What is Leber Congenital Amaurosis?
- What is Leber Congenital Amaurosis?
- What are the symptoms?
- How is LCA inherited?
- What treatments are available?
- What testing is available?
- What gene mutations have been found to cause LCA?
What is Leber Congenital Amaurosis?
Leber Congenital Amaurosis (LCA) is a rare, hereditary disorder that leads to retinal dysfunction and visual impairment at an early age – often from birth. Of all the retinal degenerations, LCA has the earliest age of onset and can be the most severe. LCA vision loss varies from child to child but remains stable over time in 75% of cases. About 15% of children will have progressive vision loss and 10% may experience some modest, often temporary, improvement.
LCA bears the name of Dr. Theodore Leber (1840-1917), a German ophthalmologist, who first described the condition in 1869. Congenital means "a condition existing since birth, usually hereditary," and Amaurosis refers to any condition of blindness or marked loss of vision, especially loss of vision in which there is little or no change in the appearance of the eye itself. This is why LCA eyes usually look normal upon initial examination.
LCA is sometimes confused with another condition termed Leber’s Hereditary Optic Neuropathy (LHON) that also leads to visual impairment. However, LCA is a separate and distinct disease.
What are the symptoms?
The symptoms of LCA are often noticed very early in a child's life - in the first weeks or months after birth. Parents may observe the child does not focus on things in his/her environment, notice 'wobbly' back and forth movements called nystagmus and some children may press or push on their eyes.
How is LCA inherited?
LCA is an autosomal recessive disease. This means both parents must be carriers of the defective gene that causes LCA. Carriers bear the defective gene but are not necessarily afflicted with the disease.
What treatments are available?
Foundation-funded researchers are currently working towards treatments for LCA. For the latest information on the work that is being done, please click here.
What testing is available?
Genetic testing is available for LCA. It helps assess the risk of passing the disorder from parent to offspring. It also helps with attaining an accurate diagnosis. A patient with an accurate diagnosis is in a better position to keep track of new findings, research developments, and treatment approaches.
What gene mutations have been found to cause LCA?
To date, 20 genes have been identified whose mutations lead to forms of LCA. Three other areas have been identified on human chromosomes in which an LCA gene resides but has not been specifically identified. Mutations in these genes do not always cause LCA. For example, mutations in some areas cause other retinal degenerations that have characteristics different from LCA. Investigators believe that not all LCA genes have been found and that there are several yet to be identified. Following is a listing of the known genes whose mutations can cause LCA.
Ongoing research continues to identify new genetic mutations.
1) CRX Cone-Rod Homeobox - LCA7
The protein product of the gene is known to control the synthesis of several functionally important genes in the retina such as opsin, the visual protein. It is thus very important in proper development of the retina. A specific CRX mutation will result in a dominantly inherited form of LCA while another mutation results in the more usual recessive form. LCA cases with CRX mutations are very rare. One study reports that CRX mutations are thought to cause 1-3% of LCA cases another study on a different group of patients yields a figure of 0.6%. CRX gene mutations are associated with other retinal dystrophies as well as LCA.
2) AIPL1 Aryl Hydrocarbon Receptor - LCA4
Interacting Protein-Like 1 gene. The AIPL1 protein product is found in rod photoreceptor cells. Its function is yet unknown but may be involved in directing proper structure (folding) of important photoreceptor proteins. AIPL1 mutations account for 5-10% of recessive LCA cases as reported in one study and 3.4% in another.
3) CRB1 Crumbs Homologue 1 - LCA8
This gene mutation was first seen to cause retinal degeneration in the eye of the fruitfly, Drosophila. The human gene is similar (homologous) to that in the fruitfly and a mutation also causes LCA-like vision loss. Other mutations in the CRB1 gene cause other retinal degeneration phenotypes such as a recessive form of RP. The function of the protein is unknown but is thought to be involved in development of retinal neurons. In the fruitfly, the protein probably functions in maintaining proper cell-cell interactions. In the human, one study estimates that CRB1 mutations account for 9-13% of LCA cases, another study reports a figure of 10%.
4) GUCY2D Retinal Guanylate Cyclase - LCA1
Guanylate Cyclase is a protein enzyme that makes a critical messenger in photoreceptors called cyclic GMP that is a major intermediate in the light-dark visual cycle. A Guanylate Cyclase mutation leads to an abnormal cyclic GMP concentration, inducing dysfunction and degeneration of the photoreceptor cell. In a strain of chickens, an analogous mutation in the guanylase cyclase protein also leads to severe, early (LCA-like) visual loss. In one study, GUCY2D mutations are reported to account for 10-20% of LCA cases another study reports 21.2%.
