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): 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.

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. LissencephalyOne@aol.com. 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. askus@ 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. nichcy@aed.org. 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. NICHDClearinghouse@mail.nih.gov. http://www.nichd.nih.gov.

Walsh Lab Web Site. 4 Blackfan Circle, Boston, MA 02115. (617) 667-0813; Fax: (617) 667-0815. cwalsh@ bidmc.harvard.edu. http://walshlab.bidmc.harvard.edu/.

Peter T. Lin, MD

See agyria.

A malformation in which the gyri of the cerebral cortex are not normally developed. In dogs it has been associated with behavioral abnormalities, visual deficits, ataxia and seizures. Called also agyria.

This article needs additional citations for verification. Please help improve this article by adding reliable references. Unsourced material may be challenged and removed. (July 2009)

Lissencephaly
Classification and external resources
ICD-10	Q04.3
ICD-9	742.2
DiseasesDB	29492
MeSH	D054082

Lissencephaly, which literally means smooth brain, is a rare brain formation disorder caused by defective neuronal migration during the 12th to 24th weeks of gestation, resulting in a lack of development of brain folds (gyri) and grooves (sulci).^[1] It is a form of cephalic disorder. Terms such as 'agyria' (no gyri) or 'pachygyria' (broad gyri) are used to describe the appearance of the surface of the brain. Children with lissencephaly are severely neurologically impaired^[2] and often die within several months of birth.^[3]

Contents 1 Symptoms 2 Diagnosis 3 Causes 4 Classification 5 Treatment 6 Prognosis 7 External links 8 References

Symptoms

Affected children display severe psychomotor retardation, failure to thrive, seizures, and muscle spasticity or hypotonia.^[4] Other symptoms of the disorder may include unusual facial appearance, difficulty swallowing, and anomalies of the hands, fingers, or toes.

Diagnosis

The diagnosis of lissencephaly is usually made at birth or soon after by ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI). Before birth, complex ultrasounds performed routinely during pregnancy may indicate the presence of cerebral abnormality, but this method of diagnosis is not reliable, and an absence of abnormal cerebral pathology should only inspire cautious optimism at best. In any case, diagnosis by ultrasound probably cannot be reliably made until 26 to 28 weeks, when the normal gyri and sulci become well defined. Up to this time, the fetal brain normally has a smooth appearance.^[5] If lissencephaly is suspected, chorionic villus sampling can test for some lissencephaly variants, but only those with a known genetic mutation.

Causes

Causes of lissencephaly can include viral infections of the uterus or the fetus during the first trimester, or insufficient blood supply to the fetal brain early in pregnancy. There are also a number of genetic causes of lissencephaly, including mutation of the reelin gene (on chromosome 7),^[6] as well as other genes on the X chromosome and on chromosome 17. Genetic counseling is usually offered if there is a risk of lissencephaly, coupled with genetic testing.

Classification

The spectrum of lissencephaly is only now becoming more defined as neuroimaging and genetics has provided more insights into migration disorders. There are around 20 different types of lissencephaly which make up the spectrum. Other causes which have not yet been identified are likely as well.

Different systems for classifying lissencephaly exist. One major distinction is "classic" (type I) vs. "cobblestone" (type II),^[7] but some systems add additional forms that fit into neither of these categories.

Some types of lissencephaly are described below (OMIM numbers are included where available):

Category	Types
Classic (or Type 1) lissencephaly - 607432	LIS1: lissencephaly due to PAFAH1B1 gene mutation, which subdivides into: type 1 isolated lissencephaly (601545) Miller-Dieker syndrome (247200) LISX1: lissencephaly due to doublecortin (DCX) gene mutation (300121) lissencephaly, type 1, isolated, without other known genetic defects
Cobblestone (or Type 2) lissencephaly	Walker-Warburg syndrome (236670), also called HARD(E) syndrome Fukuyama syndrome (253800) Muscle-eye-brain disease (MEB) (253280)
Other types	LIS2: Norman-Roberts syndrome (mutation of reelin gene, 257320) LIS3: TUBA1A, 611603 LISX2: ARX, 300215 Microlissencephaly (lissencephaly and microcephaly)[8]

Treatment

Treatment for those with lissencephaly is symptomatic and depends on the severity and locations of the brain malformations. Supportive care may be needed to help with comfort and nursing needs. Seizures may be controlled with medication and hydrocephalus may require shunting. If feeding becomes difficult, a gastrostomy tube may be considered.

Prognosis

The prognosis for children with lissencephaly varies depending on the degree of brain malformation. Many individuals show no significant development beyond a 3- to 5-month-old level. Some may have near-normal development and intelligence. With modern medications and care, some children live into their teens. Respiratory problems are the most common causes of death.

External links

• lissencephaly at NINDS
• Lissencephaly.org.uk
• Lissencephaly Launch Pad (support)
• Lissencephaly, generic term (pdf document) - concise and thorough classification of lissencephaly by prof. Alan Verloes.
• GeneReview/NIH/UW entry on DCx Lissencephaly
• GeneReview/NIH/UW entry on LIS1 Lissencephaly

References

1. ^ Dobyns, WB. Developmental aspects of lissencephaly and the lissencephaly syndromes. Birth Defects Orig Artic Ser 1987; 23:225.
2. ^ Bauman, ML. Neuroembryology--clinical aspects. Semin Perinatol 1987; 11:74.
3. ^ Jones, KL. Smith's Recognizable Patterns of Human Malformation, 6th ed. Elsevier Saunders, Philadelphia 2006.
4. ^ Jones, KL. Smith's Recognizable Patterns of Human Malformation, 6th ed. Elsevier Saunders, Philadelphia 2006.
5. ^ Dorovini-Zis K; Dolman CL. Gestational development of brain. Archives of Pathologic Laboratory Medicine 1977 Apr;101(4):192-5.
6. ^ Hong SE, Shugart YY, Huang DT, Shahwan SA, Grant PE, Hourihane JO, Martin ND, Walsh CA. (2000) Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet. 26(1):93-6. PMID 10973257
   
7. ^ Forman MS, Squier W, Dobyns WB, Golden JA (October 2005). "Genotypically defined lissencephalies show distinct pathologies". J. Neuropathol. Exp. Neurol. 64 (10): 847–57. doi:10.1097/01.jnen.0000182978.56612.41. PMID 16215456. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0022-3069&volume=64&issue=10&spage=847. 
8. ^ Microlissencephaly

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