ADAMTSL4-related eye disease is a collective term for hereditary eye diseases caused by mutations in the ADAMTSL4 gene. The main clinical phenotypes are shown below.
This disease is usually bilateral but often asymmetric. It is not accompanied by systemic skeletal or cardiovascular abnormalities, and ocular symptoms appear alone, which is an important distinguishing point from Marfan syndrome.
ADAMTSL4 gene mutations are known as the second most common cause of isolated ectopia lentis after FBN1 mutations1). In a Chinese cohort study (175 cases), ADAMTSL4 mutations were detected in 19.2% of isolated ectopia lentis cases1).
The exact prevalence is unknown, but cohort studies worldwide have reported cases in various ethnic groups. Specific pathogenic mutations appear at high frequency within ethnic populations due to founder effects.
Representative founder mutations and their frequencies are shown below.
In principle, only ocular symptoms occur, and no systemic skeletal or cardiovascular abnormalities are observed. However, three cases of association with craniosynostosis have been reported, and although rare, the possibility of systemic skeletal involvement has not been completely excluded. Unlike Marfan syndrome, regular cardiology visits are not necessary.
Patients with ADAMTSL4-related eye disease typically present in early childhood (median age at diagnosis 2–3 years) with the following symptoms1).
In early or mild cases, the condition may be asymptomatic and discovered incidentally during refractive correction.
Anterior segment findings range from mild to severe and may be asymmetric between the two eyes.
Lens and Zonules
Lens dislocation: The direction of displacement is variable. Unlike homocystinuria (inferonasal) or Marfan syndrome (superotemporal), it does not show a consistent direction.
Elongated zonules: Unlike the zonular defects in homocystinuria, the weakened zonules characteristically rupture in the middle portion.
Microspherophakia: Loss of zonular traction causes the lens to become spherical, leading to high myopia.
Phacodonesis: The lens trembles during eye movements.
Iris and Anterior Segment
Corectopia: Displacement of the iris and pupil. A characteristic feature of the lens-pupil dislocation phenotype.
Persistent pupillary membrane: Frequently observed in cases of lens-pupil dislocation.
Iris transillumination defects: Pigment defects seen on iris transillumination.
Mydriasis failure: Observed in cases of lens-pupil dislocation.
Posterior segment findings are relatively rare, but important complications include the following.
Elongation of axial length not only directly causes high myopia but also increases the risk of retinal detachment through lattice degeneration and retinal thinning. Retinal detachment has been reported at a higher frequency in patients with ADAMTSL4 mutations compared to the general population, making regular dilated fundus examinations important2).
The ADAMTSL4 gene is located on chromosome 1 at 1q21.2 and contains 17 coding exons. The inheritance pattern of pathogenic variants is autosomal recessive (AR), and both parents are asymptomatic heterozygous carriers.
To date, more than 13 pathogenic mutations have been reported. Types of mutations include the following.
The most common mutation is a 20-base pair deletion in exon 6 (c.767_786del), accounting for 58% of known cases in European populations 2). In Guo et al.’s Chinese cohort, 87.5% of ADAMTSL4 mutations were compound heterozygous mutations 1).
Heterozygous carriers do not develop lens dislocation; loss of function in both alleles (homozygous or compound heterozygous) is required for onset.
Because this is an autosomal recessive disorder, siblings born to the same parents as an affected child have a 25% chance of having the same mutation. Genetic testing can identify siblings who are homozygous or compound heterozygous for the mutation even if they are asymptomatic. Early diagnosis allows timely treatment for amblyopia, improving visual outcomes.
Diagnosis is made by combining medical history, family history, and detailed ophthalmic examination. The following tests are necessary.
Definitive diagnosis requires genetic testing to identify pathogenic ADAMTSL4 variants. The following testing strategies are available.
Next-generation sequencing (NGS) panels including multiple genes involved in ectopia lentis have a high diagnostic rate, with one study of 24 cases identifying a genetic cause in 67% (16/24) 1). Combining genetic testing with clinical data has been reported to increase the diagnostic rate from 19.43% to 40.57% 1).
After confirmation in the proband, cascade testing for family members is recommended.
It is important to differentiate from hereditary diseases with ectopia lentis as the main feature. A comparison of the three major diseases is shown below.
| Feature | ADAMTSL4-related | Marfan syndrome | Homocystinuria |
|---|---|---|---|
| Inheritance pattern | Autosomal recessive | Autosomal dominant | Autosomal recessive |
| Age at diagnosis | 2–3 years | 19 years (median) | Newborn to infant |
| Dislocation direction | Variable | Superotemporal (common) | Inferonasal / anterior |
| Systemic findings | Generally none | Cardiovascular / skeletal abnormalities | Developmental delay / thrombosis |
Marfan syndrome, like ADAMTSL4 mutations, is based on fibrillin-1 dysfunction, but differs in that it is autosomal dominant, 75% of patients have an affected parent, and it involves systemic abnormalities of the cardiovascular and skeletal systems. In homocystinuria, elevated plasma homocysteine causes early formation defects of the zonules, resulting in absent or short, disorganized remnants, which can be differentiated from ADAMTSL4 mutations by slit-lamp findings where the zonules are elongated and break in the middle.
Other differential diagnoses: Weill-Marchesani syndrome (ADAMTS17 mutation), Traboulsi syndrome, Knobloch syndrome, Cohen syndrome, Loeys-Dietz syndrome, etc.
The treatment strategy is determined based on the degree of lens dislocation, impact on visual function, and patient age.
In mild cases, surgery is not performed, and optical management and amblyopia treatment are prioritized.
