Lissencephaly with cerebellar hypoplasia (LCH) affects brain development, resulting in the brain having a smooth appearance (lissencephaly) instead of its normal folds and grooves. In addition, the part of the brain that coordinates movement is unusually small and underdeveloped (cerebellar hypoplasia). Other parts of the brain are also often underdeveloped in LCH, including the hippocampus, which plays a role in learning and memory, and the part of the brain that is connected to the spinal cord (the brainstem).

Individuals with LCH have moderate to severe intellectual disability and delayed development. They have few or no communication skills, extremely poor muscle tone (hypotonia), problems with coordination and balance (ataxia), and difficulty sitting or standing without support. Most affected children experience recurrent seizures (epilepsy) that begin within the first months of life. Some affected individuals have nearsightedness (myopia), involuntary eye movements (nystagmus), or puffiness or swelling caused by a buildup of fluids in the body's tissues (lymphedema).

Lissencephaly is a rare, gene-linked brain malformation characterized by the absence of convolutions (folds) in the cerebral cortex and an extremely small head (microcephaly). The word lissencephaly literally means "smooth brain." Children with lissencephaly usually have head sizes in the expected range at birth. Children with a smaller head size at birth are typically diagnosed with microlissencephaly.

Lissencephaly is caused by defective neuronal migration during embryonic development, the process through which nerve cells move from their place of origin to a permanent location within cerebral cortex gray matter. Symptoms of the disorder may include:

• Facial differences
• Difficulty swallowing
• Failure to thrive (slow physical development)
• Muscle spasms
• Seizures
• Severe psychomotor impairment
• Congenital limb differences in the hands, fingers, or toes

Lissencephaly may be associated with other diseases including isolated lissencephaly sequence, Miller-Dieker syndrome, and Walker-Warburg syndrome. Sometimes it can be difficult to distinguish between these conditions clinically so consultation with national experts is recommended to help ensure correct diagnosis and possible molecular testing. The prognosis for children with lissencephaly depends on the degree of the disease.

Cerebellar hypoplasia is a neurological condition in which the cerebellum is not completely developed or is smaller than it should be. It may occur with a variety of congenital syndromes, metabolic disorders and neurodegenerative disorders; therefore signs and symptoms may depend upon the associated condition an affected individual has. The most common findings are developmental and speech delay, poor muscle tone (hypotonia), ataxia and abnormal ocular (eye) movements. Cerebellar hypoplasia may range from mild or partial underdevelopment to complete absence (agenesis). It may affect only the cerebellum, or also affect other central nervous system structures.

The inheritance pattern may differ depending on the underlying cause of the condition. Treatment is generally symptomatic and supportive and depends upon the underlying disorder and the severity of symptoms.

LCH can be caused by mutations in the RELN or TUBA1A gene. The RELN gene provides instructions for making a protein called reelin. In the developing brain, reelin turns on (activates) a signaling pathway that triggers nerve cells (neurons) to migrate to their proper locations. The protein produced from the TUBA1A gene is also involved in neuronal migration as a component of 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 neurons.

Mutations in either the RELN or TUBA1A gene impair the normal migration of neurons during fetal development. As a result, neurons are disorganized, the normal folds and grooves of the brain do not form, and brain structures do not develop properly. This impairment of brain development leads to the neurological problems characteristic of LCH.

Normal Function

The RELN gene provides instructions for making a protein called reelin. This protein is produced in the brain both before and after birth. Reelin is released by certain brain cells. After being released, it attaches (binds) to specific receptor proteins. In the developing brain, this binding turns on (activates) a signaling pathway that triggers nerve cells (neurons) to migrate to their proper locations.

After birth, reelin likely plays a role in many brain processes, including the extension of axons and dendrites, which are specialized outgrowths from nerve cells that are essential for the transmission of nerve impulses. Reelin may also regulate synaptic plasticity, which is the ability of connections between neurons (synapses) to change and adapt over time in response to experience. Additionally, reelin controls the release of chemicals that relay signals in the nervous system (neurotransmitters).

Health Conditions Related to Genetic Changes

Autosomal dominant epilepsy with auditory features

Variants (also called mutations) in the RELN gene can cause autosomal dominant epilepsy with auditory features (ADEAF). People with this rare form of epilepsy typically hear sounds, like buzzing or humming, during seizures.

RELN gene variants associated with ADEAF reduce the amount of reelin in the body. Research suggests that a shortage of reelin impairs the formation or function of synapses, where cell-to-cell communication occurs. Abnormal communication between neurons can lead to seizure activity in the brain.

Lissencephaly with cerebellar hypoplasia

Several variants in the RELN gene have been found to cause lissencephaly with cerebellar hypoplasia (LCH). This condition affects brain development, resulting in the brain having a smooth appearance (lissencephaly) instead of its normal folds and grooves. In addition, the brain region involved in coordinating movements is unusually small and underdeveloped (cerebellar hypoplasia).

The RELN gene variants that cause LCH lead to a complete lack of reelin. As a result, the signaling pathway that triggers neuronal migration is not activated. Without reelin, neurons are disorganized, the normal folds and grooves of the brain do not form, and brain structures do not develop properly. This leads to intellectual disabilities, delays in overall development, movement problems, and other signs and symptoms of LCH.

Autism spectrum disorder

Certain genetic changes that reduce but do not eliminate the production of reelin may increase a person's risk of autism spectrum disorder, a condition that affects communication and social interaction. However, some studies have not supported these findings. Many genetic and environmental factors are believed to contribute to this complex condition.

Myoclonus-dystonia

MedlinePlus Genetics provides information about Myoclonus-dystonia

Other disorders

Studies have shown that certain variations (polymorphisms) in the RELN gene are associated with an increased risk of psychiatric disorders such as schizophrenia and bipolar disorder. Women with these polymorphisms are at particular risk of developing bipolar disorder. However, many genetic and environmental factors likely contribute to the development of these complex conditions.

Other Names for This Gene

• LIS2
• PRO1598
• RELN_HUMAN
• RL

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

When LCH is caused by mutations in the RELN gene, the condition 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.

When LCH is caused by mutations in the TUBA1A gene, the condition 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 of these cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

LCH is a rare condition, although its prevalence is unknown.