Neuronal Migration Disorders
Neuronal migration disorders
Neuronal migration disorders are a diverse group of congenital brain abnormalities that arise specifically from defective formation of the central nervous system . During early brain development, neurons are born and move over large distances to reach their targets and thereby give rise to the different parts of the brain. The control of this process is highly orchestrated and dependent on the expression of various environmental and genetic factors that continue to be discovered in genetic studies of mice and humans. The critical role neuronal migration plays in brain development is evident from the variety of gross malformations that can occur when it goes wrong. Defective neuronal migration leads to a broad range of clinical syndromes, and most affected patients will have a combination of mental retardation and epilepsy .
Neuronal migration disorders include lissencephaly as part of the agyria-pachygyria-band spectrum, cobblestone lissencephaly, periventricular heterotopia, and other variants such as Zellweger and Kallman syndrome. Patients may have only focal collections of abnormally located neurons known as heterotopias. The common factor in these disorders is a defect in neuronal migration, a key process in brain development that occurs during weeks 12 to 16 of gestation. Some disorders such as polymicrogyria and schizencephaly are presumably due to abnormal neuronal migration due to studies showing heterotopias in other parts of the brain, but the exact relationship is unclear. Early in brain development, neurons are born in specific locations in the brain and migrate to their final destinations to create distinct brain regions. Each step of this process, from starting, continuing, and stopping migration, is controlled by distinct molecular mechanisms that are regulated by the activity of genes. Defects in these genes lead to the various presentations of neuronal migration disorders seen in clinical practice.
Lissencephaly is the most extreme example of defective neuronal migration. In lissencephaly or agyria, neuronal migration fails globally, causing the brain to appear completely smooth and have abnormal layering in the cortex. Various genes have been associated with varying levels of severity of lissencephaly giving rise to a spectrum of disorders ranging from classical lissencephaly to milder forms such as double cortex syndrome or pachygyria. Classical or type I lissencephaly differs from type II or cobblestone lissencephaly. In cobblestone lissencephaly, the defect is presumably an overmigration of neurons past their targets, giving rise to the abnormally bumpy surface.
Periventricular heterotopia is a disorder where neurons fail to begin the process of migration. Neurons are generated near the ventricular zone but do not start the process of migration to their destinations. Instead, they are stuck and collect around the ventricles, giving rise to the distinct appearance on brain imaging.
Other neuronal migration disorders
Zellweger syndrome is a disorder of neuronal migration that may consist of abnormally large folds (pachygyria) and heterotopias spread throughout the brain. It is thought to be due to a defect in peroxisome metabolism, a pathway by which cells break down waste products. The relationship between this metabolic defect and neuronal migration is unclear at this time. Kallman syndrome is a disorder where cells fail to migrate to the portion of the brain controlling smell as well as the hypothalamus, a region that controls hormone secretion. The mechanism underlying this disease is unclear.
Schizencephaly is grouped as a neuronal migration disorder although the exact etiology is unknown. Schizencephaly is an example of abnormal neuronal migration that may occur locally rather than globally. In schizencephaly, an early insult to the brain in the form of an infection, stroke , orgenetic defect leads to abnormal migration of neurons in a portion of the brain and subsequent lack of developed brain tissue, giving rise to the characteristic brain clefts that define this syndrome. Schizencephaly may show a wide range of presentations, with bilateral clefts that vary in size and extent of involvement.
Polymicrogyria refers to an abnormal amount of small convolutions (gyri) in affected areas of the cerebral cortex and is believed to be a neuronal migration disorder, although the exact etiology is unknown.
Neuronal migration disorders are rare overall, but the exact incidence is unknown. Patients may have very mild degrees of the different disorders and may not be diagnosed if they do not manifest symptoms, making the actual incidence difficult to determine.
Causes and symptoms
The majority of neuronal migration disorders seen in clinical practice are thought to be genetic in cause. Much of what is known about neuronal migration disorders to date has been discovered from intense research identifying the genes affected in individuals with these diseases. The widespread abnormal expression of defective genes leads to the global nature of the disorders, contrary to acquired developmental brain insults, which lead to more localized defects. Several genes have been implicated in causing the various disorders, and they continue to be identified. The most well characterized genes include DCX on the X chromosome, responsible for double cortex syndrome, and LIS1 on chromosome 17, the first gene identified for lissencephaly. Cobblestone lissencephaly is associated with abnormalities in fukutin, a gene responsible for Fukuyama muscular dystrophy , a syndrome consisting of muscle weakness and cobblestone lissencephaly. Periventricular heterotopia is associated with abnormalities of the filamin1 gene on the X chromosome. DCX, LIS1, and filamin1 are genes responsible for controlling the mechanics of cell movement during neuronal migration. Schizencephaly has been associated with abnormalities in EMX2, a transcription factor gene whose role in neuronal migration is as yet unidentified. Neuronal migration disorders can also be associated with early insults to the brain from infections or damage from stroke.
