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Megalencephalic Leukoencephalopathy (MLC) Fast Facts

Megalencephalic leukoencephalopathy (MLC) is a condition in which a child’s brain is abnormally large. The disorder also features progressive degeneration of brain tissue in which a substance essential for nerve cell function, called myelin, breaks down.

MLC is usually diagnosed at birth or during infancy.

Most cases of MLC are caused by abnormal changes in a child’s genes. However, a small number of cases have an unknown cause.

MLC symptoms can include problems with movement, speech difficulties, and intellectual impairments.

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MLC is usually diagnosed at birth or during infancy.

What is Megalencephalic Leukoencephalopathy (MLC)?

Megalencephalic leukoencephalopathy (MLC) is a neurological condition characterized by a larger than usual brain size. The disorder involves problems with an essential brain-cell component called myelin, leading to brain-tissue degeneration and neurological symptoms. Many people with MLC also develop fluid-filled cysts deep inside the brain.

Symptoms of MLC

MLC is typically apparent at birth or in the first few months of a baby’s life. The symptoms that develop from the condition primarily affect muscles and movement, but some people with MLC also experience mild to moderate intellectual impairment.

Common symptoms include:

  • Enlarged brain size and enlarged head size (macrocephaly)
  • Brain cysts
  • Stiff muscles
  • Problems with coordination
  • Difficulty walking
  • Involuntary muscle tensing or writhing movements
  • Speech impairments
  • Difficulty swallowing
  • Seizures

Types of MLC

MLC is categorized into three different types according to their genetic causes and symptoms.

  • Type 1. This type is caused by mutations in the MLC1 gene and is the most common type.
  • Type 2A. This type is caused by mutations in the HEPACAM gene. The symptoms of this type are very similar to those of Type 1.
  • Type 2B. HEPACAM mutations also cause this type. It differs from Type 2A in that its symptoms begin to improve after about a year.

What Causes Megalencephalic Leukoencephalopathy (MLC)?

MLC is caused by abnormal changes (mutations) in one of two different genes. Type 1 MLC is caused by mutations in the MLC1 gene, and mutations in the HEPACAM gene cause types 2A and 2B. These gene mutations affect the production and function of proteins essential for the proper function and health of brain cells. In the case of MLC1 mutations, the affected protein is called MLC1 protein. HEPACAM mutations impair the function of a protein called GlialCAM.

Scientists don’t yet know the function of MLC1 and GlialCAM proteins in the brain. However, both proteins seem to play a vital role in the junction between separate brain cells. In particular, the disorder appears to affect glial cells, which protect and support nerve cells in the brain.

In about 5% of cases, people with MLC have no MLC1 or HEPACAM mutations. The cause of the disorder in these cases is unknown.

Is Megalencephalic Leukoencephalopathy (MLC) Hereditary?

Most cases of MLC are inherited. However, the pattern and risk of inheritance vary depending on the type of the disorder. 

Types 1 and 2A MLC are 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 usually 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.

Type 2B MLC 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. However, in most cases of Type 2B, the mutation occurs during the formation of the sperm or egg cells or early in embryonic development. Most people with Type 2B do not have a family history of the disorder. 

How Is Megalencephalic Leukoencephalopathy (MLC) Detected?

MLC is usually detected at birth or in infancy due to the baby’s atypically large head. However, further diagnostic exams can confirm an MLC diagnosis.

How Is Megalencephalic Leukoencephalopathy (MLC) Diagnosed?

MLC may be suspected when a physical exam shows an abnormally head circumference and the baby exhibits neurological symptoms. 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
  • Genetic testing to look for MLC1 or HEPACAM mutations

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Megalencephalic Leukoencephalopathy (MLC) Treated?

MLC 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
  • Speech therapy
  • Safety measures to avoid head injuries, which can worsen symptoms
  • Special education

How Does Megalencephalic Leukoencephalopathy (MLC) Progress?

The long-term outlook for children with MLC depends on the disorder type and severity.

Long-term complications of Types 1 and 2A may include:

  • Loss of ability to walk. Some people with MLC are unable to walk in childhood. Others maintain the ability well into adulthood.
  • Impaired speech
  • Epilepsy
  • Complications caused by head injuries. Even minor head injuries can make symptoms worse or cause a coma. Children may be advised to wear a helmet and avoid risky situations such as contact sports.
  • Mild intellectual impairment

Long-term effects of Type 2B can include:

  • Permanently enlarged head size
  • Movement-related symptoms that improve or stabilize after about a year
  • Persistent coordination problems
  • Mild intellectual impairment or autism
  • Epilepsy

How Is Megalencephalic Leukoencephalopathy (MLC) Prevented?

