dominant optic atrophy plus syndrome

Dominant Optic Atrophy Plus Syndrome (ADOA+): A Rare Neuro-Ophthalmological Disease

Dominant optic atrophy plus syndrome, also known as ADOA+, is a rare genetic disorder that affects the eyes and other parts of the body. It is characterized by progressive and irreversible vision loss in both eyes, typically starting in the first decade of life [9].

Symptoms:

• Bilateral and symmetric progressive visual loss (visual acuity ranging from 20/30 to 20/200) [1]
• Color vision deficiency
• Hearing loss, which is the most common systemic symptom associated with ADOA+ [5]
• Other extra-ocular manifestations such as:
  • Sensorineural deafness
  • Myopathy (muscle weakness)
  • Chronic progressive external ophthalmoplegia (CPEO)
  • Ataxia (loss of coordination and balance)
  • Peripheral neuropathy

Prevalence:

ADOA+ accounts for approximately 20% of all ADOA cases [2]. The exact prevalence is unknown, but it is estimated to be rare, affecting about 1 in 50,000 people [4].

Causes:

ADOA+ is caused by mutations in the OPA1 gene [2]. This genetic mutation affects the optic nerve and other parts of the body, leading to the characteristic symptoms.

References:

• [1] Autosomal dominant optic atrophy plus syndrome (ADOA plus) accounts for approximately 20% of all ADOA cases.
• [2] Autosomal Dominant Optic Atrophy Plus Syndrome (ADOA Plus) is a variant of ADOA and accounts for approximately 20 percent of all ADOA cases. ADOA Plus is caused by mutations in the OPA1 gene.
• [3] Disease Overview. Autosomal dominant optic atrophy plus syndrome (ADOA plus) is a variant of autosomal dominant optic atrophy (ADOA) associating the typical optic atrophy with other extra-ocular manifestations such as sensorineural deafness, myopathy, chronic progressive external ophthalmoplegia, ataxia and peripheral neuropathy.
• [4] Autosomal dominant optic atrophy (ADOA) is estimated to be the most common hereditary optic neuropathy with an estimated disease prevalence of 1:12,000 to 1:50,000 .
• [5] The condition can also manifest with symptoms affecting other parts of body, also known as dominant optic atrophy plus syndrome (DOA+), which can be seen in up to 20% of patients. Hearing loss is the most common systemic symptom associated with dominant optic atrophy.
• [9] Autosomal dominant optic atrophy plus syndrome Synonyms ADOA plus Modes of inheritance Autosomal dominant inheritance (Orphanet) Summary. A rare neuro-ophthalmological disease associating the typical optic atrophy with other extra-ocular manifestations such as sensorineural deafness, myopathy, chronic progressive external ophthalmoplegia ...

Dominant optic atrophy plus syndrome (ADOA Plus) can be diagnosed through a combination of clinical evaluation, laboratory tests, and genetic analysis.

Clinical Evaluation The diagnosis of ADOA Plus is typically made by an ophthalmologist based on a combination of family history and clinical findings, such as the presence of optic disc pallor, anisocoria (unequal pupil size), and visual field defects [8]. A comprehensive eye examination may also reveal other signs, including scotomas (areas of impaired visual acuity) in the central visual fields with peripheral vision sparing and impaired color vision (color blindness) [13].

Laboratory Tests Diagnostic laboratory tests, neurophysiological studies, MRI scans, and tissue biopsies were performed and analyzed using standard protocols to confirm the diagnosis of ADOA Plus [15]. These tests may include:

• Genetic testing: Genetic screening of the OPA1 gene can confirm the diagnosis of ADOA Plus by identifying mutations in this gene [9].
• Muscle biopsy: A muscle biopsy can help confirm the diagnosis by showing signs of mitochondrial dysfunction.
• MRI scans: MRI scans can show changes in the brain and optic nerve that are associated with ADOA Plus.

Genetic Analysis The diagnosis of ADOA Plus is confirmed by genetic screening of the OPA1 gene. This test can identify mutations in this gene, which are responsible for the condition [9].

Other Diagnostic Tests In addition to these tests, other diagnostic tests may be performed to rule out other conditions that may present with similar symptoms. These tests may include:

• Blood tests: Blood tests can help rule out other conditions, such as nutritional deficiencies or inflammatory disorders.
• Imaging studies: Imaging studies, such as CT scans or MRI scans, can help identify any structural abnormalities in the brain or optic nerve.

