Leber congenital amaurosis is a hereditary disease characterized by a congenital lesion of the photosensitive cells of the retina of the eye and in some cases other common disorders (kidney abnormalities, central nervous system). With this pathology, in the first months of a child’s life or immediately after birth, nystagmus appears, weakening or lack of reaction of the pupil to light. In the future, the child may rub his eyes (Franceschetti’s symptom), hyperopia and photophobia occur, complete loss of vision is possible. Diagnosis is based on the data of the patient’s examination by an ophthalmologist, electroretinography, research of hereditary history and genetic analyses. A specific treatment for Leber congenital amaurosis has not been developed to date.
H35.5 Hereditary retinal dystrophy. Retinitis pigmentosa
Leber congenital amaurosis is a heterogeneous group of diseases caused by mutations in 18 genes encoding various retinal proteins, including opsin. Amaurosis was first described in the XIX century (in 1867) by T. Leber, who indicated the main manifestations of this disease – pendulum nystagmus, blindness, the appearance of pigment spots and inclusions on the fundus. The average prevalence of the disease is 3:100,000 of the population.
Leber congenital amaurosis affects both men and women equally. The disease accounts for approximately 5% of all hereditary retinopathy. Modern genetics is developing methods for the treatment of this pathology, there are encouraging results of gene therapy of one of the forms of Leber congenital amaurosis caused by a mutation in the RPE65 gene. Separately, Leber’s optic nerve atrophy is distinguished, which is also characterized by a gradual loss of visual acuity and subsequently complete blindness. However, this disease is of a completely different genetic nature and is caused by damage to mitochondrial DNA, which has its own unique type of inheritance (on the maternal side).
The main mechanism of visual impairment in Leber congenital amaurosis is a metabolic disorder in rods and cones, which leads to fatal damage to photoreceptors and their destruction. However, the immediate cause of such changes varies depending on which gene mutation caused the disease.
One of the most common types ofLeber congenital amaurosis (type 2, LCA2) is caused by the presence of the mutant RPE65 gene on the first chromosome. More than 80 mutations of this gene are known, some of which, in addition to Leber congenital amaurosis, cause certain forms of retinal pigment abiotrophy. The protein encoded by PRE65 is responsible for the metabolism of retinol in the pigment epithelium of the retina of the eye, therefore, in the presence of a genetic defect, this process is disrupted with the development of side metabolic pathways. As a result, the synthesis of rhodopsin in photoreceptors stops, which leads to a characteristic clinical picture of the disease. Mutant forms of the gene are inherited by an autosomal recessive mechanism.
A less common form of Leber congenital amaurosis (type 14) is caused by a mutation of the LRAT gene on the 4th chromosome. It encodes the protein lecithin-retinol-acyltransferase, which is located in the microsomes of hepatocytes and is found in the retina of the eye. This enzyme participates in the metabolism of retinoids and vitamin A, due to the presence of mutations in the gene, the resulting protein cannot fully perform its functions, which is why photoreceptor degeneration develops, which is clinically manifested by Leber congenital amaurosis or juvenile retinal pigment abiotrophy. It has an autosomal recessive nature of inheritance.
Leber congenital amaurosis type 8 most often leads to congenital blindness, the CRB1 gene responsible for the development of this form of the disease is located on the 1st chromosome and has an autosomal recessive nature of inheritance. It was found that the protein encoded by this gene is directly involved in the embryonic development of photoreceptors and retinal pigment epithelium. More accurate data on the pathogenesis of this form of Leber congenital amaurosis has not been accumulated to date. A similar situation is with the mutation of the LCA5 gene located on the 6th chromosome and associated with the 5th type of amaurosis. Currently, only the protein encoded by this gene, lebercilin, has been identified, but its functions in the retina are unclear.
Two forms of Leber congenital amaurosis were also identified, which are inherited by an autosomal dominant mechanism – type 7, caused by a mutation of the CRX gene, and type 11, associated with a violation of the IMPDH1 gene. The CRX gene encodes a protein that has many functions – controlling the development of photoreceptors in the embryonic period, maintaining their adequate level in adulthood, participating in the synthesis of other retinal proteins (it is a transcription factor). Therefore, depending on the nature of the CRX gene mutation, the Leber type 7 amaurosis clinic can be diverse – from congenital blindness to relatively late and sluggish visual impairment.
Inosine-5′-monophosphate dehydrogenase 1, encoded by the IMPDH1 gene, is an enzyme that regulates cell growth and the formation of nucleic acids, but this does not yet clarify the pathogenesis of how violations of this protein lead to type 11 Leber amaurosis.
Currently, the relationship between clinical manifestations and mutations of certain genes for 16 types of Leber congenital amaurosis has been fully proven. There are also indications of the discovery of two more genes, damage in which leads to such a disease, but so far additional research is being conducted in this regard.
- Type 1 (LCA1, from English Leber’s congenital amaurosis) is a damaged GUCY2D gene on the 17th chromosome, the type of inheritance is autosomal recessive.
- Type 2 (LCA2) is a damaged RPE65 gene on the 1st chromosome, autosomal recessive inheritance, there are the first positive results on gene therapy of this form of Leber congenital amaurosis.
- Type 3 (LCA3) is a damaged RDH12 gene on the 14th chromosome, autosomal recessive inheritance.
- Type 4 (LCA4) – damaged AIPL1 gene on chromosome 17, autosomal recessive inheritance.
