What is Aicardi syndrome

Aicardi syndrome is an extremely rare genetic neurological disorder that occurs almost exclusively in female babies, first described by the French neurologist, Dr. Jean Aicardi, in 1965 ¹. Aicardi syndrome occurs in about 1 in 105,000 to 167,000 newborns in the United States, there are currently about 1,000 cases in the United States. Researchers estimate that there are approximately 4,000 affected individuals worldwide ². The severity of Aicardi syndrome and the associated signs and symptoms vary from person to person. The three main features of Aicardi syndrome that occur together in most affected individuals are ³:

1. Complete or partial absence of the nerve tissue that allows the right and left sides of the brain to communicate (corpus callosum)
2. Seizures beginning in infancy (infantile spasms), that may become hard to control (refractory epilepsy)
3. Defects or holes in the light sensitive tissue at the back of the eye (retina) known as chorioretinal lacunae

Other signs and symptoms may include ⁴:

• Developmental delay
• Intellectual disability that ranges from very mild to severe
• Characteristic facial features, such as a short distance between the nose and lips, a flat nose, large ears and thin eyebrows.
• Other brain malformations such as a very small head (microcephaly)
• Other eye defects, such as very small eyes (microphthalmia) or a defect of the nerve connecting the retina to the brain (optic nerve) known as coloboma.

People with Aicardi syndrome have absent or underdeveloped tissue connecting the left and right halves of the brain (agenesis or dysgenesis of the corpus callosum) ². They have seizures beginning in infancy (infantile spasms), which tend to progress to recurrent seizures (epilepsy) that can be difficult to treat. Affected individuals also have chorioretinal lacunae, which are defects in the light-sensitive tissue at the back of the eye (retina).

People with Aicardi syndrome often have additional brain abnormalities, including asymmetry between the two sides of the brain, brain folds and grooves that are small in size or reduced in number, cysts, and enlargement of the fluid-filled cavities (ventricles) near the center of the brain. Some have an unusually small head (microcephaly). Most affected individuals have moderate to severe developmental delay and intellectual disability, although some people with this disorder have milder disability.

In addition to chorioretinal lacunae, people with Aicardi syndrome may have other eye abnormalities such as small or poorly developed eyes (microphthalmia) or a gap or hole (coloboma) in the optic nerve, a structure that carries information from the eye to the brain. These eye abnormalities may cause blindness in affected individuals.

Some people with Aicardi syndrome have unusual facial features including a short area between the upper lip and the nose (philtrum), a flat nose with an upturned tip, large ears, and sparse eyebrows. Other features of this condition include small hands, hand malformations, and spinal and rib abnormalities leading to progressive abnormal curvature of the spine (scoliosis). They often have gastrointestinal problems such as constipation or diarrhea, gastroesophageal reflux, and difficulty feeding.

The severity of Aicardi syndrome varies. Some people with this disorder have very severe epilepsy and may not survive past childhood. Less severely affected individuals may live into adulthood with milder signs and symptoms.

There is no cure for Aicardi syndrome nor is there a standard course of treatment. Treatment generally involves medical management of seizures and programs to help parents and children cope with developmental delays. Long-term management by a pediatric neurologist with expertise in the management of infantile spasms is recommended.

What is Aicardi Goutieres syndrome?

Aicardi Goutieres syndrome is an inherited, subacute encephalopathy characterized by the association of basal ganglia calcification, leukodystrophy and cerebrospinal fluid (CSF) lymphocytosis ⁵. Note that Aicardi Goutieres syndrome is not the same as Aicardi syndrome.

Aicardi Goutieres syndrome is caused by mutations in four genes: TREX1, encoding a 3′->5′ exonuclease, and in RNASEH2A, RNASEH2B and RNASEH2C, genes encoding subunits of the RNase H2 endonuclease complex. TREX1 (25% of cases), RNASEH2C (14% of cases) and RNASEH2A (4% of cases) mutations result in a severe phenotype, whereas RNASEH2B (41% of cases) mutations generally lead to a milder phenotype. No mutations in any of these genes are found in the remaining cases. Aicardi Goutieres syndrome is inherited in autosomal recessive pattern but rare cases of autosomal dominant inheritance have been reported.

There are just over 120 Aicardi Goutieres syndrome cases that have been reported in the literature so far ⁵.

The majority of Aicardi Goutieres syndrome infants are born at full term with normal growth parameters. Onset occurs within the first few days or month of life with severe, subacute encephalopathy (feeding problems, irritability and psychomotor regression or delay) associated with epilepsy (53% of cases), chilblain skin lesions on the extremities (43% of cases) and episodes of aseptic febrile illness (40% of cases). Symptoms progress over several months (with the development of microcephaly and pyramidal signs) before the disease course stabilises. However, less severe forms have been described with onset after 1 year of age and preservation of language skills and cognitive function, and normal head circumference. The phenotype shows inter- and intrafamilial variation.

