Lissencephaly is a congenital brain malformation in which the formation of cerebral gyri is impaired due to fetal neuronal migration disorders. The term originates from the Greek words “lissos” (smooth) and “encephalus” (brain). It is characterized by the absence of gyri (agyria) or broad gyri (pachygyria).
Lissencephaly is primarily a genetic disorder. Viral infections during the first trimester of pregnancy and fetal cerebral blood flow insufficiency can also be causes. Systemic symptoms frequently include microcephaly, epilepsy, facial abnormalities, limb malformations, growth impairment, and psychomotor developmental delay.
Ocular abnormalities are observed in all types of lissencephaly, but type 2 (cobblestone) presents with more severe and diverse findings. This article provides an overview of ocular findings by disease type.
Lissencephaly is a rare disease, and reports of its exact prevalence are limited. There are also few studies that systematically investigate the incidence of ocular findings. With the spread of genetic testing, the number of diagnosed cases is increasing.
Most ocular abnormalities associated with lissencephaly are congenital and detected in infancy. Because severe psychomotor developmental delay is present, it is difficult for affected children to report symptoms themselves.
Symptoms that are easy for caregivers to notice include the following.
Ophthalmic findings differ significantly between type 1 and type 2.
Type 1
VEP abnormalities: Decreased amplitude and prolonged latency of visual evoked potentials.
Cortical blindness: Caused by developmental disorders of the occipital lobe.
Optic nerve hypoplasia: Observed as a small optic disc.
Foveal hypoplasia: Underdevelopment of the foveal structure in the macula.
Optic atrophy: Reflects progressive optic nerve damage.
Strabismus: Esotropia or exotropia. Common in children with developmental delays.
Type 2
Microphthalmia: Underdevelopment of the entire eyeball. Frequently observed.
Persistent fetal vasculature (PFV): Remnants of embryonic vitreous structures.
Retinal dysplasia: Structural abnormality of the retina. May be accompanied by retinal detachment.
Coloboma: Congenital defect of the iris, retina, or optic nerve.
Congenital glaucoma / anterior chamber angle anomaly: Anterior segment abnormality with elevated intraocular pressure.
Cataract: Congenital lens opacity.
In type 2, these findings often occur in combination. Optic nerve hypoplasia is a common finding frequently observed in both types 1 and 2. A retrospective study of 20 patients with lissencephaly reported that some ophthalmic abnormality was found in approximately 67% of type 1 and 100% of type 2 patients [1].
Type 1 is caused by under-migration of neurons and mainly reflects damage to the cerebral cortex. Type 2 is caused by over-migration of neurons and extensively affects not only the brain but also the development of the eye, presenting various findings from the anterior to posterior segments.
Lissencephaly is mainly caused by genetic mutations. It is broadly classified into type 1 and type 2 based on phenotype, but with advances in genetic analysis, classification by causative gene is considered more accurate.
Type 2 is strongly associated with congenital muscular dystrophy (CMD). The following three diseases are representative.
The diagnosis of lissencephaly is confirmed by brain imaging. Ophthalmic evaluation should be performed early as part of systemic management.
When lissencephaly is diagnosed, the following ophthalmic evaluations are performed.
There is no curative treatment for lissencephaly itself. For ophthalmic abnormalities, symptomatic treatment is provided according to individual findings.
If significant refractive error is present, glasses are prescribed. This maximizes visual stimulation and encourages the use of residual visual function.
Strabismus is frequently observed in children with developmental delay. Surgery is considered when visual acuity improves to the level of fixation and pursuit, and the strabismic angle stabilizes. Surgery may also be performed in cases of poor visual acuity for psychosocial reasons.
When congenital glaucoma is present, intraocular pressure control is necessary. It is managed with eye drops or surgical therapy (such as trabeculotomy).
Congenital cataracts that affect the visual axis are indications for early surgery. Intervention should be performed as early as possible to prevent amblyopia.
Epilepsy frequently accompanies lissencephaly. Appropriate selection of antiepileptic drugs is fundamental to systemic management. In Fukuyama type, steroid therapy has been reported to improve motor function in the progressive stage.
Many ocular abnormalities in lissencephaly are congenital and structural, making significant vision improvement difficult. However, refractive correction, strabismus surgery, and glaucoma management can maximize residual visual function. Early visual support and rehabilitation are important.
The fundamental pathology of lissencephaly is impaired neuronal migration. During brain development, neural progenitor cells migrate from the ventricular zone to the cortical surface. Disruption of this migration prevents normal gyrus formation.
WWS is the most severe of the three related CMDs. It is associated with cerebellar malformation, occipital encephalocele, congenital hydrocephalus, and severe intellectual disability. Cleft lip/palate, cryptorchidism, and anal atresia have also been reported. The frequency of ocular abnormalities is extremely high.
