Muscle-Eye-Brain Disease

What Causes Muscle-Eye-Brain Disease?

MEB is caused by abnormal changes (mutations) in a gene called the POMGNT1 gene. This gene carries instructions for producing a protein involved in making another protein called alpha-dystroglycan. Alpha-dystroglycan protein is crucial during the process of muscle contraction and relaxation. When mutations occur in the production of alpha-dystroglycan, the muscular symptoms of MEB result. Alpha-dystroglycan is also present in brain cells, and its deficiency is also the likely cause of the disease’s neurological and visual symptoms.

Is Muscle-Eye-Brain Disease Hereditary?

MEB is an inherited disorder. The disorder-causing gene mutations are inherited in an autosomal recessive pattern. This means 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 MEB 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 MEB 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 Muscle-Eye-Brain Disease Detected?

Prenatal imaging scans late in pregnancy may identify some of the brain malformations characteristic of MEB. However, the physical features of the disease may not develop noticeably until well after birth, making prenatal diagnosis difficult.

MEB symptoms are often similar to those of other congenital muscular dystrophies such as Walker-Warburg syndrome and Fukuyama congenital muscular dystrophy, leading to the potential for misdiagnosis. However, the three disorders are distinct from one another.

Genetic screening may be conducted to look for the mutations that cause MEB if the parents are known carriers.

How Is Muscle-Eye-Brain Disease Diagnosed?

A doctor may confirm a diagnosis of MEB after birth if the symptoms and physical features of the disorder are present. The diagnostic process may include:

• Assessment of the child’s medical and family history
• Physical and neurological exams
• Magnetic resonance imaging (MRI) or computerized tomography (CT) to look for distinctive brain malformations, including an abnormally bumpy cerebral cortex (cobblestone lissencephaly), hydrocephalus, and brain stem malformations. These malformations may not be apparent until several months after birth.
• Blood tests or muscle biopsies to look for signs of muscle degeneration
• Ophthalmological exams to look for eye abnormalities
• Genetic testing to look for disorder-causing mutations

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Muscle-Eye-Brain Disease Treated?

MEB has no cure, and the progression of its symptoms generally cannot be stopped or reversed. Treatments and therapies aim to lessen the impact of symptoms and prevent complications. Common treatments and therapies include:

• Surgery to install a thin tube (a shunt) to drain fluid from the brain in the case of hydrocephalus
• Anti-seizure medications
• Physical therapy

How Does Muscle-Eye-Brain Disease Progress?

MEB cases vary in severity; in some cases, only the muscular symptoms are present, but most cases also involve neurological and ophthalmological symptoms. Long-term impacts of MEB can include:

• Severe intellectual impairment
• Vision loss
• Loss of mobility
• Seizures
• Rigid, inflexible joints (contractures)

How Is Muscle-Eye-Brain Disease Prevented?

There is no known way to prevent MEB when the disorder-causing gene mutations are present. Therefore, parents with a family history of the disorder or who have had another child with MEB are encouraged to consult a genetic counselor to assess their risk if they plan to have another child.

Muscle-Eye-Brain Disease Caregiver Tips

• Caring for your child will take a tremendous amount of your time and energy. Sometimes it will feel like your obligations require more of you than you have to give. It’s essential you take care of yourself as you care for your child. Accept help from your family and friends, and don’t feel guilty when taking time away from caregiving.
• Online support groups can help you find information and comfort in a community of people like you who are living with MEB and other congenital muscular dystrophies.

Some people with MEB also suffer from other brain-related issues, a condition called co-morbidity. Here are a few of the disorders commonly associated with MEB and other congenital muscular dystrophies:

• Hydrocephalus is sometimes a complication of MEB.
• People with MD are more likely to suffer from depression.
• People with MD are at increased risk of anxiety disorders such as generalized anxiety disorder.
• Obsessive-compulsive disorder (OCD) risk is higher in people with MD.