5) LRAT Lecithin Retinol Acyltransferase - LCA14
The LRAT protein is an enzyme that is important in vitamin A metabolism in the visual process, catalyzing the first step in the visual cycle. The enzyme is specifically found in retinal pigment epithelial (RPE) cells. RPE cells adjoin retinal photoreceptor cells and partner with the photoreceptor cells in the visual process as discussed above. LRAT mutations profoundly disturb the normal chemical transformations of Vitamin A that are intrinsic in the visual cycle thus leading to photoreceptor cell dysfunction. Prevalence estimates of LRAT mutations are unavailable.
6) RPE65 Retinal Pigment Epithelium 65 - LCA2
Like LRAT, the RPE65 protein is specifically expressed in retinal pigment epithelial (RPE) cells. It also is important in Vitamin A metabolism in the visual cycle. An excellent canine (Briard) model exhibiting a mutation in the RPE65 gene has been identified. Gene therapy studies on this model are in progress preliminary to human clinical trials that will test replacement of the RPE65 gene in the human eye. In one study, RPE65 mutations are reported to cause 6-16% of LCA cases another study reports 6.1%.
7) RDH12 Retinol Dehydrogenase 12 - LCA13
The RDH 12 protein, like the LRAT and RPE65 proteins, is involved in chemical transformations of vitamin A (retinol) in the visual cycle. Unlike LRAT and RPE65, however, it is selectively found in retinal photoreceptor cells, probably cone photoreceptor cells. Mutation of RDH12 leads to a severe, progressive form of LCA with extensive macular atrophy. In the human, RDH12 mutations are reported to account for about 4% of LCA cases.
8) RPGRIP1 RPGR-Interacting Protein 1 - LCA6
THE RPGRIP1 protein is actually a member of a closely related family of proteins that, as the name implies, interacts with a protein named RPGR. RPGRIP1 and RPGR are localized in photoreceptor cell outer segments in the human. Here, the interacting proteins appear to be vital in transport processes into the outer segment. Disruption of this transport process would be expected to lead to retinal degeneration. In the human, one study reports that RPGRIP1 mutations account for 4-6% of LCA patients another study gives a figure of 4.5%
9) TULP1 Tubby-like Protein 1 - LCA15
The human TULP1 protein is very similar (homologous) to a protein previously identified in the mouse whose mutations lead to several problems including early progressive retinal degeneration. The protein is thought to function in facilitating the transport of important proteins like opsin to where they function in the photoreceptor outer segment. In a singl study, TULP1 mutations are reported to cause 1.7% of LCA cases.
Some mutations in the TULP1 gene can lead to LCA while others lead to retinal degeneration that is of an RP phenotype (1). A number of clinical reports are in the scientific literature describing the characteristics of the degeneration in specific families –Suranamese (2), Algerian and Dominican (3). A good mouse model has been developed and characterized (4). It demonstrated an early-onset retinal degeneration but seems to be normal in other regards. The availability of the model would allow for testing of different types of therapy in the future.
10) CEP290 - LCA10
Centrosomal protein of 290 kDa is a protein that in humans is encoded by the CEP290 gene.
This gene encodes a protein with 13 putative coiled-coil domains, a region with homology to SMC chromosome segregation ATPases, six KID motifs, three tropomyosin homology domains and an ATP/GTP binding site motif A. The protein is localized to the centrosome and cilia and has sites for N-glycosylation, tyrosine sulfation, phosphorylation, N-myristoylation, and amidation. Mutations in this gene have been associated with Joubert syndrome and nephronophthisis, and recently with a frequent form of LCA, called LCA10. The presence of antibodies against this protein is associated with several forms of cancer.
11) LCA5 Lebercillin - LCA5
The lebercillin protein gets its name from "Leber" and the fact that it is found in the "cilium" area of the photoreceptor cell. The cilium connects the photoreceptor inner segment where proteins like rhodopsin are synthesized and the outer segment where they are utilized in the visual process. Lebercillin apparently forms functional complexes with a number of other proteins in the connecting cilium. A lack of lebercillin disrupts these complexes and protein transport in the cilium. The result is a retinal degeneration. LCA mutations lead to early and severe retinal degeneration with nystagmus. Recent studies on two young patients with LCA5 mutations, however, indicate that photoreceptors are fairly well maintained in the central retina. LCA5 mutations account for 1-2% of LCA cases.