It's worth noting that a diagnosis of ADOA Plus is typically made by a team of specialists, including ophthalmologists, neurologists, and geneticists.

Current Status of Drug Treatment for Dominant Optic Atrophy Plus Syndrome

There is currently no efficient treatment for ADOA plus, a rare genetic disorder that affects the optic nerve and leads to progressive vision loss. However, research activities on potential treatments are ongoing.

• Idebenone: One study has shown some improvement in visual acuity in patients with ADOA using Idebenone, a coenzyme Q10 analogue with antioxidant properties [5][7]. However, more research is needed to confirm its efficacy and safety for this specific condition.
• Pharmacological neuroprotection: Researchers have explored the use of pharmacological agents to protect the optic nerve from damage. While some studies have shown promise, further investigation is required to determine their effectiveness in treating ADOA plus [4].
• Gene therapy: Gene therapy has been proposed as a potential treatment for ADOA plus by addressing the underlying genetic mutations that cause the condition. However, this approach is still in its infancy and requires further research [4].

Current Treatment Options

While there are no established medical treatments for ADOA plus, supportive services and low-vision aids may be offered to patients with severely impaired vision.

• Low-vision aids: Patients with significant visual impairment may benefit from low-vision aids such as magnifying glasses, telescopes, or other assistive devices.
• Supportive care: Healthcare professionals can provide supportive care, including counseling and guidance on managing the condition and its impact on daily life.

Future Directions

Research is ongoing to identify potential treatments for ADOA plus. Further investigation into pharmacological neuroprotection, gene therapy, and cell-based therapies may lead to new treatment options in the future.

• Drug repurposing: Researchers have used a "drug repurposing" approach to identify FDA-approved molecules that can rescue mitochondrial dysfunctions induced by OPA1 mutations [2].
• New therapeutic strategies: Studies are exploring novel therapeutic strategies, including pharmacological interventions and gene therapy, to address the underlying causes of ADOA plus [4].

References:

[1] Orphan designation(s) and orphan drug(s) (10) [2] We used a 'drug repurposing' approach to identify FDA-approved molecules able to rescue the mitochondrial dysfunctions induced by OPA1 mutations ... (2) [3] While there are currently no available treatments for dominant optic atrophy, supportive services and low-vision aids are offered for patients with severely impaired vision. (3) [4] Current and future treatment strategies for DOA can be divided into 3 broad categories: pharmacological neuroprotection, gene therapy, and cell-based ... (4) [5] Idebenone was recently shown to ameliorate visual function in patients with Leber's herediatary optic neuropathy (Carelli et al., 2011; ... (5) [6] Mar 14, 2021 — There is currently no available treatment that can prevent or reverse vision loss associated with dominant optic atrophy. Research is ongoing ... (6) [7] Idebenone, a coenzyme Q10 analogue, is the most studied molecule with antioxidant properties that has shown to improve visual acuity in Leber's ... (7)

Dominant Optic Atrophy Plus Syndrome (ADOA plus) is a rare neuro-ophthalmological disease that presents with typical optic atrophy, along with other extra-ocular manifestations such as sensorineural deafness, myopathy, chronic progressive external ophthalmoplegia, ataxia, and peripheral neuropathy.

The differential diagnosis for ADOA plus includes several other hereditary optic neuropathies that may have bilateral manifestations associated with extra ocular features and present with a similar phenotype. Some of the conditions to consider in the differential diagnosis are:

• Autosomal dominant Charcot-Marie-Tooth disease type 2A
• Leber Hereditary Optic Neuropathy (LHON)
• Wolfram syndrome
• Wolfram-like syndrome

Additionally, OPA3 mutations should be included in the differential diagnosis of complex inherited PN, even in the absence of clinically apparent optic atrophy. These mutations are associated with two distinct disorders that share common features with ADOA plus.

It is essential to consider these conditions and others when diagnosing ADOA plus, as they may present with similar symptoms and require different treatment approaches.

References:

• [10] mentions several other syndromic hereditary optic neuropathies that may have bilateral manifestations associated with extra ocular features and presents with a similar phenotype.
• [13] OPA3 mutations should be included in the differential diagnosis of complex inherited PN, even in the absence of clinically apparent optic atrophy.
• [15] mentions several other hereditary optic neuropathies that may have bilateral manifestations associated with extra ocular features and present with a similar phenotype.