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Lissencephaly

NORD is very grateful to Joseph G. Gleeson, MD, Department of Neurosciences, University of California, San Diego, for assistance in the preparation of this report.

Synonyms of Lissencephaly

  • agyria
  • lissencephaly, type I

Disorder Subdivisions

  • isolated lissencephaly sequence (ILS)
  • lissencephaly 1 (LIS1)
  • Miller-Dieker syndrome
  • Norman-Roberts syndrome
  • subcortical band heterotopia
  • x-linked lissencephaly

General Discussion

Classical lissencephaly, also known as lissencephaly type I, is a brain malformation that may occur as an isolated abnormality (isolated lissencephaly sequence [ILS]) or in association with certain underlying syndromes (e.g., Miller-Dieker syndrome, Norman-Roberts syndrome). The condition is characterized by absence (agyria) or incomplete development (pachygyria) of the ridges or convolutions (gyri) of the outer region of the brain (cerebral cortex), causing the brain's surface to appear unusually smooth.

In infants with classical lissencephaly, the head circumference may be smaller than would otherwise be expected (microcephaly). Additional abnormalities may include sudden episodes of uncontrolled electrical activity in the brain (seizures), severe or profound intellectual disability, feeding difficulties, growth retardation, and impaired motor abilities. If an underlying syndrome is present, there may be additional symptoms and physical findings.

Researchers indicate that there may be various possible causes of isolated lissencephaly, including viral infections or insufficient blood flow to the brain during fetal development or certain genetic factors. Changes (mutations) of at least two different genes have been implicated in isolated lissencephaly: a gene located on chromosome 17 (known as LIS1) and a gene located on the X-chromosome (known as XLIS or Doublecortin). There is a third gene known as TUBA1A that has been identified as the 3rd genetic cause for this disorder.

Symptoms

Newborns with classical lissencephaly who have no underlying syndrome are said to have isolated lissencephaly sequence (ILS). ILS due to mutations of the LIS1 gene may be referred to as classical lissencephaly with a LIS1 mutation. In addition to lissencephaly, those with the condition may have associated brain malformations, such as underdevelopment of the thick band of nerve fibers that join and carry messages between the brain's two cerebral hemispheres (hypoplasia of the corpus callosum). Affected infants may also have an unusually small head, seizures, and severe or profound intellectual disability. In addition, those with the condition may have a normal facial appearance or subtle facial changes, such as a relatively small jaw or slight indentation of the temples. Additional symptoms and findings may include feeding difficulties, growth failure, abnormally diminished muscle tone (hypotonia) early in life, increased muscle tone (hypertonia) later during infancy, and impaired motor abilities. Potentially life-threatening complications may occur during infancy or childhood.

Lissencephaly caused by mutations of the XLIS gene may be referred to as X-linked lissencephaly. Males who inherit the disease gene (hemizygotes) are more likely to manifest the full spectrum of abnormalities associated with the disorder and therefore are usually more severely affected than females with a mutated copy of the XLIS gene (heterozygotes). In males with X-linked lissencephaly, associated features may include classical lissencephaly; absence of the band of nerve fibers that normally join the two cerebral hemispheres; a normal facial appearance or subtle facial changes; severe seizures that may be resistant to treatment (intractable seizures); severe or profound intellectual disability; feeding difficulties; growth failure. Life-threatening complications may develop during infancy or childhood. Females who inherit a mutated copy of the XLIS gene may have a malformation in which there are abnormal bands of brain tissue beneath the outer region of the brain (cerebral cortex). This developmental abnormality may be referred to as subcortical band heterotopia (SBH) or double cortex. Females with SBH typically have milder intellectual disability and less severe seizures than those occurring in males with lissencephaly due to XLIS mutations.

