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Lissencephaly

Lissencephaly

Definition

Lissencephaly is a neurological disorder of early brain development that leads to the gross appearance of a smooth brain. The malformed brain lacks the characteristic convolutions of the normal cerebral cortex and is abnormally thick. Lissencephaly is part of a spectrum of brain malformations, which are referred to as the agyriapachygyria-band spectrum and are caused by abnormalities in neuronal migration, a critical process in brain development. These disorders range from complete absence of folds (agyria) to milder forms such as subcortical band heterotopia or double cortex syndrome, a neurological disorder where the malformed brain has two distinct

layers of cerebral cortex. In pachygyria, there are localized areas of abnormally large folds and, in general, it is less severe than agyria. Scientific research on mice and humans has revealed several important genes responsible for causing lissencephaly.

Description

Lissencephaly was first described by Owen in 1868 and means "smooth brain," which describes the gross appearance of the brain. Microscopically, the brain appears abnormally thick and disorganized. The layering of the cerebral cortex is grossly abnormal, with four layers instead of the normal six layers.

Lissencephaly can be divided into two main subtypes. Type I, also known as classical lissencephaly, is distinguished by the smooth surface of the cerebral cortex and an abnormal four-layered cortex. Classical lissencephaly can be associated with abnormalities of the rest of the brain, including malformation of the corpus callosum or cerebellum . Lissencephaly can also be associated with other developmental abnormalities such as facial deformities in a syndrome known as the Miller-Dieker syndrome. Type II, or "cobblestone" lissencephaly, is characterized by a bumpy appearance of the abnormal surface of the brain. The cortex in Type II lissencephaly is completely abnormal and there are no distinguishable layers. This subtype tends to be associated with genetic syndromes affecting muscles, as in the Walker-Warburg syndrome. Different genes and distinct processes are thought to be responsible for causing the two types of lissencephaly.

Demographics

Type I lissencephaly is more common and comprises 43% of lissencephaly syndromes in some studies. Type II lissencephaly accounted for 14% of lissencephalies. The remainder in these studies were comprised of various disorders such as pachygyria.

Causes and symptoms

Lissencephaly is due to a defect in neuronal migration, a sequence of events in early brain development in which nerve cells travel to their final destinations to populate and form the six layers of the cerebral cortex. This process occurs between 12 and 16 weeks gestation. When the brain first forms, neurons are generated in a region of the brain known as the ventricular zone. From there, they travel by crawling outward along other cells, known as radial glia, to reach the cortical surface. The traveling neurons need instructions on when to start, continue, and stop moving, and these processes are controlled by a complicated molecular machinery.

Several genes have been implicated in causing lissencephaly, and their roles in neuronal migration are currently being characterized. The first gene causing lissencephaly, LIS1, was identified in patients with Miller-Dieker syndrome, a genetic syndrome caused by deletions of chromosome 17 that is a combination of lissencephaly and other facial deformities. So far, five genes have been identified that cause type I lissencephaly in humans. Among them, LIS1, DCX, and RELN have been implicated as important at various steps during neuronal migration. DCX, a gene on the X-chromosome, is responsible for the double cortex syndrome, a milder sub-type of lissencephaly, which has the unusual appearance of a brain with two layers of cerebral cortex, one normal and one abnormally situated in the white matter. This abnormal layer, called a band heterotopia, represents the neurons that have started and failed to migrate completely to their destination. For type II lissencephaly, only one gene, fukutin, has been identified. Presumably, the disorder in type II lissencephaly is an abnormal overmigration of neurons, which causes nerve cells to accumulate beyond the cortical surface, leading to the cobblestone appearance. Other nongenetic causes of lissencephaly include cytomegalovirus infection.

Babies with lissencephaly may appear normal at birth, but then progress to severe developmental delay, seizures , and failure to thrive at several months of age. There may be abnormally small head size, known as microcephaly . Seizures are usually difficult to treat and start out in the first few months of life. Patients may also develop cerebral palsy and decreased muscle tone. Patients with milder forms such as double cortex syndrome may not develop symptoms until later in early childhood. They may have only mild developmental delay and seizures without microcephaly.

