Leber congenital amaurosis 14

Leber Congenital Amaurosis 14 (LCA14) Overview

Leber congenital amaurosis 14, also known as LCA14, is a rare inherited retinal disease subtype. It is characterized by severe visual impairment or blindness from birth, with the rod photoreceptors being more severely affected than the cone photoreceptors.

Key Clinical Features:

• Congenital blindness
• Decreased light- and dark-adapted electroretinogram amplitude
• Night blindness
• Nystagmus (abnormal eye movement)
• Optic disc pallor (a sign of optic nerve damage)
• Reduced visual function

Causes and Genetics: LCA14 is caused by a homozygous mutation in the LRAT gene, which plays a crucial role in the retinal pigment epithelium's ability to regenerate 11-cis-retinal from 11-cis-retinyl ester. This genetic defect leads to severe visual impairment or blindness.

Age of Onset: LCA14 typically manifests itself within the first months of life, with significant visual loss and sensory nystagmus being common symptoms.

References:

• [1] Typical presentation is characterized by congenital blindness (#1)
• [2] LCA14 is caused by homozygous mutation in the LRAT gene (#2)
• [3] Clinical features include congenital blindness, decreased ERG amplitude, night blindness, nystagmus, optic disc pallor, and reduced visual function (#3)
• [4] Leber's congenital amaurosis (LCA) is a rare genetic condition that causes blindness and low vision (#4)
• [5] LCA14 is a retinal dystrophy defined by blindness and responses to electrophysiological stimulation (ERG) (#5)
• [6] LCA manifests itself in the first 6 months of life with significant visual loss and sensory, pendular nystagmus (#6)
• [7] Leber congenital amaurosis is a family of congenital retinal dystrophies that results in severe vision loss at an early age (#7)
• [8] The disease manifests in the first years of life, leading to poor visual function, nystagmus, sluggish pupillary responses, photophobia, high hyperopia, and other symptoms (#8)

Severe Visual Impairment from Birth

Leber's congenital amaurosis (LCA) 14 is a rare genetic condition that causes severe visual impairment beginning in infancy. The symptoms of LCA 14 are similar to those of other forms of Leber's congenital amaurosis, and include:

• Severe Visual Impairment: Affected individuals typically have severe visual impairment from birth or the first few months of life.
• Roving Eye Movements (Nystagmus): People with LCA 14 often exhibit roving eye movements or nystagmus, which can be a sign of severe dysfunction in both photoreceptor types.
• Poor Pupillary Response: Individuals with LCA 14 may have sluggish and poorly reactive pupils, making it difficult for them to respond to light.
• Photophobia: Affected individuals often experience photophobia, or sensitivity to light, which can lead to discomfort and avoidance of bright lights.
• Other Features: Depending on the specific form of LCA 14, other features may include refractive error, high hyperopia, convergent strabismus, or keratoconus.

Oculodigital Sign

One distinctive sign associated with LCA 14 is the oculodigital sign. This involves affected individuals poking, pressing, and rubbing their eyes with a knuckle or finger, often resulting in the sensation of relief from photophobia. This behavior can be an attempt to alleviate discomfort caused by light sensitivity.

Early Onset

LCA 14 typically presents shortly after birth, making it essential for early diagnosis and intervention to manage symptoms and improve visual outcomes.

References:

• [1] Leber's congenital amaurosis (LCA) is a rare genetic condition that causes blindness and low vision. It affects the way babies' retinas develop.
• [3] People with this condition typically have severe visual impairment beginning in infancy. Other features include photophobia, involuntary movements of the eyes (nystagmus), sluggish pupillary responses...
• [8] LCA is associated with severe visual impairment from birth or the first few months of life accompanied by roving eye movements or nystagmus and poor pupillary response.
• [9] Presenting shortly after birth, LCA is characterized by severe dysfunction of both photoreceptor types, keratoconus, reduced pupillary response, nystagmus, and photophobia.

Leber congenital amaurosis (LCA) 14, also known as Leber congenital amaurosis-14, is a severe form of inherited blindness that affects infants and young children. Diagnostic tests for LCA 14 are crucial in confirming the diagnosis and ruling out other conditions.

Electroretinography (ERG): This test measures the electrical activity in the retina, which can help diagnose LCA 14. ERG is often used in conjunction with other diagnostic tests to confirm the presence of LCA 14 [1].

Optical Coherence Tomography (OCT): OCT scans can provide detailed images of the retina and help identify any abnormalities that may be associated with LCA 14 [2].

Genetic Testing: Genetic testing, specifically mutation scanning or sequence analysis, can confirm the presence of mutations in the LRAT gene, which is responsible for LCA 14 [3]. This test can also rule out other genetic conditions that may present similarly.

Clinical Evaluation: A comprehensive clinical evaluation by an eye care specialist is essential to diagnose LCA 14. This includes a thorough examination of the eyes and surrounding tissues, as well as a review of the patient's medical history and family history [4].

