DiagnosisClinical DiagnosisThe form of congenital or early-infantile blindness known as Leber congenital amaurosis (LCA) was first defined by Theodor Leber in 1869 and 1871 on the basis of clinical findings [Leber 1869, Leber 1871]. While no universally agreed-upon diagnostic criteria are available, the following features are highly suggestive:Blindness or severe visual impairment presenting in infancy, frequently before age six months. Individuals with LCA usually do not achieve visual acuity better than 20/400 [Cremers et al 2002].Extinguished or severely reduced scotopic and photopic electroretinogram (ERG). Normal ERG responses rule out a diagnosis of LCA. Visual evoked responses are variable.The oculo-digital sign, characterized by poking, rubbing, and/or pressing of the eyes [Fazzi et al 2003]. The oculo-digital sign has been claimed to be virtually pathognomonic for LCA; however, it can also be seen in other syndromic forms of severe vision impairment.Family history typically consistent with autosomal recessive inheritanceIndividuals with LCA also frequently exhibit the following:Sluggish or near-absent pupillary reactions reflecting the severe retinal dysfunctionNystagmus that is pendular or roving and present in all positions of gazeHigh hyperopia (>5 diopters), which is thought to result from impaired emmetropization (the ability of the eye to accommodate to visual stimuli) as a consequence of early-onset visual impairmentPhotophobiaKeratoconus, a noninflammatory, self-limiting axial ectasia of the central cornea. Keratoconus can significantly interfere with vision in normal individuals but usually does not become a vision-limiting factor in LCA.Retinal findings. No retinal lesion is diagnostic of LCA or specific for certain genetic subtypes. Although fundus abnormalities are frequently present later in life, infants with LCA typically show either a normal fundus appearance or only subtle retinal pigment epithelial (RPE) granularity, retinal vessel attenuation and, uncommonly, various stages of macular atrophy.Of note, three more specific retinal phenotypes can be observed:Preserved para-arteriolar retinal pigment epithelium (PPRPE) in individuals with CRB1 mutations"Translucent RPE," white dots, and a peculiar star-shaped maculopathy in individuals with RPE65 mutationsA progressive macular atrophic lesion presenting in infancy or later in some individuals. Because of its sharply defined borders, this lesion has been at times called a “macular coloboma.” While it has been reported to occur with mutations in AIPL1 and CRB1, the correlation of this LCA phenotype is most prominent with mutations in NMNAT1 [Chiang et al 2012, Falk et al 2012, Koenekoop et al 2012, Perrault et al 2012].Molecular Genetic Testing Genes. Mutations in seventeen genes are known to cause Leber congenital amaurosis (LCA) (Table 1).Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Leber Congenital AmaurosisView in own windowGene Symbol
(Locus)Proportion of LCA Attributed to Mutations in This GeneTest MethodMutations DetectedTest AvailabilityGUCY2D(LCA1)6%-21%Sequence analysisSequence variants ^{1ClinicalTargeted mutation analysisSee footnote 2Deletion/duplication analysis 3Partial- and whole-gene deletion/duplication 4RPE65(LCA2)3%-16%Sequence analysisSequence variants 1ClinicalTargeted mutation analysisSee footnote 2Deletion/duplication analysis 3Partial- and whole-gene deletion/duplication 4SPATA7(LCA3)UnknownSequence analysisSequence variants 1ClinicalSequence analysis of select exons 5Sequence variants 1 in exons 5,6,11,12Targeted mutation analysisSee footnote 2Deletion/duplication analysis 3Partial- and whole-gene deletion/duplication 4AIPL1(LCA4)4%-8%Sequence analysis Sequence variants 1ClinicalSequence analysis of select exons 5Sequence variants 1 in exons 2-6 Deletion/duplication analysis 3Partial- and whole-gene deletion/duplication 4LCA5(LCA5)~1%-2%Sequence analysisSequence variants 1ClinicalSequence analysis of select exons 5Sequence variants in exons 3,4,5,7 1, 2Targeted mutation analysisSee footnote 2Deletion/duplication analysis 3Partial- and whole-gene deletion/duplicationRPGRIP1(LCA6)~5%Sequence analysis of select exonsSequence variants 1ClinicalSequence analysis of select exons 2Sequence variants 1 in selected exonsTargeted mutation analysisSee footnote 2Deletion/duplication analysis 3Partial- and whole-gene deletion/duplication 4CRX(LCA7)~3%Sequence analysisSequence variants 1ClinicalSequence analysis of select exons 2Sequence variants 1Deletion/duplication analysis 3Partial- and whole-gene deletion/duplication 4Targeted mutation analysisSee footnote 2CRB1(LCA8)UnknownSequence analysisSequence variants 1ClinicalSequence analysis of select exons 2Sequence variants 1 in selected exonsDeletion/duplication analysis 3Partial- and whole-gene deletion/duplication 6NMNAT1(LCA9)UnknownSequence analysisSequence variants 1ClinicalDeletion/duplication analysis 3Partial- and whole-gene deletion/duplication 4CEP290(LCA10)≤20%Sequence analysisSequence variants 1ClinicalSequence analysis of select exons 2Sequence variants 1 in selected exonsTargeted mutation analysis41-mutation panel 2Deletion/duplication analysis 3Partial- and whole-gene deletion/duplication 4IMPDH1(LCA11)Rare cause of dominant LCASequence analysisSequence variants 1ClinicalDeletion/duplication analysis 3Partial- and whole-gene deletion/duplication 4RD3(LCA12)UnknownSequence analysisSequence variants 1ClinicalTargeted mutation analysisSee footnote 2Deletion/duplication analysis 3Partial- and whole-gene deletion/duplication 4RDH12(LCA13)~4%Sequence analysisSequence variants 1ClinicalTargeted mutation analysisSee footnote 2Deletion/duplication analysis 3Partial- and whole-gene deletion/duplication 4LRAT
(LCA14)UnknownSequence analysisSequence variants 1ClinicalSequence analysis of select exons 2Sequence variants 1 in selected exonsTargeted mutation analysisSee footnote 2 Deletion/duplication analysis 3Partial- and whole-gene deletion/duplication 4TULP1(LCA15)UnknownSequence analysisSequence variants 1ClinicalSequence analysis of select exons 2Sequence variants 1 in exons 9,10,12,13,14Targeted mutation analysisSee footnote 2Deletion/duplication analysis 3Partial- and whole-gene deletion/duplication 4KCNJ13(LCA16)UnknownSequence analysisSequence variants 1Clinical Deletion/duplication analysis 3Partial- and whole-gene deletion/duplication 4IQCB1UnknownSequence analysisSequence variants 1Clinical 1. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected.2. Mutations in panel may vary.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.4. No deletions or duplications involving GUCY2D, AIPL1, CEP290, IMPDH1, LRAT, NMNAT1, RD3, RDH12, RPGRIP1, RPE65, SPATA7, CRX, or KCNJ13 as causative of LCA have been reported. 5. Exons sequenced may vary by laboratory.6. Whole-gene deletion reported [Stone 2007]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo establish the diagnosis in a proband. Hanein et al [2004] proposed a clinical flowchart using the presence or absence of photophobia, night blindness, hyperopia, macular/peripheral retinal abnormalities, and measurable acuity to help direct the order of genes selected for molecular studies. Multi-gene testing. Consider using a multi-gene Leber congenital amaurosis panel that includes many genes associated with LCA. These panels vary by methods used and genes included; thus, the ability of a panel to detect a causative mutation or mutations in any given individual also varies. Carrier testing for autosomal recessive LCA for relatives at-risk requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for these autosomal recessive disorders and are not at risk of developing the disorder. