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Agenesis of corpus callosum (ACC) is a rare disorder that is present at birth (congenital). It is characterized by a partial or complete absence (agenesis) of an area of the brain that connects the two cerebral hemispheres. This part of the brain is normally composed of transverse fibers. The cause of agenesis of corpus callosum is usually not known, but it can be inherited as either an autosomal recessive trait or an X-linked dominant trait. It can also be caused by an infection or injury during the twelfth to the twenty-second week of pregnancy (intrauterine) leading to developmental disturbance of the fetal brain. Intrauterine exposure to alcohol (Fetal alcohol syndrome) can also result in ACC. In some cases mental retardation may result, but intelligence may be only mildly impaired and subtle psychosocial symptoms may be present.
ACC is frequently diagnosed during the first two years of life. An epileptic seizure can be the first symptom indicating that a child should be tested for a brain dysfunction. The disorder can also be without apparent symptoms in the mildest cases for many years.
Agenesis of corpus callosum (ACC) may initially become evident through the onset of epileptic seizures during the first weeks of life or within the first two years. However, not all individuals with ACC have seizures. (For more information on these types of seizures choose “epilepsy” as your search term in the Rare Disease Database).
Other symptoms that may begin early in life are feeding problems and delays in holding the head erect. Sitting, standing and walking may also be delayed. Impairment of mental and physical development, and/or an accumulation of fluid in the skull (hydrocephalus) are also symptomatic of the early onset type of this disorder. (For more information, choose “hydrocephalus” as your search term in the Rare Disease Database.)
Non-progressive mental retardation, impaired hand-eye coordination and visual or auditory (hearing) memory impairment can be diagnosed through neurological testing of patients with ACC.
In some mild cases, symptoms may not appear for many years. Older patients are usually diagnosed during tests for symptoms such as seizures, monotonous or repetitive speech, or headaches. In mild cases it may be overlooked due to lack of obvious symptoms during childhood.
Some patients may have deep-set eyes and a prominent forehead. An abnormally small head (microcephaly), or sometimes an unusually large head (macrocephaly), may be present. Tags of skin in front of the ears (pre-auricular skin tags), one or more bent fingers (camptodactyly), and delayed growth have also been associated with some cases of agenesis of corpus callosum. In other cases wide-set eyes (telecanthus), a small nose with upturned (anteverted) nostrils, abnormally shaped ears, excessive neck skin, short hands, diminished muscle tone (hypotonia), abnormalities of the larynx, heart defects, and symptoms of Pierre-Robin syndrome may be present. (For more information choose “Pierre-Robin” as your search term in the Rare Disease Database).
Aicardi syndrome, thought to be inherited as an X-linked dominant disorder, consists of agenesis of corpus callosum, infantile spasms, and abnormal eye structure. This disorder is an extremely rare congenital disorder in which frequent seizures, striking abnormalities of the eye’s middle coat (choroid) and retinal layers, and the absence of the structure linking the two cerebral hemispheres (the corpus callosum), accompany severe mental retardation. Only females are affected. (For more information on this disorder, choose “Aicardi” as your search term in the Rare Disease Database).
Andermann syndrome, identified in 1972, is a genetic disorder characterized by a combination of agenesis of corpus callosum, mental retardation, and progressive sensorimotor nervous system disturbances (neuropathy). All known cases of this disorder originate from Charlevois County and the Saguenay-Lac St. Jean area of Quebec, Canada. The gene causing this rare form of ACC was recently identified and testing for this gene (SLC12A6) is currently available.
XLAG (X linked lissencephaly with ambiguous genitalia is a rare genetic disorder in which males have small and smooth brains (lissencephaly), small penis, severe mental retardation and intractable epilepsy. This is caused by mutations in the ARX gene. In females, these same mutations can cause ACC alone, whereas less severe mutations in males can cause mental retardation. Testing for this disorder is also clinically available.
In most cases, the cause of ACC is unknown. However, agenesis of corpus callosum can be inherited as an autosomal recessive trait or an X-linked dominant trait. This disorder may also be due in part to an infection during pregnancy (intrauterine) leading to abnormal development of the fetal brain.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
In X-linked dominant disorders, a female with only one X chromosome with an abnormal gene will develop the disease. However, the affected male always has a more severe condition. Sometimes, affected males die before birth so that only female patients survive. This seems to be true for one form of agenesis of corpus callosum known as Aicardi syndrome. The majority of patients diagnosed so far have been females. Aicardi syndrome has been seen occasionally in males with an extra X chromosome.
Agenesis of Corpus Callosum produces symptoms during the first two years of life in approximately ninety percent of those affected. It has been thought to be a very rare condition but the increased use of neuro-imaging techniques, such as MRI, is resulting in an increased rate of diagnosis. This condition may also be identified during pregnancy through an ultrasound. Currently, the highest estimate of incidence is 7 in 1000 individuals.
Ultrasound and magnetic resonance imaging (MRI) are imaging techniques that aid in diagnosis of agenesis of corpus callosum.
Treatment
Treatment is symptomatic and supportive. Anti-seizure medications, special education, physical therapy, and related services may be of benefit depending upon the range and severity of symptoms. When hydrocephalus is present it may be treated with a surgical shunt to drain the fluid from the brain cavity, thereby lowering the increased pressure on the brain. Genetic counseling may also be of benefit to families with this disorder.
Cognitive, psychosocial research and genetic studies of agenesis of corpus callosum are ongoing.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
REVIEW ARTICLES
Dupre N, Howard HC, Mathieu J, et al. Hereditary motor and sensory neuropathy with agenesis of the corpus callosum. Ann Neurol 2003;54(1):9.
Richards L, Plachez C, Ren T. Mechanisms regulating the development of the corpus callosum and it’s agenesis in mouse and human. Clin Genet 2004;66(4):276.
Sherr EH. The ARX story (epilepsy, mental retardation, autism, and cerebral malformations): one gene leads to many phenotypes. Curr Opin Pediatr 2003;15(6):567.
del Campo M, et al., Albinism and agenesis of the corpus callosum with profound developmental delay: Vici syndrome, evidence for autosomal recessive inheritance. Am J Med Genet. 1999;85:479-85.
JOURNAL ARTICLES
Marszal E, et al., Agenesis of corpus callosum: clinical description and etiology. J Child Neurol. 2000;15:401-05.
Desai AK, et al., Agenesis of corpus callosum – a rare case. J Postgrad Med. 1999;45:20-22.
Abdel-Salam GM, et al., A new case of neonatal progeroid syndrome with agenesis of corpus callosum. Genet Couns. 1999;10:377-81.
Agarwal HS, et al., Interhemispheric arachnoid cyst with agenesis of corpus callosum. Indian J Pediatr. 1997;34:737-40.
Naritomi K, et al., Agenesis of corpus callosum in three sibs. Jpn J Hum Genet
1997;42:539-541.
Dobyns WB., Absence makes the search grow longer. Am J Hum Genet. 1996;58:7-16.
FROM THE INTERNET
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 217990; Last Update: 8/12/99; Entry No: 217990; Last Edit: 7/15/04.
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