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Disease Profile

Megalencephalic leukoencephalopathy with subcortical cysts

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

Age of onset

Infancy

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ICD-10

E75.2

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

MLC; Vacuolating megalencephalic leukoencephalopathy with subcortical cysts; LVM;

Categories

Congenital and Genetic Diseases; Nervous System Diseases

Summary

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a condition that affects brain development and function. Individuals with this condition have an enlarged brain (megalencephaly) and an abnormality of the white matter in the brain (leukoencephalopathy). White matter consists of nerve fibers covered by a fatty substance called myelin that promotes the rapid transmission of nerve impulses. In MLC, the myelin is swollen and contains numerous fluid-filled pockets (vacuoles). Over time, the swelling decreases and the myelin begins to waste away (atrophy).[1]

Leukoencephalopathy can lead to abnormal muscle tensing (spasticity), difficulty coordinating movements (ataxia), cysts in the brain (subcortical cysts), abnormal muscle tone (dystonia), swallowing difficulties, mild to moderate intellectual disabilities, speech difficulties, seizures, and difficulties walking.[1][2] There are three types of MLC, which are distinguished by their signs and symptoms and genetic cause. Type 1 is caused by mutations in the MLC1 gene. Types 2A and 2B are caused by mutations in the HEPACAM gene. MLC types 1 and 2A are inherited in an autosomal recessive manner, while type 2B is inherited in an autosomal dominant manner. In approximately 5% of individuals with MLC, the cause is unknown.[1][3] 

Although there is no specific treatment or cure for MLC, there are ways to manage the symptoms, such as use of antiepileptic drugs, physical therapy, and speech therapy. Management additionally includes avoiding injury to the head, which can temporarily worsen symptoms. A team of doctors or specialists is often needed to figure out the treatment options for each person.[3]

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
Percent of people who have these symptoms is not available through HPO
Ataxia
0001251
Autosomal recessive inheritance
0000007
Diffuse spongiform leukoencephalopathy
0006943
Diffuse swelling of cerebral white matter
0007341
Infantile onset
Onset in first year of life
Onset in infancy

[ more ]

0003593
Intellectual disability, mild
Mental retardation, borderline-mild
Mild and nonprogressive mental retardation
Mild mental retardation

[ more ]

0001256
Macrocephaly
Increased size of skull
Large head
Large head circumference

[ more ]

0000256
Megalencephaly
0001355
Motor delay
0001270
Seizure
0001250
Spasticity
Involuntary muscle stiffness, contraction, or spasm
0001257

Cause

The majority of individuals with MLC have mutations in the MLC1 gene. Mutations within this gene account for approximately 75% of all cases. The MLC1 gene provides instructions for making a protein found primarily in astroglial cells in the brain. Astroglial cells are a specialized type of glial cell, which are cells that protect and maintain nerve cells. The role of the MLC1 protein is not fully understood; however, it is suspected to be involved in the control of fluids into cells or the strength of cells' attachment to one another. 

Approximately 20% of individuals with MLC have mutations in the HEPACAM gene. The HEPACAM gene provides instructions for making a protein called GlialCAM, which primarily functions in the brain, particularly in glial cells. GlialCAM attaches to other GlialCAM proteins or to the MLC1 protein and guides them to the space between cells (cell junctions). The function of GlialCAM at the cell junction is unclear.

About 5% of individuals with MLC do not have identifiable mutations in either the MLC1 or HEPACAM gene. In these individuals, the cause of MLC is not known.[1]

Diagnosis

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.
  • Orphanet lists international laboratories offering diagnostic testing for this condition.

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Supporting this Disease

      Organizations Providing General Support

        Learn more

        These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

        Where to Start

        • The Cleveland Clinic has developed an information page on megalencephaly. Click on the link above to view this information page
        • Medline provides a list of resources on leukodystrophies. MedlinePlus is a Web site designed by the National Library of Medicine to help you research your health questions.
        • Genetics Home Reference (GHR) contains information on Megalencephalic leukoencephalopathy with subcortical cysts. This website is maintained by the National Library of Medicine.
        • The National Institute of Neurological Disorders and Stroke (NINDS) provides more information on megalencephaly. NINDS collects and disseminates research information related to neurological disorders.
        • The United Leukodystrophy Foundation has developed an information page on Megalencephalic leukoencephalopathy with subcortical cysts. Click on the link above to view this information page.

          In-Depth Information

          • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
          • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
          • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
          • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
          • PubMed is a searchable database of medical literature and lists journal articles that discuss Megalencephalic leukoencephalopathy with subcortical cysts. Click on the link to view a sample search on this topic.

            References

            1. Megalencephalic leukoencephalopathy with subcortical cysts. Genetics Home Reference. March 2015; https://ghr.nlm.nih.gov/condition/megalencephalic-leukoencephalopathy-with-subcortical-cysts#synonyms.
            2. Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC). United Leukodystrophy Foundation. https://ulf.org/megalencephalic-leukoencephalopathy-with-subcortical-cysts-mlc-2. Accessed 9/7/2016.
            3. van der Knaap, Marjo, Scheper C, Gert. Megalencephalic Leukoencephalopathy with Subcortical Cysts. GeneReveiws. November 3, 2011; https://www.ncbi.nlm.nih.gov/books/NBK1535/.

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