autosomal recessive

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. 

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

Jacobson SG, Cideciyan AV. Treatment possibilities for retinitis pigmentosa. N Engl J Med. 2010 Oct 21;363(17):1669-71.

PubMed ID: 
20961252

Busskamp V, Duebel J, Balya D, Fradot M, Viney TJ, Siegert S, Groner AC, Cabuy E, Forster V, Seeliger M, Biel M, Humphries P, Paques M, Mohand-Said S, Trono D, Deisseroth K, Sahel JA, Picaud S, Roska B. Genetic reactivation of cone photoreceptors restores visual responses in retinitis pigmentosa. Science. 2010 Jul 23;329(5990):413-7.

PubMed ID: 
20576849

Jan√°ky M, P√°lffy A, De√°k A, Szil√°gyi M, Benedek G. Multifocal ERG reveals several patterns of cone degeneration in retinitis pigmentosa with concentric narrowing of the visual field. Invest Ophthalmol Vis Sci. 2007 Jan;48(1):383-9.

PubMed ID: 
17197558

Berger AS, Tezel TH, Del Priore LV, Kaplan HJ. Photoreceptor transplantation in retinitis pigmentosa: short-term follow-up. Ophthalmology. 2003 Feb;110(2):383-91.

PubMed ID: 
12578785

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. 

Treatment Options

There is no treatment that effectively alters the disease course. 

References

Brunetti-Pierri N, Scaglia F. GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects. Mol Genet Metab. 2008 Aug;94(4):391-6. Review.

PubMed ID: 
18524657

Giugliani R, Dutra JC, Pereira ML, Rotta N, Drachler Mde L, Ohlweiller L, Pina Neto JM, Pinheiro CE, Breda DJ. GM1 gangliosidosis: clinical and laboratory findings in eight families. Hum Genet. 1985;70(4):347-54.

PubMed ID: 
3926630

Emery JM, Green WR, Wyllie RG, Howell RR. GM1-gangliosidosis. Ocular and pathological manifestations. Arch Ophthalmol. 1971 Feb;85(2):177-87.

PubMed ID: 
4250987

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, and 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.

There is considerable diagnostic confusion regarding the clinical phenotypes and classification of many patients no doubt due to the considerable genetic heterogeneity.  The ABCA4 gene is huge and and contains 50 exons among which 700 mutations have been identified. Not surprisingly, the impact of specific mutations on the ABCA4 gene product is variable and those expected to have the most severe functional impact through truncation or misfolding usually result in the most severe clinical disease.  Complicating matters further, intrafamilial variations in phenotypes suggest that epigenetic factors play a role as well.

Genomics should help clarify the nosology especially among individuals reported to have areolar macular dystrophy, retinitis pigmentosa, juvenile macular degeneration, and cone dystrophies in association with several of these mutations.  Reports have also associated Stargardt disease with mutations in RDS.  

 

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

Heathfield L, Lacerda M, Nossek C, Roberts L, Ramesar RS. Stargardt disease: towards developing a model to predict phenotype. Eur J Hum Genet. 2013 May 22. doi: 10.1038/ejhg.2013.92. [Epub ahead of print].

PubMed ID: 
23695285

Zahid S, Jayasundera T, Rhoades W, Branham K, Khan N, Niziol LM, Musch DC, Heckenlively JR. Clinical Phenotypes and Prognostic Full-Field Electroretinographic Findings in Stargardt Disease. Am J Ophthalmol. 2012 Dec 4. [Epub ahead of print] PubMed PMID: 23219216.

PubMed ID: 
23219216

Rotenstreich Y, Fishman GA, Anderson RJ. Visual acuity loss and clinical observations in a large series of patients with Stargardt disease. Ophthalmology. 2003 Jun;110(6):1151-8.

PubMed ID: 
12799240

Sparrow JR. Therapy for macular degeneration: insights from acne. Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4353-4.

PubMed ID: 
12682280

Weleber RG, Carr RE, Murphey WH, Sheffield VC, Stone EM. Phenotypic variation including retinitis pigmentosa, pattern dystrophy, and fundus flavimaculatus in a single family with a deletion of codon 153 or 154 of the peripherin/RDS gene. Arch Ophthalmol. 1993 Nov;111(11):1531-42.

PubMed ID: 
8240110

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).

 

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

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 Aug 15. [Epub ahead of print] PubMed PMID: 22901948.

PubMed ID: 
22901948

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

Chang B, Grau T, Dangel S, Hurd R, Jurklies B, Sener EC, Andreasson S, Dollfus H, Baumann B, Bolz S, Artemyev N, Kohl S, Heckenlively J, Wissinger B. A homologous genetic basis of the murine cpfl1 mutant and human achromatopsia linked to mutations in the PDE6C gene. Proc Natl Acad Sci U S A. 2009 Nov 17;106(46):19581-6.

PubMed ID: 
19887631

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. 

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

Rosenberg T, Baumann B, Kohl S, Zrenner E, Jorgensen AL, Wissinger B. Variant phenotypes of incomplete achromatopsia in two cousins with GNAT2 gene mutations. Invest Ophthalmol Vis Sci. 2004 Dec;45(12):4256-62.