Around 80% of Aicardi Goutieres syndrome patients presenting with the severe form die within the first 10 years of life but prolonged survival after the first decade of life has been reported in milder forms.

Treatment of Aicardi Goutieres syndrome is symptomatic (management of the feeding problems, psychomotor delay and, if present, epilepsy).

Aicardi syndrome prognosis

The prognosis for girls with Aicardi syndrome varies according to the severity of their symptoms ². Some people with Aicardi syndrome have very severe epilepsy and may not survive past childhood and adolescence. Less severely affected individuals may live into adulthood with milder signs and symptoms have been described.

Development and Long Term Outcomes

Most affected individuals have moderate to severe developmental and intellectual disability, although some children with Aicardi syndrome have a more mild form of disability. The severity of Aicardi syndrome can vary greatly. Affected children should enter the early intervention system as soon as possible although it is not clear how much of the disabilities can be attenuated through therapies or are pre-determined. Many children with Aicardi will learn to sit independently and feed themselves and many are able to walk. Some children can speak in short sentences but complex oral language is the exception. The majority of children with Aicardi syndrome communicate with gestures, sounds and other nonverbal means and receptive communication is more advanced than expressive. Chronic developmental regressions have been documented, mostly due to a change or increase in seizures.

Aicardi syndrome life expectancy

Aicardi goutieres syndrome life expectancy is highly variable depending on the number and severity of features present in a child with Aicardi syndrome.

Survival is highly variable and likely depends on the severity of seizures and other organ system involvement, particularly conditions that affect the respiratory system. Median survival from birth is more than 30 years, and as children age, their chance of survival increases. For example, the probability of surviving another 5 years is over 85% for an affected person that is 25 years old. The ages of highest mortality risk are in the first few years of life and in adolescence. Common causes of death include respiratory failure, systemic infections with difficult to treat pathogens, and sudden unexpected death in epilepsy (SUDEP).

Aicardi syndrome signs and symptoms

Aicardi syndrome signs and symptoms (are not present in all Aicardi syndrome cases):

• Vascular malformations or vascular malignancy;
• Microcephaly;
• Hypotonia;
• Spasticity or hypertonia;
• Scoliosis;
• Prominent premaxilla;
• Cleft lip or palate;
• Gastroesophageal reflux;
• Feeding problems;
• Small or malformed hands;
• Precocious or delayed puberty; and/or
• Global developmental disabilities.

Aicardi syndrome typically begins as involuntary muscle spasms between four months and four years of age. Other symptoms may include epilepsy, intellectual disability, profound muscle weakness (hypotonia), an abnormally small head (microcephaly), abnormally small eyes (microphthalmia), prominent premaxilla, upturned nasal tip, decreased angle of the nasal bridge, and sparse lateral eyebrows, an incomplete development of the retina and nerve in the back of the eye (colobomas), and/or abnormalities of the ribs and/or spinal column with marked scoliosis present in up to one third of affected individuals. Periventricular heterotopias (nerve cells migration disorder in the brain during early fetal development characterized by the presence of clumps of neurons near the brain’s ventricles), microgyria (poorly formed cerebral cortex), enlarged ventricles or porencephalic cysts, axial hypotonia, and appendicular hypertonia with spasticity may occur. Epilepsy that is refractory to medication develops over time, with a variety of seizure types (infantile spasms that can be asymmetric or unilateral, partial seizures) and ‘split’ brain electroencephalogram (EEG).

Children of all ages with Aicardi syndrome have significant delay in motor development and intellectual deficit. Aicardi syndrome can be life-threatening during childhood due to complications from upper respiratory infections.

Gastrointestinal disorders, vascular malformations, small hands, pigmentary skin lesions, and an increased incidence of tumors are rare.

Seizures

Seizures usually begin in the first few months of life, but may occur in utero or immediately at birth. The seizures are difficult to treat and refractory epilepsy is almost universal. Seizure onset almost always begins with infantile spasms which eventually evolve into a number of other difficult to control seizure types. A pediatric neurologist with expertise in the management of infantile spasms and medically refractory epilepsy is important for the long-term management of the seizures. Finding a balance between minimizing the frequency and severity of seizures, the adverse effects of the anti-epileptic drugs, and optimizing the quality of life for child and family is essential.