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersDifferent mutations within each of the LCA-associated genes are known to cause other retinal dystrophies, such as retinitis pigmentosa (RP) and cone-rod dystrophy. Sequence changes that cause LCA have therefore been considered to be at the severe end of the spectrum of retinal abnormalities and are presumed to render the protein product non-functional or absent:GUCY2D (LCA1). Mutations also cause autosomal dominant cone-rod dystrophy 6.RPE65 (LCA2). Mutations also cause autosomal recessive RP, or an attenuated form of LCA with better visual function [Morimura et al 1998, Lorenz et al 2008].AIPL1 (LCA4). Mutations also cause autosomal dominant cone-rod dystrophy and autosomal dominant juvenile RP [Sohocki et al 2000].RPGRIP1 (LCA6). Specific mutations (p.Arg827Leu and p.Ala547Ser) have been reported to cause autosomal recessive cone-rod dystrophy-13 (CORD13) in four consanguineous Pakistani families [Hameed et al 2003].CRX (LCA7). Mutations also cause autosomal dominant cone-rod dystrophy-2 (CORD2), autosomal dominant RP, and autosomal dominant LCA [Lotery et al 2000]. De novo dominant mutations of CRX have been recognized [Perrault et al 2003].CRB1 (LCA8). Mutations also cause autosomal dominant pigmented paravenous chorioretinal atrophy and autosomal recessive retinitis pigmentosa. The most common allele, p.Cys948Tyr, is found in the homozygous state only in individuals with LCA [den Hollander et al 2001, Lotery et al 2001]. Individuals with compound heterozygosity for the p.Cys948Tyr allele and a "milder" missense mutation on the other allele have RP [den Hollander et al 2001]. Less deleterious mutations of CRB1 cause RP, RP with Coats-like vasculopathy, and RP with preserved para-arteriolar RPE (PPRPE) [den Hollander et al 1999].CEP290 (LCA10). Mutations also cause a number of syndromic phenotypes (often involving abnormalities of the retina): Bardet-Biedl syndrome 14; an autosomal recessive condition characterized by rod-cone dystrophy, obesity, polydactyly, cognitive impairment, genitourinary and renal abnormalities.Joubert syndrome 5; an autosomal recessive condition characterized by brain abnormalities, hypotonia, developmental delays, and early onset retinal dystrophy.Meckel syndrome 4; an autosomal recessive condition characterized by renal cysts, CNS anomalies, hepatic abnormalities, and polydactyly. See Congenital Hepatic Fibrosis Overview.Senior-Loken syndrome 6; an autosomal recessive condition characterized by nephronophthisis and Leber congenital amaurosis. Nephronophthisis (NPHP), which manifests initially as a urine-concentrating defect and anemia before progressing to end-stage renal disease (ESRD) in childhood in most individuals [Hildebrandt & Zhou 2007, Otto et al 2008, Salomon et al 2009]. Renal ultrasound examination shows normal-size or small kidneys with increased echogenicity. Approximately 10%-20% of individuals with NPHP have central nervous system and/or ocular involvement that includes structural cerebellar and midbrain abnormalities overlapping with Joubert syndrome and related disorders (JSRD) and retinal degeneration (Senior-Løken syndrome). Locus name is NPHP6 (SLSN6). See Congenital Hepatic Fibrosis Overview.IMPDH1 (LCA11). Mutations are also associated with autosomal dominant RP.RDH12 (LCA13). In their series of unrelated individuals with LCA, Perrault et al [2004] identified RDH12 mutations only in individuals affected with "congenital severe yet progressive rod-cone dystrophy." In contrast, Janecke et al [2004] described three consanguineous Austrian kindreds with onset between ages two and four years, severe retinal dystrophy affecting both rods and cones, and progression to legal blindness between ages 18 and 25 years. The ERG was "extinguished" at the first investigation, as early as age five years.TULP1 (LCA15). Mutations also cause autosomal recessive RP.KCNJ13 (LCA16). Mutations also cause snowflake vitreoretinal degeneration.IQCB1. Mutations also cause Senior-Loken syndrome-1; an autosomal recessive condition characterized by nephronophthisis and Leber congenital amaurosis.}

Natural HistoryLeber congenital amaurosis (LCA) has retinal, ocular, and extraocular features and occasionally, systemic associations [Fazzi et al 2003].Retina. The retina may appear normal initially; later, a variety of abnormalities may develop either in isolation or combination:"Macular coloboma"; not a true coloboma, but reflecting discrete chorioretinal degeneration and atrophy centered about the fovea"Bone-spicule" intraretinal pigment migrationWidespread subretinal flecks resembling retinitis punctata albescens"Marbled" fundusDiscrete pigmented nummular lesions at the level of the retinal pigment epithelium (RPE)Optic disc abnormalities: swelling, drusen formation, and peripapillary neovascularizationOculo-digital sign. The characteristic extraocular sign in LCA is Franceschetti's oculo-digital sign, comprising three components: eye poking, pressing, and rubbing. It is not known why this behavior occurs. The major sequelum is enophthalmos, a physical defect in which the eye recedes into the orbit, presumably from atrophy of orbital fat. Keratoconus has been said to result from the repetitive trauma to the cornea, but others have suggested that this may be a feature of LCA itself.Intellectual disability. Rarely, LCA is seen in association with neurodevelopmental delay, intellectual disability, and oculomotor apraxia-type behavior. However, many if not most of the historical reports date to earlier studies in which systemic phenocopies of LCA (see Differential Diagnosis) were not considered or ruled out. Still, some studies suggest that as many as 20% of children with LCA without associated anomalies develop intellectual disability [Schuil et al 1998]. Whether these individuals represent undiagnosed systemic disorders or a genetic subtype of LCA is unknown. Prior to the identification of CEP290, none of the molecularly defined types of LCA was shown to be associated with intellectual disability or neurodevelopmental degeneration. Perrault et al [2007] reported a subset of individuals (15%) with CEP290-related LCA who have intellectual disability or autistic features, but no other extraretinal manifestations. Two of the six individuals in the study with intellectual disability or autism were later reclassified as having Joubert syndrome based on the presence of the “molar tooth” sign on MRI. In others, the MRI was apparently normal. Visual impairment. Profound visual impairment is usually present from birth. One third of individuals with LCA have no perception of light. The visual impairment is generally stable or very slowly progressive. Occasionally in the early stages, a mild degree of visual improvement is observed. This improvement has been attributed to development of the central visual pathways rather than retinal maturation. Sustained improvements in acuity, visual field, and electrophysiologic measurements have been reported in one individual with a c.529delG mutation in CRX [Koenekoop et al 2002b]. Loss of visual acuity typically results from keratoconus, cataract, or evolving macular lesions.Carriers. Carriers (heterozygotes) are usually asymptomatic; however, some heterozygotes for GUCY2D mutations have been shown to have mild cone dysfunction measured by decreased cone responses on electroretinogram [Koenekoop et al 2002a]. However, this is not associated with any findings on ophthalmologic examination and does not appear to interfere with vision.

