Identification of brain malformations: neuropathological approach

Introduction: The sophistication of prenatal brain imaging (US, MRI) has awakened interest in fetal neuropathology and changed the concept of brain malformations, defined until recently through descriptive terms and considered as senseless accidents of development. Usually, most CNS malformations are documented from a clinical and radiological point of view. However, only a detailed neuropathological study permits their exact phenotype to be established, which is instrumental for a precise diagnosis and cause analysis. Discussion: After pregnancy termination for fetal malformations (or prenatal death) full autopsy and frozen tissue storage for DNA analysis are mandatory. The delay between death and autopsy should be limited because of the rapid autolysis of brain tissue. Detailed neuropathological and cause analysis have made it clear that each brain malformation is phenotypically "unique" and causally heterogeneous. Molecular studies have shown that mutations in different genes involved in a signaling pathway may result in a similar malformation. In addition, signaling pathways may be a possible target of toxic agents, which will mimic the genetic causes of malformations. These findings have raised growing interest in the early patterning of the developing nervous system in humans and its molecular controlling pathways. Consequently, brain malformations are now evaluated with special regard to their mechanism and cause analysis, considering fetal, maternal, and placental pathology. The predictive value of this multidisciplinary approach is now well demonstrated and has led, in some conditions, to gene identification, which is crucial for genetic counseling. It permits a prenatal molecular diagnosis as early as the 10-12th gestational week on chorionic villus sampling.