA 8                    613835                 1q31-q32             CRB1

LCA 9                    608553                 1p36                    NMNAT1

LCA 10                  611755                 12q21                  CEP290

LCA 11                  613837                 7q31.3-q332        IMPDH1

LCA 12                  610612                 1q32.3                 RD3

LCA 13                  612712                 14q24.1               RDH12

LCA 14                  613341                 4q31                    LRAT

LCA 15                  613843                 6p21-31              TULP1

LCA 16                  614186                 2q37                    KCNJ13

LCA 17                  615360                 8q22.1                 GDF6

LCA 18                  608133                 6p21.1                 PRPH2***

It is likely that more mutant genes will be identified since these are found in only about half of patients studied in large series.  

*(Heterozygous mutations in CRX may also cause a cone-rod dystrophy).

**(Mutations in RPE65 has been described as also causing retinitis pigmentosa (RP20; 613794)  with choroidal involvement.)

***Mutations in PRPH2 (RDS) has also been reported to cause retinitis pigmentosa 7, choroidal dystrophy, and vitelliform macular dystrophy (179605) among others.

See also Leber Congenital Amaurosis with Early-Onset Deafness.

Mutations in the GUCY2D gene seem to be the most common being present in about 21% of LCA patients with CRB1 next at 10%.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Until recently, no treatment was available for LCA.  However, results from early clinical trials with adeno-associated virus vector mediated gene therapy for RPE65 mutations in LCA 2 show promise.  Subretinal placement of recombinant  adeno-virus carrying RPE65 complementary DNA results in both subjective and objective improvements in visual function.  Patients generally report subjective improvement in light sensitivity and visual mobility.  Some recovery of rod and cone photoreceptor function has been documented.  Studies have also documented an improvement in visual acuity, size of visual field, pupillary responses, and in the amouunt of nystagmus.  More than 230 patients have now  been treated and improvements seem to be maintained for at least 3 or more years.  However, we have also learned that along with the enzymatic dysfunction of RPE65 that disrupts the visual cycle, there is also degeneration of photoreceptors which continues after treatment and the long term prognosis remains guarded. Multiple phase I clinical trials have demonstrated the safety of this approach and phase III trials are now underway.

It is crucial for patients to be enrolled early in sensory stimulation programs to ensure optimum neural development.  For patients with residual vision, low vision aids can be beneficial.  Vocational and occupational therapy should be considered for appropriate patients.

References
Article Title: 

Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease

Koenekoop RK, Wang H, Majewski J, Wang X, Lopez I, Ren H, Chen Y, Li Y,
Fishman GA, Genead M, Schwartzentruber J, Solanki N, Traboulsi EI, Cheng J, Logan
CV, McKibbin M, Hayward BE, Parry DA, Johnson CA, Nageeb M; Finding of Rare
Disease Genes (FORGE) Canada Consortium, Poulter JA, Mohamed MD, Jafri H, Rashid
Y, Taylor GR, Keser V, Mardon G, Xu H, Inglehearn CF, Fu Q, Toomes C, Chen R.
Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease
pathway for retinal degeneration. Nat Genet. 2012 Jul 29.
 

PubMed ID: 
22842230

A dominant mutation in RPE65 identified by whole-exome sequencing causes retinitis pigmentosa with choroidal involvement

Bowne SJ, Humphries MM, Sullivan LS, Kenna PF, Tam LC, Kiang AS, Campbell M, Weinstock GM, Koboldt DC, Ding L, Fulton RS, Sodergren EJ, Allman D, Millington-Ward S, Palfi A, McKee A, Blanton SH, Slifer S, Konidari I, Farrar GJ, Daiger SP, Humphries P. A dominant mutation in RPE65 identified by whole-exome sequencing causes retinitis pigmentosa with choroidal involvement. Eur J Hum Genet. 2011 Oct;19(10):1074-81. Erratum in: Eur J Hum Genet. 2011 Oct;19(10):1109.

PubMed ID: 
21654732

Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial

Hauswirth WW, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, Wang L, Conlon TJ, Boye SL, Flotte TR, Byrne BJ, Jacobson SG. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008 Oct;19(10):979-90.

PubMed ID: 
18774912

Effect of gene therapy on visual function in Leber's congenital amaurosis

Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A, Holder GE, Stockman A, Tyler N, Petersen-Jones S, Bhattacharya SS, Thrasher AJ, Fitzke FW, Carter BJ, Rubin GS, Moore AT, Ali RR. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med. 2008 May 22;358(21):2231-9.

PubMed ID: 
18441371

Leber congenital amaurosis

Perrault I, Rozet JM, Gerber S, Ghazi I, Leowski C, Ducroq D, Souied E, Dufier JL, Munnich A, Kaplan J. Leber congenital amaurosis. Mol Genet Metab. 1999 Oct;68(2):200-8. Review.

PubMed ID: 
10527670

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