- Type 5 (LCA5) is a damaged LCA5 gene on the 6th chromosome, autosomal recessive inheritance.
- Type 6 (LCA6) – damaged RPGRIP1 gene on chromosome 14, autosomal recessive inheritance.
- Type 7 (LCA7) is a damaged CRX gene on chromosome 19, autosomal dominant inheritance. It is characterized by a variable clinical picture.
- Type 8 (LCA8) is a damaged CRB1 gene on the 1st chromosome, autosomal recessive inheritance. Statistically, it leads to congenital blindness more often than other types.
- Type 9 (LCA9) is a damaged LCA9 gene on the 1st chromosome, autosomal recessive inheritance.
- Type 10 (LCA10) is a damaged CEP290 gene on chromosome 12, autosomal recessive inheritance.
- Type 11 (LCA11) is a damaged IMPDH1 gene on chromosome 7, autosomal dominant inheritance.
- Type 12 (LCA12) is a damaged RD3 gene on the 1st chromosome, autosomal recessive inheritance.
- Type 13 (LCA13) is a damaged RDH12 gene on the 14th chromosome, autosomal recessive inheritance.
- Type 14 (LCA14) is a damaged LRAT gene on the 4th chromosome, autosomal recessive inheritance.
- Type 15 (LCA15) is a damaged TULP1 gene on chromosome 6, autosomal recessive inheritance.
- Type 16 (LCA16) is a damaged KCNJ13 gene on the 2nd chromosome, autosomal recessive inheritance.
In addition, sometimes in the clinical classification, not only the name of the damaged gene is distinguished, but also the nature of the mutation, since this has a significant impact on the course of Leber congenital amaurosis. Moreover, different types of mutations in the same gene can lead to completely different diseases – for example, some types of deletions in the CRX gene can lead not to amaurosis, but to rod-cone dystrophy. Some mutations of the RPE65, LRAT and CRB1 genes cause various forms of retinal pigment abiotrophy.
The symptoms of Leber congenital amaurosis are quite variable and depend on the type of disease and the nature of the gene mutation. In most cases, pathology is not determined at the birth of a child – even when examining the fundus, changes are observed only in a few percent of cases. As he grows, parents may notice that the child does not linger on objects and others, and at an older age may react painfully to light (photophobia appears), often rub his eyes and point at them with his finger (Franceschetti’s symptom, oculopalic syndrome). Nystagmus is detected, which occurs in the first 2-3 months of life and is often one of the first manifestations of Leber congenital amaurosis, a delayed reaction of the pupil to light or its complete absence.
In some cases, congenital blindness is observed. If the child was born with a relatively intact visual function, then in the first years of life, in addition to these symptoms, he also develops hyperopia, strabismus, visual acuity suffers greatly. Usually, by the age of 10, most patients with Leber congenital amaurosis go completely blind. In the future, they may have other disorders of the visual apparatus – keratoconus, cataract, glaucoma. In some types of the disease, concomitant disorders can also be observed – central nervous system lesions, deafness.
In modern ophthalmology, the diagnosis of Leber congenital amaurosis is made on the basis of an examination of the fundus, monitoring of the dynamics of changes in it, and electroretinography data. An important role is also played by the study of hereditary anamnesis, and for some types of disease – genetic sequencing of the sequence of key genes.
- Ophthalmoscopy. When examining the fundus for a relatively long time (the first few years of life), no changes may be recorded. The first, but not specific ophthalmic symptoms of amaurosis are nystagmus, strabismus, delayed or absent pupil response to light. Changes in the retina that occur over time are reduced to the appearance of pigmented or non-pigmented spots of various sizes, narrowing of arterioles, pallor of the optic disc. By the age of 8-10, almost all patients have bone pigment corpuscles located on the periphery of the fundus.
- Visometry. A characteristic feature is a faster progression of changes on the retina compared to functional visual impairments, which develop relatively slowly. Before the development of blindness, visual acuity is 0.1 or less, farsightedness and photophobia are often recorded.
- Electroretinography. ERG in Leber congenital amaurosis, as a rule, reflects a strong decrease in the amplitude of all waves or their complete absence.
- Genetic research. They allow to identify the damaged gene and the type of mutation only in 50-60% of cases (the frequency of the most common gene damage). The vast majority of clinics perform sequence sequencing in order to detect mutations only in relation to the RPE65, CRX, CRB1, LCA5 and KCNJ13 genes.
Differential diagnosis is performed with various forms of retinal pigment abiotrophy (with it, the normal or slightly reduced amplitude of waves on the electroretinogram is preserved) and some types of optic nerve atrophy.
To date, there is no specific treatment for any type of Leber congenital amaurosis. At the stage of clinical trials, the genetically engineered introduction of the RPE65 gene into the retina of the eye of patients with type 2 amaurosis is underway, there is the first evidence of a significant improvement in the vision of experimental patients. In the case of other forms of the disease, there is no such progress yet. Supportive treatment is reduced to vitamin therapy, intraocular injections of vasodilators. With farsightedness, wearing glasses is prescribed.
In terms of maintaining vision, the prognosis is extremely unfavorable, almost 95% of patients completely lose the ability to see by the 10th year of life. In addition, this hereditary disease can be complicated by problems with the central nervous system, kidneys, and endocrine system, which requires more thorough medical monitoring to detect such disorders in a timely manner.