Agenesis of corpus callosum (ACC) is a rare birth defect in which there is a complete or partial absence of the corpus callosum that is present at birth (congenital). It occurs when the development of the corpus callosum, the band of white matter connecting the two hemispheres in the brain, in the embryo is disrupted. 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 the 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 brain dysfunction. The disorder can also be without apparent symptoms in the mildest cases for many years.
Causes
In most cases, the cause of ACC is unknown. However, agenesis of the 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 is 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 of 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 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.
Associated brain anomalies
Brain anomalies that can sometimes occur in syndromes that cause callosal disorders include:
- Aplasia of the cerebellar vermis
- Chiari malformation
- Colpocephaly
- Dandy–Walker syndrome
- Holoprosencephaly
- Hydrocephalus
- Neuronal migration disorders such as grey matter heterotopia
- Schizencephaly
Associated syndromes and conditions
Some syndromes that frequently include ACC are:
- Acrocallosal syndrome
- Aicardi syndrome
- Andermann syndrome
- Donnai–Barrow syndrome
- Dwarfism
- FG syndrome
- L1CAM syndrome
- Microcephalic osteodysplastic primordial dwarfism type II
- Mowat–Wilson syndrome
- Oculocerebrocutaneous syndrome
- Saal Bulas syndrome
- Septo-optic dysplasia (optic nerve hypoplasia)
- Shapiro syndrome
- Vici syndrome
Some conditions that can sometimes be associated with ACC or other callosal disorders include:[citation needed]
- 1p36 deletion syndrome
- 13q deletion syndrome
- CDK13-related disorder
- Craniofacial abnormalities and other oral and maxillofacial pathologies
- Fetal alcohol syndrome
- Fetal warfarin syndrome
- Genitopatellar syndrome
- Gomez-Lopez-Hernandez syndrome
- Joubert syndrome
- Lujan–Fryns syndrome
- Marden–Walker syndrome
- Maternal nutritional deficiencies or infections
- Metabolic disorders
- Okamoto syndrome
- Opitz G/BBB syndrome
- Pascual-Castroviejo syndrome
- Pitt–Hopkins syndrome
- Sensenbrenner syndrome
- Strømme syndrome
- Triploid syndrome
- Trisomy 9
- Xia-Gibbs syndrome
Diagnosis
Depending on the part of corpus callosum affected, agenesis of the corpus callosum may classify into one of two varieties:
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Complete agenesis
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Partial agenesis (hypogenesis or dysgenesis), in which only the splenium and/or rostrum are absent.
As a rule of thumb, primary agenesis of the corpus callosum (total agenesis) can be excluded by the presence of the rostrum. One exception is holoprosencephaly. In this condition, there may be atypical callosal dysgenesis, in which anterior parts of the corpus callosum are absent.
Morphologically, agenesis of the corpus callosum classifies into two types:
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Type 1 – Axons form, but these are unable to cross the midline. Hence they form large aberrant Probst bundle fibers along the medial hemispheric walls.
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Type 2 – Commissural axons fail to form, and so Probst fiber bundles are not found.
Probst fiber bundles run parallel to the medial walls of the lateral ventricles and enlarge and deform their medial borders, especially at the level of the frontal horns. Recently a reduction in the number of von Economo neurons, which are large spindle-shaped neurons localized to the anterior cingulate cortex and frontoinsular cortex, has been described in agenesis of the corpus callosum. Partial agenesis of the corpus callosum has correlations with ‘sigmoid bundles,’ which asymmetrically connect the frontal lobe with the contralateral occipitoparietal cortex.[rx]
History and Physical
The affected patients are mostly asymptomatic. Most of the patients present within the first two years of life.
Patients with agenesis of corpus callosum usually present with:
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Mental retardation (60%)
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Vision problems (33%)
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Delay in the development of speech (29%)
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Seizures (25%)
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Feeding problems (20%)
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Impaired hand-eye coordination and
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Socio-behavioral disorders like attention-deficit-hyperactivity disorder (ADHD) and psychosis
Isolated agenesis of corpus callosum patients may have normal intelligence quotient, but may have some cognitive deficits which group under the “core syndrome” which includes[rx]:
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Reduced interhemispheric transfer of sensory-motor information
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Reduced cognitive processing speed
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Deficits in complex reasoning and novel problem-solving
Fetal ultrasound can detect agenesis of the corpus callosum as early as the 16th week of gestation.[rx] But it is associated with a false-positive rate of 0% to 20%.[rx]
An antenatal ultrasound scan may show some findings suggestive of agenesis of the corpus callosum:
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Dilated and elevated third ventricle
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Lateral ventricles may appear as widely spaced parallel bodies with small frontal horns
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Colpocephaly gives rise to a “teardrop” configuration on axial scans.
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Absent septum pellucidum with widened interhemispheric fissure
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Color Doppler may show that the normal semicircular arterial loop, formed by the pericallosal artery, along with the superior surface of the corpus callosum, is missing or distorted
Magnetic resonance imaging of the brain is the investigation of choice for agenesis of the corpus callosum.
The following signs are suggestive of the diagnosis[rx][rx]:
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Racing car sign: Axial imaging of the lateral ventricles will show the similarity to a Formula One car viewed from above
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“Moose head appearance” or “Viking helmet sign” or “Longhorn appearance”: Coronal views at the level of the frontal horns have this characteristic appearance due to CCA and eversion of bilateral cingulate gyri into the frontal horns
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Sunray appearance: Sagittal imaging shows gyri radiating outward in a radial pattern from the ventricle
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Lateral ventricles appear to be parallel to each other and non-converging
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ACC is also typically accompanied by colpocephaly (dilatation of the trigones and occipital horns)
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High riding third ventricle
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Along the superomedial surface of lateral ventricles, inverted Probst bundles may be present
Neuropsychological evaluation of all patients with agenesis of the corpus callosum is mandatory.
- Anatomy ultrasound – a high-resolution ultrasound to confirm the diagnosis and assess for other anomalies
- Fetal MRI – a non-invasive imaging technique to help provide additional details of the baby’s organs that may not have been visualized on ultrasound
- Fetal echocardiogram – a specialized ultrasound to evaluate the baby’s heart structure and function
- Cell-Free fetal DNA testing – Your doctor can take a sample of your blood to look for copies of fetal (baby) DNA. This is only a screening test. A positive result means that there could be problems with the baby’s DNA. This should be confirmed with another test to be sure of the result. A normal result does not mean that there are no underlying genetic problems. Another testing can be done before or after birth depending on your needs and the needs of the baby.
- Amniocentesis – A small sample of the amniotic fluid that surrounds the baby in the womb is taken and tested for DNA problems. This test is usually done in the middle of the second trimester. An amniocentesis can be used to confirm findings on the cell-free fetal DNA test.
- Testing the baby – After birth, a test is done with a sample of your baby’s blood to look for chromosome problems. This is called either a “karyotype” (basic chromosome study), or microarray (a more detailed look at smaller sections of DNA).
Callosal disorders can be diagnosed through brain imaging studies or during autopsy. They may be diagnosed through an MRI, CT scan, Sonography, prenatal ultrasound, or prenatal MRI.[rx]
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.
There are currently no specific medical treatments for callosal disorders, but individuals with ACC and other callosal disorders may benefit from a range of developmental therapies, educational support, and services. It is important to consult with a variety of medical, health, educational, and social work professionals. Such professionals include neurologists, neuropsychologists, occupational therapists, physical therapists, speech and language pathologists, pediatricians, recreation therapists, music therapists, geneticists, social workers, special educators, early childhood intervention specialists, and caregivers for adults.[rx]
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