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Megalencephalic Leukoencephalopathy with Subcortical Cysts

Synonym: Van der Knaap Disease

, MD, PhD, , PhD, and , PhD.

Author Information

Initial Posting: ; Last Update: March 29, 2018.

Summary

Clinical characteristics.

The classic phenotype of megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterized by early-onset macrocephaly, often in combination with mild gross motor developmental delay and seizures; gradual onset of ataxia, spasticity, and sometimes extrapyramidal findings; and usually late onset of mild mental deterioration. Macrocephaly, observed in virtually all individuals, may be present at birth but more frequently develops during the first year of life. The degree of macrocephaly is variable and can be as great as 4 to 6 SD above the mean in some individuals. After the first year of life, head growth rate normalizes and growth follows a line parallel to and usually several centimeters 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, then minor signs of pyramidal dysfunction and brisk deep-tendon stretch reflexes. Almost all individuals have epilepsy from an early age. The epilepsy is typically well controlled with medication, but status epilepticus occurs relatively frequently. Mental deterioration is late and mild. Disease severity ranges from independent walking for a few years only to independent walking in the fifth decade. Some individuals have died in their teens or twenties; others are alive in their fifties.

An improving phenotype has a similar initial presentation with delayed mental 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 have intellectual disability that is stable, with or without autism. Epilepsy and status epilepticus may occur.

Diagnosis/testing.

The diagnosis of MLC is established in individuals with typical clinical findings and characteristic abnormalities identified on brain MRI examination, including abnormal and swollen cerebral hemispheric white matter and presence of subcortical cysts in the anterior temporal region and often in the frontoparietal region. Identification of biallelic pathogenic variants in MLC1 or HEPACAM by molecular genetic testing can confirm the diagnosis of classic MLC (MLC1 or MLC2A, respectively) – particularly important if clinical features are inconclusive – and allow for family studies. Identification of a heterozygous HEPACAM pathogenic variant can confirm the diagnosis of MLC with improving phenotype (MLC2B) if clinical features are inconclusive, and/or allow for family studies.

Management.

Treatment of manifestations: Physical therapy to improve motor function; speech therapy as needed; special education; antiepileptic drugs to control epileptic seizures.

Prevention of secondary complications: A helmet should be considered for situations involving increased risk of head trauma.

Agents/circumstances to avoid: Contact sports and other activities with a high risk of head trauma should be avoided.

Genetic counseling.

MLC1 and MLC2A are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if both pathogenic alleles have been identified in the family.

MLC2B is inherited in an autosomal dominant manner. De novo pathogenic variants are common. Each child of an individual with MLC2B has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant has been identified in an affected family member.

Diagnosis

Suggestive Findings

Two phenotypes are observed in megalencephalic leukoencephalopathy with subcortical cysts (MLC).

MLC classic phenotype should be suspected in individuals with the following clinical and radiographic features:

  • Macrocephaly (onset in the first year of life or congenital)
  • Early development normal or mildly delayed
  • Slow deterioration of motor functions with cerebellar ataxia and mild spasticity
  • Dysarthria
  • Mental decline (occurs later and is much milder than motor decline)
  • Seizures
  • Behavioral problems in some individuals
  • Temporary exacerbation of signs and symptoms after minor head trauma
  • On brain MRI (see Figure 1):
    • Cerebral hemispheric white matter is diffusely abnormal and mildly swollen.
    • Central white matter structures, including the corpus callosum, internal capsule, and brain stem, are better preserved than other structures, although they are not usually entirely normal.
    • Cerebellar white matter usually has a mildly abnormal signal and is not swollen.
    • Subcortical cysts are almost invariably present in the anterior temporal region and often in the frontoparietal region.
    • Over time, the white matter swelling decreases and cerebral atrophy ensues. The subcortical cysts may increase in size and number. In some individuals, the cysts become huge, occupying a large part of the frontoparietal white matter. In others, the cerebral white matter abnormalities decrease over time, and the signal intensity of the cerebral white matter becomes less abnormal.
    • Diffusion-weighted imaging reveals increased diffusivity of abnormal white matter [Itoh et al 2006, van der Voorn et al 2006].
Figure 1.

Figure 1.

Brain images of an individual with MLC (A, C) and an unaffected individual (B, D)

MLC improving phenotype should be suspected in individuals with the following clinical features:

  • Macrocephaly (onset in the first year of life or congenital macrocephaly)
  • Early development normal or mildly delayed
  • Motor function improves after the first year of life (clumsiness and hypotonia may persist)
  • Seizures in some individuals
  • