Lissencephaly

Definition

Lissencephaly, literally meaning smooth brain, is a rare birth abnormality of the brain that results in profound mental retardation and severe seizures.

Lissencephaly is caused by an arrest in development of the fetal brain during early pregnancy. The cerebral cortex, the top layer of the brain controlling higher thought processes, does not develop the normal sulci, the indentations or valleys in the cortex, and gyri, the ridges or convolutions seen on the surface of the cortex. Instead, the cortex in a person with lissencephaly is thickened and smooth with disorganized neurons that have not migrated to their proper places. The typical cortex has six layers of neurons, but brains with lissencephaly usually have only four.

Description

The condition was first reported in 1914 by pathologists Culp and Erhardt, who described a human brain with a smooth surface, lacking the normal gyri. They called it lissencephaly.

Lissencephaly is one of a number of conditions called "neural migration disorders" that occur because the developing neurons do not proceed correctly to their normal place in the brain's cortex during fetal development. In fact, the brain of a person with lissencephaly, with its smooth and immature cortex, resembles a typical human fetal brain at about 10 to 14 weeks of development.

Children with lissencephaly are almost always severely to profoundly mentally retarded, and the vast majority develop seizures that are difficult to treat. Life expectancy is reduced, and survivors need constant care.

Lissencephaly can occur as an isolated birth abnormality or can be one of many birth abnormalities occurring together in a specific inherited syndrome. There are at least 10 inherited syndromes that include lissencephaly and many more that include variants of this brain malformation. Lissencephaly can also occur by itself without other characteristics.

Some cases of lissencephaly are caused by new changes in the genetic material of that particular baby—these cases are caused by sporadic, or random, gene mutations (also called de novo). This means that the genetic change is not present in the parents or anyone else in the family. Some cases of lissencephaly are caused by rearrangements of chromosome material that can be inherited from a healthy parent. Other types of lissencephaly are inherited in an autosomal recessive pattern. This means that a couple who has a child with an autosomal recessive lissencephaly syndrome has a 25% chance in any future pregnancy to have another affected child. There are also types of lissencephaly caused by changes in a gene or genes on the X chromosome. X-linked lissencephaly affects mainly males, who have only one X chromosome. Females who carry an X-linked gene change on one of their two X chromosomes often have mild brain changes.

Other known causes of lissencephaly include viral infections of the fetus or insufficient blood supply to the brain during the first trimester of pregnancy.

Genetic profile

There are a number of subtypes of lissencephaly that are distinguished by differences in the physical structure of the brain. "Classical," or type 1, lissencephaly and cobblestone dysplasia , or type 2, lissencephaly are the most common subtypes.

Classical, or type 1, lissencephaly consists of a brain surface that is completely smooth except for a few shallow valleys (sulci). The cortex is thicker than normal and there are clumps of neurons found in areas outside the cortex (heterotopia). The corpus callosum, the band of tissue between the hemispheres of the brain, is often small and is sometimes absent. The posterior ventricles, the fluid-filled spaces in the center of the brain, are often larger than normal.

Type 1 lissencephaly can be seen in a number of genetic syndromes and can also occur by itself in a condition called Isolated Lissencephaly Sequence (ILS). The vast majority of cases of ILS is a result of mutations or deletions (missing sections) in one of two different genes involved in brain development.

The gene causing the majority of cases of ILS is called the LIS1 and is located on the short arm of chromosome 17. Between 40% and 64% of persons with ILS have a deletion of a portion of the LIS1 gene, and about 24% have a mutation that disrupts the normal function of the gene. Most deletions and mutations in the LIS1 gene are sporadic and are not present in other family members.

Another 12% of persons with ILS have a mutation in a gene called XLIS (or DCX), located on the long arm of the X chromosome. Mutations in XLIS cause X-linked lissencephaly in males and may or may not cause symptoms in the mothers who carry the mutation.

There are also a few cases of ILS that appear to be inherited in an autosomal recessive pattern. As of 2001, the mutated genes for this and other types of ILS have not been discovered.

An example of a genetic syndrome involving type 1 lissencephaly is Miller-Dieker syndrome (MDS). This disorder is caused by a deletion of part of the short arm of chromosome 17 (17p13) that includes the LIS1 gene. In addition to lissencephaly, children with MDS have distinctive facial features including a high forehead, short upturned nose, and thin lips. They also have narrowing at the temples and a small jaw, although these traits can also be seen in ILS and other lissencephaly syndromes. Children with MDS occasionally have other birth abnormalities of the heart, kidneys, or palate. Calcium deposits in the midline of the brain are common in MDS, but not in ILS or other syndromes.

