Corpus Callosum, Agenesis Of
The corpus callosum is the largest fiber tract in the central nervous system and the major interhemispheric fiber bundle in the brain. Formation of the corpus callosum begins as early as 6 weeks' gestation, with the first fibers crossing the midline at 11 to 12 weeks' gestation, and completion of the basic shape by age 18 to 20 weeks (Schell-Apacik et al., 2008). Agenesis of the corpus callosum (ACC) is one of the most frequent malformations in brain with a reported incidence ranging between 0.5 and 70 in 10,000 births. ACC is a clinically and genetically heterogeneous condition, which can be observed either as an isolated condition or as a manifestation in the context of a congenital syndrome (see MOLECULAR GENETICS and Dobyns, 1996). Also see mirror movements-1 and/or agenesis of the corpus callosum (MRMV1; 157600).
Schell-Apacik et al. (2008) noted that there is confusion in the literature regarding radiologic terminology concerning partial absence of the corpus callosum, where various designations have been used, including hypogenesis, hypoplasia, partial agenesis, or dysgenesis.Clinical Features
The most frequent clinical findings in patients with ACC are mental retardation (60%), visual problems (33%), speech delay (29%), seizures (25%), and feeding problems (20%) (Schell-Apacik et al., 2008).
In 2 brothers and a sister, da-Silva (1988) described a lethal and perhaps previously undescribed syndrome of hypoplastic corpus callosum, microcephaly, severe mental retardation, preauricular skin tag, camptodactyly, growth retardation, and recurrent bronchopneumonia. Death occurred at 32 months, 23 months, and 10 months.
Naritomi et al. (1994) described what they called the da-Silva syndrome in a 6-month-old Japanese boy with agenesis of the corpus callosum, hypertonicity, severe growth and psychomotor retardation, microcephaly, large prominent ears, and delayed bone age. At age 7 years, his growth and mental development was severely retarded. Persistent hypertonia resulted in dislocation of the left hip joint and a bedridden state. Cardiac catheterization showed an atrial septal defect and partial anomalous pulmonary venous return.
Schell-Apacik et al. (2008) performed a retrospective study of 172 patients with reported corpus callosum abnormalities and 23 patients with chromosomal rearrangements associated with corpus callosum abnormalities. A review of neuroimaging studies, when available, revised the findings in 43 cases and showed that 19 cases did not have corpus callosum abnormalities. Genetic or cytogenetic abnormalities were found in 13 (32%) of 41 cases studied in further detail.Inheritance
Young et al. (1985) reported an affected brother and sister, suggesting autosomal recessive inheritance. The forehead was prominent and the eyes deep-set. They found other examples of possible autosomal recessive inheritance (e.g., Naiman and Fraser, 1955; Shapira and Cohen, 1973; Pineda et al., 1984).
Lynn et al. (1980) reported affected father and son, suggesting autosomal dominant inheritance.
Naritomi et al. (1997) reported 3 sibs with agenesis of corpus callosum and severe psychomotor retardation, 2 of whom were dizygotic twins. Their phenotype was similar to that of the cases reported by Young et al. (1985). The parents were normal and nonconsanguineous.
Inbar et al. (1997) observed ACC in a mother and her son who had moderately severe coordination problems and low to normal intelligence. They suggested that agenesis of the corpus callosum, when transmitted as an autosomal dominant trait, is clinically relatively mild as compared with autosomal or X-linked recessive forms and may be more common than generally thought. They stated that the affected mother and her husband were not related. Her parents had normal cranial CT scans and were healthy.Pathogenesis
In a review of the embryology of the corpus callosum, Dobyns (1996) suggested that several different mechanisms can result in ACC. Two primary or 'true' types of ACC and 2 secondary types have been recognized. The 2 types of true ACC include (1) defects in which exons form but are unable to cross the midline because of absence of the massa commissuralis and leave large aberrant longitudinal fiber bundles known as Probst bundles along the medial hemispheric walls; and (2) defects in which the commissural axons or their parent cell bodies failed to form in the cerebral cortex. The former, probably the most common type of ACC, occurs in all ACC syndromes in which Probst bundles are seen. The latter occurs in Walker-Warburg syndrome, now known as congenital muscular dystrophy-dystroglycanopathy type A (see MDDGA1, 236670) and in other types of lissencephaly in which Probst bundles are generally not seen despite absence of the corpus callosum. Dobyns (1996) noted that one type of callosal abnormality that may be confused with ACC is absence of the corpus callosum associated with major malformations of the embryonic forebrain prior to formation of the anlage of the corpus callosum. Examples include frontal encephaloceles and holoprosencephaly. A second type of confusion with ACC occurs when there is degeneration or atrophy of the corpus callosum resulting in striking thinning, as in the Lyon syndrome (225740) and other syndromes in which the corpus callosum is thin but not foreshortened.Molecular Genetics
Dobyns (1996) reviewed the genetics of agenesis of the corpus callosum and noted that ACC has been reported in more than 20 autosomal malformation syndromes. These include Miller-Dieker syndrome (MDLS; 247200), Rubinstein-Taybi syndrome (RSTS; 180849), acrocallosal syndrome (ACLD; 200990), and Joubert syndrome (JBTS; 213300).
