Isolated lissencephaly sequence (ILS) is a condition that affects brain development before birth. Normally, the cells that make up the exterior of the brain (cerebral cortex) are well-organized, multi-layered, and arranged into many folds and grooves (gyri). In people with ILS, the cells of the cerebral cortex are disorganized, and the brain surface is abnormally smooth with an absence (agyria) or reduction (pachygyria) of folds and grooves. In most cases, these abnormalities impair brain growth, causing the brain to be smaller than normal (microcephaly). This underdevelopment of the brain causes severe intellectual disability, delayed development, and recurrent seizures (epilepsy) in individuals with ILS.

More than 90 percent of individuals with ILS develop epilepsy, often within the first year of life. Up to 80 percent of infants with ILS have a type of seizure called infantile spasms, these seizures can be severe enough to cause brain dysfunction (epileptic encephalopathy). After the first months of life, most children with ILS develop a variety of seizure types, including persisting infantile spasms, short periods of loss of consciousness (absence seizures); sudden episodes of weak muscle tone (drop attacks); rapid, uncontrolled muscle jerks (myoclonic seizures); and episodes of muscle rigidity, convulsions, and loss of consciousness (tonic-clonic seizures).

Infants with ILS may have poor muscle tone (hypotonia) and difficulty feeding, which leads to poor growth overall. Hypotonia also affects the muscles used for breathing, which often causes breathing problems that can lead to a life-threatening bacterial lung infection known as aspiration pneumonia. Children with ILS often develop muscle stiffness (spasticity) in their arms and legs and an abnormal side-to-side curvature of the spine (scoliosis). Rarely, the muscle stiffness will progress to paralysis (spastic paraplegia). Individuals with ILS cannot walk and rarely crawl. Most children with ILS do not develop communication skills.

Mutations in the PAFAH1B1, DCX, or TUBA1A gene can cause ILS. PAFAH1B1 gene mutations are responsible for over half of ILS cases; DCX gene mutations cause about 10 percent of cases; and TUBA1A gene mutations cause a small percentage of ILS. These genes provide instructions for making proteins that are involved in the movement (migration) of nerve cells (neurons) to their proper locations in the developing brain. Neuronal migration is dependent on cell structures called microtubules. Microtubules are rigid, hollow fibers that make up the cell's structural framework (the cytoskeleton). Microtubules form scaffolding within the cell that elongates in a specific direction, altering the cytoskeleton and moving the neuron. The protein produced from the TUBA1A gene is a component of microtubules. The proteins produced from the DCX and PAFAH1B1 genes promote neuronal migration by interacting with microtubules.

Mutations in any of these three genes impair the function of microtubules and the normal migration of neurons during fetal development. As a result, the layers of the cerebral cortex are disorganized and the normal folds and grooves of the brain do not form. This impairment of brain development leads to the smooth brain appearance and the resulting neurological problems characteristic of ILS.

Some individuals with ILS do not have an identified mutation in any of these three genes; the cause of the condition in these individuals may be unidentified mutations in other genes that affect neuronal migration or other unknown factors.

Normal Function

The DCX gene provides instructions for producing a protein called doublecortin. This protein is involved in the movement of nerve cells (neurons) to their proper locations in the developing brain, a process called neuronal migration. Doublecortin attaches (binds) to microtubules, which are rigid, hollow fibers that make up the cell's structural framework (the cytoskeleton). The binding of doublecortin promotes the stability of microtubules. Microtubules help propel neurons by forming scaffolding within the cell that elongates in a specific direction, altering the cytoskeleton and moving the neuron.

Health Conditions Related to Genetic Changes

Isolated lissencephaly sequence

More than 70 mutations in the DCX gene have been found to cause isolated lissencephaly sequence (ILS). This condition is characterized by abnormal brain development that results in the brain having a smooth surface (lissencephaly) instead of its normal folds and grooves. Individuals with ILS have severe neurological problems, including severe intellectual disability and recurrent seizures (epilepsy) that begin in infancy. Most of the DCX gene mutations that cause ILS change a single protein building block (amino acid) in doublecortin and usually result in a protein with little or no function. A lack of normal doublecortin affects the stability and organization of microtubules, impairing their ability to move neurons. Neurons in the developing brain are particularly affected, resulting in the neurological problems associated with ILS.

