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Megalencephalic leukoencephalopathy with subcortical cysts 1(MLC1)

MedGen UID:
1826136
Concept ID:
C5779875
Disease or Syndrome
Synonyms: Leukoencephalopathy with swelling and cysts; Megalencephaly-cystic leukodystrophy; MLC1; MLC1-Related Megalencephalic Leukoencephalopathy with Subcortical Cysts; Vacuolating megalencephalic leukoencephalopathy with subcortical cysts
 
Genes (locations): HEPACAM (11q24.2); MLC1 (22q13.33)
 
Monarch Initiative: MONDO:0024555
OMIM®: 604004

Disease characteristics

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterized by two phenotypes: classic MLC and improving MLC. Individuals with classic MLC present with macrocephaly, often in association with seizures, gradual onset of ataxia, spasticity, and sometimes extrapyramidal findings, mild gross motor developmental delays, and late-onset cognitive deterioration. Macrocephaly, observed in most affected individuals, may be present at birth but more frequently develops during the first year of life. The degree of macrocephaly is variable, with head circumferences reaching four to six standard deviations greater than the mean. After the first year of life, head growth trajectory typically normalizes and growth follows a line parallel to, although several standard deviations above, the 98th centile. Initial mental and motor development is normal in most individuals. Walking is often unstable, followed by ataxia of the trunk and extremities, pyramidal dysfunction, and brisk deep tendon reflexes. Early-onset seizures are common, and approximately 60% of individuals have epilepsy that is typically well controlled with anti-seizure medication, but status epilepticus occurs relatively frequently. Cognitive deterioration occurs later in the course of the disease and is usually mild in severity. Overall disease severity varies, with some individuals being able to ambulate independently for only a few years from disease onset to other individuals continuing to independently walk in the fifth decade of life. Individuals with improving MLC have a similar initial presentation with delayed cognitive or motor development, followed by an improving clinical course: macrocephaly usually persists, but some children become normocephalic; motor function improves or normalizes; hypotonia and clumsiness may persist in some or neurologic examination may become normal. Some individuals have intellectual disability that is stable, with or without autism spectrum disorder. Epilepsy is much less frequent than in classic MLC. [from GeneReviews]
Authors:
Rogier Min  |  Truus EM Abbink  |  Marjo S van der Knaap   view full author information

Additional description

From MedlinePlus Genetics
There are three types of megalencephalic leukoencephalopathy with subcortical cysts, which are distinguished by their signs and symptoms and genetic cause. Types 1 and 2A have different genetic causes but are nearly identical in signs and symptoms. Types 2A and 2B have the same genetic cause but the signs and symptoms of type 2B often begin to improve after one year. After improvement, individuals with type 2B usually have macrocephaly and may have intellectual disability.

The brain abnormalities in people with megalencephalic leukoencephalopathy with subcortical cysts affect the use of muscles and lead to movement problems. Affected individuals typically experience muscle stiffness (spasticity) and difficulty coordinating movements (ataxia). Walking ability varies greatly among those affected. Some people lose the ability to walk early in life and need wheelchair assistance, while others are able to walk unassisted well into adulthood. Minor head trauma can further impair movements and may lead to coma. Affected individuals may also develop uncontrolled muscle tensing (dystonia), involuntary writhing movements of the limbs (athetosis), difficulty swallowing (dysphagia), and impaired speech (dysarthria). More than half of all people with this condition have recurrent seizures (epilepsy). Despite the widespread brain abnormalities, people with this condition typically have only mild to moderate intellectual disability.

Megalencephalic leukoencephalopathy with subcortical cysts is a progressive condition that affects brain development and function. Individuals with this condition typically have an enlarged brain (megalencephaly) that is evident at birth or within the first year of life. Megalencephaly leads to an increase in the size of the head (macrocephaly). Affected people also have leukoencephalopathy, an abnormality of the brain's white matter. White matter consists of nerve fibers covered by a fatty substance called myelin. Myelin insulates nerve cells (neurons) and promotes the rapid transmission of nerve impulses. In megalencephalic leukoencephalopathy with subcortical cysts, the myelin is swollen and contains numerous fluid-filled pockets (vacuoles). Over time, the swelling decreases and the myelin begins to waste away (atrophy). Individuals affected with this condition may develop cysts in the brain; because these cysts form below an area of the brain called the cerebral cortex, they are called subcortical cysts. These cysts can grow in size and number.  https://medlineplus.gov/genetics/condition/megalencephalic-leukoencephalopathy-with-subcortical-cysts

Clinical features

From HPO
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Megalencephaly
MedGen UID:
65141
Concept ID:
C0221355
Congenital Abnormality
Diffuse enlargement of the entire cerebral hemispheres leading to macrocephaly (with or without overlying cortical dysplasia).
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Diffuse swelling of cerebral white matter
MedGen UID:
347007
Concept ID:
C1858855
Finding
Diffuse spongiform leukoencephalopathy
MedGen UID:
347735
Concept ID:
C1858857
Finding
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.

Professional guidelines

PubMed

DiBardino DM, Saqi A, Elvin JA, Greenbowe J, Suh JH, Miller VA, Ali SM, Stoopler M, Bulman WA
Clin Lung Cancer 2016 Nov;17(6):517-522.e3. Epub 2016 Jun 8 doi: 10.1016/j.cllc.2016.05.017. PMID: 27378171

Recent clinical studies

Etiology

DiBardino DM, Saqi A, Elvin JA, Greenbowe J, Suh JH, Miller VA, Ali SM, Stoopler M, Bulman WA
Clin Lung Cancer 2016 Nov;17(6):517-522.e3. Epub 2016 Jun 8 doi: 10.1016/j.cllc.2016.05.017. PMID: 27378171

Diagnosis

Simon MJ, Wang MX, Murchison CF, Roese NE, Boespflug EL, Woltjer RL, Iliff JJ
Sci Rep 2018 Aug 17;8(1):12389. doi: 10.1038/s41598-018-30779-x. PMID: 30120299Free PMC Article
DiBardino DM, Saqi A, Elvin JA, Greenbowe J, Suh JH, Miller VA, Ali SM, Stoopler M, Bulman WA
Clin Lung Cancer 2016 Nov;17(6):517-522.e3. Epub 2016 Jun 8 doi: 10.1016/j.cllc.2016.05.017. PMID: 27378171

Prognosis

DiBardino DM, Saqi A, Elvin JA, Greenbowe J, Suh JH, Miller VA, Ali SM, Stoopler M, Bulman WA
Clin Lung Cancer 2016 Nov;17(6):517-522.e3. Epub 2016 Jun 8 doi: 10.1016/j.cllc.2016.05.017. PMID: 27378171

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