Mediobasal prosencephalic defects, including holoprosencephaly and cyclopia, in relation to the development of the human forebrain

Abstract

Four very early synophthalmic embryos were studied in serial sections and reconstructed graphically by the point-plotting method. Three belonged to stage 16 (5 weeks) and one to stages 19/20 (7 weeks). Recently completed accounts and reconstructions of the normal brains of staged human embryos served as controls for comparison with the abnormal examples. The embryos shared in common: holoprosencephaly, arhinencephaly sensu stricto (absence of olfactory nerve fibers, bulbs, and tracts), presence of a proboscis, synophthalmia with two lens vesicles, a retarded telencephalic wall, absence of the mediobasal part of the telencephalon (the future septal area and the commissural plate: future anterior commissure and corpus callosum), irregularity of the diencephalon, mensural changes in the brain, absence of the rostral part of the notochord and consequent cranial defects, and small ganglia of the cranial nerves. Where it could be determined (at least in the three less advanced specimens), the adenohypophysial primordium was either small and isolated or was absent; a tentorial condensation appeared to be missing; and disturbances of the primordia of the orbital muscles and their innervation were noted. The corpus striatum is single and corresponds to only the diencephalic part (medial eminence) of normal embryos. Interference with induction by the prechordal plate at or before stage 8 (18 days) would be expected to affect the future mediobasal part of the neural plate (median prosencephalic dysgenesis) and the future optic primordium (cyclopia sensu stricto). Insufficient formation of material from the prechordal plate would account for disorders of the orbital musculature and, possibly, for inadequacy of the tentorium cerebelli. Disturbance a couple of days later (stage 9) would result in synophthalmia. Cyclopia and synophthalmia entail arhinencephaly and holoprosencephaly, both of which may arise independently. Defective distribution of the cephalic mesenchyme points to a derangement of the mesencephalic neural crest (stages 10 and 11), causing such features as an incomplete chondrocranium and reduction in size of the ganglia of the cranial nerves. Failure of bilateral division of the telencephalon would occur at or before 4 weeks (stages 13 and 14). It is concluded that all the above conditions arise during the first 4 postovulatory weeks.

The Prechordal Plate, the Rostral End of the Notochord and Nearby Median Features in Staged Human Embryos

“…For example, faulty interaction between the notochordal plate, the neural plate and the oropharyngeal membrane may be significant, and the rostral tip of the notochordal plate may be critical [Cohen et al, 1971]. In agreement with these proposals is the finding that the rostral part of the notochord was absent in synophthalmic (future holoprosencephalic) embryos of stage 16 [Müller and O'Rahilly, 1989].…”

“…1 and 2] and the likelihood of a contribution to the tentorium is confirmed in holoprosencephaly, where that structure is lacking [Müller and O'Rahilly, 1989].…”

“…The prechordal plate, therefore, is required for the formation of the two retinae, and its absence results in the development of a single retinal primordium. Lack of the Shh gene in the mouse results in holoprosencephaly with cyclopia [Chiang et al, 1996] and morphological appearances that resemble those in correspondingly abnormal human embryos [Müller and O'Rahilly, 1989]. …”

Holoprosencephaly with agenesia of the prosencephalic ventricle

“…During embryological development the prosencephalon is the primitive forebrain vesicle at the rostral end of the neural tube following closure of the anterior neuropore [18]. The lamina terminalis is the membrane that closes the anterior neuropore.…”

“…Defect of neural induction at the lamina terminalis and inappropriate patterning of the rostral neural tube into the prosencephalon with a significant role of the prechordal plate play crucial roles [18,23].The prosencephalon fails to divide sagittally into the cerebral hemispheres, transversely into the telencephalon and diencephalon, and horizontally into the olfactory tracts and bulbs [3]. An abnormally small prosencephalic protrusion with a single ventricle was observed early during embryogenesis [26,31].…”