Genotype-Phenotype CorrelationsA number of genotype-phenotype correlations appear to have emerged.GUCY2D (LCA1). Mutations in GUCY2D, which encodes retinal guanylyl cyclase 1 (RetGC), have been associated with a congenital severe cone-rod dystrophy characterized by photophobia, high hyperopia, and poor but stable vision with no visual improvement [Perrault et al 1999, Lorenz et al 2000, Hanein et al 2004]. However, Perrault et al [2005] described a man with early-onset RP resulting from the homozygous 4-bp mutation p.[His1079Glnfs*54]+[His1079Glnfs*54] in GUCY2D. The man has night blindness, peripheral vision loss, and preservation of central vision typical of RP. Unlike most null mutations described in GUCY2D to date, p.His1079Glnfs*54 is predicted to result in an elongation of the protein and residual protein function [Perrault et al 2005].RPE65 (LCA2). Mutations in RPE65 have been associated with night blindness, some transient improvement in vision, and eventual progressive visual loss [Perrault et al 1999, Dharmaraj et al 2000b]. Lorenz found that four individuals with LCA and RPE65 mutations had measurable visual acuity at age six to ten years, despite severe visual impairment from infancy and nystagmus in three of the four [Lorenz et al 2000]. Photophobia was not a feature and all individuals had preservation of measurable peripheral vision. Rod ERG responses were undetectable, whereas cone ERG responses were detectable in early childhood.Paunescu et al [2005] presented detailed follow-up data on three adult siblings with LCA suggesting that photophobia and progressive visual loss occur with age. Using a genotyping microarray, Zernant et al [2005] found that only five of 69 individuals with LCA (7%) with detectable mutations had an RPE65 genotype. This detection rate, lower than previous studies would predict, suggests that allelic variation in RPE65 may be more highly associated with early-onset severe retinal dystrophy than with classic LCA [Authors, personal observation].Individuals with mutations in RPE65 may also demonstrate "translucent RPE," white dots, and a peculiar star-shaped maculopathy [Weleber et al 2011]. AIPL1 (LCA4). Dharmaraj et al [2004] studied 303 individuals with LCA and found that 26 probands (8.5% of their cohort) harbored homozygous or heterozygous mutations in AIPL1. Fifty-four percent of these individuals (14/26) had at least one allele with the p.Trp278* mutation. The authors described the phenotype of LCA in these individuals and compared them to those observed and reported with LCA from mutations of GUCY2D, RPE65, CRX, CRB1, and RPGRIP1. The phenotype of LCA in individuals with AIPL1 mutations was found to be relatively severe, with maculopathy and marked bone-spicule pigmentary retinopathy in most and keratoconus and cataract in a large subset. The authors conclude that the visual loss associated with mutation of AIPL1 is similar in severity to that observed with mutation of GUCY2D. Pennesi et al [2011] reported a unique electroretinogram phenotype characterized by slow insensitive scotopic responses (SISR), which if present on testing may suggest this genetic form of LCA.LCA5 (LCA5). In the Old River Brethren family originally linked to LCA5, severe visual dysfunction, nystagmus, the oculodigital sign, and a normal fundus were noted in all affected individuals in infancy. High hyperopia and attenuated retinal vasculature developed over time, and ERG recordings were severely reduced [Dharmaraj et al 2000a]. Den Hollander et al [2007] defined mutations within LCA5 in multiple unrelated families, all of whom presented with a similar, severe congenital retinal dystrophy. One of the families, reported earlier by Mohamed et al [2003], developed macular abnormalities including macular coloboma and atrophy. Renal, neurologic, cognitive, and hepatic functions have been normal across all affected families. Individuals with LCA5 have been shown to have spared photoreceptors, mostly in the macular region, that are adjacent to disorganized retina [Jacobson et al 2009]. RPGRIP1 (LCA6). Hanein et al [2004] described the following features as characteristic of RPGRIP1 mutations: early photophobia, hypermetropia less than +7 diopters, and visual acuity in the range of 20/400 to count fingers (CF). In follow-up of individuals with LCA, Galvin et al [2005] found that visual acuity in children with mutations in RPGRIP frequently progresses to light perception (LP) or no light perception (NLP) within the first decade of life.CRX (LCA7). Mutations of CRX have also been reported to be associated with stable vision [Dharmaraj et al 2000b] or even some modest improvement [Koenekoop et al 2002b]. Single or double base-pair deletions of the gene account for only the dominant forms of LCA, as a result of either an inherited dominant mutation or a de novo mutational event [Sohocki et al 1998, Rivolta et al 2001, Tzekov et al 2001, Perrault et al 2003].CRB1 (LCA8). Night blindness is a constant feature of LCA resulting from CRB1 mutations. Jacobson et al [2003] found thick unlaminated retinas by optical coherence tomography (OCT) in individuals with LCA and CRB1 defects. Although some individuals with RP resulting from CRB1 mutations have the fundus appearance of preserved para-arteriolar RPE (PPRPE), no individuals with LCA resulting from CRB1 mutations have yet been reported to have PPRPE [den Hollander et al 2001].CEP290 (LCA10). Two independent series of individuals with CEP290 mutations [den Hollander et al 2006, Perrault et al 2007] confirm a “typical” ophthalmologic LCA phenotype consisting of a severe infantile-onset cone-rod dystrophy with high hyperopia and severe ERG abnormalities. In addition, each series described a single individual with a reticular pigment epithelium in the peripheral retina with multiple white dots. This specific phenotype has not been reported with the other LCA-associated genes. Extraretinal findings were described in a subset of individuals in Perrault’s study, and primarily included hypotonia and ataxia or intellectual disability and autistic behaviors. In fact, six of 40 families segregating CEP290 mutations were reported to have at least one affected individual with intellectual disability or autism. Two of those individuals were later reclassified as having