Lissencephaly

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Lissencephaly is a rare brain malformation in which the surface of the brain is smooth rather than full of ridges and valleys (folds). It results from the inability of nerve cells to connect with one another to reach the surface of the brain due to the nerve cells being stuck in an abnormal position. As a result, the layers of cells in the cerebral cortex are found to be abnormal. In a typical brain, the cerebral cortex is divided into six distinct layers, whereas, the brain of an individual with lissencephaly has only four.

The first documented case of lissencephaly was described in 1914 where physicians found that the children had a thickened cortex with thin white matter, reduced or missing cortical lamina, and lacked an orderly arrangement of cortical neurons. Other cases were described in the 1960's, including Dr. Miller’s observations of siblings with the disorder (indicating a possible genetic link) and Dr. Dieker’s, who observed two siblings and a first cousin with lissencephaly (giving credibility to the hypothesis that there is a genetic link).

In 1977, researchers identified an anomaly on chromosome 17 that corresponded to the lissencephaly phenotype. By 1983, a microdeletion at 17p13 was found to be a genetic cause of lissencephaly. However, Dr. William B. Dobyns, a lissencephaly expert, says there are other causes of lissencephaly as well, such as viral infections of the baby during the first trimester and an insufficient flow of blood to the brain during the first trimester.

 

Features and Characteristics

There are several different disorders associated with lissencephaly, however, the most common are Isolated Lissencephaly Sequence (ILS), Miller-Dieker syndrome (MDS), and Walker-Warburg syndrome (WWS). Following is a list of common features found in each of the three syndromes:

Isolated Lissencephaly Sequence

• Subtle facial abnormalities (mild indentation of temples and small jaw)
• Severe to profound mental retardation
• Abnormal visual tracking
• Hypotonia
• Poor head control
• Spasticity
• Seizures
• Feeding problems
• Increased risk of pneumonia
• Shortened life span

Mental Retardation - There are basically two developmental levels found in children with ILS. Developmental level 1 represents children with profound mental retardation. They are floppy, have poor head control, have inconsistent visual tracking and are not able to roll over. Developmental level 2 represents children who reach a developmental age of 3-5 months. They are less floppy, have social smiling, have good head control, can reach for objects, can roll over, and may even learn to sit.

Seizures - Most children with ILS have seizures which begin in the first year of life. Children have many different types of seizures including infantile spasms (which do not respond to typical anticonvulsants). Other types of seizures can be controlled, although not completely, with typical anti-seizure medications.

Feeding Problems - Some infants are able to feed normally, while others have a weak suck. The feeding problems occur or become worse as the child becomes more stiff. The child may choke and gag, refuse to eat, and may spit-up (most of which is caused by reflux).

Miller-Dieker Syndrome

• Characteristic facial appearance (broad and high forehead, subtle indentation of the temples, slightly upturned tip of nose, thin upper lip, small jaw)
• Profound mental retardation
• Feeding problems
• Seizures
• Recurrent pneumonia
• Shortened life span
• Heart defects and other abnormalities affecting the kidneys and other organ systems

Children with MDS are similar to those with ILS who are considered to be at "developmental level 1." They also have similar types of problems with seizures, feeding, and recurrent pneumonia as those with ILS.

Walker-Warburg Syndrome

• Birth defects of the cerebellum
• Severe to profound mental retardation
• Seizures
• Hydrocephalus
• Birth defects of the eyes (causing poor vision)
• Unusual type of muscular dystrophy
• Weak breathing
• Hypotonia
• Poor head control
• Spasticity
• Feeding problems
• Cleft lip, cleft palate
• Shortened life span

Mental Retardation - There are varying degrees of retardation in children with WWS. For those with the most severe form, children make essentially no developmental gains. They are very inactive and floppy, have poor head control, and are frequently blind from eye abnormalities. Those with mild WWS, however, can reach "developmental level 2," as described in the ILS section, while some have even learned to walk and talk.

Birth Defects of the Eye - Eye abnormalities are often severe and result in poor vision. The retina does not develop or function properly, the outer covering of the eye may be cloudy, the lenses may have cataracts, and the eyes may not drain properly, resulting in glaucoma.

Muscular Dystrophy (MD) - All children with WWS have some form of MD. For children with severe cases of WWS, the muscle disease may go unnoticed because of the other medical problems, however, in children with a mild form of WWS, children get weaker during later childhood.

 

Diagnosis

Lissencephaly is usually diagnosed with the use of an MRI or CT-scan of the brain. For those with a clinical diagnosis of ILS or MDS, a FISH probe is available to detect deletions (or missing pieces of genes) on one of the two number 17 chromosomes. For those who have no deletion on chromosome 17, they may be able to participate in research studies aimed at finding genetic mutations which are also responsible for causing ILS or MDS.

 

Treatment

As with any brain malformation, there is no cure for lissencephaly. However, medication is available to control seizures, and occupational therapy and/or medication may be helpful for those with feeding difficulties (although a G-tube may be necessary). For those with hydrocephalus, a shunt can be inserted. Aquatic therapy may be useful to treat stiffness (spasticity) and conventional physical therapy may be used for improving gross motor skills. In terms of providing an education for the child with lissencephaly, if the child is considered medically fragile, he or she is entitled to receive a free and appropriate education in the home.

 

What to Expect

The prognosis for children with lissencephaly varies depending on the malformation. Many individuals remain in a 3-5 month developmental level, while others may appear to have near normal intelligence and development. Some children with lissencephaly will be able to roll-over, sit, reach for objects, and smile socially. Aspiration and respiratory disease are the most common causes of illness or death. The life expectancy is said to be around two years of age, however, many children live well beyond that age, as you will see when you read the personal stories below.

 

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Resources

If you are interested in meeting other parents and individuals who are involved in raising a child with lissencephaly, the following listservs are available:

Lissencephaly List - To subscribe, simply click here: http://www.onelist.com/viewarchive.cgi?listname=lissencephaly

Walker-Warburg List - To subscribe, simply click here: http://www.onelist.com/viewarchive.cgi?listname=walkerwarburg

For more information on lissencephaly, please visit these helpful sites:

• The Lissencephaly Network http://www.lissencephaly.org
• National Institute of Health http://www.ninds.nih.gov/patients/Disorder/lissencephaly/lissencephaly.htm
• Reiner, O., Lombroso, P., Development of the Cerebral Cortex: II Lissencephaly, J Am Acad Child Adolesc Psychiatry, 37(2):231-232, 1998 http://info.med.yale.edu/chldstdy/plomdevelop/011998121998/february.html
• University of Chicago, Department of Genetics http://genes.uchicago.edu/ucgs/special-diagnostics/MD-IL/md-il.html
• Lissencephaly Launch Pad http://www.foliot.demon.co.uk/lissinfo.html
• Klaff, L.; Creekmore, J.; Breimayer, D.; Syed, S.; Lissencephaly, Washington University http://www.foliot.demon.co.uk/lissinfo.html