Classical lissencephaly also occurs as a primary manifestation of certain genetic syndromes, including Miller-Dieker and Norman-Roberts syndromes. Miller-Dieker syndrome is associated with lissencephaly and a characteristic facial appearance due to abnormalities of the skull and facial (craniofacial) region that may be relatively subtle. Craniofacial malformations may include an unusually small head (microcephaly) with a broad, high forehead; subtle indentation or hollowing of both temples (bitemporal hollowing); a relatively wide face; a small jaw (micrognathia); a long, thin upper lip; a short nose with upturned nostrils (anteverted nares); low-set, malformed ears; and/or other abnormalities. Lissencephaly may occur in association with underdevelopment or absence of the corpus callosum. Infants with Miller-Dieker syndrome typically have severe or profound intellectual disability, seizures, feeding difficulties, growth failure, and delayed motor development. Affected infants may also have additional abnormalities, including extra fingers or toes (polydactyly); abnormal skin ridge patterns on the palms of the hands (palmar creases); cataracts; and/or malformations of the heart (congenital heart defects), kidneys, and/or other organs. Due to such abnormalities, life-threatening complications may develop during infancy or childhood.

Norman-Roberts syndrome is also characterized by classical lissencephaly in association with certain craniofacial abnormalities, such as a low, sloping forehead; abnormal prominence of the back portion of the head (occiput); a broad, prominent nasal bridge; and widely set eyes (ocular hypertelorism). Additional symptoms and findings typically include severe or profound intellectual disability, seizures, abnormally increased muscle tone (hypertonia), exaggerated reflexes (hyperreflexia), and severe growth failure.

Causes

Investigators indicate that lissencephaly may be due to various non-genetic and genetic factors. Such factors may include intrauterine infection; insufficient supply of oxygenated blood to the brain (ischemia) during fetal development; alteration or deletion of a specific region on chromosome 17; or autosomal recessive or X-linked inheritance.

Evidence suggests that isolated lissencephaly may result from mutations in at least two different genes: a gene known as LIS1 on the short arm (p) of chromosome 17 (17p13.3) or a gene designated as XLIS located on the long arm (q) of chromosome X (Xq22.3-q23). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Chromosomes are further subdivided into bands that are numbered. Therefore, for example, 17p13.3 refers to band 13.3 on the short arm of chromosome 17.

In some individuals with isolated lissencephaly, the condition may result from certain mutations or small deletions of the LIS1 gene. The gene (also known as "PAFAH1B1") regulates the production of a protein (platelet-activating factor acetylhydrolase, isoform 1B) that is thought to play some role in the development of the outer region of the brain. In addition, Miller-Dieker syndrome may be caused by slightly larger 17p deletions including the LIS1 gene. Evidence suggests that classical lissencephaly associated with Miller-Dieker syndrome is due to deletion of the LIS1 gene, while certain craniofacial and other abnormalities may result from deletion of additional, adjacent genes. Such deletions may appear to occur randomly (sporadically) or may result due to a chromosomal rearrangement in one of the parents (e.g., balanced translocations). (If a chromosomal rearrangement consists of an altered but balanced set of chromosomes, it is usually harmless to the carrier. However, balanced translocations may be associated with an increased risk of abnormal chromosomal development in the carrier's offspring. Chromosomal testing may determine whether a parent is a carrier of a balanced translocation or other chromosomal abnormality.)

In other individuals with isolated lissencephaly, the condition may be caused by mutations of the XLIS gene. According to researchers, this gene regulates production of a protein (doublecortin [DCX]) that is required for proper neuronal migration (see below). In some cases, XLIS mutations may appear to occur randomly for unknown reasons in the apparent absence of a family history. In other instances, the disorder appears to be inherited as an X-linked trait.

X-linked disorders are conditions that result from changes (mutations) of a gene coded on the X chromosome. Females have two X chromosomes, while males have one X chromosome from the mother and one Y chromosome from the father. In females, certain disease traits on the X chromosome may in some cases be "masked" by the normal gene on the other X chromosome. However, since males have only one X chromosome, if they inherit a gene for a disease present on the X, they are more likely to have an associated disease. Therefore, in females who inherit a copy of a disease gene for an X-linked trait, expression of the disorder may be more variable and less severe than in affected males. Males who inherit such a disease gene are more likely to fully express the spectrum of abnormalities associated with the disorder and therefore are typically more severely affected.