Joubert syndrome on the basis of the classic “molar tooth” sign on MRI. Interestingly, a high degree of intrafamilial variability was observed with respect to the presence or absence of intellectual disability, leading the authors to suggest the possibility of a third allele or modifier gene in the development of cognitive disability in this subtype of LCA.IMPDH1 (LCA11). Bowne et al [2006] described heterozygous, apparently de novo IMPDH1 mutations in two unrelated individuals with a diagnosis of LCA. IMPDH1 is a gene previously known to be associated with autosomal dominant retinitis pigmentosa. The clinical description of one of the individuals reported by Bowne et al [2006] fits the classic LCA phenotype; the other appears to have an early-onset retinal dystrophy better fitting the diagnosis of SECORD (see Differential Diagnosis). Additional studies must be undertaken to assess the prevalence of IMPDH1 mutations in the LCA population.RDH12 (LCA13). In a further study of the individuals studied by Hanein et al [2004], Perrault et al [2004] identified 11 distinct mutations of RDH12 in 8/44 individuals with LCA characterized by congenital severe progressive rod-cone dystrophy. All eight with RDH12 mutations had a clinical course similar to that of individuals with RPE65 mutations: mild or absent hyperopia, transient improvement of visual acuity, and eventual macular atrophy with severe disease progression. Loss of visual acuity, however, occurred at an earlier age in those with RDH12 mutations than in those with RPE65 mutations. No RDH12 mutations were observed in persons with LCA presenting with the congenital stationary cone-rod dystrophy form of the disease.IQCB1. Individuals with mutations in IQCB1 often have greater loss of rod function than loss of cone function. All newly diagnosed individuals with LCA should have testing for mutations in this gene and, if found, should undergo careful monitoring of renal function. Keratoconus has been reported to occur in individuals with specific mutations in the CRB1 and AIPL1 genes [Hameed et al 2000]. Photophobia and night blindness. Hanein et al [2004] performed molecular screening on 179 unrelated individuals with LCA and reported the genotype-phenotype correlations on 85 who were found to harbor mutations on one or both alleles in one of seven LCA-associated genes. Frequencies of mutations in each gene were as follows: GUCY2D. 21.2% (38/179 families) CRB1. 10% (18/179) RPE65. 6.1% (11/179)RPGRIP1. 4.5% (8/179) AIPL1. 3.4% (6/179)TULP1. 1.7% (3/179)CRX. 0.6% (1/179)The authors found that the presence of photophobia or night blindness at ages one and two years distinguished two groups:Those with photophobia constituted a cone-rod dystrophy class and were found to have mutations of GUCY2D, RPGRIP1, and AIPL1.Those with night blindness constituted a rod-cone dystrophy class and were found to have mutations of CRB1, RPE65, TULP1, and CRX.

Differential DiagnosisLeber congenital amaurosis (LCA) typically presents as an isolated ocular anomaly without systemic involvement. Occasionally, the same or similar retinal findings can be seen as part of a systemic disorder. Systemic abnormalities including renal anomalies, deafness, skeletal abnormalities, microcephaly, neurodevelopmental delay, intellectual disability, or oculomotor apraxia should alert the clinician to consider syndromic disorders associated with early-onset retinal dystrophy. Systemic disorders to consider include the following:Senior-Loken syndrome (OMIM 266900) comprises:Juvenile nephronophthisis (medullary cystic renal disease) andEarly-onset retinal dystrophy.Conorenal syndrome (OMIM 266920) comprises:Cone-shaped digital epiphyses, Cerebellar hypoplasia, and Early-onset retinal dystrophy.Joubert syndrome (OMIM 243910) comprises: Nephronophthisis (a juvenile-onset cystic kidney disease),Hypoplasia of the cerebellar vermis,Early-onset retinal dystrophy, and Either or both of the following:Episodic hyperpnea and/or apnea Atypical eye movementsPeroxisomal biogenesis disorders, Zellweger syndrome spectrum is a continuum of three phenotypes described before the biochemical and molecular bases of the disorders were known: Zellweger syndrome (ZS) (OMIM 214100)Neonatal adrenoleukodystrophy (NALD) (OMIM 202370)Infantile Refsum disease (IRD) (OMIM 266510)ZS is the most severe and IRD the least severe. Children with ZS have retinal dystrophy, sensorineural hearing loss, developmental delay with hypotonia, and liver dysfunction; they usually die during the first year of life. The clinical courses of NALD and IRD are variable. Retinal degeneration is associated with congenital, liver, and renal abnormalities.Infantile neuronal ceroid-lipofuscinosis (Santavuori-Haltia disease) (CLN1). Affected children are normal at birth but develop retinal vision impairment, loss of milestones, and progressive microcephaly by age six to 12 months. Virtual blindness ensues by age two years, seizures and progressive mental deterioration develop, and death generally occurs between ages three and 11 years [Weleber 1998, Mole & Williams 2010]. Affected children have characteristic electronegative electroretinograms early in the course of disease [Weleber et al 2004]. The diagnosis can be established by assay of the enzyme palmitoyl-protein thioesterase 1 (PPT1), and/or identification of the causative mutations within CLN1, the gene encoding PPT1 [Mole & Williams 2010].OtherIn addition, an LCA-like retinal dystrophy has been documented in individuals with abetalipoproteinemia (OMIM 200100), hyperthreoninemia (OMIM 273770), and disorders of mitochondrial dysfunction (see Mitochondrial Disorders Overview). Common clinical features of mitochondrial disease include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. The central nervous system findings are often fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity.CABP4 mutations most often cause autosomal recessive congenital stationary night blindness, CSNB2. CABP4, located at 11q13.1, encodes calcium-binding protein 4, which plays a role in bipolar cell signaling. Calcium-binding protein 4 is localized intracellularly to the synaptic terminals of photoreceptors and is essential for neurotransmission to the bipolar cells. Loss of function results in three seemingly distinct