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Molecular Diagnosis & Therapy Jan 2022Achromatopsia (ACHM), also known as rod monochromatism or total color blindness, is an autosomal recessively inherited retinal disorder that affects the cones of the... (Review)
Review
Achromatopsia (ACHM), also known as rod monochromatism or total color blindness, is an autosomal recessively inherited retinal disorder that affects the cones of the retina, the type of photoreceptors responsible for high-acuity daylight vision. ACHM is caused by pathogenic variants in one of six cone photoreceptor-expressed genes. These mutations result in a functional loss and a slow progressive degeneration of cone photoreceptors. The loss of cone photoreceptor function manifests at birth or early in childhood and results in decreased visual acuity, lack of color discrimination, abnormal intolerance to light (photophobia), and rapid involuntary eye movement (nystagmus). Up to 90% of patients with ACHM carry mutations in CNGA3 or CNGB3, which are the genes encoding the alpha and beta subunits of the cone cyclic nucleotide-gated (CNG) channel, respectively. No authorized therapy for ACHM exists, but research activities have intensified over the past decade and have led to several preclinical gene therapy studies that have shown functional and morphological improvements in animal models of ACHM. These encouraging preclinical data helped advance multiple gene therapy programs for CNGA3- and CNGB3-linked ACHM into the clinical phase. Here, we provide an overview of the genetic and molecular basis of ACHM, summarize the gene therapy-related research activities, and provide an outlook for their clinical application.
Topics: Animals; Color Vision Defects; Cyclic Nucleotide-Gated Cation Channels; Genetic Therapy; Humans; Mutation; Retinal Cone Photoreceptor Cells
PubMed: 34860352
DOI: 10.1007/s40291-021-00565-z -
Current Opinion in Ophthalmology Jul 2015The purposes of this article are to examine the literature published on achromatopsia and provide a comprehensive review of the clinical disease, genetic... (Review)
Review
PURPOSE OF REVIEW
The purposes of this article are to examine the literature published on achromatopsia and provide a comprehensive review of the clinical disease, genetic characteristics, and potential for therapy. Specifically, this article will describe recent advances in gene therapy in animal models, clinical features in human, and barriers to human translation.
RECENT FINDINGS
Building on prior success with adeno-associated virus (AAV) therapy in mice models for achromatopsia with mutations in the CNGB3, CNGA3, or GNAT2 genes, multiple cone-specific promoters have recently been developed and shown success in mice and nonhuman primates. A sheep CNGA3 model has also been characterized. Two clinical trials are under way: one to better characterize humans with achromatopsia and another to study a ciliary neurotrophic factor (CNTF) implant as a treatment for patients with the CNGB3 mutation.
SUMMARY
Genetic understanding and disease characterization of achromatopsia continues to evolve, as do gene therapy tools and animal models. The potential for the treatment of achromatopsia in humans with gene therapy shows great promise.
Topics: Animals; Ciliary Neurotrophic Factor; Color Vision Defects; Genetic Therapy; Genetic Vectors; Humans; Mutation
PubMed: 26196097
DOI: 10.1097/ICU.0000000000000189 -
Advances in Experimental Medicine and... 2018Rod monochromatism (achromatopsia) is a congenital cone photoreceptor disorder, which is rare, affecting about 1 in 30,000 individuals. These patients have normal rod... (Review)
Review
Rod monochromatism (achromatopsia) is a congenital cone photoreceptor disorder, which is rare, affecting about 1 in 30,000 individuals. These patients have normal rod function but no detectable cone function; therefore, everything they see is in shades of gray (total color blindness). Patients usually present in infancy with nystagmus and photophobia. Vision is usually about 20/200 or worse; patients have a hyperopic refractive error. Some patients show paradoxical pupillary response; that is, the pupils dilate in bright light. Fundus examination is normal, though pigmentary mottling and atrophic changes may be observed at the macula. Incomplete achromatopsia: Patients in this group have somewhat better visual acuity, about 20/80 to 20/120, with some residual functioning of cone photoreceptors. This milder form allows some color discrimination. Complete achromatopsia: It occurs in about 4-10% of Pingelapese islanders, who live on one of the Eastern Caroline Islands of Micronesia.
