The proposed CCA classification system can be applied when evaluating a single midline sagittal MRI from any patient, and does not require 3-dimensional reconstruction or volumetric analysis. Although future studies might utilize more advanced imaging technologies such as fMRI or fractional anisotropy for more highly precise anatomic subclassification, for most clinicians, a simple system based upon routine MRI is a necessary first step. We found that within a given family, the appearance of the CCA was remarkably similar, though in some instances there were different subtypes of a given class of abnormality seen within the same family. Clearly there is some interfamilial variability, although COMPLETE AGENESIS can be observed in family members as an “end phenotype” associated with most of the subtypes. Due to the relatively small cohort size, statistical analysis could not be applied, and we could not determine whether particular CNS or non-CNS clinical features consistently associated with specific CCA subtype.
The sequence of CC development begins with the differentiation of the commissural plate around 6 weeks gestation (GW), followed by crossing of pioneer axons, first in the rostrum and then proceeding more casually from 10 to 12 GW.9
CC myelination does not occur until after birth and proceeds until adolescence. Given this sequence, we might imagine that the insult timing of apple core
and anterior remnant
might be prior to midgestation, whereas hypoplasia without dysplasia
might be later. Pinpointing genetic etiologies could better clarify precise mechanisms.
The clinical phenotype tended to be similar in siblings of a given family, but there was greater heterogeneity than for MRI findings. Some of the patients had evidence of a small brainstem/pons, which might represent deficient longitudinal pontine axons as part of an overall axonal deficiency in CCA, but a more comprehensive volumetric analysis of brainstem was not possible in this cohort due to limited image availability. Previous studies comparing neurodevelopmental outcome in relationship to partial or complete CCA have shown mixed results, some finding that complete CCA shows a poorer prognosis,15
whereas others have not validated this correlation.4,16
We found that the AC was present in most cases; however, in cases with COMPLETE AGENESIS, it tended to be absent or decreased in size.
Our observation fits well with the current understanding of CC development as a process that takes place along distinct anatomic axes, and a number of early events that are guided by independent signaling systems for each anatomic group of axons that cross the midline.17,18
Disturbance of an essential early event might therefore lead to hypoplasia or to complete agenesis, depending upon environmental or modifier gene influences. The predominant type of HYPOPLASIA WITHOUT DYSPLASIA showed some level of posterior CC hypoplasia, while only 2 cases showed near complete posterior CC hypoplasia (the anterior remnant CCA
type). Presumptively in anterior remnant CCA
patients, the genetic defect alters neurodevelopmental processes at an early time point, and involves the coordination of axons crossing in all but the most anterior regions of the CC.
A number of genetic disorders in humans have been associated with CCA, including several X-linked diseases, metabolic disorders, and contiguous gene deletion syndromes.17
However, in each of these, the CCA is usually secondary to a more defining characteristic (such as in X-linked lissencephaly with ambiguous genitalia syndrome19
), or is just one of a number of defining characteristics (such as in Aicardi or Andermann syndromes).20,21
To date, no genes have been identified in which CCA has been the primary defining characteristic. A classification system such as the one that we propose may help lead to the identification of causes of this important neurologic disorder, by allowing patients with the same type of CCA to be grouped together for genetic analysis.
Investigations have identified several potential gene dose-dependent candidate loci for CCA.22,–24
Additionally, cytogenetic abnormalities are detected in approximately 10% of patients with CCA.1
Analysis in mice has uncovered a large number of genes that when mutated lead to CCA, including guidance molecules, transcription factors, extracellular matrix molecules, signaling/cytoplasmic molecules, growth factors, as well as certain strains of mice that are particularly vulnerable to CCA.17
Thus, a large number of genes contribute to the development, morphology, and maintenance of the CC, some of which appear to play primary roles, while in others the effect on the CC may be secondary to a more notable structural CNS defect.
Our preliminary genetic mapping data from these consanguineous families suggest a multitude of new causative loci, which reflects the anatomic complexity that we describe here. Using a recessive disease model, it is possible to identify causative genes using homozygosity mapping and next-generation sequencing strategies in a straightforward manner. Therefore, the ability to select patients for evaluation at newly identified genes based upon similarities in the appearance of the CC will improve the ability to molecularly classify CCA patients.
Given this substantial proportion of sporadic patients with CCA and PBs, we felt our classification scheme should reflect their presence or absence, but rather than further subdivide the aforementioned types, we propose to indicate the presence of PBs by denoting + PBs next to the type. The explanation for the relatively low percentage of patients with PBs in our cohort compared with historic controls5
is not immediately apparent but may relate to the bias for large consanguineous families in this study.