PubMed ID: 
15557429

Aligianis IA, Forshew T, Johnson S, Michaelides M, Johnson CA, Trembath RC, Hunt DM, Moore AT, Maher ER. Mapping of a novel locus for achromatopsia (ACHM4)to 1p and identification of a germline mutation in the alpha subunit of cone transducin (GNAT2). J Med Genet. 2002 Sep;39(9):656-60.

PubMed ID: 
12205108

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. 

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

Vars√°nyi B, Somfai GM, Lesch B, V√°mos R, Farkas A. Optical coherence tomography of the macula in congenital achromatopsia. Invest Ophthalmol Vis Sci. 2007 May;48(5):2249-53.

PubMed ID: 
14760287

Holopigian K, Greenstein VC, Seiple W, Hood DC, Carr RE. Rod and cone photoreceptor function in patients with cone dystrophy. Invest Ophthalmol Vis Sci. 2004 Jan;45(1):275-81.

PubMed ID: 
14691184

Park WL, Sunness JS. Red contact lenses for alleviation of photophobia in patients with cone disorders. Am J Ophthalmol. 2004 Apr;137(4):774-5.

PubMed ID: 
15059731

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).   

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

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

PubMed ID: 
14736794

Vars√°nyi B, Somfai GM, Lesch B, V√°mos R, Farkas A. Optical coherence tomography of the macula in congenital achromatopsia. Invest Ophthalmol Vis Sci. 2007 May;48(5):2249-53.

PubMed ID: 
14760287

Park WL, Sunness JS. Red contact lenses for alleviation of photophobia in patients with cone disorders. Am J Ophthalmol. 2004 Apr;137(4):774-5.

PubMed ID: 
15059731

Winick JD, Blundell ML, Galke BL, Salam AA, Leal SM, Karayiorgou M. Homozygosity mapping of the Achromatopsia locus in the Pingelapese. Am J Hum Genet. 1999 Jun;64(6):1679-85.

PubMed ID: 
10330355

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 17 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 17 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

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

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

Arcot Sadagopan K, Battista R, Keep RB, Capasso JE, Levin AV. Autosomal-dominant Leber Congenital Amaurosis Caused by a Heterozygous CRX Mutation in a Father and Son. Ophthalmic Genet. 2013 Oct 4. [Epub ahead of print] PubMed PMID: 24093488.

PubMed ID: 
24093488

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

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

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

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

Zernant J, Külm M, Dharmaraj S, den Hollander AI, Perrault I, Preising MN, Lorenz B, Kaplan J, Cremers FP, Maumenee I, Koenekoop RK, Allikmets R. Genotyping microarray (disease chip) for Leber congenital amaurosis: detection of modifier alleles. Invest Ophthalmol Vis Sci. 2005 Sep;46(9):3052-9.

PubMed ID: 
16123401

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

Galvin JA, Fishman GA, Stone EM, Koenekoop RK. Clinical phenotypes in carriers of Leber congenital amaurosis mutations. Ophthalmology. 2005 Feb;112(2):349-56. PubMed PMID: 15691574.

PubMed ID: 
15691574

Sergouniotis PI, Davidson AE, Mackay DS, Li Z, Yang X, Plagnol V, Moore AT, Webster AR. Recessive Mutations in KCNJ13, Encoding an Inwardly Rectifying Potassium Channel Subunit, Cause Leber Congenital Amaurosis. Am J Hum Genet. 2011 Jul 15;89(1):183-90.

PubMed ID: 
21763485

Hurler and Scheie Syndromes (MPS IH, IS, IH/S)

Clinical Characteristics

Ocular Features

Progressive corneal clouding is a major feature and appears early in life.  Intracellular accumulations of heparan and dermatan sulfate are responsible for the ground glass appearance.  However, congenital glaucoma also occurs in MPS I and must be considered as a concomitant cause of a diffusely cloudy cornea.

Abnormal storage of mucopolysaccharides has been found in all ocular tissues and in the retina leads to a pigmentary retinopathy.  The ERG may be abolished by 5 or 6 years of age.  Papilledema is often followed by optic atrophy.  Photophobia is a common symptom.  Shallow orbits give the eyes a prominent appearance.

Systemic Features

This group of lysosomal deficiency diseases is probably the most common.  MPS I is clinically heterogeneous encompassing three clinical entities: Hurler, Hurler-Scheie, and Scheie.  In terms of clinical severity, Hurler is the most severe and Scheie is the mildest.  Infants generally appear normal at birth and develop the typical coarse facial features in the first few months of life.  Physical growth often stops at about 2 years of age.  Skeletal changes of dysostosis multiplex are often seen and kyphoscoliosis is common as vertebrae become flattened.  The head is large with frontal bossing and a depressed nasal bridge.  Cranial sutures, especially the metopic and sagittal sutures, often close prematurely.  The lips are prominent and an open mouth with an enlarged tongue is characteristic.  The neck is often short.  Odontoid hypoplasia increases the risk of vertebral subluxation and cord compression.  Joints are often stiff and arthropathy eventually affects all joints.  Claw deformities of the hands and carpal tunnel syndrome are common.  Most patients are short in stature and barrel-chested.