Topics: Color Vision Defects; Humans; Nystagmus, Pathologic; Photophobia; Retinal Cone Photoreceptor Cells; Visual Acuity
PubMed: 30578497
DOI: 10.1007/978-3-319-95046-4_24 -
Der Ophthalmologe : Zeitschrift Der... Jun 2010Hereditary cone diseases manifest as progressive or stationary disorders. Among the stationary cone disorders autosomal recessive achromatopsia occurs most frequently... (Review)
Review
Hereditary cone diseases manifest as progressive or stationary disorders. Among the stationary cone disorders autosomal recessive achromatopsia occurs most frequently and begins within the first months of life with nystagmus and photophobia. Color discrimination is not possible, and visual acuity is severely reduced. In addition to a thorough ophthalmic examination, color vision tests and electrophysiology are prerequisites to establish a diagnosis of achromatopsia. A genetic examination is very helpful to distinguish achromatopsia from other stationary cone disorders like X-linked recessive blue cone monochromatism and from progressive cone and cone-rod dystrophies. It is the correct clinical and genetic diagnosis that eventually will allow an individual prognosis, accurate genetic counseling, and the optimal choice of low vision aids.
Topics: Adolescent; Chromosome Aberrations; Chromosomes, Human, X; Color Vision Defects; Cyclic Nucleotide-Gated Cation Channels; DNA Mutational Analysis; Diagnosis, Differential; Female; Fundus Oculi; Genes, Recessive; Genetic Testing; Genotype; Humans; Sex Chromosome Aberrations; Vision Tests; Visual Acuity; Visual Field Tests
PubMed: 20533046
DOI: 10.1007/s00347-010-2178-8 -
Ophthalmic Research 2015Achromatopsia (ACHM) is a rare autosomal recessive inherited retinal disorder with an incidence of approximately 1 in 30,000. It presents at birth or early infancy and... (Review)
Review
Achromatopsia (ACHM) is a rare autosomal recessive inherited retinal disorder with an incidence of approximately 1 in 30,000. It presents at birth or early infancy and is typically characterized by reduced visual acuity, nystagmus, photophobia, and very poor or absent color vision. The symptoms arise from isolated cone dysfunction, which can be caused by mutations in the crucial components of the cone phototransduction cascade. Although ACHM is considered a functionally nonprogressive disease affecting only the cone system, recent studies have described progressive age-dependent changes in retinal architecture. Currently, no specific therapy is available for ACHM; however, gene replacement therapy performed on animal models for three ACHM genes has shown promising results. Accurate genetic and clinical diagnosis of patients may therefore enhance and enable therapeutic intervention in the near future. This short review summarizes the genetic background, pathophysiology, clinical findings, diagnostics, and therapeutic perspectives in ACHM.
Topics: Animals; Color Vision Defects; Disease Models, Animal; Drug Evaluation, Preclinical; Electroretinography; Eye Proteins; Genetic Therapy; Humans; Mutation; Pedigree; Retinal Cone Photoreceptor Cells; Retinal Degeneration
PubMed: 26304472
DOI: 10.1159/000435957 -
Ophthalmic Genetics Apr 2018Achromatopsia is an autosomal recessive condition, characterised by reduced visual acuity, impaired colour vision, photophobia and nystagmus. The symptoms can be... (Review)
Review
Achromatopsia is an autosomal recessive condition, characterised by reduced visual acuity, impaired colour vision, photophobia and nystagmus. The symptoms can be profoundly disabling, and there is no cure currently available. However, the recent development of gene-based interventions may lead to improved outcomes in the future. This article aims to provide a comprehensive review of the clinical features of the condition, its genetic basis and the underlying pathogenesis. We also explore the insights derived from animal models, including the implications for gene supplementation approaches. Finally, we discuss current human gene therapy trials.
