Lissencephaly Health Article

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.