On this page
Megalencephalic leukoencephalopathy with subcortical cysts
MLC is characterised by an unusually large head (megalencephaly) and changes in the brain's white matter, including subcortical cysts. It typically presents in early childhood and can lead to progressive neurological symptoms.
Available at Jeen Health
Clinical tests that include this
Overview
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare genetic disorder affecting the central nervous system. It is characterised by macrocephaly, which means an abnormally large head circumference, usually noticeable from birth or early infancy [PMID:17918260]. The condition also involves abnormalities in the brain's white matter, which is crucial for communication between different brain regions, and the presence of fluid-filled sacs called subcortical cysts [PMID:24409321]. These features can lead to a range of neurological symptoms that typically become apparent during the first year of life.
Symptoms & clinical features
Individuals with MLC generally present with symptoms in early childhood, often before the age of two [PMID:17918260]. The most common early sign is an enlarged head, or megalencephaly. As the condition progresses, affected children may experience problems with movement, such as ataxia (lack of muscle coordination), spasticity (muscle stiffness), and dystonia (involuntary muscle contractions). These motor difficulties can affect walking and overall mobility. Additionally, some individuals may have mild intellectual disability or learning difficulties, and in some cases, epilepsy can occur. The severity and specific combination of symptoms can vary between individuals, even within the same family.
Video: Genetics 101
Affected organs
MLC primarily affects the brain. The main structural abnormalities are found in the white matter, which consists of nerve fibres coated in myelin that facilitate rapid transmission of signals. In MLC, the white matter is swollen and appears abnormal on brain imaging. Subcortical cysts, which are fluid-filled cavities, are also characteristic findings in certain areas of the brain, particularly in the temporal lobes and anterior frontal regions. While the brain is the primary organ affected, the neurological dysfunction can impact various bodily functions controlled by the brain, such as movement and coordination.
Risks & severity
MLC is a progressive condition, meaning that symptoms typically worsen over time, though the rate of progression can vary. The overall severity can range from relatively mild to more severe, with some individuals retaining the ability to walk independently into adulthood, while others experience significant motor impairment [PMID:24409321]. The exact prevalence of MLC is not well established, but it is considered a rare disorder. The neurological symptoms usually become apparent within the first year of life, with motor skill deterioration often observed during childhood. There is currently no cure for MLC, and management focuses on supporting individuals and addressing symptoms.
Genetic causes
MLC is a genetic condition caused by pathogenic variants in specific genes. The most common cause is variants in the MLC1 gene, which accounts for approximately 75-80% of cases. The MLC1 gene provides instructions for making the MLC1 protein, primarily found in brain astroglial cells. This protein is thought to play a role in maintaining the integrity of the blood-brain barrier, which protects the brain, and in regulating fluid balance and cell adhesion within the brain [PMID:24409321]. Pathogenic variants in MLC1 disrupt the normal function of this protein, leading to the characteristic brain abnormalities seen in MLC. More rarely, variants in the HEPACAM gene have also been identified as a cause of MLC, often leading to a slightly milder or later-onset form of the condition [PMID:17918260]. The HEPACAM gene produces a protein called hepatic and glial cell adhesion molecule, which is also important for cell-to-cell communication and adhesion in the brain.
- HEPACAM hepatic and glial cell adhesion molecule
- MLC1 modulator of VRAC current 1The MLC1 gene provides instructions for a protein primarily found in the brain, where it is thought to be involved in fluid balance and cell adhesion.
Inheritance pattern
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of a pathogenic variant - one from each parent - to develop the condition. Parents who carry one copy of the pathogenic variant are known as carriers; they typically do not show symptoms of MLC themselves. When both parents are carriers, there is a 25% chance with each pregnancy that their child will inherit two copies of the variant and be affected by MLC. There is also a 50% chance that the child will be a carrier like their parents, and a 25% chance that the child will inherit two normal copies of the gene and not be affected or a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of MLC is typically suspected based on clinical features, such as megalencephaly and progressive neurological symptoms, alongside characteristic findings on brain imaging, particularly magnetic resonance imaging (MRI). MRI scans often reveal widespread white matter abnormalities and subcortical cysts. The diagnosis is confirmed through genetic testing, which identifies pathogenic variants in the MLC1 or HEPACAM genes. In the UK, genetic testing for MLC is available through the NHS Genomic Medicine Service (GMS) and is typically requested by a clinical geneticist or a neurologist. Relevant NHS R-codes would be used for ordering the appropriate genomic tests following a referral to a clinical genetics service.
