Congenital fibrosis of the extraocular muscles (CFEOM) is a disorder of the nervous system that affects use of the muscles that surround the eyes (extraocular muscles). These muscles control eye movement and the direction of the eyes (for example, looking straight ahead). CFEOM impairs control of these muscles. As a result, affected individuals are unable to move their eyes normally. Most people with this condition have difficulty looking upward, and their side-to-side eye movement may also be limited. The eyes may look in different directions (strabismus). Instead of moving their eyes, affected individuals may need to turn their head to track moving objects. Additionally, most people with CFEOM have droopy eyelids (ptosis), which further limits their vision.

Researchers have identified several forms of CFEOM, designated CFEOM1, CFEOM2, CFEOM3, and Tukel syndrome (sometimes called CFEOM4). The specific problems with eye movement vary among the types, and some types are associated with additional signs and symptoms. People with CFEOM1 and CFEOM2 have only the eye problems described above. In CFEOM1, the eyes typically point downward, whereas in CFEOM2, the eyes usually turn outward.

CFEOM3 can include additional neurological problems, such as intellectual disability; difficulty with social skills; a smaller-than-normal head size (microcephaly); muscle weakness in the face; nonfunctioning vocal cords; and a set of symptoms called Kallmann syndrome, which features delayed or absent puberty and an impaired sense of smell. Some affected individuals develop pain, weakness, or a decreased ability to feel sensations in the limbs (peripheral neuropathy), which can begin in childhood or adulthood.

Brain abnormalities can also occur in people with CFEOM3. Some have abnormal development of the white matter, which is brain tissue containing nerve cell fibers (axons) that transmit nerve impulses. A particular form of CFEOM3, known as CFEOM3 with polymicrogyria, is characterized by abnormal development of the brain, in which the folds and ridges on the surface of the brain are smaller and more numerous than usual.

Tukel syndrome is characterized by missing fingers (oligodactyly) and other hand abnormalities in addition to problems with eye movement.

Several genes involved in CFEOM have been identified. Mutations in the KIF21A gene cause CFEOM1 and rare cases of CFEOM3; mutations in the TUBB3 gene cause CFEOM3 and rare cases of CFEOM1; a mutation in the TUBB2B gene causes CFEOM3 with polymicrogyria; and mutations in the PHOX2A gene cause CFEOM2. The genetic cause of Tukel syndrome is unknown. The CFEOM-related genes are important for growth or development of nerve cells (neurons).

Mutations in the KIF21A, TUBB3, or TUBB2B gene impair a process called axon guidance. Through this process, the specialized extensions of neurons (axons) are directed to their correct positions. Once in the right position, axons relay messages from the brain to muscles and sensory cells and back to the brain, which is critical for controlling muscle movement and detecting sensations such as touch, pain, and heat. As a result of these mutations, axons do not reach their proper locations. Nerves in the head and face (known as cranial nerves) that control muscles that move the eyes and eyelids are particularly affected, although other nerves can also be involved. Abnormal growth of cranial nerves impairs extraocular muscle function and leads to the characteristic features of CFEOM, including restricted eye movement and droopy eyelids. Problems with other nerves likely underlie additional neurological features in people with CFEOM3.

The protein produced from the PHOX2A gene is involved in neuron development, particularly of cranial nerves III and IV, which are necessary for normal eye movement. Mutations likely eliminate the function of the PHOX2A protein, which prevents the normal development of these cranial nerves and impairs control of the extraocular muscles.

Studies suggest that a gene associated with Tukel syndrome may be located near one end of chromosome 21. Some people with features of CFEOM do not have mutations in the genes mentioned above, indicating that other genes that have not been identified may also be involved in the condition.

Normal Function

The KIF21A gene provides instructions for making a protein that is part of the kinesin family. Many proteins in the kinesin family are essential for the transport of materials within cells. Kinesin proteins function like freight trains that transport cargo along a track-like system made from structures called microtubules. Some kinesins also help maintain microtubules. As well as functioning like a track, microtubules make up the structural framework of cells and help cells move.

The KIF21A protein is found in nerve cells (neurons) and many other cell types. Researchers believe that this protein plays an important role in neuron development by helping control the growth of microtubules. By blocking microtubule growth at critical times, the KIF21A protein may help direct the path of neuron extensions known as axons so they can reach their correct locations. Once in the right position, axons relay messages to and from the brain to control muscle movement and detect sensations such as touch, pain, and heat.

For proper neuron development, the KIF21A protein must be turned on and off at particular times. When a segment of the protein known as the regulatory region interacts with another segment of the protein known as the motor domain, the protein is turned off (which is known as autoinhibition).

Health Conditions Related to Genetic Changes

Congenital fibrosis of the extraocular muscles

At least 12 mutations in the KIF21A gene have been identified in people with congenital fibrosis of the extraocular muscles (CFEOM). These mutations cause the most common form of the disorder, CFEOM1, and are a rare cause of another form of the condition called CFEOM3. Individuals with 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 or other neurological problems.

Each of the known KIF21A gene mutations changes a single protein building block (amino acid) in the KIF21A protein. Most of these changes occur in the regulatory region of the protein. These mutations alter the protein's structure, which interferes with its ability to turn itself off. As a result, the KIF21A protein is always on (constitutively active) and cannot regulate microtubule growth. Without proper control of microtubule elongation, the axons of nerves develop abnormally and do not reach the muscles they control. Nerves in the head and face (cranial nerves) that control muscles that surround the eyes (extraocular muscles) are particularly affected. Problems with cranial nerve development impair extraocular muscle function, resulting in the characteristic features of CFEOM such as restricted eye movement and droopy eyelids.