Aicardi syndrome causes

The cause of Aicardi syndrome is unknown. Because Aicardi syndrome occurs almost exclusively in females, researchers believe that it is probably the result of a mutation in a gene on the X chromosome. People normally have 46 chromosomes in each cell. Two of the 46 chromosomes, known as X and Y, are called sex chromosomes because they help determine whether a person will develop male or female sex characteristics. Genes on these chromosomes are also involved in other functions in the body. Females typically have two X chromosomes (46,XX), and males have one X chromosome and one Y chromosome (46,XY).

Early in embryonic development in females, one of the two X chromosomes is permanently inactivated in somatic cells (cells other than egg and sperm cells). X-inactivation ensures that females, like males, have only one active copy of the X chromosome in each body cell. Usually X-inactivation occurs randomly, so that each X chromosome is active in about half the body’s cells. Sometimes X-inactivation is not random, and one X chromosome is active in more than half of cells. When X-inactivation does not occur randomly, it is called skewed X-inactivation.

Skewed X-inactivation sometimes occurs when there is a severe gene mutation in one of the X chromosomes in each cell. Because the cells where this chromosome is active will not be able to survive as well, X-inactivation will appear to be skewed. Skewed X-inactivation has been identified in girls with Aicardi syndrome, further supporting the idea that the disorder is caused by a mutation in a gene on the X chromosome. However, this gene has not been identified, and it is unknown how the genetic change that causes Aicardi syndrome results in the various signs and symptoms of this disorder.

Inheritance pattern

Nearly all known cases of Aicardi syndrome are sporadic, which means that they are not passed down through generations and occur in people with no history of the disorder in their family. Aicardi syndrome is believed to result from new gene mutations.

Aicardi syndrome is classified as an X-linked dominant condition. While the gene associated with this disorder is not known, it is believed to be located on the X chromosome. In females (who have two X chromosomes), a mutation in one of the two copies of the gene in each cell is sufficient to cause the disorder. In males (who have only one X chromosome), a mutation in the only copy of the gene in each cell is nearly always lethal very early in development, so almost all babies with Aicardi syndrome are female. However, a few affected males with an extra copy of the X chromosome in each cell (47,XXY) have been identified. Males with a 47,XXY chromosome pattern also have a condition called Klinefelter syndrome.

Aicardi syndrome diagnosis

It is usual to have an magnetic resonance imaging (MRI) of the brain. This study makes pictures of the brain to look for a small or missing corpus callosum and other problems with the formation of the brain. Individuals with Aicardi syndrome should have a test to look at the brain waves (EEG) to diagnose and treat seizures. An ophthalmologist should look into the eyes at the retina. In Aicardi syndrome, this almost always reveals small cream-colored cavities (lucunae) within the retina.

Aicardi syndrome is classically defined in over 90% of cases by three cardinal features ⁶:

1. Agenesis of the corpus callosum;
2. Chorioretinal lacunae; and
3. Infantile spasms.

In 1999, the diagnostic spectrum of Aicardi syndrome was broadened to include patients with present, but usually abnormal, corpus callosum or absence of infantile spasms or lacunae, if other typical brain abnormalities are present. Specifically, the revised criteria were expanded to include two classic features plus at least two other major or supporting features. Retinal lacunae and seizures are present in all, or almost all, of the cases. Major and supporting features include:

Major Features

• Cortical malformations (mostly polymicrogyria);
• Periventricular and subcortical heterotopia;
• Cysts around third cerebral ventricle and/or choroid plexus;
• Papillomas of choroid plexuses; and/or
• Optic disc/nerve coloboma.

Supporting Features

• Vertebral and costal abnormalities;
• Microphthalmia or other eye abnormalities;
• “Split-brain” EEG; and/or
• Gross cerebral hemispheric asymmetry.

Aicardi syndrome treatment

Medications may be used to suppress the seizures caused by Aicardi syndrome. The seizures are often hard to treat. The doctor may need to try a number of medicines to see which medication works best. Studies have shown that there is not one medicine that works for everyone with Aicardi syndrome.

The treatment for Aicardi syndrome is based on the clinical and developmental manifestations and may include a number of medical and therapeutic specialties such as pediatric neurology or epileptology, neurosurgery, ophthalmology, orthopedics, gastroenterology, physical therapy, speech therapy and occupational therapy. Treatment of seizures is initiated at the time of onset and often includes ACTH and vigabatrin for the treatment of infantile spasms. As refractory epilepsy continues, placement of a vagus nerve stimulator or brain surgery is often considered. Most children are not candidates for brain surgery due to multiple areas of epileptogenesis. Brain surgery, such as hemispherectomy or cortical resection, has been performed in many children with Aicardi syndrome although virtually all continue to have seizures. However, surgery may have provided better seizure control or a temporary period of seizure-freedom, allowing progress in development and/or improved quality of life.

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