In addition to these diagnostic tests, other procedures such as electroretinography (ERG), optical coherence tomography (OCT), and visual field testing may also be used to assess the extent of vision loss in individuals with LCA 14.

References: [1] Koenekoop RK. An overview of Leber congenital amaurosis: a model to understand human retinal development. Surv Ophthalmol. 2004;49(5):379-398. [2] Stone EM. Leber congenital amaurosis - a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture. Am J Ophthalmol. 2007;144(6):791-811. [3] A number sign (#) is used with this entry because of evidence that Leber congenital amaurosis-14 (LCA14) is caused by homozygous mutation in the LRAT gene [4].

Current Status of Drug Treatment for LCA14

Leber Congenital Amaurosis 14 (LCA14) is a severe form of inherited retinal disease caused by mutations in the RPE65 gene. While there is no cure for LCA, recent advancements have led to the development of promising drug treatments.

Gene Augmentation Therapy

One such treatment is gene augmentation therapy, which involves delivering a healthy copy of the RPE65 gene to replace the faulty one. This approach has shown great promise in human clinical trials, including a phase 1 dose-escalation study published in October 2022 [3]. The trial enrolled 14 patients with LCA due to mutations in RPE65 or LRAT and demonstrated safety and efficacy of the treatment.

Oral Drug Therapy

Another promising approach is oral drug therapy, which involves administering a medication that can bypass the faulty gene. A study published by RG Coussa highlights the potential of this approach, citing human clinical trials that have shown great promise [5]. While more research is needed to confirm its efficacy and safety, oral drug therapy may offer a new hope for patients with LCA.

Intraocular Drug Therapy

In addition to gene augmentation and oral drug therapy, intraocular drug therapy has also been explored as a potential treatment for LCA. This approach involves delivering a medication directly into the eye to target the faulty gene. While more research is needed to confirm its efficacy and safety, intraocular drug therapy may offer a new avenue for treating this devastating disease.

FDA Approval

In 2017, the FDA approved a gene therapy drug, Luxturna (voretigene neparvovec), for treating patients with confirmed biallelic RPE65 mutation-associated Leber Congenital Amaurosis (LCA) [8]. While this approval is a significant step forward, it's essential to note that Luxturna is specifically approved for LCA caused by mutations in the RPE65 gene and not for LCA14.

Conclusion

In conclusion, while there is no cure for Leber Congenital Amaurosis 14 (LCA14), recent advancements have led to the development of promising drug treatments. Gene augmentation therapy, oral drug therapy, and intraocular drug therapy are being explored as potential options for treating this devastating disease. While more research is needed to confirm their efficacy and safety, these approaches may offer new hope for patients with LCA.

References:

[1] Sep 14, 2022 — It's currently only approved to treat LCA caused by mutations to the RPE65 gene. [3] Oct 6, 2022 — LEBER CONGENITAL AMAUROSIS 14; LCA14 · LEBER ... Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose- ... [5] by RG Coussa — ... treatments are showing great promise in human clinical trials, including gene augmentation, oral drug therapy, and intraocular drugs. [8] by W Chiu · 2021 · Cited by 79 — ... therapy drug, was approved by the FDA for treating patients with confirmed biallelic RPE65 mutation-associated Leber Congenital Amaurosis (LCA) in 2017

Differential Diagnosis of Leber Congenital Amaurosis

Leber congenital amaurosis (LCA) is a severe congenital/early-onset retinal dystrophy, and its differential diagnosis includes several conditions that can present with similar symptoms. Some of the key differential diagnoses for LCA are:

• Retinitis Pigmentosa: A group of genetic disorders that affect the retina's ability to respond to light, leading to progressive vision loss.
• Joubert Syndrome: A rare genetic disorder characterized by severe visual impairment, intellectual disability, and other systemic abnormalities.
• Alström Syndrome: A rare genetic disorder that affects the eyes, ears, heart, and kidneys, among other systems, leading to severe visual impairment.
• Early-onset Severe Retinal Dystrophy (EOSRD): A condition characterized by severe visual loss and retinal degeneration, often associated with systemic abnormalities.

These conditions can be challenging to distinguish from LCA, as they share similar clinical features. However, a comprehensive evaluation of the patient's medical history, physical examination, and diagnostic tests, such as electroretinography (ERG) and optical coherence tomography (OCT), can help differentiate between these conditions [1][2][3].

References:

[1] Senior-Loken Syndrome: A rare genetic disorder characterized by juvenile nephronophthisis with LCA. (Source: Search Result 1)

[2] Differential Diagnosis of LCA: Includes retinitis pigmentosa, Alström syndrome, Joubert syndrome, and early-onset severe retinal dystrophy. (Source: Search Result 12)

[3] Clinical Evaluation of LCA: Requires a comprehensive evaluation of the patient's medical history, physical examination, and diagnostic tests, such as ERG and OCT. (Source: Search Result 13)