What is Lissencephaly?
Lissencephaly is a malformation of the brain in which the folds and wrinkles (called gyri) that normally cover the cerebral cortex do not develop. During normal development, the brain’s outer part, called the cerebral cortex, develops complex folds and wrinkles over its surface. In the case of lissencephaly, the cerebral cortex is abnormally smooth and ungrooved. The abnormal formation of the cerebral cortex produces a range of severe developmental and neurological symptoms.
Symptoms of Lissencephaly
Common symptoms of the disorder include:
- Small head size
- Malformation of facial features
- Slow growth
- Physical developmental delays
- Intellectual developmental delays
- Muscle spasms
- Swallowing and eating problems
Lissencephaly may occur as part of other disorders and syndromes, including:
- Miller-Dieker syndrome
- Norman-Roberts syndrome
- Walker-Warburg syndrome
What Causes Lissencephaly?
Lissencephaly can be caused by external environmental factors or by genetic factors. Environmental factors that can cause the condition include a uterine infection or a disruption of blood flow during fetal brain development.
Lissencephaly is often caused by abnormal genetic changes (mutations) that affect brain development before birth. Mutations in several different genes have been associated with varying types of lissencephaly. Associated genes include:
All of these genes play a role in neuronal migration, a crucial process in embryonic brain development. The abnormal development of the cerebral cortex seen in lissencephaly results when mutations interfere with normal neuronal migration.
Is Lissencephaly Hereditary?
In cases where genetic mutations cause lissencephaly, the disorder-causing mutations may be inherited by a child from their parents. The pattern of inheritance varies depending on which gene mutation is involved. For example, DCX and ARX mutations are called X-linked mutations because the genes are located on the X chromosome. Females have two X chromosomes, one inherited from each parent, but males only have one X chromosome inherited from their mother. In the case of X-linked lissencephaly, males typically develop a more severe form of the condition, while females with the mutation are more likely to have milder symptoms or no symptoms at all.
Some other mutations, such as the RELN mutation associated with Norman-Roberts syndrome, are inherited in an autosomal recessive pattern. This means that a child must inherit two copies of the disorder-causing gene mutation, one from each parent, to develop the condition. A parent who carries only one copy of the mutation will usually show no symptoms but may pass the mutation to their children. Two parents who each carry the mutation have a 25 percent chance of having an affected child with each pregnancy. Fifty percent of their pregnancies will produce a carrier child. Twenty-five percent of the time, their child will not inherit a mutated gene, meaning they will not have the disorder or be able to pass on the mutation to their children.
How Is Lissencephaly Detected?
In some cases, lissencephaly may be detected before birth. Prenatal ultrasound exams may show abnormal brain development and the lack of gyri in the cerebral cortex. However, this detection method is not reliable until late in the second trimester of pregnancy because normal cerebral folds don’t develop before that time.
Prenatal tests such as cell-free fetal DNA screening, amniocentesis, and chorionic villus sampling (CVS) may also detect the genetic abnormalities that cause lissencephaly.
Signs of lissencephaly in infancy may include:
- Small head size
- Problems with feeding
- Slow growth
- Physical developmental delays
- Intellectual developmental delays
How Is Lissencephaly Diagnosed?
Doctors may wish to conduct prenatal screening exams and tests if there is a family history of lissencephaly or if prenatal ultrasound imaging raises suspicion that the disorder might exist. When a baby presents symptoms consistent with lissencephaly after birth, the diagnostic process may include:
- Imaging scans such as magnetic resonance imaging (MRI) or computerized tomography (CT) to look for brain abnormalities
- Electroencephalogram (EEG) tests to look for patterns of electrical brain activity characteristic of lissencephaly
- Genetic testing to look for the gene mutations associated with the disorder
PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.
How Is Lissencephaly Treated?
There is no cure for lissencephaly, and no treatments can reverse the disorder’s symptoms. Treatment programs typically focus on improving quality of life and preventing complications. Treatment options may include anti-seizure medications and feeding assistance, possibly with a feeding tube.
How Does Lissencephaly Progress?
The prognosis for children with lissencephaly varies widely depending on the severity of the brain malformation and any underlying condition associated with it. Some disorders, such as Miller-Dieker syndrome, may have additional symptoms or complications that significantly shorten life expectancy.
Some children with lissencephaly will not survive childhood, and some who survive will have severe, life-long impairments and disabilities. However, some may have relatively mild symptoms and no significant impairments.
Among the potentially life-threatening risks and complications of lissencephaly, the most common is the aspiration of food or fluids caused by swallowing difficulties, respiratory infections, and seizures.
How Is Lissencephaly Prevented?
There is no known way to prevent lissencephaly when the disorder-causing gene mutations are present. Parents with a family history of the disorder or who have had another child with lissencephaly are advised to consult a genetic counselor to assess their risks if they plan to have another child.
Avoidance of risk factors during pregnancy may reduce the risk of non-genetic lissencephaly:
- Get vaccinations as recommended by your doctor and take steps to avoid infections.
- Don’t use drugs or alcohol during pregnancy.
- Get good prenatal care to lessen the chance of pregnancy complications.
Lissencephaly Caregiver Tips
Don’t try to go it alone. Instead, ask your healthcare provider for referrals to support services that can provide physical therapy, occupational therapy, speech therapy, and all the other things your child needs.