phenotypes—autosomal congenital stationary night blindness (CSNB2), associated with alleles c.370C>T (p.Arg124Cys) and c.800_801delAG (p.Glu267fs*91) [Zeitz et al 2006], a cone-rod dystrophy associated with c.646C>T (p.Arg216*) [Littink et al 2009], and Leber congenital amaurosis in a single Bedouin family associated with c.81_82insA (p.Pro28Thrfs*44) in a homozygous state. This mutation is considered a true null allele [Aldahmesh et al 2010]. In a child presenting without systemic involvement, other inherited retinal dystrophies may be considered. Compared to LCA, early-onset retinitis pigmentosa (RP) has a later age of onset, better preservation of central visual acuity, and no nystagmus. The electroretinogram (ERG) is useful in distinguishing between LCA and RP: in the early stages of RP, the photopic component of the ERG typically shows some degree of sparing, while in LCA both the photopic and scotopic ERG are profoundly abnormal.An intermediate category of retinal disease, presenting in early childhood with night blindness, variable degrees of central vision loss, and a severely abnormal but recordable ERG is now emerging. The authors favor the term "SECORD" (severe early-childhood onset retinal dystrophy) to describe this entity, although terms such as early-onset severe retinal dystrophy (EOSRD) and early-onset severe RP have been variably used in the literature. SECORD is distinguished from LCA primarily by the age of onset and severity: the diagnosis of LCA should be reserved for infants presenting before age one year with nystagmus, severely impaired vision, and an unrecordable or nearly unrecordable ERG.Other retinal conditions that can be confused with Leber congenital amaurosis include congenital retinal disorders that are typically stationary, such as achromatopsia and congenital stationary night-blindness, which can usually be easily distinguished by characteristic patterns of electroretinographic abnormality. However, rare combinations of mutant alleles for these disorders can lead to progressive disease.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Leber congenital amaurosis (LCA), the following evaluations are recommended:Electroretinogram (ERG) to confirm the diagnosis and to assess retinal functionClinical genetic assessment to evaluate for the presence of systemic abnormalitiesMedical genetics consultationTreatment of ManifestationsExcept for RPE65-related LCA (see Therapies Under Investigation), no substantial treatment or cure for LCA exists, and, thus, care is supportive. Parents should be referred to programs for the visually impaired child within their state or locality.Affected individuals benefit from correction of refractive error, use of low-vision aids when possible, and optimal access to educational and work-related opportunities.Prevention of Secondary ComplicationsChildren should be discouraged from repeatedly poking and pressing on their eyes, although attempts to alter such behavior are not always successful.SurveillanceAffected individuals should be periodically seen for assessment of vision, trials of correction for refractive error, and when residual vision is present, assessment of the presence of amblyopia, glaucoma, or cataract.Rarely, vision appears to improve beyond expectations; in such cases, a repeat ERG is indicated.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationIn a naturally occurring Briard dog model of LCA resulting from mutations in RPE65, gene therapy utilizing AAV-mediated RPE65 was shown to restore visual function, an effect that has been documented to last for more than five years [Acland et al 2005]. More than 50 dogs have now been treated, with sustained success in 95% of treated eyes. The results of three simultaneous Phase I clinical treatment trials of AAV-mediated RPE65 gene therapy in humans were recently reported [Bainbridge et al 2008, Cideciyan et al 2008, Hauswirth et al 2008, Maguire et al 2008]. Initial results demonstrated safety, and showed slight improvement in vision in both bright and dim light.Clinical and laboratory studies suggest that persons with CEP290-related LCA may also be good candidates for gene therapy. Cideciyan et al [2008] studied the retinal architecture of CEP290-mutant mice and humans. In the mouse retina, dramatic retinal remodeling was evident by age four to six weeks. Cross-sectional imaging of affected human retinas performed using optical coherence tomography (OCT) indicated preservation of foveal cones. The relative sparing of foveal cone cells, despite severe visual dysfunction, suggests an opportunity for cell rescue.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Leber Congenital Amaurosis: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDIQCB13q13​.33IQ calmodulin-binding motif-containing protein 1IQCB1 @ LOVDIQCB1LCA1GUCY2D17p13​.1Retinal guanylyl cyclase 1Retina International Mutations of the Retinal Guanylate Cyclase Gene and the Retinal Guanylate Cyclase-activating Protein GeneGUCY2DLCA2RPE651p31​.3-p31.2Retinoid isomerohydrolaseRetina International Mutations of the RPE65 GeneRPE65LCA3SPATA714q31​.3Spermatogenesis-associated protein 7SPATA7 @ LOVDSPATA7LCA4AIPL117p13​.2Aryl-hydrocarbon-interacting protein-like 1Retina International Mutations of the Aryl Hydrocarbon Receptor-interacting Protein-like 1 (AIPL1)AIPL1LCA5LCA56q14​.1LebercilinLCA5 homepage - Mendelian genesLCA5LCA6RPGRIP114q11​.2X-linked retinitis pigmentosa GTPase regulator-interacting protein 1Retina International Mutations of the Retinitis Pigmentosa GTPase Regulator Interacting Protein Gene (RPGRIP)RPGRIP1LCA7CRX19q13​.33Cone-rod homeobox proteinRetina International Mutations of the Cone Rod Homeobox GeneCRXLCA8CRB11q31​.3Crumbs homolog 1Retina International Mutations of the Human Crumbs Homologue 1 (CRB1)CRB1LCA9NMNAT11p36​.22Nicotinamide mononucleotide adenylyltransferase 1 NMNAT1LCA10CEP29012q21​.32Centrosomal protein of 290 kDaFinnish Disease DatabaseCEP290LCA11IMPDH17q32​.1Inosine-5'-monophosphate dehydrogenase 1Retina International Mutations of the Inosine Monophosphate DehydrogenaseType 1 Gene (IMPDH1)IMPDH1LCA12RD31q32​.3Protein RD3RD3 @ LOVDRD3LCA13RDH1214q24​.1Retinol dehydrogenase 12RDH12 @ LOVDRDH12LCA14LRAT4q32​.1Lecithin retinol acyltransferaseRetina International Mutations of the Lecithin Retinol