Management & lifestyle
Currently, there is no specific cure for MLC, and management focuses on supportive care to address symptoms and improve quality of life. This can involve a multidisciplinary team approach including neurologists, physiotherapists, occupational therapists, and speech and language therapists. Physical therapy and occupational therapy can help manage motor difficulties like spasticity and improve mobility. Medication may be prescribed to manage symptoms such as epilepsy or dystonia, if present. Regular monitoring by medical specialists is important to track disease progression and adjust management strategies as needed. Genetic counsellors can provide essential information and support to affected individuals and their families, discussing the genetic aspects of MLC and implications for family planning.
UK care pathway
In the UK, individuals suspected of having a rare genetic condition like MLC would typically be referred by their GP or another specialist to a regional Clinical Genetics service. Within this service, genetic counsellors and clinical geneticists guide patients through the diagnostic process, including genomic testing via the NHS Genomic Medicine Service (GMS). The GMS uses a national test directory (PanelApp R-codes) to ensure appropriate and consistent genetic testing. Following a confirmed diagnosis, individuals are generally supported by multidisciplinary teams within the NHS to manage their symptoms and access appropriate care.
Frequently asked questions
What is megalencephaly?
Megalencephaly refers to an abnormally large head circumference. In MLC, this is typically present from birth or early infancy and is an important early indicator of the condition.
Can MLC be inherited if only one parent is a carrier?
No, MLC follows an autosomal recessive inheritance pattern. This means a child must inherit a pathogenic gene variant from both parents to develop the condition. If only one parent is a carrier, their child will not be affected but may become a carrier themselves.
Is there a cure for MLC?
Currently, there is no specific cure for MLC. Treatment focuses on managing symptoms and providing supportive care to improve the individual's quality of life, using therapies like physiotherapy and occupational therapy.
How is MLC diagnosed?
MLC is suspected based on clinical symptoms and brain imaging (MRI) findings. The diagnosis is confirmed through genetic testing, which identifies specific pathogenic variants in the MLC1 or HEPACAM genes.
What is the prognosis for individuals with MLC?
MLC is a progressive condition, with symptoms typically worsening over time. The rate of progression and severity can vary widely among individuals, but generally, individuals experience motor difficulties and may have mild intellectual disability.
References
- Passchier EMJ, Bisseling Q, Helman G. Megalencephalic leukoencephalopathy with subcortical cysts: a variant update and review of the literature. Frontiers in genetics. 2024. PMID: 38487253
- Singhal BS, Gorospe JR, Naidu S. Megalencephalic leukoencephalopathy with subcortical cysts. Journal of child neurology. 2003. PMID: 14572144
- Estévez R, Elorza-Vidal X, Gaitán-Peñas H. Megalencephalic leukoencephalopathy with subcortical cysts: A personal biochemical retrospective. European journal of medical genetics. 2018. PMID: 29079544
- Ashrafi MR, Amanat M, Garshasbi M. An update on clinical, pathological, diagnostic, and therapeutic perspectives of childhood leukodystrophies. Expert review of neurotherapeutics. 2020. PMID: 31829048
- Adam MP, Bick S, Mirzaa GM. Megalencephalic Leukoencephalopathy with Subcortical Cysts. 1993. PMID: 20301707
- Pla-Casillanis A, Ferigle L, Alonso-Gardón M. GPR37 Receptors and Megalencephalic Leukoencephalopathy with Subcortical Cysts. International journal of molecular sciences. 2022. PMID: 35628339
- Perlman SJ, Mar S. Leukodystrophies. Advances in experimental medicine and biology. 2012. PMID: 22411242
- Blattner R, Von Moers A, Leegwater PA. Clinical and genetic heterogeneity in megalencephalic leukoencephalopathy with subcortical cysts (MLC). Neuropediatrics. 2003. PMID: 12973664