12) IMPDH1 gene - LCA11
The IMPDH1 gene is the blueprint to synthesize the protein called Inosine Monophosphate Dehydrogenase 1. IMPDH1 is an important enzyme in the body that functions in the formation of the compound guanine which is a building block of DNA. Although protein is expressed in many tissues, it it particularly high in retina. This and the fact that there are unique "isoforms" of the IMPDH1 protein in the retina may explain why only the retina demonstrates pathology in IMPDH1 mutations. IMPDH1 mutations lead to a dominant form of LCA. Mutations in other parts of the IMPDH1 gene can lead to dominant Retinitis Pigmentosa.
13) RD3 gene - LCA12
The RD3 protein is highly expressed in the retina, particularly in photoreceptor cells. In the photoreceptor cell, recent work (2010) shows that the RD3 protein is needed to ensure proper transport of a critical enzyme, guanylate cyclase (GC), from where it is synthesized in the photoreceptor cell body, through the cilium into the outer segment portion of the cell. Normal functioning of guanylate cyclase is essential in the Visual Process. Without the RD3 protein, the GC enzyme does not get to the outer segment and the Visual Process stops, leading to photoreceptor cell degeneration.
There are excellent mouse and canine models of lCA12. In a mouse model of RD3 mutation, loss of the RD3 protein causes a rapidly progressing LCA disease process. Mutations of the RD3 gene in humans causes a recessive form of LCA. Although the RD3 mouse model of retinal degeneration has been known for many years (1993),it was only in 2006 when the gene mutation causing the disease process was identified by a large consortium of investigators (1). The RD3 protein seems to perform many important functions in the retina Molday and coworkers (2) have recently shown that it is critical for synthesis of a signaling molecule in the photoreceptor cells called cyclic GMP,lack of which could lead to photoreceptor cell death. In the mouse, a variable phenotype is observed with siblings with the exact same mutation exhibiting different levels of degenerative severity. Danciger and colleagues (3) have begun to catalog genetic modifiers for this effect, i.e., genes/alleles that influence the inherited degenerative process. Although preclinical therapeutic experiments are yet to start on the RD3 mutation, excellent rodent and canine models (4) are available that are similar to humans with the RD3 mutation.
14) SPATA7 gene - LCA3
This is one of the more recent genes (2009) to be reported whose mutations lead to a form of LCA. Other SPATA7 mutations can lead to juvenile RP. Although the SPATA7 protein is expressed in the retina, its subcellular localization within the cell has not been determined. Similarly, the function of the protein in the retina is not known. A clue is obtained from the known importance of the protein spermatogenesis, ergo the name "Spermatogenesis-Associated-Protein7". Since cilial structures are important in protein transport in both spermatogenesis and vision, the connecting cilium of the photoreceptor cell would be an obvious place to look for SPATA7. An excellent review of the spectrum of SPATA7 mutations and associated LCA phenotypes has recently been published by Kaplan, Rozet and their colleagues (2010). Mutations in the human SPATA7 gene causing LCA were only reported in the scientific literature in 2009 (1). Since then, a few publications have described the screening of SPATA7-specific patients within the LCA population ( 1.7% of cases of childhood retinal dystrophy), the genetic spectrum of SPATA7 mutations and the delineation of the associated disease phenotype . Even though there is severe visual loss in infancy, some preservation of photoreceptor structure has been described in the central retina (2). This gives hope for successful therapy in restoring at least some visual function in an appropriate animal model and ultimately in the human.
15) MERTK gene
The MERTK protein is a "receptor tyrosine kinase" enzyme that is expressed in many tissues but quite highly in Retinal Pigment Epithelial (RPE) cells. It is thought to be involved in a process called phagocytosis in which some cells engulph and degrade other cells or portions of them. For example, RPE cells phagocytize shed tips of photoreceptor outer segments (OS)in a normal process that renews the outer segments. With a MERTK mutation, the RPE cell can no longer phagocytize the shed OS tips and there is a buildup of "OS garbage" between the retina and the RPE cells. Photoreceptor cell degeneration is the result. MERTK mutations account for only a small percentage of LCA cases. Other MERTK gene mutations have been reported to lead to RP or sever rod-cone dystrophy. MERTK mutations – For many years, the RCS rat has been used as a model in Retinitis Pigmentosa studies. The MERTK mutation in Retinal Pigment Epithelial cells makes them incapable of phagocytizing shed tips of photoreceptor outer segments that normally occurs on a daily basis. There is a resultant buildup of a debris layer between the photoreceptor and RPE cells and rapid photoreceptor degeneration. Besides RP, MERTK mutations can also cause a rare form of LCA. Recently, for example, Moore and his colleagues in London have described novel mutations in the MERTK gene that are associated with childhood rod-cone dystrophy (1). Investigators such as Dr. Ali and coworkers have demonstrated that AAV-mediated gene transfer can slow photoreceptor loss in the RCS rat model of retinal degeneration (2,3). Morphologically, there is a decrease in debris buildup demonstrating at least partial restoration of function in the RPE cells. The number of remaining photoreceptor cells was also higher in the treated vs. control retinas. This success could pave the way for human trials in the future.
