Last updated:
5/8/2026
Years published: 2026
NORD gratefully acknowledges the following for the preparation of this report:
Molly Heck, M.S., Angelica Raney, M.S., and Jason Simmons, M.S.; Stanford’s Master’s Program in Human Genetics and Genetic Counseling, as well as Hetanshi Naik, PhD, MS, CGC, Associate Professor, Department of Genetics, Stanford University, and review by Rogier Min, PhD, Assistant Professor, Pediatric Neurology, Amsterdam University Medical Center and Marjo van der Knaap, PhD, Professor, Pediatric Neurology, Amsterdam University Medical Center.
Megalencephalic Leukoencephalopathy with Subcortical Cysts (MLC) is a rare genetic brain disease. It is classified as a leukodystrophy, as it mainly affects the brain white matter. The white matter consists of bundles of nerve fibers, wrapped by an insulating layer called myelin. It acts as the brain’s communication network, allowing different brain regions to send signals to each other and to the rest of the body.
MLC patients develop an abnormally large head (macrocephaly) in the first year of life. The diagnosis of the disease is based on the characteristic appearance of the brain on an MRI scan, which reveals pronounced swelling of the white matter. In addition, fluid-filled cysts located just beneath the brain’s cortex at the surface (subcortical cysts) can often be observed. When examined under a microscope, the white matter shows many small vacuoles (fluid-filled spaces) in the myelin that surrounds nerve fibers.1-4
Early learning and motor skills are often normal or slightly delayed. But during development problems with balance and coordination (ataxia) and stiff muscles (spasticity) often develop.3 By adolescence, many patients require a wheelchair for mobility. In addition, many MLC patients experience seizures, often leading to a diagnosis of epilepsy. Seizures are mostly well controlled with medication, although severe seizures can occur, particularly after events such as mild head injury. Mild intellectual disability and/or autism may present, even in the presence of normal or near normal intellectual development in childhood. Overall, thinking and learning abilities are often only mildly affected.4 Because MLC is rare, information on long-term outcomes and life expectancy is limited.3 While some individuals have died in their teens or twenties, sometimes following a severe epileptic seizure, others are alive in their fifties.
There are different types of MLC. In the classic type, which is most common, symptoms slowly get worse over time. In another type, called remitting MLC, children may show early symptoms such as a large head and delayed development. The typical motor and cognitive decline does not occur. Some patients are normal or close to normal as adults, while others have significant cognitive impairment, autism and/or behavioral problems. Head size often remains large, but in some children it becomes closer to average.4
MLC is caused by changes in genes that help keep the brain’s white matter healthy. Most known cases are caused by differences in the MLC1 or GLIALCAM genes, but differences in other genes have also been reported. The disease is inherited, or passed down in families, in different ways depending on the altered gene.4, 5
The effects of MLC can vary widely from person to person. Some individuals are able to walk and live independently well into adulthood, while others need more support. Treatment focuses on managing symptoms, such as seizures and movement difficulties, and on supporting mobility and daily functioning.4
MLC was first described in 1995 by Professor Marjo van der Knaap and independently in 1996 by Prof. Singhal in India.1, 2
People with MLC can have an assortment of signs and symptoms, so no two patients will look exactly alike. There are even cases of siblings with the same genetic cause of MLC that do not have the same symptoms.6 MLC can be subdivided into different types based on genetics, with a broad division into classic and remitting (discussed more in the next section).4 The term remitting (sometimes referred to as ‘improving’) refers mainly to the changes seen on brain MRI over time, where the white matter abnormalities partially or completely resolve. In general, individuals with remitting MLC have no motor symptoms and display no decline, and are therefore better off than those with classic MLC, but the cognitive deficit and behavioral issues can be significant. Only two patients have been reported with the MLC Type 4 subtype, and these have severe cognitive deficit and epilepsy.
