2.1. Congenital Fibrosis of the Extraocular Muscles

At least one mutation in the TUBB2B gene has been found to cause a rare form of congenital fibrosis of the extraocular muscles (CFEOM) called CFEOM3 with polymicrogyria. Individuals with this condition are unable to move their eyes normally; they have difficulty looking up, and they have droopy eyelids (ptosis). In addition, affected individuals have a brain malformation called polymicrogyria, in which the surface of the brain develops too many folds, and the folds are unusually small. Individuals with this form of CFEOM3 typically have intellectual disability.

The TUBB2B gene mutation that causes CFEOM3 with polymicrogyria changes a single protein building block (amino acid) in the β-tubulin protein. It replaces the amino acid glutamate with the amino acid lysine at protein position 421 (written as Glu421Lys or E421K). Microtubules that contain the altered β-tubulin protein do not grow and shrink as they should, which prevents axons from reaching their proper location. Nerves in the head and face (cranial nerves) that control muscles that surround the eyes (extraocular muscles) are particularly affected. Abnormal development of cranial nerves impairs the function of extraocular muscles, leading to the characteristic features of CFEOM such as restricted eye movement and droopy eyelids. It is unclear how the CFEOM-related change in the TUBB2B gene results in polymicrogyria.

2.2. Isolated Lissencephaly Sequence

2.3. Polymicrogyria

3. Other Disorders

Mutations in the TUBB2B gene have been identified in people with brain abnormalities affecting the surface of the brain (the cortex), which are classified as malformations of cortical development. These individuals do not have problems with extraocular muscles (described above). The brain abnormalities typically lead to intellectual disability in affected individuals. Brain malformations commonly associated with TUBB2B gene mutations result from abnormal development of the cortex and can include polymicrogyria (described above); reduced folding (simplified gyration); an abnormally smooth surface (lissencephaly), sometimes with an abnormally small head size (microlissencephaly); slits or clefts in one or both halves of the brain (schizencephaly); or other cortical abnormalities. In some affected individuals, a region of the brain called the cerebellum is particularly affected (cerebellar dysplasia). It is thought that mutations in the TUBB2B gene disrupt the movement of neurons and axons to their correct locations, altering brain development and leading to brain malformations.