Aicardi syndrome

# Overview
Aicardi syndrome is a rare malformation characterized by the partial or total absence of the corpus callosum, the presence of retinal abnormalities, and seizures in the form of infantile spasms. Physical examination demonstrate microcephaly, axial hypotonia, and appendicular hypertonia with spasticity. Aicardi syndrome is thought to be an inherited X-linked dominant disorder due to affection almost exclusively to females and boys with Klinefelters syndrome.

# Historical Perspective
- In 1946, Krause described a 2-months old girl with seizures, mental retardation, and microcephalus which later died from pneumonia.
- In 1959, Klein described in an article called "The Pathogenesis of an Atypical Coloboma of the Choroid" an almost identical case of a 2-months old girls with same clinical and anatomopathological findings as Krause.
- Aicardi syndrome was first fully described by the French neurologist Jean Aicardi in 1965 in his article "A new syndrome: Spasm in flexion, Callosal agenesis, Ocular abnormalities".
- Historically, Aicardi syndrome was characterized by the triad of infantile spasms, chorioretinal lacunae and agenesis of the corpus callosum.

# Classification
- There is no established system for classification of Aicardi syndrome.

# Pathosphysiology

## Genetics
- The mutated gene in Aicardi syndrome has not been identified.
- It is thought that Aicardi syndrome is caused by de novo mutations in X-chromosome that cause its inactivation. There are no reported cases of transmitted deflective X chromosome. 
- Attempts to identify the mutated gene in Aicardi syndrome by  X-chromosome DNA microarrays, comparative hybridization, and genome sequencing have been unsuccessful.
- Most of the cases, Aicardi syndrome appears to be lethal in males with only one X chromosome.
- Rare cases of males with Aicardi syndrome have been reported, these present with a XXY karyotype (Klinefelter syndrome). Cases with XY karyotype are thought to be caused by mosaicisms.

# Causes
- The cause of Aicardi syndrome has not been identified. Due to almost exclusive involvement to females, it is thought that causative mutation is located in X chromosome, but this altered gene has not been identified.

# Differentiating Aicardi syndrome from Other Diseases
- Aicardi syndrome must be differentiated from other diseases, such as:
Agenesis of the corpus callosum. Is a rare congenital (may be inherited) condition characterized by early onset of seizures since the first weeks of life, failure to thrive, and or hydrocephalus. Aicardi syndrome may be composed by absence corpus callosum, but not necessary all agenesis are Aicardi syndrome.
Microcephaly. Is a congenital defect present in most of the cases of Aicardi syndrome, but may be as well an isolated condition.
Neuronal migration disorders. Are congenital conditions that lead to development abnormalities in brain structure. These include lissencephaly, heterotopia, polymicrogyria, focal cortical dysplasia, and Aicardi syndrome.
Oculocerebrocutaneous syndrome (OCCS).
Infantile spasms.
- Agenesis of the corpus callosum. Is a rare congenital (may be inherited) condition characterized by early onset of seizures since the first weeks of life, failure to thrive, and or hydrocephalus. Aicardi syndrome may be composed by absence corpus callosum, but not necessary all agenesis are Aicardi syndrome.
- Microcephaly. Is a congenital defect present in most of the cases of Aicardi syndrome, but may be as well an isolated condition.
- Neuronal migration disorders. Are congenital conditions that lead to development abnormalities in brain structure. These include lissencephaly, heterotopia, polymicrogyria, focal cortical dysplasia, and Aicardi syndrome.
- Oculocerebrocutaneous syndrome (OCCS).
- Infantile spasms.

# Epidemiology and Demographics
- Aicardi syndrome is a very rare condition. A precise prevalence and incidence have not been calculated.
- Around 500 cases of Aicardi syndrome have been reported worldwide.
- The incidence of Aicardi syndrome has been estimated between 1:105,000 and 1:167,000 in the United States and between 1:93,000 and 1:99,000 in some European countries.
- The prevalence of Aicardi syndrome in the United States has been calculated to be over 853 in the US and over 4,000 worldwide.

## Gender
- Females are more commonly affected with Aicardi syndrome than males.

## Age
- Aicardi syndrome is a congenital disorder, but most cases are identified around 5 months of age.

## Race
- Apparently, there is no racial predilection for Aicardi syndrome.

# Risk Factors
- There are no recognized risk factors associated with Aicardi syndrome development.

# Screening
- Since the vast majority of Aicardi syndrome cases are caused by de novo mutations, there is no indication for screening in family members of an affected patient. There is only 1% chance that a sibling of an affected individual will have the disease.
- Females with Aicardi syndrome have 50% of chances to transmit the affected allele to offspring, while conceptuses in males are nonviable.
- Some features from Aicardi syndrome may be detected by prenatal ultrasound.
- Molecular genetic testing is not feasible due to the unawareness of the responsible gene mutation.

