2.1. Congenital Fibrosis of the Extraocular Muscles

More than 10 mutations in the TUBB3 gene can cause congenital fibrosis of the extraocular muscles (CFEOM). These mutations most commonly cause a form of the condition called CFEOM3, and they are a rare cause of another form called CFEOM1. Individuals with any form of CFEOM are unable to move their eyes normally; they have difficulty looking upward or, less commonly, side-to-side, and most also have droopy eyelids (ptosis). In addition, people with CFEOM3 can have intellectual disability; behavioral, social, or language problems; or other neurological problems.

The TUBB3 gene mutations that cause CFEOM change single protein building blocks (amino acids) in the β-tubulin protein. The altered proteins assemble into microtubules, although some do so more readily than others. Research shows that when more altered β-tubulin protein is incorporated into microtubules, the signs and symptoms of the condition are more severe.

Microtubules made with altered β-tubulin proteins do not grow and shrink as they should, which prevents neurite growth. Nerves in the head and face (cranial nerves) that control muscles that surround the eyes (extraocular muscles) are particularly affected, although other nerves can also be involved. Abnormal growth of cranial nerves impairs the function of extraocular muscles, leading to the characteristic features of CFEOM such as restricted eye movement and droopy eyelids. Researchers suspect that abnormal growth of neurites within the brain leads to brain abnormalities that underlie intellectual disability and other neurological problems in some people with CFEOM3.

Certain mutations in the TUBB3 gene also appear to prevent motor proteins from attaching to microtubules. These mutations typically cause severe CFEOM3 that is associated with additional neurological problems, such as pain, weakness, or a decreased ability to feel sensations in the limbs (peripheral neuropathy) that begins in childhood or adulthood. It is unclear how these genetic changes contribute to specific signs and symptoms in severely affected individuals.

2.2. Other Disorders

Mutations in the TUBB3 gene can also cause a condition called cortical dysplasia, complex, with other brain malformations 1 (CDCBM1). The brain abnormalities associated with this condition lead to intellectual disability, weak muscle tone (hypotonia), and progressive muscle stiffness (spasticity) in affected individuals. Brain malformations in CDCBM1 result from abnormal development of the surface of the brain (the cortex) and other regions such as a group of structures deep in the brain called the basal ganglia, which helps control movement; the tissue that connects the left and right halves of the brain (the corpus callosum); and the brainstem, which connects the upper parts of the brain with the spinal cord and regulates many basic body functions. Affected individuals do not typically have problems with the extraocular muscles as in CFEOM (described above). It is thought that mutations in the TUBB3 gene disrupt the movement of neurons and axons to their correct locations, altering brain development and leading to brain malformations.