ADAMTSL4-related eye disorders are rare autosomal recessive conditions characterized by lens displacement (ectopia lentis), often with pupillary displacement in some cases (ectopia lentis et pupillae). The ADAMTSL4 gene encodes a secreted glycoprotein that binds to fibrillin-1 microfibrils in the extracellular matrix, playing a crucial role in the formation and stability of the zonular fibers that suspend the lens; pathogenic biallelic variants lead to truncated or dysfunctional protein, resulting in weakened zonules and subsequent lens dislocation. These disorders typically present in early childhood, with a median age at diagnosis around 2–3 years, and most cases exhibit isolated ocular findings with rare systemic involvement such as craniosynostosis EyeWikiPMC.
ADAMTSL4-related eye disorders are a group of inherited conditions caused by biallelic mutations in the ADAMTSL4 gene, which encodes an extracellular matrix protein essential for the formation and maintenance of the zonular fibers that suspend the crystalline lens. Clinically, this continuum ranges from autosomal recessive isolated ectopia lentis—where the lens is displaced without other ocular anomalies—to ectopia lentis et pupillae, which also involves pupillary displacement. Patients often present in childhood with lens subluxation or dislocation in any direction, iris abnormalities, refractive errors leading to amblyopia, early-onset cataract, and occasionally increased intraocular pressure or retinal detachment. Zonal fiber weakness is the principal pathogenic mechanism: loss of ADAMTSL4 function disrupts microfibril assembly in the ciliary zonule, causing lens instability NCBIJournal of Medical Case Reports.
Types of ADAMTSL4-Related Eye Disorders
Autosomal Recessive Isolated Ectopia Lentis (ECTOL2).
In this most common phenotype, bilateral lens subluxation occurs without pupillary displacement or systemic manifestations. Patients display variable directions of lens dislocation but lack significant involvement of other ocular structures WikipediaThinkGenetic Foundation.
Ectopia Lentis et Pupillae (ELeP).
Here, the lens and pupil are displaced in opposite directions, producing iris coloboma and megalocornea. Despite these characteristic anterior segment anomalies, systemic features are generally absent ThinkGenetic Foundation.
Ectopia Lentis with Craniosynostosis.
A rarer presentation involves lens subluxation accompanied by premature cranial suture closure, suggesting occasional skeletal involvement and hinting at broader roles of ADAMTSL4 in extracellular matrix biology EyeWiki.
Genetic Causes
Below are fifteen pathogenic ADAMTSL4 variants—each leading to dysfunctional protein and zonular fiber instability:
c.767_786del20 (p.Gln256ProfsTer38). A founder frameshift deletion common in European populations that truncates ADAMTSL4, disrupting zonule assembly EyeWiki.
c.1785T>G. A nonsense mutation in exon 11 introducing a premature stop codon, yielding truncated protein and loss of function PreventionGenetics.
c.2177+4A>G. An intronic splice-site variant causing exon 11 skipping and nonsense-mediated mRNA decay, markedly reducing protein levels PubMed.
c.2237G>A (p.Arg746His). A missense change in the thrombospondin domain that impairs fibrillin-1 binding and extracellular matrix interactions EyeWiki.
c.2594G>A (p.Arg865His). Alters a critical residue in a conserved domain, weakening microfibril stabilization EyeWiki.
c.2663G>A (p.Arg888His). Single amino acid substitution that disrupts zonular fiber adhesion EyeWiki.
c.21-2A>G. Splicing mutation at exon-intron junction leading to aberrant transcripts and absent functional protein in Chinese cohorts PubMed.
c.1174G>C (p.Gly392Arg). Missense variant affecting protein folding and secretion in the extracellular matrix PubMed.
c.2169C>A (p.Asn723Lys). Predicted to alter a conserved residue, disturbing protein conformation and microfibril formation PubMed.
c.2236C>T (p.Arg746Cys). Disrupts disulfide bonding within the TSP1-like domain, weakening structural integrity PubMed.
c.2263delG (p.Gly755fs). Frameshift causing premature termination and rapid degradation of ADAMTSL4 PubMed.
c.2397C>A (p.Asp799Glu). Changes a charged residue, impairing protein-microfibril interactions PubMed.
c.2488dupC (p.Leu830ProfsTer7). Duplication leading to truncation via nonsense-mediated decay PubMed.
c.2935T>C (p.Ser979Pro). Substitution of a serine in a conserved region, likely compromising post-translational folding PubMed.