Males with a disease gene for an X-linked disorder transmit the gene to their daughters but not to their sons. Heterozygous females have a 50 percent risk of transmitting the disease gene to their daughters and their sons.

In other familial cases of isolated lissencephaly, evidence may suggest autosomal recessive inheritance. In autosomal recessive disorders, the condition does not appear unless a person inherits the same mutated gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.

In addition, the rare syndrome known as Norman-Roberts syndrome is transmitted as an autosomal recessive trait. The parents of some individuals with Norman-Roberts syndrome have been closely related by blood (consanguineous). With closely related parents, there may be an increased likelihood that both carry the same recessive disease gene, increasing the risk that their children may inherit the two genes necessary for the development of the autosomal recessive disease.

According to researchers, the underlying genetic alterations and non-genetic abnormalities described above are thought to play some role in causing impaired development of the outer region of the brain (cerebral cortex), ultimately resulting in the symptoms associated with the condition. The cerebral cortex, which is responsible for conscious movement and thought, normally consists of several deep convolutions (gyri) and grooves (sulci), which are formed by "infolding" of the cerebral cortex. During embryonic growth, newly formed cells that will later develop into specialized nerve cells normally migrate to the brain's surface (neuronal migration), resulting in the formation of several cellular layers. However, in cases of clasical lissencephaly, the cells fail to migrate to their destined locations (neuronal dysmigration) and the cerebral cortex develops an insufficient number of cellular layers, with absence or incomplete development of gyri.

Affected Populations

Observed ratios of males and females with classical lissencephaly may be variable due to a number of factors, including the sporadic occurrence of the condition in many instances and the fact that many affected individuals may have remained undiagnosed in the past. Today, recognition of the condition has increased due to current use of advanced imaging techniques during neurological evaluations.

Related Disorders

As discussed above, in classical (type I) lissencephaly, the brain’s outer region, the cerebral cortex, is abnormally thickened and has four rather than six cellular layers. Classical lissencephaly is seen in isolated lissencephaly sequence, Miller-Dieker syndrome, and Norman-Roberts syndromes. Researchers have also designated a related brain abnormality as lissencephaly type II, also known as cobblestone lissencephaly, which is characterized by severe brain malformations and associated obstructive hydrocephalus. Obstructive hydrocephalus is a condition in which there is obstructed flow of the fluid surrounding the brain and spinal cord (cerebrospinal fluid [CSF]), resulting in increasing fluid pressure in the brain. Associated symptoms and findings may include abnormal enlargement of the cavities (ventricles) of the brain, rapid enlargement of the head, and seizures. Type II lissencephaly is a major manifestation of Walker-Warburg syndrome (see below).

Walker-Warburg syndrome is also known as hydrocephalus, agyria, and retinal dysplasia (HARD) syndrome. It is characterized by type II lissencephaly in association with abnormal development of the nerve-rich membrane at the back of the eyes (retinal dysplasia), obstructive hydrocephalus, and incomplete development or absence of the thick band of nerve fibers that join the brain’s two cerebral hemispheres. Affected infants also typically have severe growth failure; an unusually small head; seizures; and additional abnormalities of the eyes, including detachment of the retinas, small eyes (microphthalmia), and loss of transparency of the lenses (cataracts) and the corneas. In addition, in some affected infants, there may be abnormal protrusion of the brain through a defect at the back of the skull (occipital encephalocele). Walker-Warburg syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose "Walker Warburg" as your search term in the Rare Disease Database.)