# Natural History, Complications, Prognosis
- Prognosis for Aicardi syndrome is variable, with the mean age of death about 8.3 years and the median age of death about 18.5 years.
- Most of affected females are apparently normal at birth and present infantile spasms around the age of 3 months.
- The majority of females with Aicardi syndrome develop seizures before age 1.

# Diagnosis

## Diagnostic Criteria
- The diagnosis of Aicardi syndrome according to Sutton et al. (modified from Aicardi 1999)is made by the presence of all 3 classic features or 2 classic features plus 2 major features; in addition there are supporting features that make diagnosis more reliable.

## History and Symptoms
- Most of individuals with Aicardi syndrome are asymptomatic, but symptoms may vary depending on clinical presentation.

## Physical Examination
- The following characteristics have been present among the reported cases of Aicardi syndrome, it should be noted that most of these features are not present and do not confirm the diagnostic criteria:

### Neurologic
- Axial hypotonia
- Appendicular hypertonia with spasticity
- Brisk deep tendon reflexes
- Hemiparesis
- With or without intellectual disability
- Nystagmus

### Ophthalmologic
- Chorioretinal lacunae
- Unilateral microphthalmia
- Optic nerve coloboma
- Detached retina
- Optic nerve dysplasia or hypoplasia
- Persistent fetal vasculature

### Craniofacial
- Microcephaly
- Short philtrum
- Prominent premaxilla
- Large ears
- Sparse lateral eyebrows
- Plagiocephaly
- Cleft lip and palate
Skeletal
- Costovertebral defects (hemivertebrae, block vertebrae, fused vertebrae, and missing ribs)
- Scoliosis
- Hip dysplasia
Gastrointestinal
- Constipation
- Gastroesophageal reflux
- Diarrhea
- Feeding difficulties
Extremities
- Small hands
Dermatologic
- Vascular malformations
- Pigmentary lesions
Tumors/malignancies
- Choroid plexus papillomas
- Also lipomas, angiosarcomas, hepatoblastomas, intestinal polyposis, embryonal carcinomas,and large-cell medulloblastomas has been reported
Endocrine
- Precocious puberty
- Delayed puberty

## Laboratory Findings
- There are no specific laboratory findings associated with Aicardi syndrome.

## EEG
- EEG findings associated with Aicardi syndrome include asynchronous multifocal epileptiform defects with breach subduing and separation between the two hemispheres (split-brain).

## Electrocardiogram
- There are no electrocardiogram findings associated with Aicardi syndrome.

## X-ray
- X-ray of the spine may reveal scoliosis and rib abnormalities.

## Echocardiography or Ultrasound
- There are no characteristic echocardiography/ultrasound findings associated with Aicardi syndrome.

## CT scan
- CT scan of the head in Aicardi syndrome reveals agenesis of the corpus callosum.
- CT scan of the head in Aicardi syndrome may reveal cortical malformations, periventricular cysts around the third ventricle, choroid plexus, and periventricular and subcortical heterotopia, porencephalic cysts, hydrocephalus, and gross cerebral hemispheric asymmetry.

## MRI
- MRI of the head in Aicardi syndrome reveals agenesis of the corpus callosum.
- MRI of the head in Aicardi syndrome may reveal cortical malformations, periventricular cysts around the third ventricle, choroid plexus, periventricular and subcortical heterotopia, porencephalic cysts, hydrocephalus, and gross cerebral hemispheric asymmetry.

## Other Imaging Findings
- There are no other imaging findings associated with Aicardi syndrome.

## Other Diagnostic Studies
- There are no other diagnostic studies associated with Aicardi syndrome.

# Treatment

## Medical Therapy
- Tere is no treatment for Aicardi syndrome; the mainstay of therapy is supportive care.
- Antiepileptic medications are used to control these challenging episodes, although studies have demonstrated that no antiepileptic drug works for all cases of Aicardi syndrome and that many times it is necessary to use more than one type.
- Thre has been shown improvement with the use of vigabatrin and vagus nerve stimulation.
- Physiotherapy, occupational therapy, speech therapy, and ocular therapy should be started as soon as possible.

## Surgery
- Corrective surgery may be performed in patients with severe scoliosis.
- Patients with hydrocephalus have shown improvement with resection of large choroid plexus papillomas and shunt insertions.

## Prevention
- There are no primary preventive measures available for Aicardi syndrome.
- Secondary preventive measures include routine dermatologic, gastrointestinal, and orthopedic evaluations to monitor for malignancies, gastrointestinal problems, and degree of scoliosis respectively.

# Support Organizations
Aicardi Syndrome Foundation Support and information for families caring for children with Aicardi Syndrome.
A.A.L Syndrome d'Aicardi
Sindrome di Aicardi