Genetics of human hydrocephalus

Abstract

Human hydrocephalus is a common medical condition that is characterized by abnormalities in the flow or resorption of cerebrospinal fluid (CSF), resulting in ventricular dilatation. Human hydrocephalus can be classified into two clinical forms, congenital and acquired. Hydrocephalus is one of the complex and multifactorial neurological disorders.A growing body of evidence indicates that genetic factors play a major role in the pathogenesis of hydrocephalus. An understanding of the genetic components and mechanism of this complex disorder may offer us significant insights into the molecular etiology of impaired brain development and an accumulation of the cerebrospinal fluid in cerebral compartments during the pathogenesis of hydrocephalus. Genetic studies in animal models have started to open the way for understanding the underlying pathology of hydrocephalus. At least 43 mutants/loci linked to hereditary hydrocephalus have been identified in animal models and humans. Up to date, 9 genes associated with hydrocephalus have been identified in animal models. In contrast, only one such gene has been identified in humans. Most of known hydrocephalus gene products are the important cytokines, growth factors or related molecules in the cellular signal pathways during early brain development. The current molecular genetic evidence from animal models indicate that in the early development stage, impaired and abnormal brain development caused by abnormal cellular signaling and functioning, all these cellular and developmental events would eventually lead to the congenital hydrocephalus. Owing to our very primitive knowledge of the genetics and molecular pathogenesis of human hydrocephalus, it is difficult to evaluate whether data gained from animal models can be extrapolated to humans. Initiation of a large population genetics study in humans will certainly provide invaluable information about the molecular and cellular etiology and the developmental mechanisms of human hydrocephalus. This review summarizes the recent findings on this issue among human and animal models, especially with reference to the molecular genetics, pathological, physiological and cellular studies, and identifies future research directions.

Fig. 1

Comparison of rat brain morphology by MRI and histology at 4, 11 and 21 days of age in non-hydrocephalic and hydrocephalic HTX rats. T2-weighted MRI scans of coronal sections from a non-hydrocephalic HTX rat at the level of the thalamus at 4, 11 and 21 days (A, D, G) shows small ventricular and subarachnoid spaces compared to an age-matched HTX littermate (B, E, H) that exhibits large cerebral ventricles, a progressively-thinned cortical mantle, and stretched internal capsule fibers (*). Congenital closure of the cerebral aqueduct becomes life-threatening by 21 days of age. Histological sections (C, F, I) at the level of the midbrain at the same ages demonstrate extreme thinning of the cortical mantle. MRI images are modified from Jones et al (2000) [123] with permission by Maney Publishing; histological samples are from the doctoral thesis of Janet M. Miller, PhD