Neu-Laxova syndrome is a rare genetic disorder in which there is severely delayed growth before birth (intrauterine growth retardation), excessive fluid surrounding the developing fetus within the amniotic sac (polyhydramnios), an abnormally small placenta, and an unusually short umbilical cord. The disorder is typically characterized by marked smallness of the head, a characteristic facial appearance, permanent flexion and immobilization of several joints, abnormal accumulations of fluid in tissues throughout the body (generalized edema), and abnormalities of the brain and spinal cord. Affected infants may have a prominent nasal bridge, a sloped forehead, a small mouth (microstomia), an underdeveloped jaw (micrognathia), malformed ears, prominent eyes with retracted or absent eyelids, loss of transparency of the lenses of the eyes (cataracts), and a short neck. Additional characteristic features may include underdeveloped (hypoplastic) fingers and toes (digits); permanent flexion (camptodactyly), abnormal bending (clinodactyly), and/or overlapping of fingers; webbing or fusion of the digits (syndactyly); and short, contracted arms and legs. In addition, central nervous system abnormalities typically include a form of lissencephaly in association with absence of the corpus callosum, impaired flow of CSF resulting in increased fluid pressure within the brain (hydrocephalus), underdevelopment of the cerebellum (cerebellar hypoplasia), degeneration of certain areas of the brain (brain atrophy), and/or other findings. Infants with Neu-Laxova syndrome may also have abnormal yellowish, scaly (ichthyotic) skin; malformations of the genitals, the kidneys, and/or the heart; and/or other abnormalities. Life-threatening complications may develop early in life. Neu-Laxova syndrome is thought to be inherited as an autosomal recessive trait. (For more information on this disorder, choose "Neu Laxova" as your search term in the Rare Disease Database.)

There are a number of other disorders that may be characterized by lissencephaly or other related malformations of the brain's cerebral hemispheres.

Standard Therapies

Diagnosis
In some cases of classical lissencephaly, it is possible that the condition may be suggested before birth in some families by specialized testing, such as amniocentesis or chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and studied. During chorionic villus sampling, a tissue sample is removed from a portion of the placenta. In some cases, for example, studies performed on fluid or tissue samples may indicate deletion of material from the short arm of chromosome 17.

Classical lissencephaly may be diagnosed or confirmed based upon a thorough clinical evaluation; brain imaging studies, including computerized tomography (CT) scanning and/or magnetic resonance imaging (MRI); electroencephalography (EEG); chromosomal analysis; DNA analysis; and/or other studies. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of the brain's tissue structure. With MRI, a magnetic field and radio waves create cross-sectional images of the brain. During an EEG, the brain's electrical impulses are recorded; such studies may reveal brain wave patterns that are characteristic of certain types of seizure activity. DNA analysis that may detect certain mutations of the LIS1 or XLIS gene may only be available through research laboratories with a special interest in the disease.

Researchers have demonstrated that careful evaluation of brain imaging studies may assist in distinguishing between isolated lissencephaly caused by deletions or mutations of the LIS1 gene (lissencephaly 1) and mutations of the XLIS gene (X-linked lissencephaly). The research team compared CT and MRI images from children with mutations or deletions of the LIS1 gene (lissencephaly 1 and Miller-Dieker syndrome) and males with mutations of the XLIS gene. (Although excluded from the lissencephaly study results, brain imaging studies were also analyzed from females with subcortical band heterotopia due to XLIS mutations.) Results of the final analysis demonstrated that there were consistent differences in the brain malformation patterns between children with XLIS mutations and those with LIS1 mutations. Specifically, the researchers concluded that gyral malformation is typically more severe toward the front of the brain in children with XLIS mutations, while such malformation tends to be more severe toward the back of the brain in those with LIS1 alterations. According to the research team, such results suggest that, in some cases, it may be possible to predict the underlying genetic cause of classical lissencephaly based upon careful review of brain imaging studies in association with clinical findings. The researchers also noted that they detected subtle differences in gyral malformations between children with isolated lissencephaly due to LIS1 mutations and children with Miller-Dieker syndrome.

Treatment
The treatment of classical lissencephaly is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.

Therapies for individuals with classical lissencephaly are symptomatic and supportive. Treatment may include measures to improve the intake of nutrients in infants with feeding difficulties; the administration of anticonvulsant drugs to help prevent, reduce, or control seizures; and/or other measures. Genetic counseling will also be of benefit for families of affected children.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Dr. William Dobyns of the University of Washington and Dr. Joseph Gleeson at the University of California, San Diego are conducting genetic research on lissencephaly and related brain malformations.