Acyltransferase Gene (LRAT)LRATLCA15TULP16p21​.31Tubby-related protein 1Retina International Mutations of the Tubby-like Protein 1 GeneTULP1LCA16KCNJ132q37​.1Inward rectifier potassium channel 13KCNJ13 @ LOVDKCNJ13Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Leber Congenital Amaurosis (View All in OMIM) View in own window 146690IMP DEHYDROGENASE 1; IMPDH1 180040RETINAL DEGENERATION 3, MOUSE, HOMOLOG OF; RD3 180069RETINAL PIGMENT EPITHELIUM-SPECIFIC PROTEIN, 65-KD; RPE65 204000LEBER CONGENITAL AMAUROSIS 1; LCA1 204100LEBER CONGENITAL AMAUROSIS 2; LCA2 600179GUANYLATE CYCLASE 2D, MEMBRANE; GUCY2D 602225CONE-ROD HOMEOBOX-CONTAINING GENE; CRX 603208POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 13; KCNJ13 604210CRUMBS, DROSOPHILA, HOMOLOG OF, 1; CRB1 604232LEBER CONGENITAL AMAUROSIS 3; LCA3 604392ARYLHYDROCARBON-INTERACTING RECEPTOR PROTEIN-LIKE 1; AIPL1 604393LEBER CONGENITAL AMAUROSIS 4; LCA4 604537LEBER CONGENITAL AMAUROSIS 5; LCA5 604863LECITHIN RETINOL ACYLTRANSFERASE; LRAT 605446RETINITIS PIGMENTOSA GTPase REGULATOR-INTERACTING PROTEIN; RPGRIP1 608553LEBER CONGENITAL AMAUROSIS 9; LCA9 608700NICOTINAMIDE NUCLEOTIDE ADENYLYLTRANSFERASE 1; NMNAT1 608830RETINOL DEHYDROGENASE 12; RDH12 609237IQ MOTIF-CONTAINING PROTEIN B1; IQCB1 609254SENIOR-LOKEN SYNDROME 5; SLSN5 610142CENTROSOMAL PROTEIN, 290-KD; CEP290 610612LEBER CONGENITAL AMAUROSIS 12; LCA12 611408LCA5 GENE; LCA5 611755LEBER CONGENITAL AMAUROSIS 10; LCA10 612712LEBER CONGENITAL AMAUROSIS 13; LCA13 613341LEBER CONGENITAL AMAUROSIS 14; LCA14 613843LEBER CONGENITAL AMAUROSIS 15; LCA15 614186LEBER CONGENITAL AMAUROSIS 16; LCA16GUCY2D (LCA1)Normal allelic variants. GUCY2D has 20 exons.Pathologic allelic variants. See Table A.Table 2. GUCY2D Pathologic Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.3233-3236dup
(4-bp insertion)p.His1079Glnfs*54NM_000180​.3
NP_000171​.1See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. Retinal guanylyl cyclase 1 (retGC-1), a transmembrane protein located in the photoreceptor outer segments, is critical in the recovery process of the phototransduction cascade.Abnormal gene product. Most mutations result in, or predict, truncation of the protein and complete loss of function. Complete loss of function of retGC-1 catalytic activity from mutations in GUCY2D consistently results in LCA [Rozet et al 2001]. Pathologic study of the eyes of a 33-week aborted fetus disclosed cell loss of the outer nuclear layer, decreased immunolabeling of phototransduction proteins, and aberrant synaptic and inner retinal organization, suggesting that pathophysiologic events are well established prior to birth [Porto et al 2002]. Clinicopathologic correlation in an 11½-year-old affected subject disclosed retention of substantial numbers of cones and rods in the macula and far periphery, portending well for therapeutic intervention at this age [Milam et al 2003].RPE65 (LCA2)Normal allelic variants. RPE65 has 14 exons.Pathologic allelic variants. See Table A.Normal gene product. Retinal pigment epithelium-specific 65-kd protein forms a complex with LRAT to act as the isomerolhydrolase in the regeneration of the visual pigment, vitamin A [Redmond et al 2005].Abnormal gene product. In the absence of the protein encoded for by RPE65, isomerization of all-trans retinal to 11-cis retinal in the retinal pigment epithelium is inhibited.SPATA7 (LCA3)Normal allelic variants. SPATA7 has at least 12 exons.Pathologic allelic variants. Wang et al [2009] found a homozygous 322C>T transition in exon 5 that resulted in a (p.Arg108*) substitution that segregated with disease in a Saudi Arabian family and was present also in a Dutch patient with LCA. Other sequence changes include homozygosity for different truncating mutations: c.1183C>T transition in exon 11, resulting in an p.Arg395* substitution, and 1-bp duplication (c.960dupA) in exon 8, resulting in a frameshift. LCA with a more severe phenotype was seen with nonsense mutations involving the middle of the SPATA7 coding region, whereas homozygosity for mutations in the last twoexons of SPATA7 – including the p.Arg395* in exon 11 and a 1-bp deletion (c.1395delA) in exon 12 — were associated with juvenile RP. See Table 3.Table 3. SPATA7 Pathologic Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide Change
(Alias ¹) Protein Amino Acid Change
(Alias ¹)Reference Sequencesc.322C>Tp.Arg108*NM_018418​.3
NP_060888​.2 c.960dupA
(961dupA)p.Pro321Thrfs*6
(Pro321Thrfs*326)c.1183C>Tp.Arg395*c.1395delA
(1546delA)p.Gln465Hisfs*41
(Q465fs*505)See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. The gene encodes a 599-amino acid protein that includes several DNA-binding sites and three phosphorylation sites. Human and rat protein have 77% sequence identity. Expression in mouse is in the testis, where it localizes to primary spermatocytes, and in several layers of the retina. Abnormal gene product. How the abnormal gene product results in disease is not known. AIPL1 (LCA4)Normal allelic variants. AIPL1 has six exons.Pathologic allelic variants. The majority of mutations result in a null genotype. The most frequent allele, p.Trp278*, probably represents a founder effect in the Pakistani population. See Table A.Table 4. AIPL1 Pathologic Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.589G>Cp.Ala197ProNM_014336​.3
NP_055151​.3c.617T>Ap.Ile206Asnc.715T>Cp.Cys239Argc.784G>Ap.Gly262Serc.834G>Ap.Trp278*c.905G>Tp.Arg302Leuc.1126C>Tp.Pro376SerSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. The role of aryl-hydrocarbon interacting protein-like 1 (AIPL1) has yet to be defined, although it may act as a molecular chaperone. AIPL1 is expressed in adult retina only in rods, but expression coincides with both rod and cone photoreceptors during fetal development and AIPL1 may be essential for the normal development of both photoreceptor types [van der Spuy et al 2003].Abnormal gene product. Certain mutations of AIPL1 (p.Trp278*, p.Ala197Pro, p.Cys239Arg), but not others (e.g., p.Ile206Asn, p.Gly262Ser, p.Arg302Leu, p.Pro376Ser), abolish an interaction with NEDD8 ultimate buster-1 (encoded by NUB1), which is an inducible protein that recruits ubiquitin-like proteins to the proteasome for degradation [Kanaya et al 2004]. The loss of the AIPL1 binding site that supports this interaction has been suggested to contribute to the pathogenesis of LCA in these cases [Kanaya et al 2004]. Clinicopathologic correlation of a 22-year-old subject with mutation of AIPL1 and LCA demonstrated almost total loss of photoreceptors, retinal gliosis, decreased ganglion cells, increased vacuolizations of the nerve fiber layer, and unusual vascular morphology [Heegaard et al 2003].LCA5 (LCA5)Normal allelic variants. The gene has nine exons and two normal splice variants.Pathologic allelic variants. den Hollander et al [2007] reported three Pakistani families with a shared homozygous haplotype. These families had a homozygous c.1151delC mutation in exon 6 that results in a frameshift mutation. Three other mutations were found—a homozygous 1-bp duplication (c.1476dupA) in exon 9, a homozygous c.835C>T transition in exon 5, and a 1,598-bp deletion that encompassed 1, 077 bp of the promoter region and non-coding exon 1 (g.