Other intronic/promoter mutations. Rare non-coding variants affecting ADAMTSL4 transcription or splicing have also been implicated in zonular fiber dysfunction NCBI.
Symptoms
Lens Subluxation. Partial dislocation of the clear crystalline lens due to zonular weakness, causing visual distortion. NCBI
Pupillary Displacement. In ELeP, the pupil shifts opposite the lens, leading to irregular pupil shape and asymmetric light entry. ThinkGenetic Foundation
Refractive Errors. High myopia, hyperopia, or astigmatism from lens malposition, resulting in blurred vision. NCBI
Amblyopia. ‘Lazy eye’ develops if childhood refractive errors remain uncorrected, impairing visual pathway maturation. NCBI
Early-Onset Cataract. Opacification of lens fibers due to instability accelerates cataract formation. NCBI
Elevated Intraocular Pressure. Anterior lens subluxation may obstruct aqueous flow, raising eye pressure and glaucoma risk. NCBI
Retinal Detachment. Increased risk from lens instability or post-surgical changes, potentially leading to vision loss. PMC
Iris Transillumination. Thinned iris tissue lets light shine through, revealing transillumination defects. NCBI
Increased Axial Length. Abnormal ocular growth responses have been observed, possibly linked to lens malposition and refractive shifts. EyeWiki
Photophobia. Light sensitivity from irregular pupil and lens positions, causing discomfort in bright environments. ThinkGenetic Foundation
Diagnostic Tests
Visual Acuity Assessment. Standard chart testing to quantify clarity loss from lens displacement. NCBI
Refraction Testing. Determines corrective lens prescription for induced myopia, hyperopia, or astigmatism. NCBI
Tonometry. Measures intraocular pressure to detect ocular hypertension from lens-induced angle closure. NCBI
Slit-Lamp Examination. High-magnification view of the anterior segment to evaluate lens position and iris anomalies. NCBI
Dilated Fundus Exam. Ophthalmoscopy of the retina for complications like retinal detachment. NCBI
Lens Wobble Test. Gentle eye movements to elicit dynamic lens shift, confirming zonular fiber weakness. NCBI
Iris Transillumination Test. Light shone through the iris to detect transillumination defects. NCBI
Genetic Panel Testing. Next-generation sequencing including ADAMTSL4 to identify biallelic pathogenic variants. NCBI
Sanger Sequencing. Confirms specific ADAMTSL4 variants and refines genotype interpretation. NCBI
Serum Homocysteine. Differentiates from homocystinuria (which can mimic ectopia lentis) by measuring homocysteine levels. NCBI
Histopathology of Excised Lens Capsule. Microscopic examination reveals zonular fiber disorganization. NCBI
Electroretinography (ERG). Assesses retinal cell function, useful if media opacity hinders fundus view. Wikipedia
Visual Evoked Potentials (VEP). Measures cortical responses to visual stimuli, detecting functional deficits from amblyopia. Wikipedia
Electrooculography (EOG). Evaluates outer retinal and RPE integrity via standing potential changes. Wikipedia
Anterior Segment OCT. High-resolution optical imaging of anterior structures, visualizing zonules and lens tilt. Wikipedia
Ultrasound Biomicroscopy (UBM). High-frequency ultrasound for microscopic imaging of zonular fibers and iris. Wikipedia
A-Scan Biometry. Measures axial length and lens thickness to guide lensectomy planning. Wikipedia
B-Scan Ultrasonography. Cross-sectional ultrasound of the posterior segment to detect detachment when the view is limited. Wikipedia
Orbital CT. X-ray tomography to exclude trauma or mass lesions affecting lens position. Wikipedia
Orbit MRI. Soft-tissue contrast imaging to assess extraocular structures and rule out alternative pathologies. Wikipedia
Non-Pharmacological Treatments
Conservative (non-drug) management focuses on optimizing vision, preventing amblyopia, and protecting the eye from trauma. Below are 20 evidence-based approaches categorized by modality.