- Learn about the disorder. Lissencephaly is a complex disorder that will impact your child’s life in many different ways. Learn as much as you can about the condition in general and your own child’s specific challenges. Education can help you know that you’re doing everything you can to improve your child’s quality of life.
- Find a community of other families like yours. Knowing that you’re not alone is essential. Support groups, either locally or online, can put you in touch with other parents living with lissencephaly.
Lissencephaly Brain Science
In normal embryonic brain development, nerve cells move from where they originate to other areas in the brain in a process called neuronal migration. In their new locations, the cells differentiate and develop to form specialized brain structures. Some cells move to the brain’s outer surface, the cerebral cortex, and form several layers, which will eventually become the folds and grooves characteristic of a normal brain.
In lissencephaly, the nerve cells that should migrate to the cerebral cortex don’t move as they should, resulting in the formation of insufficient layers of cells on the surface of the cortex. In some cases, the resulting cerebral folds are underdeveloped (pachygyria), and in some cases, the folds don’t develop at all (agyria).
Title: Human Epilepsy Genetics–Neuronal Migration Disorders Study
Principal investigator: Christopher A. Walsh, MD, PhD
Boston Children’s Hospital
The purpose of this study is to identify genes responsible for epilepsy and disorders of human cognition.
Epilepsy is responsible for tremendous long-term healthcare costs. Analysis of inherited epilepsy conditions has allowed for the identification of several key genes active in the developing brain. Although many genetic abnormalities of the brain are rare and lethal, rapidly advancing knowledge of the structure of the human genome makes it a realistic goal to identify genes responsible for several other epileptic conditions.
This study aims to identify genes responsible for epilepsy and disorders of human cognition (EDHC). The Walsh Laboratory at the Children’s Hospital Boston and Beth Israel Deaconess Medical Center is looking for genes involved in brain development. Conditions that we study include brain malformations, such as polymicrogyria, lissencephaly, Walker-Warburg syndrome, heterotopias and cerebellar hypoplasia, and inherited disorders of cognition such as familial mental retardation and familial autism; people with these conditions also often have epilepsy. Structural brain abnormalities are usually diagnosed by brain MRI or sometimes CT scans. Adults and children with these conditions, and their family members, are invited to participate in our study. By comparing the DNA of individuals or families that carry EDHC to the DNA of people in the general population, it may be possible to learn more about the genetic bases of certain forms of EDHC.
Study participants must have a brain malformation or disorder of cognition such as mental retardation or autism in addition to epilepsy to take part in this research.
Title: Congenital Muscle Disease Study of Patient and Family Reported Medical Information (CMDPROS)
Principal investigators: Gustavo Dziewczapolski, PhD and Anne Rutkowski, MD
Congenital Muscle Disease International Registry
The Congenital Muscle Disease Patient and Proxy Reported Outcome Study (CMDPROS) is a longitudinal 10-year observational study to identify care and trend key care parameters and adverse events in the congenital muscle diseases using the Congenital Muscle Disease International Registry (CMDIR). The CMDIR registers individuals with and without genetic confirmation who have been given a clinical diagnosis of congenital muscular dystrophy, congenital myopathy, congenital myasthenic syndrome, or myofibrillar myopathy through the limb-girdle/late onset spectrum.
Identifying care parameters and adverse events in rare genetic neuromuscular diseases can be difficult. Care is fragmented; genetic confirmation may not be prioritized by the medical community or covered by medical insurance, and patients are scattered globally with potential challenges aggregating data across centers. Natural history studies are currently being launched. However, potential biases to participation include recruiting less severely affected patients given difficulty traveling secondary to a medically fragile condition. There is currently no treatment for these conditions, though optimizing and standardizing care and care delivery can promote significant gains in quality of life and survival. Identifying disease-specific care parameters and correlating those parameters with adverse event rates will not only contribute to the development of evidence-based guidelines but inform clinically meaningful outcomes for future clinical trials.
Title: The Global FKRP Patient Registry
Principal investigator: Volker Straub, MD, PhD
The John Walton Muscular Dystrophy Research Centre
Newcastle upon-Tyne, UK
Mutations in the Fukutin Related Protein (FKRP) gene cause the condition Limb-Girdle Muscular Dystrophy type 2I (LGMD2I), also known as LGMDR9, and the rarer conditions Congenital Muscular Dystrophy (MDC1C), Muscle Eye Brain Disease (MEB), and Walker-Warburg Syndrome (WWS). LGMD2I is the most common FKRP-related condition and is especially prevalent in Northern Europe.
The aim is to facilitate a questionnaire-based research study to better characterize and understand the disease globally. In addition, maintaining a global registry will help identify potential participants eligible for clinical trials in the future.
The Global FKRP Registry is an international registry for patients with an FKRP-related condition; no experimental intervention is involved. Patients will receive information on the most up-to-date standards of care relating to their disease and may be invited to participate in relevant clinical trials. Their data will be updated annually and stored indefinitely, or until they request their data to be removed.
The data will be collected via an online form and stored on a secure server based in the United Kingdom and looked after by the registry staff at Newcastle University. Data collected from patients will include demographic information, diagnosis, current condition, age of onset, medication, contractures, family history, and genetic testing results, if available. Other optional questionnaires will focus on patients’ pain and quality of life. Further information collected from patients’ doctors will include heart and lung function, muscle strength, muscle and brain MRI findings, and genetics.