Dobyns (1996) also identified 17 X-linked malformation syndromes with ACC, including pyruvate dehydrogenase deficiency (312170). X-linked ACC is seen in patients with mutations in the L1CAM gene (308840), a cell surface glycoprotein implicated in migration of neurons and axonal growth: see X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (307000), the MASA syndrome (303350), and partial ACC (304100).
Schell-Apacik et al. (2008) noted that ACC and dysgenesis of the corpus callosum has been associated with at least 7 autosomal dominant, 23 autosomal recessive, and 12 X-linked complex genetic syndromes.
Schell-Apacik et al. (2008) were able to identify a genetic cause in 4 of 28 patients with complete ACC who had available neuroimaging results and underwent clinical evaluation. The cause remained unknown in the remaining patients.
Associations Pending Confirmation
In 3 adult sibs, born of unrelated French Canadian parents, with isolated agenesis of the corpus callosum, Jouan et al. (2016) identified compound heterozygous missense variants (G94R and N1232S) in the CDK5RAP2 gene (608201). The variants, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both variants affected highly conserved nucleotides. Lymphoblastoid cells from 1 of the patients showed biallelic expression of the variants; functional studies of the variants were not performed. Jouan et al. (2016) suggested that hypomorphic CDK5RAP2 variants with residual function may predispose to agenesis of the corpus callosum, while more detrimental loss of function variants may result in the more severe phenotype of microcephaly (MCPH3; 604804). The patients had mild features, including borderline IQ (77 to 84), variable motor delay and ataxia, and delayed speech. Brain imaging in all 3 patients showed complete ACC with preservation of the anterior commissure.Cytogenetics
ACC has been associated with several consistent chromosome rearrangements. One of the best documented of these is del(4p16), or Wolf-Hirschhorn syndrome (194190). ACC malformation syndromes have also been associated with cytogenetic deletions involving Xp22.3 and Xq13-q21 (Dobyns, 1996).
Pirola et al. (1998) demonstrated deletion of an 8-cM region between D6S1496 and D6S437 at 6q25 in a child with agenesis of the corpus callosum with Probst bundles (see 612863).
Schell-Apacik et al. (2008) were able to identify a cytogenetic abnormality in 7 of 28 patients with complete ACC and 2 of 13 patients with dysgenesis/partial malformation who had available neuroimaging results and underwent clinical evaluation. The cause remained unknown in the remaining patients. Cytogenetic abnormalities represented the most common underlying etiology.
In an analysis of 374 individuals with abnormalities of the corpus callosum and structural chromosome rearrangements, O'Driscoll et al. (2010) identified 12 ACC loci supported by 6 or more subjects (Class 1), another 18 loci supported by 3 to 5 subjects (Class 2), and numerous other possible loci supported by 2 to 3 subjects (Class 3). These data confirmed a strong genetic contribution to ACC. Class 1 deleted regions include chromosome 1p36 (see 607872), 1q43-q44 (see 612337), 4p16 (see 194190), 6q26-q27, 13q32.3-q33.1 (see 613884), 14q12-q13 (see 164874), 14qter, 21q22, and Xp22.3. Class 1 duplicated regions include chromosome 8p22-p21.3, 11q25, 13q34, 21q22, and Xp27.3-q28. Some of the regions were associated with related anomalies, including microcephaly, various types of cortical malformations, and cerebellar malformations.Animal Model
Dobyns (1996) pointed out that the inbred BALB strain of mice show partial or total ACC in 2%-28% of adult mice, depending on the substrain. Mice homozygous for disruption of the MACS gene (177061) also show ACC.