Aicardi syndrome is a congenital rare disease first described in 1967 by French neurologist Jean Aicardi. It is presumed to be X-linked dominant, and almost all patients are girls. In boys, it is lethal in the hemizygous state, so only a few cases have been reported in boys with XXY karyotype (Klinefelter syndrome).
The incidence is estimated at about 1:110,000 births, and the number of affected individuals worldwide is approximately 4,000 1). All cases are de novo mutations, with no parent-to-child transmission, and the recurrence risk for siblings is less than 1% 1).
The classic triad consists of the following three features 1):
The prognosis is poor. The average survival age is 18 years, and the probability of surviving to age 27 is reported to be 0.62% 1).
This disease occurs almost exclusively in girls. It is presumed to be X-linked dominant, as it is lethal in hemizygous males. However, there are a few reported cases worldwide in boys with XXY karyotype (Klinefelter syndrome).
The initial symptom of this disease is usually infantile spasms appearing around 3-4 months of age. Epilepsy often becomes drug-resistant and is accompanied by various seizure types.
Among the ophthalmic findings of this disease, chorioretinal lacunae are considered pathognomonic.
Chorioretinal Lacunae
Distribution: Bilateral. Dense around the optic disc and posterior pole, but also extends to the periphery.
Appearance: Round to oval, yellow-white to pink lesions. Prevalence is 70–90%1).
Histology: Defects in the retinal pigment epithelium (RPE) extending from the choroidal layer to the bare sclera2).
Course: May increase in size and number over time after surgery2).
Other Ocular Findings
Optic nerve coloboma: Present in approximately 44% of cases.
Microphthalmos: Observed in about 20% of cases.
Peripheral avascular retina: A 360-degree avascular zone may form2).
Tractional retinal detachment (TRD): May occur in association with stalk tissue2).
Case reports have documented an example with preretinal hemorrhage and 360-degree peripheral avascular zone in the right eye, and stalk tissue (fibrovascular stalk) with tractional retinal detachment in the left eye2). It can also cause cortical visual impairment (CVI)3).
They may progress. New lacunae have been reported to become visible after ophthalmic surgical intervention, and their size or number may increase over time2). Regular fundus examination follow-up is important.
Aicardi syndrome is presumed to be X-linked dominant, but the causative gene has not been identified to date1). All cases are de novo mutations, and familial occurrence is essentially absent. The recurrence risk for siblings is less than 1%, and genetic counseling is recommended when planning future children1).
In a recent case report, a TREX1 gene mutation (c.292_293insA, p.(Cys99Metfs)) was detected in one patient2). TREX1 is located on chromosome 3, which partially contradicts the X-linked hypothesis, so the location of the causative gene remains under debate.
Since the causative gene has not been identified, the diagnosis of Aicardi syndrome is primarily clinical. Confirmation of the classic triad is central to diagnosis1).
Even if only two of the three cardinal features are present, diagnosis is possible using the expanded diagnostic criteria established in 1999.
The components of the expanded diagnostic criteria are shown below.
| Category | Main items |
|---|---|
| Major features | Optic nerve coloboma, cortical malformation, heterotopic gray matter, intracranial cyst, choroid plexus papilloma |
| Supportive features | Vertebral rib abnormalities, microphthalmia, split-brain EEG, hemispheric asymmetry, vascular malformations |
Two of the three cardinal features + two or more major or supportive features confirms the diagnosis.
Currently, no causative gene has been identified that allows definitive diagnosis, so genetic testing alone cannot provide a definitive diagnosis 1). Clinical diagnosis based on a combination of clinical symptoms, fundus findings, and imaging findings is the main approach. Advances in comprehensive genomic analysis are expected to identify causative genes in the future.
There is no curative treatment. The goals of treatment consist of three pillars: seizure control, management of ophthalmic complications, and developmental support through rehabilitation.
Seizure management
First-line drugs: Phenytoin, levetiracetam, clobazam, etc. are used 1).
Refractory cases: Cannabidiol (CBD), ketogenic diet therapy, corpus callosotomy, and vagus nerve stimulation are attempted 1).
