Macrencephaly

What Causes Macrencephaly?

In some cases, macrencephaly seems to result from a problem early in brain development and is present at birth. In other cases, the condition results from a disorder that causes brain cells to grow abnormally.

Macrencephaly is divided into three categories according to its underlying cause:

• Metabolic macrencephaly. This condition is caused by metabolic disorders, including organic acid disorders, metabolic leukoencephalopathies (Alexander disease, Canavan disease, etc.), and lysosomal storage diseases (Tay-Sachs disease, Sandhoff disease, etc.).
• Anatomic macrencephaly. This type of macrencephaly is caused by genetic disorders that affect growth, such as Sotos syndrome, achondroplasia, and megalencephaly-capillary malformation syndrome (MCAP).
• Benign or idiopathic macrencephaly. This type of macrencephaly has no identifiable underlying cause and typically does not cause neurological symptoms.

Is Macrencephaly Hereditary?

Macrencephaly is not an inherited condition, but its underlying causes are often genetic and run in families.

The risk of inheriting the underlying disorder varies depending on the disease. For example, achondroplasia is inherited in an autosomal dominant pattern. This means that children may develop the condition if they inherit even one copy of the mutated gene from either of their parents. If a parent carries the disorder-causing mutation, they will have a 50 percent chance of having an affected child with each pregnancy.

However, Tay-Sachs disease, for example, is inherited in an autosomal recessive pattern, meaning that a child must inherit two copies of the gene mutation, one from each parent, to develop the disorder. People who have only one copy of the mutated gene will not develop the disease but will be carriers who can pass the mutation on to their children. Two carrier parents have a 25 percent chance of having a child with the disease with each pregnancy. Half of their pregnancies will produce a carrier, and a quarter of the pregnancies will produce a child with no mutated genes.

How Is Macrencephaly Detected?

In some cases, depending on the underlying cause, macrencephaly may be diagnosed before birth during ultrasound imaging exams. However, in many cases, the condition does not develop until later and is detected when abnormal head growth is apparent.

How Is Macrencephaly Diagnosed?

Macrencephaly may be suspected when a physical exam shows an abnormally large head circumference. Doctors will take diagnostic steps to rule out other possible causes for the abnormal growth and identify the underlying cause.  The diagnostic process usually includes:

• Assessment of the child’s medical and family history
• Physical and neurological exams
• Imaging scans such as magnetic resonance imaging (MRI) to look for the characteristic malformations of the disorder

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Macrencephaly Treated?

Macrencephaly has no cure, and treatment will not reverse the effects of its symptoms. Treatments and therapies aim instead to lessen the impact of symptoms and prevent complications. Common treatments and therapies include:

• Anti-seizure medications
• Physical therapy
• Occupational therapy
• Special education

How Does Macrencephaly Progress?

The long-term outlook for children with macrencephaly depends on the underlying cause of the condition. Benign macrencephaly causes no neurological symptoms, and the prognosis for people with this condition is good. However, many of the disorders associated with macrencephaly produce significant symptoms and complications. Severe disabilities and death are common when these disorders are the cause of abnormal brain development.

How Is Macrencephaly Prevented?

There is no known way to prevent macrencephaly. Parents with a family history of any disorders that cause the condition are advised to consult a genetic counselor to assess their risk if they plan to have a child.

Macrencephaly Caregiver Tips

• Be an advocate for your child. Learn all you can about macrencephaly so you can understand the challenges your child faces, and be prepared to educate others about what they can do to help and support you and your child.
• Remember that you’re not alone. Connections with others who are going through the same thing can help. The Child Neurology Foundation maintains educational resources, access to one-to-one peer networks, and links to support groups.

Macrencephaly Brain Science

Some scientists believe that hemimegalencephaly may result from a neuronal migration disorder that arises during fetal brain development. In normal embryonic brain development, nerve cells move from their origin 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. However, in hemimegalencephaly, some triggering event(s) may disrupt the process, and the nerve cells don’t move as they should. As a result, one side of the brain is enlarged and may also show other types of malformation.

Macrencephaly may also be caused by defects in the cell processes that regulate the formation of new brain cells (neuronal proliferation) and their normal lifespan (apoptosis). As a result, too many brain cells may be produced, and those cells may live longer than they are supposed to, leading to an overgrowth of brain tissue.

