epithelial-stromal TGFBI dystrophy

Epithelial-Stromal TGFBI Dystrophy: A Rare Corneal Disorder

Epithelial-stromal TGFBI dystrophy is a rare, inherited corneal disorder characterized by abnormal deposition of proteins in the cornea. This condition is caused by mutations in the TGFBI gene, which codes for a protein that plays a crucial role in maintaining the structure and function of the cornea.

Key Features:

• Abnormal Protein Deposition: The disease is marked by the accumulation of abnormal proteins in the corneal epithelium and stroma.
• Inherited Condition: Epithelial-stromal TGFBI dystrophy is inherited in an autosomal dominant pattern, meaning that a single copy of the mutated gene is sufficient to cause the condition.
• Non-Inflammatory: Unlike other corneal disorders, epithelial-stromal TGFBI dystrophy is non-inflammatory, meaning that it does not involve inflammation or immune system activation.

Causes and Risk Factors:

• Genetic Mutations: The disease is caused by mutations in the TGFBI gene, which can lead to abnormal protein deposition in the cornea.
• Corneal Surgeries: Surface corneal surgeries can induce a wound in the stromal layer, leading to upregulation of TGFBI expression and potentially triggering the disease.

References:

• [1] Epithelial-stromal dystrophies are caused by mutations in transforming growth factor beta-induced (TGFβI) gene, also known as the BIGH3 gene ... [2]
• A corneal dystrophy that is characterized by abnormal deposition of proteins in the cornea and is caused by mutations in TGFBI gene of chromosome 5q. [6][9]
• The majority of anterior corneal dystrophies are caused by dominant mutations in TGFBI collectively known as the epithelial-stromal TGFBI ... [8][10]

Clinical Signs and Symptoms

Epithelial-stromal TGFBI dystrophy, a type of inherited corneal disorder, presents with several clinical signs and symptoms.

• Abnormal Epithelial Adhesion: When stromal dystrophies involve the anterior cornea, abnormal epithelial adhesion may lead to painful erosions [2].
• Endothelial Guttata: Clinical signs include endothelial guttata, stromal or epithelial edema, bullae, low endothelial cell counts, or even corneal scarring with chronicity (Figure 3) [3].
• Decreased Vision and Photophobia: Patients may be symptomatic for decreased vision, photophobia, tearing, redness, and foreign body sensation [4].
• Mild to Moderate Pain: Many patients with a corneal dystrophy are asymptomatic, but those who do present with symptoms typically report mild to moderate pain, bilateral vision disturbances, and recurrent epithelial erosions [6].

Early Symptoms

The earliest symptoms of epithelial-stromal TGFBI dystrophy are usually due to recurrent epithelial erosions and blurring of vision caused by epithelial irregularity. As the central haze progresses, patients may experience more severe visual impairment [7].

Complications and Prognosis

Complications such as scarring from recurrent corneal erosions can result in loss of best corrected visual acuity. The prognosis is very poor once opacities have coalesced and the entire cornea is affected, with affected individuals usually experiencing severe visual impairment before the fifth decade of life [8].

References: [1] Not applicable [2] Jan 6, 2024 [3] Clinical signs include endothelial guttata, stromal or epithelial edema, bullae, low endothelial cell counts or even corneal scarring with chronicity (Figure 3) [4] Sep 15, 2021 [5] Not applicable [6] Many patients with a corneal dystrophy are asymptomatic, but those who do present with symptoms typically report mild to moderate pain, bilateral vision disturbances, and recurrent epithelial erosions. [7] The earliest symptoms are usually due to recurrent epithelial erosions and blurring of vision caused by epithelial irregularity. As the central haze progresses ... [8] Oct 16, 2024

Diagnostic Tests for Epithelial-Stromal TGFBI Dystrophy

Epithelial-stromal TGFBI dystrophies can be diagnosed based on a combination of clinical evaluation, patient history, and various diagnostic tests. Here are some of the key diagnostic tests used to diagnose this condition:

• Slit Lamp Examination: A thorough slit lamp examination is essential for diagnosing epithelial-stromal TGFBI dystrophies. This test allows clinicians to examine the cornea and detect any abnormalities in the epithelium, stroma, or endothelium [3].
• Commercially Available Genetic Test: A commercially available genetic test can detect the five most common mutations (R124H, R124C, R124L, R555W, and R555Q) associated with TGFBI dystrophies [1][2][4]. This test is particularly useful for confirming a diagnosis.
• Next-Generation Sequencing (NGS): NGS can be used to distinguish which TGFBI mutation the patient may have or if other mutations in other genes that are known to cause similar conditions are present [6].
• Clinical Evaluation and Patient History: A thorough clinical evaluation, including a detailed patient history, is essential for diagnosing epithelial-stromal TGFBI dystrophies. This involves examining the patient's medical history, family history, and any previous eye problems [9][10].

References:

[1] Chao-Shern C (2019) - At present one commercially available test examines for the five most common of these mutations: R124H, R124C, R124L, R555W, and R555Q.

[2] Chao-Shern C (2019) - A commercially available genetic test has been developed that can detect within the TGFBI gene the five most common mutations which are linked to epithelial-stromal corneal dystrophies.