Subcortical band heterotopia

More than 100 mutations in the DCX gene have been found to cause subcortical band heterotopia. This condition causes abnormal brain development that is less severe than ILS (described above). In people with subcortical band heterotopia, some neurons that should be part of a certain region of the brain do not reach their destination. The neurons stop their migration process in areas of the brain where they are not supposed to be and form band-like clusters of tissue. The signs and symptoms of subcortical band heterotopia can vary from severe intellectual disability and seizures that begin early in life to normal intelligence with mild seizures that occur later in life.

Mutations in the DCX gene are the most common cause of subcortical band heterotopia. Most of these mutations change single amino acids in the doublecortin protein. DCX gene mutations that cause subcortical band heterotopia can impair the protein's function or alter the protein's structure or stability. As a result, the doublecortin protein has a reduced ability to bind to microtubules, impairing their ability to move neurons during neuronal migration. Without proper neuronal migration, neurons in the developing brain can be misplaced, leading to the neurological problems that occur in subcortical band heterotopia.

Females with a mutation in one copy of the DCX gene in each cell usually develop subcortical band heterotopia, while males with one DCX gene mutation generally have ILS. Females can develop ILS and males can develop subcortical band heterotopia, but these instances are rare. Most males with subcortical band heterotopia have a DCX gene mutation in only some of the body's cells, a situation known as mosaicism.

Other Names for This Gene

• DBCN
• DC
• DCX_HUMAN
• doublecortex
• doublecortex; lissencephaly, X-linked (doublecortin)
• lissencephalin-X
• LISX
• XLIS

Genomic Location

Normal Function

The PAFAH1B1 gene (also known as LIS1) provides instructions for making a protein that is one part (subunit) of a complex called platelet-activating factor acetylhydrolase 1B (PAFAH1B). This complex regulates the amount of a molecule called platelet activating factor (PAF) in the brain. PAF is thought to be involved in directing the movement of nerve cells, a process known as neuronal migration. Proper neuronal migration is essential for normal brain development and function.

The PAFAH1B1 protein is also involved in the organization of the cell's structural framework (the cytoskeleton). This protein interacts with microtubules and with their associated proteins. Microtubules are the rigid, hollow fibers that make up the cytoskeleton; they play an important role in cell division and cell movement. Interactions between the PAFAH1B1 protein and the microtubules and their associated proteins are also essential for proper neuronal migration.

Health Conditions Related to Genetic Changes

Isolated lissencephaly sequence

Many variants (also called mutations) in the PAFAH1B1 gene have been found to cause isolated lissencephaly sequence (ILS), a condition characterized by abnormal brain development that results in the brain having a smooth surface (lissencephaly) instead of its normal folds and grooves. Individuals with ILS have severe intellectual disabilities and recurrent seizures (epilepsy) that begin in the first two years of life.

The PAFAH1B1 gene variants that cause ILS reduce the amount of functional protein available to help neurons in the developing brain migrate to their proper location. This impairs brain development and leads to the severe neurological problems seen in people with ILS.

Subcortical band heterotopia

Several variants in the PAFAH1B1 gene have been found to cause subcortical band heterotopia. This condition causes abnormal brain development that results in signs and symptoms that are typically less severe than those seen in ILS. Some researchers consider these two conditions to be part of the same disease spectrum and use the term PAFAH1B1-related isolated lissencephaly sequence/subcortical band heterotopia to refer to both conditions. Individuals with subcortical band heterotopia typically have developmental delays, which can range from mild to severe. Additional signs and symptoms can include intellectual disabilities and seizures that may be drug-resistant.

Some variants in the PAFAH1B1 gene change single protein building blocks (amino acids) in the PAFAH1B1 protein, while other variants change the protein's length or structure. These variants alter the protein's ability to interact with microtubules and to form the PAFAH1B complex, both of which are needed for neuronal migration. Without proper neuronal migration, neurons in the developing brain can be misplaced, leading to the neurological problems seen in people with subcortical band heterotopia.