Macrencephaly Research

Title: Use of a Tonometer to Identify Epileptogenic Lesions During Pediatric Epilepsy Surgery

Stage: Recruiting

Principal investigator: Aria Fallah, MD

University of California, Los Angeles

Los Angeles, CA

Refractory epilepsy, meaning epilepsy that no longer responds to medication, is a common neurosurgical indication in children. In such cases, surgery is the treatment of choice. Complete resection of affected brain tissue is associated with the highest probability of seizure freedom. However, epileptogenic brain tissue is visually identical to normal brain tissue, complicating complete resection. At this time, modern investigative methods are of limited use.

An important subjective assessment during surgery is that affected brain tissue feels stiffer. However, there is presently no way to determine this without committing to resecting the affected area. It is hypothesized that intraoperative use of a tonometer (Diaton) will identify abnormal brain tissue stiffness in the affected brain relative to a normal brain. This will help identify stiffer brain regions without having to resect them.

The objective is to determine if intra-operative use of a tonometer to measure brain tissue stiffness will offer additional precision in identifying epileptogenic lesions.

In participants with refractory epilepsy, various locations on the cerebral cortex will be identified using standard pre-operative investigations like magnetic resonance imaging (MRI) and positron emission tomography (PET). These are presumed normal and abnormal brain areas where the tonometer will be used during surgery to measure brain tissue stiffness. Brain tissue stiffness measurements will then be compared with the results of routine pre-operative and intra-operative tests. Such comparisons will help determine if and to what extent intra-operative brain tissue stiffness measurements correlate with other tests and help identify epileptogenic brain tissue.

Twenty-four participants have already undergone intra-operative brain tonometry. Results in these participants are encouraging: abnormally high brain tissue stiffness measurements have consistently been identified and significantly associated with abnormal brain tissue.

If the tonometer adequately identifies epileptogenic brain tissue through brain tissue stiffness measurements, it is possible that resection of identified tissue could lead to better postoperative outcomes, lowering seizure recurrences and neurological deficits.

Title: Genetic and Electrophysiologic Study in Focal Drug-resistant Epilepsies (GENEPHY)

Stage: Recruiting

Principal investigator: Georg Dorfmuller, MD

Fondation Ophtalmologique Adolphe de Rothschild

Paris, France

Brain somatic mutations in genes belonging to the mTOR pathway are well recognized in malformations of cortical development, such as focal cortical dysplasia or hemimegalencephaly. The present study aims to search for brain somatic mutations in paired blood-brain samples from children undergoing epilepsy surgery at the Rothschild Foundation, Paris. Patients and their parents will be recruited to identify genetic abnormalities both in lymphocytic and cortical DNA.

Title: Natural History Study of Individuals With Autism and Germline Heterozygous PTEN Mutations

Stage: Reiting

Principal investigator: Julian Martinez, MD, PhD

University of California, Los Angeles

Los Angeles, CA

Autism spectrum disorders (ASD) are a set of neurodevelopmental disorders characterized by social communication/intecruraction impairments and restricted/repetitive behaviors. ASD associated with germline heterozygous PTEN mutations (PTEN ASD) is a genetically defined sub-group that may be one of the more prevalent genetic disorders contributing to ASD (0.5-2%). The purpose of this research study is to carefully track the phenotypic and molecular characteristics of PTEN ASD and identify biomarkers for intervention studies.

Individuals with PTEN ASD, with macrocephalic ASD without a PTEN mutation (macro-ASD), healthy controls, and individuals with PTEN mutations without ASD (PTEN no-ASD) will be invited to participate in this study if they are 18 months and older. Both males and females will be asked to participate. Additionally, to be eligible for study participation, individuals’ primary communicative language must be English.

The study involves three on-site visits over two years. Study visits will vary in length from about 4 hours to 6 hours. Study visits involve a physical exam, medical history questions, neuropsychological assessments, and a blood draw done for laboratory studies. A subset of participants between the ages of 2 and 11 will participate in the study’s EEG portion. Individuals who have a clinically indicated MRI will have an option to provide routine clinical scans for analysis.