A survey of 40 cases reported the following frequencies.
| Ophthalmic findings | Frequency |
|---|---|
| Optic nerve hypoplasia | 95% |
| Microphthalmia | 94% |
| PFV | 80% |
前房隅角異常（58%）・瞳孔異常（58%）・白内障（57%）・緑内障（50%）・網膜異形成（43%）・コロボーマ（11%）も報告されている。微小角膜・角膜混濁・網膜グリオーシス・「豹紋状」周辺部網膜症を呈する症例もある。剖検例の検討では、虹彩・角膜・水晶体の高度奇形に加え、漏斗状の網膜異形成・原始的な網膜組織の遺残が記載されており、本症の眼科的所見が「真の網膜剥離」というよりも一次的な発生異常（dysplastic non-attachment）に起因することが示唆されている [2]。
日本人に多い常染色体劣性疾患である。フクチン遺伝子変異が原因である。WWSと類似するが表現型はより軽症である。重度知的障害・小頭症・てんかん・CK上昇を伴う筋力低下・ふくらはぎの仮性肥大を特徴とする。進行性水頭症はまれで、脳瘤の報告はない。
眼科的所見はWWSより軽度で頻度も低い。視神経蒼白・白内障・網膜の斑状変化や血管変化が報告されている。剖検眼の病理学的検討では、網膜の襞形成・癒合・異形成が認められ、Müller細胞の関与と基底膜成分の減少が示唆されている [3]。
Classically, it is common in Finnish populations. It presents with neonatal hypotonia, moderate to severe muscle weakness, severe intellectual disability, and epilepsy. The systemic phenotype varies greatly among individuals.
Ocular findings include juvenile cataract, progressive myopia, retinal detachment, retinal atrophy, optic nerve hypoplasia and atrophy, strabismus, and congenital glaucoma. In a study of 20 Finnish patients, so-called “giant VEP” (giant amplitude) on visual evoked potentials (VEP) was observed in about 75%, along with cerebral lesions reflecting cobblestone cortex, and is considered to have high diagnostic value [4].
It is caused by a microdeletion of 17p13.3 including the LIS1 mutation. It presents with intellectual disability and characteristic facial features (microcephaly, high forehead, bitemporal hollowing, long philtrum, micrognathia). Congenital heart disease and omphalocele may also be present. Ocular findings include microcornea and ptosis. Furthermore, ROP-like proliferative peripheral retinopathy (PPR) has been described in children with Miller-Dieker syndrome, and cases requiring laser photocoagulation or lens-sparing vitrectomy have been reported. Even in type 1 lissencephaly, early detailed fundus examination is recommended for cases definitively diagnosed with Miller-Dieker syndrome [6].
TUBA1A-related tubulinopathy is an autosomal dominant disorder. De novo mutations cause brain malformations including lissencephaly, microcephaly, developmental delay, and epilepsy.
Case reports have identified bilateral persistent fetal vasculature (PFV), optic nerve hypoplasia, vitreous hemorrhage, and peripheral retinal avascular areas in children with TUBA1A mutations. These findings overlap with the ophthalmic features of type 2 lissencephaly, and thorough ophthalmologic evaluation including fluorescein angiography is recommended for affected children [5].
Fukuyama congenital muscular dystrophy (FCMD) is known as a common type in the Japanese population. It is caused by mutations in the fukutin gene and classified as type 2 lissencephaly. Although milder than WWS, it may involve ocular findings, so regular ophthalmologic examinations are recommended.
With the widespread use of next-generation sequencers (NGS) and exome analysis, the identification of causative genes for lissencephaly is accelerating. In addition to traditional phenotypic classification, more precise classification based on genotype is becoming possible. This is expected to improve the accuracy of risk prediction for ophthalmic complications and prognosis evaluation.
The association between mutations in tubulin gene groups (TUBA1A, TUBB3, TUBB2B, etc.) and cerebral cortical malformations/ocular movement abnormalities is becoming clearer. These findings may serve as a foundation for the development of future molecular targeted therapies.
The effectiveness of early visual intervention programs for children with lissencephaly complicated by cortical visual impairment (CVI) is being studied. Approaches that maximize residual visual function, such as environmental adjustments and the use of backlit devices, are attracting attention. CVI is the most common cause of childhood visual impairment in developed countries, and many cases have underlying cortical malformations (lissencephaly, pachygyria, polymicrogyria, etc.). Establishing standardized assessment methods and accumulating randomized controlled trials are future challenges [7].
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Ramirez DA, Anninger WV, Scoles D. Optic Nerve Hypoplasia and Bilateral Persistent Fetal Vasculature Due to TUBA1A Tubulinopathy. Retin Cases Brief Rep. 2025;19(2):264-266. PMID: 38109746
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Chang MY, Borchert MS. Advances in the evaluation and management of cortical/cerebral visual impairment in children. Surv Ophthalmol. 2020;65(6):708-724. PMID: 32199940