A. Physiotherapy and Electrotherapy Therapies
Orthoptic Eye-Muscle Exercises
• Description: Guided exercises that train extraocular muscles to improve alignment and binocular coordination.
• Purpose: Enhance ocular motility and reduce diplopia caused by lens subluxation.
• Mechanism: Repetitive, targeted movements strengthen neuromuscular control of eye muscles, promoting better fusion of images NCBI.Saccadic Training
• Description: Rapid-motion drills that shift gaze between fixed targets.
• Purpose: Improve quick eye movements and reading speed despite lens displacement.
• Mechanism: Neuroplastic adaptation accelerates saccadic burst neuron responsiveness.Pursuit (Tracking) Exercises
• Description: Slow tracking of a moving object horizontally, vertically, and diagonally.
• Purpose: Maintain smooth pursuit despite irregular light refraction.
• Mechanism: Enhances cortical-pontine-cerebellar pathways for steady image tracking.Transcorneal Electrical Stimulation (TcES)
• Description: Low-intensity electrical currents delivered via corneal electrodes.
• Purpose: Support retinal cell survival and improve visual function.
• Mechanism: Stimulates neurotrophic factor release, aiding retinal ganglion cell health Cleveland Clinic.Low-Level Laser Therapy (LLLT)
• Description: Application of near-infrared laser light to periocular tissues.
• Purpose: Reduce oxidative stress and inflammation from lens instability.
• Mechanism: Photobiomodulation enhances mitochondrial function and cellular repair.Interferential Current Therapy
• Description: Medium-frequency alternating electrical currents applied around the orbit.
• Purpose: Relieve periocular muscle fatigue and discomfort.
• Mechanism: Deep tissue stimulation improves microcirculation and reduces edema.Therapeutic Ultrasound
• Description: High-frequency sound waves targeted at the ciliary region.
• Purpose: Promote zonular fiber health and reduce adhesions.
• Mechanism: Mechanical vibrations enhance cellular permeability and protein synthesis.Infrared Light Therapy
• Description: Exposure of the closed eyelid to IR light.
• Purpose: Alleviate subclinical inflammation around ciliary body.
• Mechanism: Heat-induced vasodilation supports nutrient delivery to zonular cells.Microcurrent Electrical Stimulation (MES)
• Description: Subsensory electrical current applied via periocular pads.
• Purpose: Stimulate repair of microfibrillar matrix.
• Mechanism: Activates ATP production and cell signaling cascades.Virtual Reality (VR) Vision Stimulation
• Description: Immersive visual tasks in a VR headset.
• Purpose: Train depth perception and accommodative facility.
• Mechanism: Controlled visual challenges activate cortical integration of binocular input.
B. Exercise Therapies
Accommodation Flexibility Drills
• Description: Alternating focus between near and far targets.
• Purpose: Enhance lens-ciliary muscle coordination despite zonular weakness.
• Mechanism: Stimulates dynamic changes in lens curvature and ciliary contraction.Convergence-Divergence Training
• Description: Pencil push-up and Brock string exercises.
• Purpose: Improve convergence insufficiency and reduce diplopia.
• Mechanism: Strengthens medial and lateral rectus muscle synergy.Dynamic Visual Acuity (DVA) Workouts
• Description: Reading moving text or identifying moving objects at various speeds.
• Purpose: Maintain clear vision during head movements.
• Mechanism: Trains vestibulo-ocular reflex to stabilize images.Eye-Hand Coordination Drills
• Description: Catch-and-throw tasks with varied speeds and distances.
• Purpose: Reinforce spatial mapping under suboptimal visual input.
• Mechanism: Integrates proprioceptive and visual feedback pathways.Peripheral Awareness Training
• Description: Responding to peripheral stimuli while fixating centrally.
• Purpose: Reduce risk of peripheral visual field neglect.
• Mechanism: Enhances attentional distribution across the retina.
C. Mind-Body Therapies
Trataka (Yogic Gazing Meditation)
• Description: Focused staring at a candle flame or point.
• Purpose: Improve ocular stamina and mental concentration.