(-19612)-(-18015)del1598) [den Hollander et al 2007]. See Table 5.Table 5. LCA5 Pathologic Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide Change Protein Amino Acid ChangeReference Sequencesc.835C>Tp.Gln279*NM_181714​.3
NP_859065​.2c.1151delCp.Pro384Glnfs*18c.1476dupAp.Pro493Thrfs*2g.(-19612)-(-18015)del1598 See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. The normal gene product, lebercilin, is a 697-amino acid protein that contains four coiled-coil domains and is expressed in adult retina, testis, kidney, and heart, and in fetal eye, cochlea, and brain. In adult eye, the expression was limited to photoreceptors. In mouse and rat, lebercelin is localized to the ciliary axoneme in ciliated lines; in mouse and rat retina, it is located between outer and inner segments of the photoreceptor layer. In human kidney cells, lebercilin was found to interact with 24 ciliary body proteins, including cytoplasmic dynein, nucleophosmin, nucleolin, 14-3-3-epsilon, and HSP70. Thus, lebercilin appears to play a role in ciliary function.Abnormal gene product. The precise nature of the effect of mutations on gene function is unknown.RPGRIP1 (LCA6)Normal allelic variants. RPGRIP1 has 24 exons.Pathologic allelic variants. See Table A.Table 6. RPGRIP1 Pathologic Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.1639G>Tp.Ala547SerNM_020366​.3
NP_065099​.3c.2480G>Tp.Arg827LeuSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. Expression of X-linked retinitis pigmentosa GTPase regulator (RPGR)-interacting protein-1 is confined to the rod and cone retinal photoreceptor, where it localizes to the connecting cilium, is presumed to anchor RPGR in the photoreceptor cilium, and appears to be required for disk morphogenesis, putatively by regulating actin cytoskeleton dynamics [Zhao et al 2003].Abnormal gene product. Most mutations result in truncation of the protein and complete loss of function.CRX (LCA7)Normal allelic variants. CRX has three exons.Pathologic allelic variants. See Table 7, Table A.Table 7. CRX Pathologic Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide Change Protein Amino Acid ChangeReference Sequencesc.529delGp.Ala177Leufs*10NM_000554​.4
NP_000545​.1See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. Cone-rod homeobox protein is a transcription factor essential for the elongation of photoreceptor outer segments and the phototransduction cascade.Abnormal gene product. The C-terminal region of CRX, between amino acids 200 and 284, is essential for CRX-mediated transcriptional activation. CRX mutations may lead to human photoreceptor degeneration by impairing CRX-mediated transcriptional regulation of the photoreceptor genes [Chen et al 2002].CRB1 (LCA8)Normal allelic variants. CRB1 has 12 exons.Pathologic allelic variants. The most common allele, observed in 20% of individuals with LCA, is p.Cys948Tyr. See Table 8.Table 8. CRB1 Pathologic Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.2843G>Ap.Cys948TyrNM_201253​.1
NP_957705​.1See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. CRB1 encodes a protein (crumbs homolog) thought to play a role in determining and maintaining photoreceptor architecture.Abnormal gene product. Mutant CRB1 protein may disturb the development of normal human retinal organization by interrupting naturally occurring apoptosis [Jacobson et al 2003].NMNAT1 (LCA9)Normal allelic variants. NMNAT1 has four exons. The LCA9 locus was associated originally with a single consanguineous Pakistani family with LCA. Four papers published in Nature Genetics 2012 report the discovery of NMNAT1 as the gene in which mutation causes LCA9 [Chiang et al 2012, Falk et al 2012, Koenekoop et al 2012, Perrault et al 2012].Pathologic allelic variants. The most common allele in individuals with LCA9, observed with an allele frequency estimated at 0.001, is p.Glu257Lys [Chiang et al 2012]. See Table 9.Table 9. NMNAT1 Pathologic Allelic Variants Discussed in This GeneReviewView in own windowNucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.769G>Ap.Glu257LysNM_022787​.3
NP_073624​.2 See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. NMNAT1 encodes the nuclear isoform of nicotinamide mononucleotide adenylytransferase, which is the rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD(+) biosynthesis [Emanuelli et al 2001]. This enzyme is implicated in the protection against axonal degeneration [Araki et al 2004]. Abnormal gene product. Mutant NMNAT1 protein disturbs enzymatic activity but the exact mechanism of disease within retinal cells has yet to be defined. [Falk et al 2012].CEP290 (LCA10)Normal allelic variants. CEP290 has 54 exons.Pathologic allelic variants. The most frequent sequence variant is c.2991+1655A>G, an intronic donor splice site mutation that inserts a cryptic exon in the CEP290 messenger RNA. To date, all individuals with LCA resulting from CEP290 have had at least one c.2991+1655A>G mutation identified [den Hollander et al 2006]. Heterozygous nonsense, frameshift, and splice-site mutations have been identified on the remaining allele.Table 10. CEP290 Pathologic Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.2991+1655A>Gp.Cys998* ^{1NM_025114​.3