Diagnosis

Diagnosis is usually made by neuroimaging. A computer tomography (CT ) or magnetic resonance imaging (MRI) scan shows a smooth brain with the lack of characteristic folds. MRI may delineate the band of abnormal nerve cells in the double cortex syndrome. MRI may also show abnormalities in other areas of the brain in certain forms of lissencephaly. Genetic testing can be performed in patients with lissencephaly to identify abnormalities in the LIS1 or DCX gene.

Treatment team

Management of lissencephaly usually involves a pediatrician, pediatric neurologist , and physical therapists. A geneticist may be involved to provide counseling and advice about family planning. Depending on the age of onset of symptoms, an adult neurologist may be involved in treating symptoms of seizures. A case manager may be involved in coordinating the different care needs of the patient and families.

Treatment

Currently, there is no cure for lissencephaly. Treatment of individuals with lissencephaly depends on the manifesting symptoms. Patients may need anticonvulsant drug therapy for treatment of seizures. Muscle relaxants may be used for symptoms of increased tone.

Recovery and rehabilitation

Due to the congenital nature of lissencephaly, patients show little recovery from their symptoms. Physical therapists may help treat symptoms of weakness or increased tone associated with lissencephaly.

Clinical trials

A clinical trial is currently ongoing and is funded by the National Institutes of Health to identify genes responsible for neuronal migration disorders such as lissencephaly and schizencephaly .

Prognosis

There is no known cure for lissencephaly. Most individuals will die at an early age due to failure to thrive or infections such as pneumonia. Patients with milder forms such as double cortex syndrome may have mild retardation and seizures only. The response to treatment varies from individual to individual.

Special concerns

Due to developmental disability, children with lissencephaly 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.

Resources

BOOKS

Menkes, John H., MD, and Harvey Sarnat, MD, eds. Childhood Neurology, 6th edition. Philadelphia: Lippincott Williams & Wilkins, 2000.

"Congenital Anomalies of the Nervous System." Nelson Textbook of Pediatrics, 17th edition, edited by Richard E. Behrman, MD, Robert M. Kliegman, MD, and Hal B. Jenson, MD. Philadelphia: Saunders, 2004.

PERIODICALS

Gleeson, J. G. "Neuronal Migration Disorders." Mental Retardation and Developmental Disabilities Research Reviews 7 (2001): 167171.

Guerrini, R., and R. Carrozzo. "Epilepsy and Genetic Malformations of the Cerebral Cortex." American Journal of Medical Genetics 106 (2001): 160173.

Kato, M., and W. B. Dobyns. "Lissencephaly and the Molecular Basis of Neuronal Migration." Human Molecular Genetics 12 (2003): R89R96.

Ross, M. E., and C. A. Walsh. "Human Brain Malformations and Their Lessons for Neuronal Migration." Annual Review of Neuroscience 24 (2001): 10411070.

WEBSITES

National Institutes of Neurological Disorders and Stroke (NINDS). Cephalic Disorders Information Page. (February 19, 2004.) <http://www.ninds.nih.gov/health_and_medical/pubs/cephalic_disorders.htm>.

ORGANIZATIONS

Lissencephaly Network. 10408 Bitterroot Court, Ft. Wayne, IN 46804. (260) 432-4310. [email protected] <http://www.lissencephaly.org>.

March of Dimes Birth Defects Foundation. 1275 Mamaroneck Avenue, White Plains, NY 10605. (914) 428-7100 or (888) MODIMES; Fax: (914) 428-8203. [email protected] marchofdimes.com. <http://www.marchofdimes.com>.

National Information Center for Children and Youth with Disabilities. P.O. Box 1492, Washington, DC 20013-1492. (202) 884-8200 or (800) 695-0285; Fax: (202) 884-8441. [email protected] <http://www.nichcy.org>.

National Institute of Child Health and Human Development (NICHD). Bldg. 31, Rm. 2A32, Bethesda, MD 20892-2425. (301) 496-5133 or (800) 370-2943. [email protected] <http://www.nichd.nih.gov>.

Walsh Lab Web Site. 4 Blackfan Circle, Boston, MA 02115. (617) 667-0813; Fax: (617) 667-0815. [email protected] bidmc.harvard.edu. <http://walshlab.bidmc.harvard.edu/>.

Peter T. Lin, MD

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