• Mechanism: Sustained fixation reduces saccadic intrusions and calms sympathetic overdrive.Guided Relaxation and Meditation
• Description: Progressive muscle relaxation with visual imagery.
• Purpose: Lower intraocular pressure spikes due to stress.
• Mechanism: Modulates autonomic balance, decreasing cortisol-mediated inflammation.Biofeedback-Assisted Vision Training
• Description: Real-time IOP or eye-movement feedback during relaxation.
• Purpose: Teach patients to self-regulate ocular parameters.
• Mechanism: Operant conditioning of physiological processes via continuous feedback.
D. Educational Self-Management
Structured Patient Education Programs
• Description: Workshops detailing lens subluxation signs, prevention, and visual hygiene.
• Purpose: Empower patients and caregivers to recognize early complications.
• Mechanism: Knowledge transfer enhances adherence to protective behaviors.Low-Vision Self-Management Workshops
• Description: Training in use of magnifiers, lighting optimization, and assistive apps.
• Purpose: Maximize functional independence despite refractive challenges.
• Mechanism: Teaches adaptive strategies that exploit residual vision.
Pharmacological Treatments
Symptomatic drug therapy addresses secondary complications such as elevated intraocular pressure, inflammation, amblyopia, and cataract-related factors.
Timolol Maleate 0.5% Eye Drops
• Class & Indication: Non-selective β-blocker for secondary glaucoma management.
• Dosage & Timing: 1 drop in affected eye twice daily.
• Side Effects: Bradycardia, bronchospasm, ocular irritation NCBI.Latanoprost 0.005% Eye Drops
• Class & Indication: Prostaglandin analog for IOP reduction.
• Dosage & Timing: 1 drop nightly.
• Side Effects: Iris pigmentation changes, eyelash growth.Dorzolamide 2% Eye Drops
• Class & Indication: Topical carbonic anhydrase inhibitor.
• Dosage & Timing: 1 drop three times daily.
• Side Effects: Bitter taste, ocular burning.Brimonidine 0.2% Eye Drops
• Class & Indication: α₂-agonist for IOP control and neuroprotection.
• Dosage & Timing: 1 drop three times daily.
• Side Effects: Dry mouth, fatigue.Acetazolamide 250 mg Oral Tablet
• Class & Indication: Systemic carbonic anhydrase inhibitor for acute IOP spikes.
• Dosage & Timing: One tablet two to three times daily.
• Side Effects: Paresthesia, metabolic acidosis.Prednisolone Acetate 1% Eye Drops
• Class & Indication: Topical corticosteroid for postoperative inflammation.
• Dosage & Timing: 1 drop four times daily for 1–2 weeks.
• Side Effects: Elevated IOP, cataract progression.Diclofenac 0.1% Eye Drops
• Class & Indication: NSAID for postoperative pain and inflammation.
• Dosage & Timing: 1 drop four times daily.
• Side Effects: Stinging, delayed wound healing.Pilocarpine 2% Eye Drops
• Class & Indication: Cholinergic agonist for mild angle-closure risk.
• Dosage & Timing: 1 drop four times daily.
• Side Effects: Brow ache, miosis.Tropicamide 1% Eye Drops
• Class & Indication: Mydriatic/cycloplegic for diagnostic pupil dilation.
• Dosage & Timing: 1 drop 30 minutes before exam.
• Side Effects: Photophobia, blurred near vision.Atropine 1% Eye Drops
• Class & Indication: Antimuscarinic for amblyopia penalization.
• Dosage & Timing: 1 drop once daily in the non-amblyopic eye.
• Side Effects: Cycloplegia, dry mouth.
Dietary Molecular Supplements
Antioxidant and micronutrient support can protect ocular tissues from oxidative stress and support extracellular matrix health.
Lutein (10 mg/day)
• Function: Macular pigment antioxidant.
• Mechanism: Filters blue light, scavenges free radicals Healthline.Zeaxanthin (2 mg/day)
• Function: Complementary macular antioxidant.
• Mechanism: Stabilizes cell membranes against photo-oxidation Healthline.Omega-3 Fatty Acids (DHA/EPA 1 g/day)
• Function: Anti-inflammatory for retina.