In advanced cases, irregular astigmatism that is difficult to correct with refraction occurs, so follow-up observation is essential.
Surgery is indicated in the following cases.
Lens Extraction
Lensectomy and anterior vitrectomy: A common surgical procedure. The lens and anterior vitreous are removed together.
Pars plana vitrectomy (PPV) + lensectomy: A procedure performed by a vitreoretinal surgeon. It has the advantage of allowing simultaneous endolaser treatment for associated lattice degeneration2).
Intraocular Lens (IOL)
Secondary intraocular lens suture fixation: When there is insufficient capsular support, a scleral-sutured intraocular lens is used. Suture fixation with 8-0 PTFE suture has been reported2).
Age-dependent decision: In young children, the eye is left aphakic, and secondary IOL implantation is considered later. In young adults, primary IOL placement is an option2).
In a series of 4 cases reported by Chiang et al., postoperative visual acuity in surgical cases (3 cases) was good, ranging from 20/20 to 20/60 in the non-amblyopic eye2). In an asymptomatic case (1 case), visual acuity of 20/25 was maintained with observation alone2).
Long-term follow-up is necessary after surgery, with continuous monitoring for complications such as glaucoma and retinal detachment. It is especially important to continue amblyopia treatment and refractive correction postoperatively.
Regular follow-up after surgery is essential. In children, continued amblyopia treatment, adjustment of refractive correction, and intraocular pressure management are necessary. Long-term monitoring for complications such as glaucoma, retinal detachment, and intraocular lens dislocation is also important 2). Lifelong ophthalmic management is recommended.
The ADAMTS (A Disintegrin And Metalloproteinase with Thrombospondin motifs) family includes 19 metalloproteases and 7 ADAMTS-like (ADAMTSL) glycoproteins. ADAMTSL4 is a glycoprotein lacking a protease domain that is secreted into the extracellular matrix (ECM) and expressed in the ciliary body, choroid, and retinal pigment epithelium within the eye 1).
Interaction with fibrillin-1: ADAMTSL4 promotes the secretion, assembly, and microfibril formation of fibrillin-1. Cell culture experiments have confirmed that the presence of ADAMTSL4 increases the deposition area and immunofluorescence signal intensity of fibrillin-11).
The zonules of Zinn (ciliary zonules) in the eye are a ring of extracellular fibers composed mainly of fibrillin microfibrils, and they serve to suspend the lens within the lens fossa. ADAMTSL4 mutations are thought to cause the following chain of events.
In homocystinuria, the zonules are deficient due to impaired initial formation, whereas in this disease, the formed zonules rupture due to insufficient tensile strength, a different pathology.
In a mouse experiment by Collin et al. (Adamtsl4-/- knockout mice), detachment of the zonules from the lens and dedifferentiation of the retinal pigment epithelium were observed, and the severity of the retinal pigment epithelium phenotype correlated with axial length elongation 1).
When the lens is freed from zonular traction, it becomes more spherical (spherophakia), causing lens-induced high myopia. Blurring due to lens dislocation promotes axial elongation, forming a vicious cycle that leads to further refractive errors. During this process, irregular lens shape also induces high astigmatism.
The pathological mechanism of iris deformation observed in the lens-pupillary dislocation phenotype remains largely unclear, but the frequent occurrence of persistent pupillary membrane suggests a component of congenital developmental abnormality.
Diagnostic strategies combining next-generation sequencing panels with clinical data are advancing.
Chen TH et al. reported that in a Chinese cohort (175 cases), a diagnostic strategy combining genetic results with clinical data increased the diagnostic rate from 19.43% to 40.57% 1). Panel-based next-generation sequencing is attracting attention as a method for highly accurate genetic diagnosis even in complex phenotypes.
A case series in the Ohio Amish-Mennonite community suggests a founder effect for ADAMTSL4-related ectopia lentis in this population 2). Analysis of five Norwegian families indicates that the c.767_786del mutation traces back to a common ancestor more than 150 generations (over 4000 years) ago 2), and the utility of population genetic screening is discussed.
Chiang et al. estimated the carrier frequency in the Ohio Amish-Mennonite community at 1:54 and reported the clinical significance of the founder effect in the diagnosis and management patterns of isolated ectopia lentis in this population 2).
The optimal age for secondary intraocular lens implantation in children remains under debate. Research also continues on intraocular lens selection for cases with insufficient zonular support.
In Chiang et al.’s report, an age-dependent surgical approach was adopted: younger cases (ages 2 and 7) were left aphakic, while a young adult case (age 17) received a scleral-sutured secondary intraocular lens (8-0 Gore-Tex suture)2). It has been noted that sutureless intrascleral fixation may not be recommended for very young patients due to scleral development considerations.
The fibrillin microfibril formation pathway associated with ADAMTSL4 function is being studied as a target for future gene replacement therapy or molecular targeted therapy, but many challenges remain for clinical application in humans.
Wei H, Meng X, Qin H, Li X. A novel ADAMTSL4 compound heterozygous mutation in isolated ectopia lentis: a case report and review of the literature. Journal of medical case reports. 2023;17(1):532. doi:10.1186/s13256-023-04272-7. PMID:38146062; PMCID:PMC10750424.
Chiang T, Kloosterboer A, Örge F, Sobol W, Echegaray JJ. Autosomal Recessive ADAMTSL4-Related Isolated Ectopia Lentis in the Ohio Old Order Amish and Mennonite Communities. Journal of vitreoretinal diseases. 2024;8(4):442-451. doi:10.1177/24741264241249024. PMID:39148561; PMCID:PMC11323518.
Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, et al. ADAMTSL4-Related Eye Disorders. . 1993. PMID: 22338190.