Muscle-Eye-Brain Disease Brain Science

The gene mutations associated with MEB are involved in a process called glycosylation. This process is a modification of the alpha-dystroglycan protein that allows the protein to function. Proper alpha-dystroglycan function is essential in several different parts of the body. In muscles, alpha-dystroglycan helps to strengthen and stabilize muscle fibers. Without the functioning protein, muscle cells are vulnerable to damage and, over time, death.

In the brain, alpha-dystroglycan seems to be involved in a process called neuronal migration. In this process, nerve cells born near the brain’s center in early development move toward the outer parts of the brain, where they become specialized brain structures. In WWS, some cells continue to migrate past the point where they should normally stop. Instead, they move to the outer surface of the brain. There they form clusters that create the lumpy texture of the cerebral cortex known as cobblestone lissencephaly.

Muscle-Eye-Brain Disease Research

Title: Congenital Muscle Disease Study of Patient and Family Reported Medical Information (CMDPROS)

Stage: Recruiting

Principal investigator:  Gustavo Dziewczapolski, PhD

Congenital Muscle Disease International Registry

Torrance, CA

The Congenital Muscle Disease Patient and Proxy Reported Outcome Study (CMDPROS) is a longitudinal ten-year study to identify and trend care parameters, adverse events in the congenital muscle diseases using the Congenital Muscle Disease International Registry (CMDIR) to acquire necessary data for adverse event calculations (intake survey and medical records curation). To support this study and become a participant, we ask that you register in the CMDIR. You can do this by visiting www.cmdir.org. There is no travel required.

The registry includes affected individuals with congenital muscular dystrophy, congenital myopathy, and congenital myasthenic syndrome and registers through the late onset spectrum for these disease groups. The CMDIR was created to identify the global congenital muscle disease population to raise awareness, standards of care, clinical trials, and a treatment or cure in the future. Simply put, we will not be successful in finding a treatment or cure unless we know who the affected individuals are, what the diagnosis is, and how the disease is affecting the individual.

Registering in the CMDIR means that you will enter demographic information and complete an intake survey. We would then ask that you provide records regarding the diagnosis and treatment of CMD, including genetic testing, muscle biopsy, pulmonary function testing, sleep studies, clinic visit notes, and hospital discharge summaries.

Title: The Global FKRP Patient Registry

Stage: Recruiting

Principal investigator:  Gustavo Dziewczapolski, PhD

Congenital Muscle Disease International Registry

Torrance, CA

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 characterize better 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 (https://www.fkrp-registry.org/) 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.

The FKRP registry is funded by LGMD2i Research Fund and CureLGMD2I.

The primary objectives of the Global FKRP Registry are to:

Accelerate and facilitate clinical trials by locating potential research subjects quickly and efficiently

Facilitate in the planning of clinical trials

Assist the neuromuscular community with the development of recommendations and standards of care

Characterize and describe the FKRP population as a whole, enhancing the understanding of the prevalence throughout the world.

Title: Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

Stage: Recruiting

Principal investigator:  Wendy Chung, MD, PhD

CUMC/New York-Presbyterian Morgan Stanley Children’s Hospital

New York, NY

Simons Searchlight collects medical, behavioral, learning, and developmental information from people with gene changes linked to autism and other neurodevelopmental disorders. The goal of this study is to improve the clinical care and treatment for these people. Simons Searchlight partners with families to collect data and distribute it to qualified researchers.

Simons Searchlight has expanded over the last several years to include additional gene changes and participation through remote formats, either online or by phone. This allows English and Spanish-speaking families from across the world to participate at times that are convenient to their schedule. Participants can donate blood, saliva, or both. These samples are then linked to medical, behavioral, learning, and developmental data to understand the effects of specific gene changes.

 Information provided by participants will be stripped of any personal identifying information and made available to qualified scientists around the world.

The Simons Foundation, a New York-based private foundation, is committed to finding science-based solutions and developing targeted treatments to improve the lives of people who have genetic and developmental differences.