Embryonic development: Abnormal neurulation and holoprosencephaly

In the early stages of human embryological development, the neural tube begins a process called ventral induction. During ventral induction, the neural tube divides into three primary brain vesicles, or subdivisions, which later differentiate into five vesicles, as shown in Figure 1.

Figure 1 Embryological development of the brain vesicles; attribution: Tauiris, CC ASA 3.0

The division of the prosencephalon into the telencephalon and diencephalon occurs between the 18th and 28th day of gestation. These two parts then undergo a cleavage process, during which the neural tissue divides and forms distinct regions within the telencephalon and diencephalon. In addition to cleavage, there is an inward rotation of the developing brain structures. These processes are shown in Figure 2.

Figure 2 Normal ventral induction process showing brain formation around ventricles

Cleavage and rotation are crucial for the proper alignment and organization of the neural components. Under normal conditions, they result in a telencephalon and diencephalon each dividing into two halves, with no missing components. However, incomplete cleavage and failure of rotation of the prosencephalon can result in a brain malformation known as holoprosencephaly. Different forms of holoprosencephaly are shown in Figure 3.

Figure 3 Development of holoprosencephaly with a single ventricle

In the most severe form, alobar holoprosencephaly, the telencephalon and diencephalon are fused and a single ventricle is formed. Individuals with the alobar form experience severe mental retardation, seizures, and facial malformations of the nose, lips and eyes, or, in extreme cases, cyclopia (fused eyes); in many cases alobar holoprosencephaly is fatal.

The other two forms result in limited clinical deficits, such as cognitive delay and seizures that can be treated; life expectancy in these individuals is not reduced. In semilobar holoprosencephaly, the diencephalon remains fused but the telencephalon presents a fissure posteriorly. In lobar holoprosencephaly the diencephalon may or may not be fused, but the telencephalon presents a nearly normal fissure.