Forms and Documents
- Molecular confirmation of a clinical diagnosis
- Distinguish between causes and forms of brain malformations
- Genetic counseling
- Prenatal diagnosis for known familial mutation(s) in at-risk pregnancies
Abnormal neuronal migration leads to a variety of brain malformation disorders, including lissencephalies and subcortical band or periventricular nodular heterotopias. Lissencephaly is characterized by a thickened cortex and the absence of folds or gyri (agyria) or the presence of abnormally wide gyri (pachygyria). Lissencephalies can present in different forms and with varying severity, ranging from complete agyria to mixed agyria and pachygyria, or simplified gyri with subcortical band heterotopia (double cortex). Mutations in distinct genes lead to overlapping forms of lissencephaly, including classic smooth lissencephaly, cobblestone lissencephaly, lissencephaly with agenesis of the corpus callosum, and lissencephaly with cerebellar hypoplasia. Subcortical band heterotopia is a mild form of lissencephaly characterized by normal gyri but the presence of an abnormal and often symmetric band of gray matter under the cortex. Lissencephalies uniformly cause developmental delay, epilepsy, and intellectual disability. A group of muscular dystrophy disorders (alpha-dystroglycanopathies) can present as Walker-Warburg syndrome at the severe end of their phenotypic spectrum; this syndrome is characterized by cobblestone lissencephaly, cerebellar abnormalities, eye defects, muscle weakness. Periventricular nodular heterotopia (PVNH) is characterized by the presence of uncalcified nodules of gray matter along the lateral ventricles. X-linked PVNH is a male-lethal disorder and affected females mainly present with focal seizures. A more severe phenotype, including microcephaly, intellectual disability, epilepsy, and quadriparesis, is seen in a rare autosomal recessive form of PVNH.
Polymicrogyria results from abnormal folding of the cerebral cortex, leading to an excessive number of small gyri that can be distinguished from the absence of gyri and thickened cortex in lissencephaly. Polymicrogyria restricted to a specific region of the cortex (focal polymicrogyria) can cause minimal neurologic impairment, but when it is widespread (generalized polymicrogyria) the phenotype is very severe and can consist of intractable epilepsy, intellectual disability, and cerebral palsy.