Ophthalmic intervention
Laser photocoagulation: Performed on peripheral avascular retina to prevent progression of proliferative retinopathy 2).
Vitrectomy: 23-gauge vitrectomy is performed for tractional retinal detachment (TRD) 2).
Rehabilitation
Early initiation: Physical therapy, occupational therapy, speech therapy, and vision therapy are started immediately after diagnosis 1).
Low vision care: Provide assistive devices and environmental adjustments for visual impairment.
Reported cases of surgical interventions for ophthalmic complications are presented.
| Eye | Findings | Treatment |
|---|---|---|
| Right eye | Preretinal hemorrhage, avascular zone 360 degrees | Laser photocoagulation |
| Left eye | Stalk tissue, TRD | 23G vitrectomy |
After vitrectomy, recovery of axial length growth was confirmed; in the left eye, axial length grew from 17.45 mm at 1 month of age to 24.41 mm at 26 months of age 2). In addition, there are reports of cases where chorioretinal lacunae became newly visible after surgery, contributing to a definitive diagnosis 2).
Yes, it is possible. Laser photocoagulation for peripheral avascular retina and 23-gauge vitrectomy for tractional retinal detachment may be effective 2). There are reports of accelerated ocular growth after surgery. However, the number of cases is small, and careful management at a specialized facility is required.
De novo mutations on the X chromosome are presumed to be the cause of this disease. The pattern of X-chromosome inactivation (lyonization) is thought to produce phenotypic variability even with the same mutation. In males, hemizygosity leads to lethality in the embryonic period, and only males with an XXY karyotype can survive.
Recently, a TREX1 gene mutation (c.292_293insA, p.(Cys99Metfs)) was detected in one case diagnosed with this disease 2). Since TREX1 is located on chromosome 3, this may contradict the X-linked hypothesis, suggesting the possibility of non-X-linked causative genes.
Histologically, chorioretinal lacunae are characterized by defects in the retinal pigment epithelium (RPE) extending from the choriocapillaris to the bare sclera 2). The defect area lacks RPE and choriocapillaris, and dysplastic undifferentiated neuroretina is observed.
Persistence of the fetal vasculature is thought to contribute to the formation of fibrovascular stalk tissue and peripheral avascular retina 2). These abnormal vessels cause tractional retinal detachment.
Cortical visual impairment (CVI) arises as an acquired visual function decline due to brain structural abnormalities such as polymicrogyria, heterotopic gray matter, and agenesis of the corpus callosum 3).
Brain malformations (polymicrogyria, agenesis of the corpus callosum) are based on impaired neuronal migration during the embryonic period. The molecular mechanisms underlying this migration disorder remain unknown, and future research is awaited along with identification of causative genes.
The causative gene remains unidentified, but detection of TREX1 gene mutations 2) is a new clue suggesting the involvement of non-X-linked mutations. The widespread use of comprehensive genomic analysis (WES/WGS) is expected to accelerate the identification of causative genes. Verification of the X-linked and non-X-linked hypotheses is a major future challenge.
Reports of variant cases showing only thinning (dysgenesis) rather than complete agenesis of the corpus callosum are accumulating 2). Even in cases that do not meet all three cardinal features, detailed fundus examination and application of expanded diagnostic criteria may improve diagnostic accuracy.
Kang et al. (2022) reported that laser photocoagulation and 23-gauge vitrectomy performed for bilateral vitreoretinopathy in Aicardi syndrome contributed to maintaining ocular growth and protecting visual function 2). They also recorded that chorioretinal lacunae became newly visible postoperatively, indicating that ophthalmic surgery can also aid in confirming the diagnosis.
There is growing recognition that early fundus screening and prompt intervention are important for protecting retinal function 2). Laser treatment to peripheral avascular areas may prevent the progression of proliferative retinopathy, and further case accumulation is desired.
Research on the application of cannabidiol (CBD) and ketogenic diet therapy for seizure control is advancing 1). Establishment of new treatment options for intractable epilepsy is anticipated.