Most neuronal migration disorders present with some combination of epilepsy, mental retardation, and abnormalities in head size, known as microcephaly . Some patients, such as those with small heterotopias, may have no symptoms at all since the severity of the defect is very mild. Patients may also have cerebral palsy or abnormalities in muscle tone. Depending on the severity of the malformation, the level of mental retardation may vary from mild to severe. Patients with lissencephaly are usually severely delayed, have failure to thrive, and are microcephalic. They may also have accompanying eye problems. Patients with double cortex syndrome or schizencephaly may have milder symptoms and may only present with seizures . Schizencephaly may have associated complications of increased fluid pressure in the brain, known as hydrocephalus . Periventricular heterotopia and polymicrogyria may present with only seizures. Some neuronal migration disorders such as lissencephaly may be part of a larger syndrome affecting other body parts such as the muscle, eyes, or face.
Diagnosis is usually made by neuroimaging. CT scan or MRI of the brain will show the characteristic abnormality. MRI has better resolution and may detect polymicrogyria or small heterotopias more easily than CT. Genetic testing is available for patients with lissencephaly to identify whether the DCX or LIS1 gene is defective. Knowledge of the genes affected allows for counseling and family planning. Laboratory tests are not useful in diagnosis.
Management of neuronal migration disorders involves a pediatrician, pediatric neurologist and physical therapists. With symptoms of later onset, an adult neurologist may be involved in treating symptoms of seizures. Rehabilitation specialists may help in prescribing medications for cerebral palsy or increased muscle tone. A case manager may be involved in coordinating care and resources.
There are no known cures for the various neuronal migration disorders at this time. The majority of treatments are directed towards symptoms caused by the malformed brain. Seizures may be treated with anticonvulsant medications. Refractory seizures may respond to neurosurgical removal of abnormal brain tissue. Neurosurgery may be required to relieve hydrocephalus, by placement of a shunt. Increased muscle tone may respond to injections of botulinum toxin or muscle relaxants. Patients may require feeding through a tube due to inability to swallow normally.
Recovery and rehabilitation
Due to the congenital nature of neuronal migration disorders, most patients do not recover from their symptoms. The course of disease tends to be static. Physical and occupational therapists may help treat symptoms of weakness or increased tone that limit mobility and daily hand use.
A clinical trial is currently under way and is funded by the National Institutes of Health to identify genes responsible for neuronal migration disorders such as lissencephaly and schizencephaly. For contact information for the Walsh Lab Site, see Resources below.
There is no known cure for any of the neuronal migration disorders. Due to the congenital nature of the diseases, the symptoms tend to be static and do not improve. The prognosis varies for each individual depending on the extent of the defect and the accompanying neurologic deficits. Most individuals with severe malformations such as classical lissencephaly or bilateral schizencephaly will die at an early age due to failure to thrive or infections such as pneumonia. Their cognitive development stays at the three month level. Patients with milder forms such as unilateral schizencephaly, periventricular heterotopia, or subcortical band heterotopia may have mild mental retardation and seizures only and live a normal life span.
Educational and Social Needs
Due to developmental disability, children with neuronal migration disorders who survive beyond the age of two may benefit from special education programs. Various state and federal programs are available to help individuals and their families with meeting these needs.
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Gleeson, J. G. "Neuronal Migration Disorders." Mental Retardation and Developmental Disabilities Research Reviews 7 (2001): 167–171.
Guerrini, R., and R. Carrozzo. "Epilepsy and Genetic Malformations of the Cerebral Cortex." American Journal of Medical Genetics 106 (2001): 160–173.
Kato, M., and W. B. Dobyns. "Lissencephaly and the molecular basis of neuronal migration." Human Molecular Genetics 12 (2003): R89–R96.
Ross, M. E., and C. A. Walsh. "Human Brain Malformations and Their Lessons for Neuronal Migration." Annual Review of Neuroscience 24 (2001): 1041–1070.
Cephalic Disorders Information Page. National Institutes of Neurological Disorders and Stroke (NINDS). <http://www.ninds.nih.gov/health_and_medical/pubs/cephalic_disorders.htm>.
March of Dimes Birth Defects Foundation. 1275 Mamaroneck Avenue, White Plains, NY 10605. (914) 428-7100 or (888) 663-4637; Fax: (914) 428-8203. [email protected] marchofdimes.com. <http://www.marchofdimes.com>.
Peter T. Lin, MD