Classic MLC
Remitting MLC
MLC is caused by disease causing changes (variants) in one of the following genes: GLIALCAM (also known as HEPACAM), GPRC5B, AQP4, and MLC1.4 Genes provide instructions for creating proteins that play a critical role in many functions of the body. When gene variants occur, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain and spinal cord.3 There are multiple types of MLC, which are distinguished from each other based on their symptoms and genetic causes.
Depending on the gene affected, MLC can follow autosomal recessive or dominant inheritance.4
Recessive genetic disorders occur when a person inherits a disease-causing gene variant from each parent. If a person receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) variant in the affected person that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. The autosomal dominant forms of MLC are frequently de novo.
Classic MLC
While the three types of classic MLC have different genetic causes, there are no differences in their clinical presentation. The MLC1, GLIALCAM, and GPRC5B genes have roles in creating proteins found primarily in the brain, in particular in supportive brain cells called astrocytes. While the function of these proteins is not fully understood, they have been found to play a part in regulating the flow of fluid in the brain. When one of these proteins is not working properly, it can lead to fluid build-up in the brain because the protein is not able to effectively help the fluid flow.3
Remitting MLC
It is important to note that the disease-causing changes in the GLIALCAM gene that underline classic MLC in MLC2A are different from the disease-causing variants in the GLIALCAM gene that cause remitting MLC in MLC2B. They affect a different part of the gene and therefore alter the GLIALCAM protein product (called GlialCAM protein) in a different way. The AQP4 gene is responsible for creating a molecular water channel called Aquaporin-4, which is primarily found in astrocytes in the brain and which, like the other MLC proteins, plays a crucial role in regulating fluid flow in the brain.
MLC is an extremely rare condition, and the exact frequency of the disease is unknown. There have been over 500 cases of MLC reported in the literature.4, 9 Founder variants are specific differences (variants) in a gene that appear at a higher frequency in certain populations. There have been founder variants in the MLC1 gene identified in individuals from East India, Libya, Türkiye, Korea, and Egypt.4
A diagnosis of classic MLC can either be made through clinical diagnosis (of specific symptoms and MRI findings) or through genetic testing. The clinical diagnosis for classic MLC occurs when patients have suggestive clinical findings (macrocephaly/large head) as well as abnormalities found on brain MRI (swollen white matter and subcortical cysts). The diagnosis can also be made or supported when genetic testing identifies variants causing both copies of the MLC1 or GLIALCAM genes to lose function, or a variant in the GPRC5B gene causing a single copy of this gene to not function properly.4
A diagnosis of remitting MLC can be made when there is a combination of suggestive clinical features and genetic testing results. In these cases a diagnosis is made when genetic testing shows a variant in the GLIALCAM gene causing a single copy of this gene to develop a new, toxic function (gain-of-function variant, meaning that the altered protein actively interferes with normal cellular processes rather than simply losing its usual function), or variants causing both copies of the AQP4 gene to lose function.4
Providers may choose to order a targeted gene panel, which would look specifically at the genes associated with MLC (GLIALCAM, GPRC5B, AQP4, and MLC1). This approach would be taken if providers are more confident that the symptoms and MRI findings are indicative of MLC rather than a different condition with overlapping characteristics. Providers may instead choose to order a larger genetic test such as exome or genome sequencing. These tests effectively look at all genes in a patient and report if there are any differences that may be related to the patient’s presentation. These broader tests may be ordered if the provider is considering multiple diagnoses (not just MLC) based on the patient’s symptoms and MRI results.
There is currently no cure or specific guidelines for the treatment of MLC. Treatment and management are directed at improving the symptoms that the affected person has and to improve their quality of life.14 This management can include physical therapy, speech therapy, special education, and prescribed anti-seizure medication. It is noted that patients with MLC should avoid contact sports and other activities that could result in head trauma, as these incidents can lead to degradation usually presenting as seizures or prolonged unconsciousness.4
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/.15 All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
http://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
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