• Mechanism: Incorporates into photoreceptor membranes, modulates eicosanoid production.Vitamin C (500 mg/day)
• Function: Water-soluble antioxidant.
• Mechanism: Regenerates other antioxidants, protects lens proteins.Vitamin E (400 IU/day)
• Function: Lipid-soluble antioxidant.
• Mechanism: Prevents lipid peroxidation in cell membranes.Zinc (80 mg/day)
• Function: Cofactor for superoxide dismutase.
• Mechanism: Stabilizes cell membranes, supports antioxidant enzymes Wikipedia.β-Carotene (15 mg/day)
• Function: Provitamin A.
• Mechanism: Converts to retinol for photoreceptor function.N-Acetylcysteine (600 mg TID)
• Function: Glutathione precursor.
• Mechanism: Enhances intracellular antioxidant capacity.Alpha-Lipoic Acid (200 mg/day)
• Function: Regenerates vitamins C and E.
• Mechanism: Multifunctional antioxidant and metal chelator.Bilberry Extract (80 mg BID)
• Function: Anthocyanin-rich antioxidant.
• Mechanism: Improves microvascular circulation in retina.
Advanced Specialized Therapies
Emerging and adjunctive interventions target tissue regeneration or structural support.
Netarsudil 0.02% Eye Drops (Regenerative)
• Dosage: 1 drop nightly.
• Function: Rho kinase inhibitor.
• Mechanism: Enhances trabecular outflow and remodels extracellular matrix EyeWiki.Cenegermin (0.002%) Eye Drops (Regenerative)
• Dosage: 1 drop six times daily.
• Function: Recombinant nerve growth factor.
• Mechanism: Promotes corneal nerve regeneration.Hyaluronic Acid Intraocular Injection (Viscosupplementation)
• Dosage: Intraoperative as needed.
• Function: Maintains anterior chamber depth.
• Mechanism: Viscoelastic support of ocular structures.Sodium Hyaluronate Eye Drops (0.1%) (Viscosupplementation)
• Dosage: 1 drop TID.
• Function: Tear film stabilization.
• Mechanism: Provides viscoelastic lubrication for corneal protection.Pamidronate 30 mg IV Monthly (Bisphosphonate)
• Dosage: 30 mg infusion once monthly.
• Function: Inhibits matrix metalloproteinases.
• Mechanism: Reduces extracellular matrix degradation.Holoclar® Autologous Limbal Stem Cell Transplant (Stem Cell Drug)
• Dosage: Single surgical application.
• Function: Regenerates corneal epithelium.
• Mechanism: Transplantation of cultured limbal stem cells to restore ocular surface Journal of Medical Case Reports.
Surgical Treatments
Surgery is indicated when conservative measures fail to provide adequate vision or when complications arise.
Lensectomy with Scleral-Fixated Intraocular Lens (IOL) Implantation
• Procedure: Removal of subluxated lens via limbal or pars plana approach, followed by suture fixation of a three-piece IOL to the scleral wall.
• Benefits: Restores axial focus and binocular symmetry, reducing anisometropia and amblyopia risk ScienceDirect.Pars Plana Vitrectomy with Lens Removal
• Procedure: Posterior segment approach to remove vitreous and dislocated lens fragments, often combined with IOL implantation.
• Benefits: Prevents retinal traction, addresses vitreous opacities, and restores anterior chamber integrity MDPI.Capsular Tension Ring (CTR) Insertion
• Procedure: Placement of a flexible ring into the capsular bag to distribute equatorial forces.
• Benefits: Stabilizes zonular-compromised lens capsule, facilitating in-the-bag IOL placement ResearchGate.Iris Repair and Pupilloplasty
• Procedure: Suturing or sector iridoplasty to reposition a displaced iris and reconstruct a functional pupil.
• Benefits: Improves cosmesis, reduces photophobic symptoms, and optimizes light entry.Scleral-Sutured Iris-Claw IOL Implantation
• Procedure: Fixation of an iris-claw lens to the mid-peripheral iris via transscleral sutures.
• Benefits: Offers a secure alternative when capsular support is absent and reduces risk of IOL decentration.