For more information about the lissencephaly project and related research, contact:

Joseph G. Gleeson, M.D.
University of California, San Diego
E-mail: gleesonlab@ucsd.edu
Web: http://www.cbd.ucsd.edu

William B. Dobyns, M.D
University of Washington
E-mail: wbd@u.washington.edu
Web: http://www.seattlechildrens.org/research/integrative-brain-research/

Organizations related to Lissencephaly

References

TEXTBOOKS
Behrman RE, et al, eds. Nelson Textbook of Pediatrics. 16th ed. Philadelphia, PA: W.B. Saunders Company; 2000:1807.

Jones KL. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W.B. Saunders Company; 1997:194-95.

Gorlin RJ, et al, eds. Syndromes of the Head and Neck. 3rd ed. New York, NY: Oxford University Press; 1990:590-92.

Buyse ML. Birth Defects Encyclopedia. Dover, MA; Blackwell Scientific Publications, Inc.; 1990:1074-75, 1774-75.

JOURNAL ARTICLES
Matsumoto N, et al. Mutation analysis of the DCX gene and genotype/phenotype correlation in subcortical band heterotopia. Eur J Hum Genet. 2001;9:5-12.

Dobyns WB, et al. Differences in the gyral pattern distinguish chromosome 17-linked and x-linked lissencephaly. Neurology. 1999;53:270-77.

Dobyns WB, et al. X-linked malformations of neuronal migration. Neurology. 1996;47:331-39.

Pavone L, et al. Clinical manifestations and evaluation of isolated lissencephaly. Childs Nerv Syst. 1993;9:387-90.

Dobyns WB, et al. Causal heterogeneity in isolated lissencephaly. Neurology. 1992;42:1375-88.

Pavone L, et al. Isolated lissencephaly: report of four patients from two unrelated families. J Child Neurol. 1990;5:52-59.

Greenberg F, et al. Familial Miller-Dieker syndrome associated with pericentric inversion of chromosome 17. Am J Med Genet. 1986;23:853-59.

Stratton RF, et al. New chromosomal syndrome: Miller-Dieker syndrome and monosomy 17p13. Hum Genet. 1984;67:193-200.

Dobyns WB, et al. Syndromes with lissencephaly. I: Miller-Dieker and Norman Roberts syndromes and isolated lissencephaly. Am J Med Genet. 1984;18:509-26.

Dobyns WB, et al. Miller-Dieker syndrome: lissencephaly and monosomy 17p. J Pediatr. 1983;102:552-58.

Garcia CA, et al. The lissencephaly (agyria) syndrome in siblings. Computerized tomographic and neuropathologic findings. Arch Neurol. 1978;35:608-11.

Norman MG, et al. Lissencephaly. Can J Neurol Sci. 1976;3:39-46.

Stewart RM, et al. Lissencephaly and pachygyria: an architectonic and topographical analysis. Acta Neuropathol. 1975;31:1-12.

INTERNET
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Muscular Dystrophy-Dystroglycanopathy (Congenital with Brain and Eye Anomalies), Type A, 1; MDDGA1. Entry No: 236670. Last Edited May 16, 2012. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed August 30, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Platelet-Activating Factor Acetylhydrolase, Isoform 1B, Alpha Subunit; PAFAH1B1. Entry No: 601545. Last Edited February 22, 2012. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed August 30, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Neu-Laxova Syndrome; NLS. Entry No: 256520. Last Edited December 21, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed August 30, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Lissencephaly, X-linked, 1; LISX1. Entry No: 300067. Last Edited December 16, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed August 30, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Miller-Dieker Lissencephaly Syndrome; MDLS. Entry No: 247200. Last Edited June 21, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed August 30, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Lissencephaly 2; LIS2. Entry No: 257320. Last Edited June 2, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed August 30, 2012.

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Report last updated: 2012/09/06 00:00:00 GMT+0

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