16) IQCB1 / NPHP5 gene
This is one of the latest genes to be identified (2010) whose mutations lead to a form of LCA. The protein appears to be important in functioning of both retina and kidney. In the retina, gene mutations lead to a "ciliopathy", i.e., where the cilium of the photoreceptor cell dysfunctions.The LCA condition caused by problems with IQCB1 gene can also be associated with severe kidney problems called nephronophtisis. New work (2011) indicates that rod photoreceptor loss are severely affected edarly in the disease process but that cone photoreceptor cells are less severely affected. Because these IQCB1 patients are at hight risk of developing kidney failure, all new LCA patients should be screened for IQCB1 mutations. If found, patients should be closely monitored for kidney function. An animal model is being studied that might lead to gene therapy for this form of LCA as well as to the NPHP6/CEP290 form.
17) KCNJ13 gene – LCA16
Inwardly Rectifying Potassium Channel subunit-
The outside cellular membranes of many neurons have channels (pores) that will specifically allow passage of small molecules like sodium or potassium. These are important in maintaining a normal balance of these molecules within the cells and often are involved in the generation of neuronal electrical currents. Often these channel receptors consist of several protein subunits, one specific one of the potassium channel is the Kir7.1 subunit whose gene (KCNJ13) has the mutation causing an abnormal Kir7.1 protein that leads to this particular form of LCA. Mutations in the KCNJ13 gene lead to early onset vision loss. This suggests both impaired retinal development and progressive retinal degeneration. The degeneration involves both rod and cone photoreceptor pathways. This form of LCA is just one of a family of diseases caused by other mutations in genes for potassium channel proteins that affect other organs. Mutations in this gene have only recently been reported to cause LCA (1). The KCNJ13 gene codes for a protein that is important in the regulation of cellular potassium. Phenotypically, patients demonstrate an early-onset retina degeneration and it is postulated that the KCNJ13 gene protein product is important in retinal development and maintenance of function.
18) NMNAT1 gene (LCA9) – The NMNAT1 gene codes for an important enzyme. It was found in 2011 to be neuroprotective against injury of neuronal axons in the peripheral nervous system (1). It has also been reported that this gene regulates the growth and morphogenesis of neurons. More recently, several groups of investigators have reported that mutations in this gene can lead to early retinal degeneration (2-5). Kopenekoop and his co-workers also report that “all individuals with NMNAT1 mutations also have macular colobomas which are severe degenerative entities of the central retina (fovea) devoid of tissue and photoreceptors.” (2).
19) DTHD1 gene - A recent scientific publication has implicated a new gene in LCA. Specifically, a mutation in a gene called DTHD1 has been shown to cause a form of LCA that accompanies a "mild-moderate form on non-specific muscle dystrophy"*. Most types of LCA reported to date are classified as "non-syndromic" in that the gene mutations do not cause other problems in the body. Here though, DTHD1 mutations are called "syndromic" since they lead to both LCA and muscle dystrophy. This appears to be a very rare form of LCA and has been reported by Dr. L. Abu-Safieh and coworkers*. More work needs to be done to characterize the gene mutation and determine how it results in the disease processes.
*published in Genome Research, vol 23, pp:236-247, 2013
20) PNPLA6 gene - encodes the patatin-like phospholipase domain containing protein 6, also known as neuropathy target esterase (NTE), which is the target of toxic organophosphates that induce human paralysis due to severe axonopathy of large neurons. Mutations in PNPLA6 also cause human spastic paraplegia characterized by motor neuron degeneration. PNPLA6 localizes mostly at the inner segment plasma membrane in photoreceptors and mutations in Drosophila, PNPLA6 lead to photoreceptor cell death, lysophosphatidylcholine and lysophosphatidic acid levels are elevated in mutant Drosophila. These findings show a role for PNPLA6 in photoreceptor survival and identify phospholipid metabolism as a potential therapeutic target for some forms of blindness.