Cardiac valves often are thickened and endocardial fibroelastosis is frequently seen.  The coronary arteries are often narrowed.  Respiratory obstructions are common and respiratory infections can be serious problems.  Hearing loss is common.

Most patients reach a maximum functional age of 2 to 4 years and then regress.  Language is limited.  Untreated, many patients die before 10 years of age.

Genetics

The Hurler/Scheie phenotypes are all the result of mutations in the IDUA gene (4p16.3).  They are inherited in an autosomal recessive pattern.  A deficiency in alpha-L-iduronidase causes three phenotypes: Hurler (607014; MPS IH), Hurler-Scheie (607015; MPS IH/S), and Scheie (607016; MPS IS) syndromes.

Treatment Options

Various treatments have had some success.  Enzyme replacement using laronidase (Aldurazyme©) has been shown to reduce organomegaly and improve motor and respiratory functions.  It has been used alone and in combination with bone marrow transplantation but therapeutic effects are greater if given to younger patients.  It does not improve skeletal defects or corneal clouding.  MRI imaging has documented improvement in CNS signs.  Gene therapy has shown promise but remains experimental.  Regular lifelong monitoring is important using a multidisciplinary approach to identify potential problems.  Joint problems may be surgically correctable with special emphasis on the need for atlanto-occipital stabilization.  Corneal transplants may be helpful in the restoration of vision in selected patients.

References

Wang RY, Cambray-Forker EJ, Ohanian K, Karlin DS, Covault KK, Schwartz PH, Abdenur JE. Treatment reduces or stabilizes brain imaging abnormalities in patients with MPS I and II. Mol Genet Metab. 2009 Dec;98(4):406-11.

PubMed ID: 
19748810

Collins ML, Traboulsi EI, Maumenee IH. Optic nerve head swelling and optic atrophy in the systemic mucopolysaccharidoses. Ophthalmology. 1990 Nov;97(11):1445-9. PubMed PMID: 2123975.

PubMed ID: 
2123975

Nowaczyk MJ, Clarke JT, Morin JD. Glaucoma as an early complication of Hurler's disease. Arch Dis Child. 1988 Sep;63(9):1091-3.

PubMed ID: 
3140740

Sanfilippo Syndrome (MPS IIIA, B, C, D)

Clinical Characteristics

Ocular Features

This form of mucopolysaccharidosis causes little or no corneal clouding.  Abnormal retinal pigmentation can be seen.

Systemic Features

Sanfilippo syndrome differs from other forms of mucopolysaccharidoses in the severity of the neurologic degeneration compared to the amount of somatic disease.  Infants usually appear healthy but developmental delay becomes evident by 2 or 3 years of age and physical growth slows.  Deterioration in mental development is progressive and seizures occur in some.  Gait and speech are impaired and by age 10 years patients have severe disabilities.  Behavioral problems including hyperactivity and aggression are often severe.

There is some hepatosplenomegaly, mild coarseness of the facial features, claw hands and mild bony changes such as biconvexity of the vertebral bodies and thick calvaria.  Hirsutism and synophrys are common.  The hair is unusually coarse.  Joints are frequently stiff and more severely affected individuals may have hearing loss.  Diarrhea is frequently a problem and most patients have some airway obstruction and are susceptible to recurrent respiratory infections.  Some patients have cardiovascular problems.

Genetics

MPS III is a lysosomal storage disease and may be caused by mutations in 1 of 4 genes that result in defective enzymes unable to break down mucopolysaccharides (glycosaminoglycans).  MPS IIIA (252900)results from a defect in the heparan sulfate sulfatase gene SGSH (17q25.3), type IIIB (252920)from a defect in the N-acetyl-alpha-D-glucosaminidase gene NAGLU (17q21), type IIIC (252930) from a defect in the acetyl-CoA:alpha-glucosaminide acetyltransferase gene HGSNAT (8p11.1), and type IIID (252940) from a defect in the N-acetylglucosamine-6-sulfatase gene GNS (12q14).  Heparan sulfate is excreted in all types.  Because of their clinical similarities these are discussed as a group in this database.  All are inherited in autosomal recessive patterns.

Treatment Options

There is no treatment for the underlying disease.  Therapy is primarily supportive.  A multidisciplinary approach with neurologists, ophthalmologists, audiologists, cardiologists, gastroenterologists, and orthopedists is most likely to result in treatments that can improve quality of life.

References

Zhao HG, Aronovich EL, Whitley CB. Genotype-phenotype correspondence in Sanfilippo syndrome type B. Am J Hum Genet. 1998 Jan;62(1):53-63.

PubMed ID: 
9443875

van de Kamp JJ, Niermeijer MF, von Figura K, Giesberts MA. Genetic heterogeneity and clinical variability in the Sanfilippo syndrome (types A, B, and C). Clin Genet. 1981 Aug;20(2):152-60.

PubMed ID: 
6796310