Miller-Dieker syndrome

A deletion of genetic material near the end of the short (p) arm of chromosome 17 causes Miller-Dieker syndrome. This region contains numerous genes, including the PAFAH1B1 gene. Signs and symptoms of Miller-Dieker syndrome include lissencephaly, intellectual disabilities, seizures, and distinctive facial features.

As a result of the deletion, people with this condition have only one copy of the PAFAH1B1 gene in each cell instead of the usual two copies. A deletion of one copy of the PAFAH1B1 gene in each cell reduces the amount of available PAFAH1B1 protein. Researchers believe that a shortage of this protein is responsible for the lissencephaly, intellectual disabilities, and seizures seen in people with Miller-Dieker syndrome.

Other deleted genes in the same region of chromosome 17 likely contribute to the other features of Miller-Dieker syndrome.

Other Names for This Gene

• LIS1
• LIS2
• MDCR
• NudF
• PAFAH
• platelet-activating factor acetylhydrolase, isoform 1b, alpha subunit

Genomic Location

Normal Function

The TUBA1A gene provides instructions for making a protein called alpha-tubulin (α-tubulin). This protein is part of the tubulin family of proteins that form and organize structures called microtubules. Microtubules are rigid, hollow fibers that make up the cell's structural framework (the cytoskeleton). They are composed of α-tubulin and a similar protein called beta-tubulin (β-tubulin) that is produced from a different gene. Microtubules are necessary for cell division and movement.

Most cells produce α-tubulin, but the protein is found in highest amounts in the developing brain. During brain development, α-tubulin partners with β-tubulin to form microtubules that move nerve cells (neurons) to their proper location (neuronal migration). Microtubules form scaffolding within the cell. The tubulin proteins that make up the microtubule are moved from one end of a microtubule to the other end. This protein transfer propels the microtubules in a specific direction, moving the cell.

Health Conditions Related to Genetic Changes

Isolated lissencephaly sequence

Approximately 40 mutations in the TUBA1A gene have been found to cause isolated lissencephaly sequence (ILS). This condition is characterized by abnormal brain development that results in the brain having a smooth appearance (lissencephaly) instead of its normal folds and grooves. Individuals with ILS have severe neurological problems, including intellectual disability and recurrent seizures (epilepsy). Most of these mutations change single protein building blocks (amino acids) in the α-tubulin protein. The resulting abnormal α-tubulin cannot form microtubules or interact with other proteins. As a result, the overall function of microtubules is reduced. In the developing brain, this decrease in microtubule function impairs the normal migration of neurons and leads to a decrease in the formation of the brain's folds and grooves or a completely smooth appearance of the brain, resulting in the neurological problems characteristic of ILS.

Lissencephaly with cerebellar hypoplasia

At least 10 mutations in the TUBA1A gene have been found to cause lissencephaly with cerebellar hypoplasia (LCH). This condition affects brain development, resulting in lissencephaly and an unusually small and underdeveloped area of the brain called the cerebellum (cerebellar hypoplasia). The TUBA1A gene mutations that cause LCH change single amino acids in the α-tubulin protein. These altered proteins can still be incorporated into microtubules, but research suggests that these microtubules have decreased or abnormal function.

In the developing brain, impaired microtubule function prevents the normal migration of neurons. As a result, the normal folds and grooves of the brain do not form and the cerebellum and other brain structures do not develop properly. This impairment of brain development leads to intellectual disability, delayed overall development, movement problems, and other signs and symptoms of LCH.

Other Names for This Gene

• B-ALPHA-1
• TBA1A_HUMAN
• TUBA3
• tubulin alpha-1A chain
• tubulin alpha-3 chain
• tubulin B-alpha-1
• tubulin, alpha 1a
• tubulin, alpha, brain-specific

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

The inheritance pattern of ILS depends on the gene involved.

When ILS is caused by mutations in the PAFAH1B1 or TUBA1A gene, it is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

When mutations in the DCX gene cause ILS, it is inherited in an X-linked pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In males (who have only one X chromosome), one altered copy of the DCX gene in each cell is sufficient to cause the condition. In females, who have two copies of the X chromosome, one altered copy of the DCX gene in each cell can lead to a less severe condition in females called subcortical band heterotopia, or may cause no symptoms at all. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

ILS affects approximately 1 in 100,000 newborns.