Aicardi syndrome

Definition

Aicardi syndrome is a rare genetic disorder that causes defects of the eyes and brain. It is believed to be an X-linked dominant genetic trait. Aicardi syndrome is named after Dr. Jean Aicardi, who first described this syndrome in 1965.

Description

Aicardi syndrome is an X-linked dominant genetic condition primarily found in females because males with the disease do not survive to birth. It is alternately

called Agenesis of Corpus Callosum (ACC) with Chorioretinal Abnormality because of the associated abnormal formation of the connection between the right and left hemispheres of the brain (the corpus callosum) and abnormal development of the choroid and retinal sections of the eye.

The eye is composed of three layers: the sclera, the choroid, and the retina. The sclera is the tough white outer coat of the eyeball; it is unaffected in individuals with Aicardi syndrome. The choroid is the middle layer of the eye. It serves to nourish the retina and absorb scattered light. The retina is the inner, light-sensitive, layer of the eye. The retina receives the image produced by the lens and contains the rods and cones that are responsible for color vision. Both the choroid and the retina are abnormally formed in individuals affected with Aicardi syndrome.

Genetic profile

The location of the gene mutation responsible for Aicardi syndrome has been localized to Xp22.3. At or near this same locus is the gene responsible for microphthalmia with linear skin defects (MLS ) and the gene responsible for Goltz syndrome . Because only one male has ever been diagnosed with Aicardi syndrome, it is assumed that Aicardi syndrome is dominant and X-linked with near 100% fetal mortality in males. Nearly all of the cases of Aicardi syndrome are believed to result from de novo mutations (new mutations that occur after conception) since parents of affected individuals have normal chromosomes.

Demographics

Approximately 300 to 500 individuals, all female except for one, have been diagnosed with Aicardi syndrome worldwide. Aicardi syndrome is not associated with any particular sub-populations. It appears with equal frequency in all races and across all geographies. Because it is an X-linked dominant trait, it is observed almost exclusively in females.

Signs and symptoms

Aicardi syndrome is characterized by abnormalities of the connection between the left and right hemispheres of the brain (the corpus callosum), infantile spasms in affected infants and seizures in older affected individuals, developmental delays, lesions and other abnormalities of the eye, and possible other defects in the brain such as holes where healthy brain tissue should be (brain cysts) and an enlargement of the connecting cavities (ventricles) of the brain. It is these abnormalities of the brain, including the corpus callosum, that lead to the observable symptoms of seizures and developmental delays. Aicardi syndrome may also be complicated by brain tumors, benign tumors of the scalp (lipomas) and cancer of the blood vessels (angiosarcoma).

The onset of infantile spasms in individuals with Aicardi syndrome is generally observed between the third and fifth months of life. It is at this time that the final connections (neural synapses) are made in the developing human brain. These infantile spasms are a form of the full seizures that are experienced by older affected individuals. A seizure is the result of sudden abnormal electrical activity in the brain. This electrical activity can result in a wide variety of clinical symptoms including muscle twitches; tongue biting; fixed, staring eyes; a loss of bladder control resulting in involuntary urination; total body shaking (convulsions); and/or loss of consciousness.

There are several types of seizures. Focal, or partial, seizures are characterized by a brief and temporary change in movement, sensation, or nerve function. Examples of this type of seizure include drooling, head turning, eye movements, lip biting, or rhythmic twitching of muscles. Focal seizures usually cause no change in awareness or alertness. An absence seizure is a brief seizure with an accompanying loss of awareness or alertness such as a staring spell. Focal and absence seizures are types of petit mal seizures. A grand mal seizure is characterized by a loss of consciousness, a loss of bladder control, generalized muscle contractions, and tongue biting. Grand mal seizures are also followed by a period of lethargy, confusion, and deep breathing (postictal state) that may last from a few minutes to several hours.

Individuals affected with Aicardi syndrome also have vision problems including blindness. These vision problems are the result of abnormal development of the two inner layers of the eye (the choroid and the retina). The most common type of malformation in the eyes of individuals with Aicardi syndrome is the appearance of small cavities or holes in the retina (retinal lacunae). Instances of small eyes (micropthalmia) and missing structures of the eye (coloboma ) are also common.

Diagnosis

Aicardi syndrome is generally first diagnosed in affected individuals between the ages of three and five months. It is at this age that the final connections in the brain are completed. Once these connections are completed in an affected individual, this individual will begin to have infantile spasms. These spasms are akin to seizures in older children. Infantile spasms combined with defects of the retina and choroid of one eye or both eyes is sufficient evidence for the diagnosis of Aicardi syndrome. Magnetic resonance imaging (MRI) can confirm the brain malformations including the absence of the corpus callosum. Prenatal diagnosis is not yet available, but connection to the Xp22.3 locus makes genetic testing for this dominant trait potentially possible.

Treatment and management

Treatment of an individual with Aicardi syndrome generally consists of seizure management, vision treatment for those individuals born with sight or partial sight, and early and continuing intervention programs for developmental delays. Because of the severe neurological damage, many individuals are unable to chew and swallow and must be fed with pureed food. The most common medications for affected individuals are anti-convulsive drugs such as valproic acid (brand names: Depakene, Valproate, Valrelease); clonazepam (brand names: Klonopin and Rivotril); phenobarbitol (available as a generic drug); and phenytoin (brand name: Dilantin).

Prognosis

Aicardi syndrome is lethal in males prior to birth. The prognosis in females varies on a case-by-case basis. The estimated survival rate is 76% at six years and 40% at 14 years of age. There has been a report of a surviving individual with Aicardi syndrome in her late forties. Most individuals with Aicardi syndrome are either born blind or will become blind. Developmental delays and mental retardation are seen in all individuals affected with Aicardi syndrome ranging from mild to severe.

Resources

PERIODICALS

Aicardi, J. "Aicardi syndrome: Old and new findings." International Pediatrics (March 1999): 5-8.

King, A., S. Buchner, and P. Itin, "Aicardi syndrome." British Journal of Ophthalmology (April 1998): 456.

Trifiletti, R. et al. "Aicardi syndrome with multiple tumors: A case report with literature review." Brain Development (July-August 1995): 283-5.

ORGANIZATIONS

Aicardi Syndrome Foundation. 450 Winterwood Dr., Roselle, IL 60172. (800) 373-8518. <http://www.aicardi.com>.

WEBSITES

"Entry 304050: Corpus callosum, agenesis of, with chorioretinal abnormality." OMIM—Online Mendelian Inheritance in Man. <http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?304050> (February 9, 2001).

Reader's Digest Health—Focal Dermal Hypoplasia. <http://rdhealth.com/kbase/nord/nord49.htm> (February 9, 2001).

Paul A. Johnson