NP_079390​.3See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. The aberrant splice product was reported in den Hollander et al [2006].Normal gene product. Centrosomal protein Cep290 (nephrocystin-6, NPHP6) is a centrosomal protein with probable ciliary function. The greatest concentration of NPHP6 occurs in the connecting cilium of mouse photoreceptor cells. NPHP6 putatively interacts with the protein retinitis pigmentosa GTPase regulator (RPGR), deficiency of which is the leading cause of X-linked retinitis pigmentosa (RP), and nephrocystin-5, which is mutated in nephronophthisis type 5. NPHP6 also interacts with and activates ATF4-mediated transcription [Sayer et al 2006].Abnormal gene product. Although the common CEP290 c.2991+1655A>G mutation leads to aberrant splicing, early studies indicate that this mutation may allow low levels of nephrocystin-6 to remain intact. den Hollander hypothesized that low residual nephrocystin-6 levels may be sufficient for normal cerebellar and renal function but insufficient for normal photoreceptor function [den Hollander et al 2006]. Subsequent research reported by Perrault et al [2007] challenges this hypothesis: in their series, nine patients with LCA were found to harbor two null alleles in CEP290. Of those, six had normal cognitive development and no evidence of the pathognomonic “molar tooth sign” indicative of Joubert syndrome on MRI. IMPDH1} (LCA11)Normal allelic variants. IMPDH1 has 14 exons.Pathologic allelic variants. See Table A.Normal gene product. IMPDH1 catalyzes the formation of xanthine monophosphate (XMP) from IMP. In the purine de novo synthetic pathway, IMP dehydrogenase is positioned at the branch point in the synthesis of adenine and guanine nucleotides and is thus the rate-limiting enzyme in the de novo synthesis of guanine nucleotides (OMIM 146690). Abnormal gene product. Inhibition of cellular IMP dehydrogenase activity results in an abrupt cessation of DNA synthesis and a cell cycle block at the G1-S interface.RD3 (LCA12)Normal allelic variants. The gene contains at least three exons. Alternately spliced transcripts that lack exon 2 or are altered at the 5’ exons may exist.Pathologic allelic variants. In two sibs with LCA, Friedman et al [2006] found a homozygous mutation c.296+1G>A in the invariant G nucleotide of the RD3 exon 2 donor splice site that would predict truncation of the protein.Table 11. RD3 Pathologic Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide Change Protein Amino Acid ChangeReference Sequencesc.296+1G>A--NM_183059​.2
NP_898882​.1 See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. The gene product is a 195-amino acid protein that contains an N-terminal mitochondrial targeting signal, a possible coiled-coil domain, and two potential phosphorylation sites. PCR analysis in human tissues detected expression only in retina. [Friedman et al 2006] suggested that RD3 is part of a subnuclear protein involved in transcription and splicing.Abnormal gene product. Nothing definitive is known about the way mutations in this gene produce disease.RDH12 (LCA13)Normal allelic variants. RDH12 has nine exons.Pathologic allelic variants. Mutations may be nonsense, missense, splice-site, or frameshift. The most frequent sequence variant is p.Ala269Glyfs*2, a frameshift deletion in exon 6 [Perrault et al 2004]. See Table 12, Table A.Table 12. RDH12 Pathologic Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.806_810delCCCTGp.Ala269Glyfs*2NM_152443​.2
NP_689656​.2See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. Retinol dehydrogenase 12 (RDH12) is a photoreceptor-specific enzyme involved in all-trans- and cis-retinol transformations, critical for the mediation of vision. RDH12 may be the key enzyme in the formation of 11-cis-retinal from 11-cis-retinol during regeneration of the cone visual pigments [McBee et al 2001, Haeseleer et al 2002].Abnormal gene product. Most RDH12 mutations result in reduced expression and activity of the retinal dehydrogenase 12 enzyme, which disrupts the cycle of synthesis of the visual pigment chromophore, 11-cis-retinal, from 11-trans-retinal [Thompson et al 2005].LRAT (LCA14)Normal allelic variants. LRAT has three exons (NM_004744.3).Pathologic allelic variants. Reported mutations include missense, splicing, small deletions, and small indels.Normal gene product. . The protein encoded by this gene has 230 amino acids and is a microsomal enzyme that catalyzes the esterification of all-trans-retinol into all-trans-retinyl ester, an essential reaction for the retinoid cycle in visual system and vitamin A status in liver. [provided by RefSeq, Jul 2008]Abnormal gene product. Mutations in this gene result in decreased enzymatic activity [Thompson et al 2001] TULP1 (LCA15)Normal allelic variants. TULP1 has 15 exons (NM_003322.3).Pathologic allelic variants. Reported mutations include missense, nonsense, splicing, small deletions, small insertions, and gross deletions. Normal gene product. The protein encoded by this gene has 542 amino acids and is a member of the tubby-like gene family (TULPs). It plays an important role in protein transport from the photoreceptor inner segment (IS) to the outer segment (OS) TULP1 is expressed exclusively in photoreceptors Abnormal gene product. Tulp1-/- mouse models suggest mutations in this gene result in abnormal protein localization within the cell. [Hagstrom et al 2012]KCNJ13 (LCA16)Normal allelic variants. KCNJ13 has three exons.Pathologic allelic variants. Missense and nonsense mutations have been reported. Normal gene product. The protein encoded by this gene has 360 amino acids and is an inwardly rectifying potassium channel (where voltage dependence is regulated by the concentration of extracellular potassium) that functions as a homotetramer and is primarily localized to the apical membranes of RPE. Abnormal gene product. Some mutant alleles may lead to nonsense-mediated decay or prevent the formation of a functional homotetramer. [Sergouniotis et al 2011].IQCB1 (NPHP5)Normal allelic variants. This gene belongs to the ciliary body genome and is important for development and function of the retina and kidneys. The longest transcript variant NP_001018864.2 has 15 exons.Pathologic allelic variants. Nonsense mutations and small intragenic deletions have been reported.Normal gene product: The longest protein isoform (NP_001018864.2) has 598 amino acids.Abnormal gene product. Nothing definitive is known about the way mutations in this gene produce disease.