Type 2 lissencephaly is also called cobblestone dysplasia because of the pebbled appearance to the surface of the cerebral cortex. Brains with cobblestone dysplasia often show abnormalities of the white matter, enlarged ventricles, underdeveloped brainstem and cerebellum, and absence of the corpus callosum. There are four known syndromes that include cobblestone dysplasia: cobblestone lissencephaly without other birth defects (CLO); Fukuyama congenital muscular dystrophy (FCMD); muscle-eye-brain disease (MEB); and Walker-Warburg syndrome (WWS). These disorders are quite rare and all are inherited in an autosomal recessive pattern. Diagnosis depends on MRI studies and clinical evaluations. As of 2001, there are no specific genetic tests available for clinical use for these conditions.

There are other rare syndromes involving lissencephaly and variants of lissencephaly, some of which are autosomal recessive and some X-linked. None of the genes responsible for these other conditions have been identified as of Spring 2001.

Demographics

Lissencephaly affects fewer than one in 100,000 individuals and occurs in all parts of the world. The sporadic and autosomal recessive types of lissencephaly occur equally in males and females. X-linked syndromes that include lissencephaly occur mainly in boys, although carrier mothers sometimes have milder signs.

Signs and symptoms

Many babies with lissencephaly appear normal at birth, although some have immediate respiratory problems. After the first few months at home, parents typically notice feeding problems, inability to visually track objects, and lessened activity in their child. Breath-holding spells (apnea) and muscle weakness are also common. Seizures frequently begin within the first year of life, are usually severe, and are difficult to treat with medication. Muscle weakness changes to spasticity (a condition of excessive muscle tension) over time. Repeated pneumonias from swallowing food down the airway and into the lungs are common.

Head size is usually within normal limits at birth; however, as the baby's body grows, head growth lags and a small head (microcephaly) results. Babies with isolated lissencephaly often have hollowing at the temples and small jaws, both thought to be a result of the abnormal brain shape. Genetic syndromes involving lissencephaly will include other symptoms and signs.

Diagnosis

The diagnosis of lissencephaly is initially based on tests using magnetic resonance imaging (MRI) and CT testing. MRI findings in type 1 lissencephaly include a lack of, or very shallow, convolutions on the surface of an unusually thick cerebral cortex. Enlargement of the ventricles is sometimes present.

On average, persons with Miller-Dieker syndrome have more severe MRI findings than persons with ILS. It is sometimes possible to distinguish between chromosome 17-related lissencephaly (ILS and MDS) and X-linked ILS based on MRI findings. The smooth brain appearance is more striking in the back portion of the brain in persons with chromosome 17 LIS1 deletions and mutations. In contrast, it is more conspicuous in the front part of the brain in persons with XLIS mutations. In addition, underdevelopment of part of the cerebellum is more commonly seen in persons with XLIS mutations.

Individuals with subcortical band heterotopia (SBH), a milder form of lissencephaly often seen in female carriers of XLIS, often have minor changes in the gyri, shallow sulci, and ribbons of white and gray matter beneath the cortex that show up on MRIs.

MRI findings in type 2 lissencephaly can include a cobblestone appearance of the cortex, enlarged ventricles, abnormalities of the white matter, and changes in the cerebellum, corpus callosum and brain stem.

A CT scan can be done to look for calcium deposits in the midline of the brain. Calcium deposits are common in MDS but not found in other lissencephaly syndromes.

In addition to MRI and CT testing, a careful clinical evaluation and examination by a medical geneticist is necessary to confirm the diagnosis and evaluate the child for the presence of a syndrome. It is essential for a child to have a precise diagnosis in order for genetic counselors to be able to give the family complete and accurate information about the inheritance pattern and chances for the condition to recur in future children.

To confirm the diagnosis of MDS or ILS, chromosome testing and other specialized genetic tests are often helpful. A test called fluorescence in situ hybridization (FISH) is used to detect LIS1 gene deletions. High resolution chromosome testing can often determine whether a deletion is sporadic or due to an inherited chromosome rearrangement. If necessary, mutation analysis, looking for specific errors in the sequence of the LIS1 or XLIS gene, can be performed.