Prevention Strategies
Protective Eyewear: Wear polycarbonate goggles during sports and labor to prevent trauma.
Genetic Counseling: For at-risk couples to understand autosomal recessive inheritance.
Regular Eye Exams: Comprehensive pediatric ophthalmology visits every 6–12 months.
UV Protection: Use sunglasses with UV-blocking lenses outdoors.
Control Systemic Health: Manage hypertension and diabetes to prevent secondary ocular damage.
Avoid Smoking: Smoking increases oxidative stress in ocular tissues.
Nutrient-Rich Diet: Include leafy greens and fatty fish for antioxidant and anti-inflammatory support.
Screen Time Breaks: Follow the 20-20-20 rule to reduce digital eye strain.
Blood Sugar Management: In diabetic carriers, tight glycemic control reduces cataract risk.
Prompt Trauma Care: Seek immediate evaluation after any ocular injury.
When to See a Doctor
Seek specialist care if you experience sudden vision changes (e.g., sudden blurring, double vision), eye pain, flashes of light, new onset floaters, halos around lights, or any signs of increased pressure (headache, nausea). Early intervention in lens dislocation, secondary glaucoma, or retinal detachment can preserve vision and prevent amblyopia in children Cleveland Clinic.
What to Do and What to Avoid
Do maintain consistent use of prescribed eye drops; Avoid skipping doses.
Do wear corrective lenses as advised; Avoid outdated or ill-fitting prescriptions.
Do practice recommended vision exercises daily; Avoid strenuous eye-straining activities without breaks.
Do attend all scheduled follow-ups; Avoid delaying evaluations after symptom changes.
Do use protective eyewear; Avoid contact sports without eye guards.
Do adhere to antioxidant-rich diet; Avoid excessive processed foods.
Do monitor IOP if at risk; Avoid OTC steroids without medical advice.
Do report any new floaters or flashes; Avoid self-medicating with unverified supplements.
Do engage in low-impact exercise; Avoid heavy lifting that spikes blood pressure.
Do seek genetic counseling for family planning; Avoid assumptions about carrier status.
Frequently Asked Questions (FAQs)
What causes ADAMTSL4-related eye disorders?
These disorders result from loss-of-function mutations in both copies of the ADAMTSL4 gene, leading to zonular fiber weakness and lens instability NCBI.How common is this condition?
It is rare; precise prevalence is unknown but it accounts for a small fraction of congenital ectopia lentis cases.Is genetic testing available?
Yes—targeted gene panels or whole exome sequencing can identify pathogenic ADAMTSL4 variants.Can children with this disorder develop amblyopia?
Yes—lens displacement can cause significant refractive error and anisometropia, risking amblyopia if not promptly managed.Are there lifestyle changes to improve outcomes?
Protective eyewear, dietary antioxidants, and regular vision exercises support structural integrity and function.Will eye drops cure the disorder?
No—drops manage complications (e.g., elevated IOP, inflammation) but do not correct the underlying genetic defect.Is surgery always required?
Not always; mild subluxations can be managed conservatively, but significant displacement or complications often necessitate surgical intervention.What are the surgical risks?
Risks include retinal detachment, infection, IOL decentration, and postoperative inflammation.How effective are viscoelastic injections?
Intraoperative viscoelastics facilitate safer surgeries but do not provide long-term lens support.Can gene therapy help?
Research is preliminary; future therapies may target ADAMTSL4 replacement but are not yet clinically available.How often should follow-ups occur?
Typically every 6–12 months, or sooner if symptoms worsen.Is stem cell therapy an option?
Limbal stem cell transplantation (e.g., Holoclar) can restore corneal surface but does not address lens displacement.Can carriers develop mild symptoms?
Carriers (single-copy mutation) are usually asymptomatic but should be counseled about reproductive risks.What other ocular conditions can mimic this disorder?
Marfan syndrome (FBN1-associated ectopia lentis), Weill-Marchesani syndrome, and homocystinuria may present similarly.Where can I find support?
Low-vision associations, pediatric cataract and glaucoma foundations, and genetic counseling services offer resources and community support.
Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.
The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members
Last Updated: July 10, 2025.