[3] Nov 30, 2020 - TFGBI-associated corneal dystrophies can be diagnosed based on history and slit lamp examination.

[4] Chao-Shern C (2019) - At present one commercially available test examines for the five most common of these mutations: R124H, R124C, R124L, R555W, and R555Q. To date, 70 different TGFBI mutations that cause epithelial-stromal corneal dystrophies have been described.

[5] Aug 20, 2015 - Epithelial-stromal dystrophies are caused by mutations in transforming growth factor beta-induced (TGFβI) gene, also known as the BIGH3 gene.

[6] Nithianandan H (2019) - Furthermore, NGS can be used to distinguish which TGFBI mutation the patient may have or if other mutations in other genes that are known to cause similar conditions are present.

[7] Evans CJ (2016) - We evaluated the spectrum of TGFBI mutations and associated phenotypes in a United Kingdom cohort with typical epithelial-stromal TGFBI dystrophies and an EBMD.

[8] Chao-Shern C (2019) - To date, 70 different TGFBI mutations that cause epithelial-stromal corneal dystrophies have been described. At present one commercially available test examines for the five most common of these mutations: R124H, R124C, R124L, R555W, and R555Q.

[9] May 1, 2024 - A diagnosis may be confirmed by a thorough clinical evaluation, a detailed patient history and a variety of tests, such as a slit lamp examination.

[10] Oct 16, 2024 - Clinical diagnosis. The clinical diagnosis is based on history and physical exam. Diagnostic procedures. No procedures are required for diagnosing epithelial-stromal TGFBI dystrophies.

Current Drug Treatments for Epithelial-Stromal TGFBI Dystrophy

Epithelial-stromal TGFBI dystrophies are a group of inherited progressive corneal diseases caused by mutations in the transforming growth factor beta-induced (TGFBI) gene. While there is no cure for these conditions, various drug treatments have been explored to manage and potentially slow down disease progression.

• Losartan: Losartan, an angiotensin II receptor blocker (ARB), has been shown to inhibit transforming growth factor (TGF) beta signaling by blocking the activation of signal transduction pathways [4]. This mechanism may help in reducing corneal scarring and inflammation associated with TGFBI dystrophies.
• Lithium chloride: Studies have found that lithium chloride decreases TGFBI protein production, which could potentially inhibit disease progression [2].
• Melatonin and rapamycin combination: A combined treatment of melatonin and rapamycin has been shown to inhibit TGF-BI signaling pathways, offering a potential therapeutic approach for managing epithelial-stromal TGFBI dystrophies [2].

Gene-Based Therapies

In addition to drug treatments, gene-based therapies are being explored as promising approaches for treating corneal diseases, including TGFBI dystrophies. These include:

• Gene supplementation: This involves introducing a healthy copy of the TGFBI gene into cells to replace the mutated one.
• Gene silencing: Techniques such as allele-specific short hairpin RNA (shRNA) can be used to silence the expression of the mutated TGFBI gene, reducing disease-causing effects [9].
• Gene editing: Gene editing technologies like CRISPR/Cas9 may offer a precise and efficient way to correct TGFBI mutations in cells.

Future Directions

While these treatments show promise, further research is needed to fully understand their efficacy and potential side effects. Ongoing studies are investigating the effectiveness of these approaches in managing epithelial-stromal TGFBI dystrophies and other corneal diseases.

References:

[1] Sciriha GG (2023) - Effective topical medications for minimally invasive treatment of TGFBI CD patients. [2] Chang MS (2023) - Combined treatment of melatonin and rapamycin inhibits TGF-BI signaling pathways. [4] Wilson SE (2023) - Losartan impedes transforming growth factor beta signaling by blocking signal transduction pathways. [5] Han KE (2016) - Transforming growth factor beta-induced (TGFBI) corneal dystrophies: a group of inherited progressive corneal diseases. [6] Ashena Z (2023) - Treatment options for epithelial-stromal and stromal corneal dystrophies. [7] Salman M (2022) - Gene-based therapy in the treatment of corneal diseases. [8] Chao-Shern C (2019) - Worldwide distribution and population differences of TGFBI mutations. [9] (2021) - Gene/allele-based therapies for treating corneal diseases.

The differential diagnosis of epithelial-stromal TGFBI dystrophy involves distinguishing it from other corneal dystrophies and conditions that may present with similar symptoms.

According to the available information, the most important clinical differential diagnosis is between epithelial-stromal TGFBI dystrophy and macular corneal dystrophy [5]. While both conditions have a similar corneal appearance, macular corneal dystrophy has less severe symptoms.

Other conditions that may be considered in the differential diagnosis of epithelial-stromal TGFBI dystrophy include:

• Epithelial and subepithelial dystrophies
• Stromal dystrophies
• Endothelial dystrophies

It's worth noting that anterior segment optical coherence tomography (AS-OCT) has improved the diagnostic accuracy for corneal dystrophies, including epithelial-stromal TGFBI dystrophy [15].

In terms of specific conditions, Reis-Bücklers corneal dystrophy and Thiel-Behnke corneal dystrophy are two types of epithelial-stromal TGFBI dystrophies that may be considered in the differential diagnosis.

References:

• [5]
• [15]