Parents of a child with ILS who has a confirmed deletion or mutation in LIS1, and who have normal genetic studies themselves, have a less than 1% chance of having another child with ILS. Similarly, MDS with a confirmed sporadic deletion in LIS1 has a low chance of recurring. MDS caused by a chromosome rearrangement carries a higher chance of happening again. Actual risks depend on the specific rearrangement.

XLIS mutations are often inherited from a carrier mother. If a woman has genetic testing and is confirmed to have an XLIS mutation, she will have a 25% chance with each pregnancy to have an affected male and a 25% chance to have a carrier female who may have SBH.

If a detectable mutation, deletion, or chromosome rearrangement has been confirmed in the affected family member, prenatal diagnosis is available during future pregnancies. Ultrasound of the fetal anatomy during pregnancy cannot diagnose lissencephaly. However, ultrasound performed by a specialist at 18 to 22 weeks of pregnancy can sometimes detect other birth abnormalities that occur in some of the syndromes involving lissencephaly.

Treatment and management

There is no treatment or cure for lissencephaly. Seizures occur in almost all children with lissencephaly and are often difficult to control, even with the strongest anti-seizure medications. A severe type of seizure called infantile spasms can occur and may need to be treated with injections of adrenocorticotropic hormone (ACTH), although this treatment is not always effective.

Feeding difficulties can include choking, gagging, or regurgitating food or liquid. Aspiration, swallowing food down the trachea and into the lungs, is a serious problem that can lead to pneumonia. Liquids and thin foods can be thickened to make swallowing easier. There are medications available to help with reflux. Children who continue to have serious problems may need a permanent feeding tube placed into the stomach to ensure adequate nutrition.

Physical and occupational therapy can help prevent or reduce tightening of the joints and help to normalize muscle tone. However, the improvements are often limited and temporary.

Prognosis

Persons with classical lissencephaly usually need lifelong care for all basic needs. Many babies will not live past infancy, but the average age of survival depends on the particular syndrome involved, the type of lissencephaly, and the severity of the brain abnormalities in a given child. Babies with MDS usually die by two years of age, but the majority of persons with ILS live into childhood, although often not into adulthood. Many babies with cobblestone dysplasia die in infancy; however, some affected people have lived into their 20s. In contrast, persons with SBH have very variable signs and symptoms, may be asymptomatic, mildly affected or severely retarded, and may have near-normal or normal lifespans.

Resources

PERIODICALS

Berg, M.J., et al. "X-linked Female Band Heterotopia-Male Lissencephaly Syndrome." Neurology 50 (1998): 1143-1146.

Dobyns, W.B., et al. "Differences in the Gyral Pattern Distinguish Chromosome 17-linked and X-linked Lissencephaly." Neurology 53 (1999): 270-277.

Dobyns, W.B., et al. "Lissencephaly and Other Malformation Syndromes of Cortical Development: 1995 Update." Neuropediatrics 26 (1995): 132-147.

Matsumoto, N., et al., "Mutation Analysis of the DCX Gene and Genotype/Phenotype Correlation in Subcortical Band Heterotopia." European Journal of Human Genetics 9 (Jan 2001): 5-12.

ORGANIZATIONS

American Epilepsy Society. 342 North Main St., West Hartford, CT 06117. (860) 586-7505. Fax: (860 586-7550. [email protected]. <http://www.aesnet.org>.

Epilepsy Foundation of America. 4351 Garden City Dr., Suite 406, Landover, MD 20785-2267. (301) 459-3700 or (800) 332-1000. <http://www.epilepsyfoundation.org>.

Lissencephaly Network, Inc. 716 Autumn Ridge Lane, Fort Wayne, IN 46804-6402. (219) 432-4310. Fax: (219) 432-4310. [email protected]. <http://www.lissencephaly.org>.

WEBSITES

Dobyns, William B. [1999]. "Lissencephaly Overview." GeneClinics: Lissencephaly Overview. University of Washington, Seattle. <http://www.geneclinics.org/profiles/lis-overview/>.

NINDS Lissencephaly Information Page. <http://www.ninds.nih.gov/health_and_medical/disorders/lissencephaly.htm?format=printable>.

Lissencephaly Contact Group (UK). <http://www.lissencephaly.org.uk/index.htm>.

The Lissencephaly Research Project (University of Chicago) http://www.genes.uchicago.edu/ucgs/lissproj.html

Barbara J. Pettersen