There is no known way to prevent MLC. However, 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.

Megalencephalic Leukoencephalopathy (MLC) Caregiver Tips

  • Be an advocate for your child. Learn all you can about MLC 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.

Megalencephalic Leukoencephalopathy (MLC) Brain Science

Scientists don’t yet fully understand how the gene mutations associated with MLC cause the disorder’s symptoms. The proteins affected by MLC1 and HEPACAM mutations appear to play a crucial role at the junctions between glial cells, the brain cells that protect nerve cells and help them function. However, the precise impact of these protein dysfunctions on the glial cells is unclear.

MLC1 mutations typically cause a deficiency or complete lack of the MLC1 protein. HEPACAM mutations usually cause a dysfunctional GlialCAM protein that may also interfere with the function of the MLC1 protein.

Some scientists suspect that a lack of functional MLC1 protein may weaken glial cells or weaken the bonds between cells, making it difficult for the cells to stick together as they should.

MLC also features the breakdown of an important substance called myelin, a fatty compound surrounding specific brain cells called white matter. When myelin breaks down, white matter cells cannot function properly and eventually die.

Megalencephalic Leukoencephalopathy (MLC) Research

Title: The Myelin Disorders Biorepository Project (MDBP)

Stage: Recruiting

Principal investigator: Keith Van Haren, MD

Stanford University

Palo Alto, CA

Genetic white matter disorders (leukodystrophies) are estimated to have an incidence of approximately 1:7000 live births. In the past, patients with white matter disease of unknown cause evaluated by the investigator achieved a diagnosis in fewer than 46% of cases after extensive conventional clinical testing. Even when a diagnosis is achieved, the diagnosis takes an average of eight years. This “odyssey” results in testing charges to patients and insurers over $8,000 on average per patient, including patients who never achieve a diagnosis at all. With next-generation approaches such as whole-exome sequencing, the diagnostic efficacy is closer to 70%, but approximately a third of individuals do not achieve a specific etiologic diagnosis. These diagnostic challenges represent an urgent and unresolved gap in knowledge and disease characterization, as obtaining a definitive diagnosis is of paramount importance for leukodystrophy patients.

Moreover, the disease mechanisms in many leukodystrophies of known cause are poorly understood, with little known about the best symptomatic management. Thus, limited standards of care are available for the management of these patients.

The purpose of this study is to: (Aim 1) Define novel homogeneous groups of patients with unclassified leukodystrophy and work toward finding the cause of these disorders; (Aim 2) assess the validity and utility of next-generation sequencing in the diagnosis of leukodystrophies; (Aim 3) establish disease mechanisms in selected known leukodystrophies; (Aim 4) track current care and natural history of these patients to define the longitudinal course and determinants of outcomes in these disorders; (Aim 5) contact subjects for future research studies and/or clinical programs.

This biorepository will use available basic science and clinical research approaches to establish novel diagnoses, biomarkers, and outcome measures for future clinical diagnostic and therapeutic approaches.

 

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. Modern investigative methods are of limited use.

An important subjective assessment during surgery is that affected brain tissue feels stiffer. However, there is currently 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 the extent to which 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, thereby lowering seizure recurrences and neurological deficits.

 

Title: Decoding Presymptomatic White Matter Changes in Huntington Disease (Win-HD)

Stage: Completed

Principal investigator: Alexandra Durr, PU-PH

Brain and Spine Institute

Paris, France

WIN-HD is a monocentric longitudinal study comparing premanifest Huntingtin (HTT) mutation carriers and non-HTT mutation carriers to determine that white-matter atrophy occurs far earlier than clinical onset in HD using Diffusion-weighted Nuclear Magnetic Resonance (N spectroscopy (DWS) and Diffusion Tensor Imaging (DTI).

The investigators will recruit up to 20 premanifest HTT mutation carriers (15 completed) and up to 20 non-HTT mutation carriers (15 completed). It is important to have those two populations for comparing the results and determining if there are significant white-matter changes far from the onset of HD. Therefore, non-HTT mutation carriers will be age and gender-matched to premanifest HTT mutation carriers.

To test the hypothesis, the study has two visits with a year interval.

This study is based on four principle criteria:

  • Imaging criteria
  • Clinical and neurological criteria
  • Psychological criteria
  • Behavioral criteria

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