Other Names for This Gene

• CFEOM
• CFEOM1
• DKFZp779C159
• FEOM
• FEOM1
• Fibrosis of extraocular muscles, congenital, 1, autosomal dominant
• fibrosis of the extraocular muscles, congenital, 1
• FLJ20052
• KI21A_HUMAN
• KIAA1708
• KIF2
• KIF21A variant protein
• Kinesin-like protein KIF2
• Kinesin-like protein KIF21A
• NY-REN-62 antigen
• Renal carcinoma antigen NY-REN-62

Genomic Location

Normal Function

The PHOX2A gene provides instructions for making a protein that is found in the nervous system. This protein acts early in development to help promote the formation of nerve cells (neurons) and regulate the process by which the neurons mature to carry out specific functions (differentiation).

Most of researchers' knowledge about the PHOX2A protein comes from studies in animals. From these studies, it is clear that the protein plays a critical role in the development of the autonomic nervous system, which controls involuntary body functions such as breathing, blood pressure, heart rate, and digestion. The PHOX2A protein is also involved in the formation of certain nerves in the head and face (cranial nerves). Specifically, it appears to be critical for the development and function of cranial nerves III and IV, which emerge from the brain and control many of the muscles that surround the eyes (extraocular muscles). These muscles direct eye movement and determine the position of the eyes.

Health Conditions Related to Genetic Changes

Congenital fibrosis of the extraocular muscles

At least four mutations in the PHOX2A gene can cause congenital fibrosis of the extraocular muscles (CFEOM). These mutations are responsible for a form of the disorder called CFEOM2, which has been identified in several families of Middle Eastern descent.

Most of the mutations that cause CFEOM2 result in the production of an abnormally short, nonfunctional version of the PHOX2A protein. A lack of this protein prevents the normal development of several cranial nerves and the extraocular muscles they control. Abnormal development and function of these muscles leads to the characteristic features of the disorder, including restricted eye movement and related problems with vision. Although the PHOX2A protein plays an important role in autonomic nervous system development, PHOX2A mutations do not seem to affect the function of this part of the nervous system.

Other Names for This Gene

• aristaless homeobox homolog
• aristaless homeobox protein homolog
• ARIX
• arix homeodomain protein
• ARIX1 homeodomain protein
• CFEOM2
• FEOM2
• MGC52227
• NCAM2
• paired like homeobox 2a
• paired mesoderm homeobox protein 2A
• paired-like homeobox 2a
• PHX2A_HUMAN
• PMX2A

Genomic Location

Normal Function

The TUBB2B gene provides instructions for making one version of a protein called beta-tubulin (β-tubulin). This protein is part of the tubulin family of proteins that form and organize cell structures called microtubules. Microtubules are rigid, hollow fibers that make up the cell's structural framework (the cytoskeleton). They are composed of β-tubulin and a similar protein called alpha-tubulin (α-tubulin) that is produced from a different gene. Microtubules grow and shrink as tubulin proteins are added to and removed from the ends of fibers. This process allows cells to move and change shape.

β-tubulin produced from the TUBB2B gene is found primarily in the brain and in nerve cells (neurons). In neurons, microtubules are integral for the cells' movement to the proper location in the brain and for a process called axon guidance, by which specialized extensions of neurons (axons) reach their correct positions. Once in the right location, axons relay messages to and from the brain to control muscle movement and detect sensations such as touch, pain, heat, and sound.

Health Conditions Related to Genetic Changes

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.

Isolated lissencephaly sequence

MedlinePlus Genetics provides information about Isolated lissencephaly sequence

Polymicrogyria

MedlinePlus Genetics provides information about Polymicrogyria

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 (linked 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.

Other Names for This Gene

• class IIb beta-tubulin
• TUBULIN, BETA, CLASS IIB
• TUBULIN, BETA-2B

Genomic Location

Normal Function

The TUBB3 gene provides instructions for making one version of a protein called beta-tubulin (β-tubulin). This protein is part of the tubulin family of proteins that form and organize cell structures called microtubules. Microtubules are rigid, hollow fibers that make up the cell's structural framework (the cytoskeleton). They are composed of β-tubulin and a similar protein called alpha-tubulin (α-tubulin) that is produced from a different gene. Microtubules grow and shrink as tubulin proteins are added to and removed from the ends of fibers. This process allows cells to move and change shape.

β-tubulin produced from the TUBB3 gene is found in nerve cells (neurons) in the brain. This β-tubulin protein plays a role in the growth of specialized nerve cell extensions called axons and dendrites (collectively called neurites). Studies show this protein is particularly important for the regrowth of neurites after injury. Neurites relay messages to and from the brain to control muscle movement and detect sensations.

In addition to their role in cell movement, microtubules also function as a track along which other proteins, called motor proteins, transport materials within cells. β-tubulin produced from the TUBB3 gene appears to be important in the attachment of motor proteins to microtubules.

Health Conditions Related to Genetic Changes

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.

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.

Other Names for This Gene

• class III beta-tubulin
• Tubulin, Beta 3 Class III Gene
• TUBULIN, BETA, CLASS III
• TUBULIN, BETA-3

Genomic Location

The different types of CFEOM have different patterns of inheritance. CFEOM1 and CFEOM3 are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

CFEOM2 is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Tukel syndrome also appears to have an autosomal recessive pattern of inheritance, although the genetic change responsible for this disorder is unknown.

CFEOM1 is the most common form of congenital fibrosis of the extraocular muscles, affecting at least 1 in 230,000 people. CFEOM1 and CFEOM3 have been reported worldwide, whereas CFEOM2 has been seen in only a few families of Turkish, Saudi Arabian, and Iranian descent. Tukel syndrome appears to be very rare; it has been diagnosed in only one large Turkish family.