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ABSTRACT

  • Holoprosencephaly (HPE) is a structural anomaly of the developing brain in which the forebrain fails to divide into two separate hemispheres and ventricles. HPE is the most common brain defect in humans with a prevalence of 1 in 250 during early embryogenesis and 1 in 10,000 to 1 in 20,000 at birth.

  • Our understanding of the pathogenesis of HPE derives largely from the study of animal models. Embryologically, HPE is associated with a loss or failure to develop midline structures of the ventral forebrain and of the face. The resulting apposition or fusion of structures that normally develop in lateral positions gives rise to the characteristic features of HPE. Internally, these features include the defining characteristic of HPE, an undivided forebrain. Externally, severe HPE is associated with development of a cyclopic eye, resulting in superior displacement of a fused, proboscis-like nasal structure.

  • The prechordal plate mesendoderm has emerged as a structure required for induction of ventral forebrain in the overlying neural plate, and for subdivision of the eye field. Surgical, teratologic, or genetic perturbations of the prechordal plate, particularly at or before early gastrulation, are associated with HPE.

  • Genetic studies originating in Drosophila and extending to mice and humans have identified Sonic hedgehog, a member of the Hedgehog family of secreted signaling proteins, as a critical signal produced in the prechordal plate and required for induction of ventral forebrain structures from the overlying neural plate. Mouse embryos homozygous for Sonic hedgehog mutations display the features of severe HPE, and humans with heterozygous SHH mutations have clinical findings of HPE with variable expressivity and penetrance. Loss of Shh signaling may also contribute to defects in midline facial development because Shh is also expressed in the processes that give rise to midline facial structures. Mutation of other Shh pathway components has also been associated with ventral forebrain deficits in animal models.

  • Several plant-derived and synthetic teratogens are known to specifically block the ability of cells to respond to Shh signaling. The mechanism of this effect is not known, but these agents all appear to affect cellular cholesterol homeostasis. In addition, certain mutations in mice or humans that perturb cholesterol homeostasis cause or increase the incidence of HPE.

  • Studies in the mouse and in the zebra fish have also implicated the signaling pathway headed by nodal and/or related members of the TGF-β family of secreted signaling proteins as playing a critical role in prechordal mesoderm formation, migration, and signaling to the overlying prosencephalic plate.

  • The processes of ventral forebrain and midline facial development represent a particularly sensitive target for genetic or environmental perturbations. HPE can also result from combinations of distinct insults that are mild and that alone do not cause HPE. These factors together may account for the high incidence of HPE in human embryos, and for the large number of autosomal dominant human syndromes associated with HPE. In addition, the increased severity produced by a combination of genetic and possibly environmental insults may ...

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