Topics: Animals; Color Vision Defects; Disease Models, Animal; Genetic Therapy; Humans; Molecular Biology
PubMed: 29303385
DOI: 10.1080/13816810.2017.1418389 -
The Journal of Gene Medicine Mar 2017The present review summarizes the current status of achromatopsia (ACHM) gene therapy-related research activities and provides an outlook for their clinical application.... (Review)
Review
The present review summarizes the current status of achromatopsia (ACHM) gene therapy-related research activities and provides an outlook for their clinical application. ACHM is an inherited eye disease characterized by a congenital absence of cone photoreceptor function. As a consequence, ACHM is associated with strongly impaired daylight vision, photophobia, nystagmus and a lack of color discrimination. Currently, six genes have been linked to ACHM. Up to 80% of the patients carry mutations in the genes CNGA3 and CNGB3 encoding the two subunits of the cone cyclic nucleotide-gated channel. Various animal models of the disease have been established and their characterization has helped to increase our understanding of the pathophysiology associated with ACHM. With the advent of adeno-associated virus vectors as valuable gene delivery tools for retinal photoreceptors, a number of promising gene supplementation therapy programs have been initiated. In recent years, huge progress has been made towards bringing a curative treatment for ACHM into clinics. The first clinical trials are ongoing or will be launched soon and are expected to contribute important data on the safety and efficacy of ACHM gene supplementation therapy.
Topics: Animals; Clinical Trials as Topic; Color Vision Defects; Cyclic Nucleotide-Gated Cation Channels; Dependovirus; Disease Models, Animal; Drug Evaluation, Preclinical; Genetic Predisposition to Disease; Genetic Therapy; Genetic Vectors; Humans; Mutation; Transgenes; Treatment Outcome
PubMed: 28095637
DOI: 10.1002/jgm.2944 -
Neurology India 2018
Review
Topics: Aged; Brain Ischemia; Cerebral Cortex; Cerebrovascular Circulation; Color Vision Defects; Databases, Bibliographic; Humans; Magnetic Resonance Imaging; Male; Stroke
PubMed: 29547203
DOI: 10.4103/0028-3886.227322 -
The Yale Journal of Biology and Medicine Dec 2017Achromatopsia is a rare congenital cause of vision loss due to isolated cone photoreceptor dysfunction. The most common underlying genetic mutations are autosomal... (Review)
Review
Achromatopsia is a rare congenital cause of vision loss due to isolated cone photoreceptor dysfunction. The most common underlying genetic mutations are autosomal recessive changes in , , , , , or . Animal models of , , and have been rescued using AAV gene therapy; showing partial restoration of cone electrophysiology and integration of this new photopic vision in reflexive and behavioral visual tests. Three gene therapy phase I/II trials are currently being conducted in human patients in the USA, the UK, and Germany. This review details the AAV gene therapy treatments of achromatopsia to date. We also present novel data showing rescue of a mouse model using an rAAV.CBA.CNGA3 vector. We conclude by synthesizing the implications of this animal work for ongoing human trials, particularly, the challenge of restoring integrated cone retinofugal pathways in an adult visual system. The evidence to date suggests that gene therapy for achromatopsia will need to be applied early in childhood to be effective.
Topics: Animals; Circadian Rhythm; Clinical Trials as Topic; Color Vision Defects; Cyclic Nucleotide-Gated Cation Channels; Dependovirus; Disease Models, Animal; Dogs; Genetic Therapy; Humans; Mice; Retina
PubMed: 29259520
DOI: No ID Found -
Survey of Ophthalmology 2016Acquired color vision deficiency occurs as the result of ocular, neurologic, or systemic disease. A wide array of conditions may affect color vision, ranging from... (Review)
Review
Acquired color vision deficiency occurs as the result of ocular, neurologic, or systemic disease. A wide array of conditions may affect color vision, ranging from diseases of the ocular media through to pathology of the visual cortex. Traditionally, acquired color vision deficiency is considered a separate entity from congenital color vision deficiency, although emerging clinical and molecular genetic data would suggest a degree of overlap. We review the pathophysiology of acquired color vision deficiency, the data on its prevalence, theories for the preponderance of acquired S-mechanism (or tritan) deficiency, and discuss tests of color vision. We also briefly review the types of color vision deficiencies encountered in ocular disease, with an emphasis placed on larger or more detailed clinical investigations.
Topics: Color Perception Tests; Color Vision; Color Vision Defects; Humans; Retinal Cone Photoreceptor Cells; Visual Field Tests
PubMed: 26656928
DOI: 10.1016/j.survophthal.2015.11.004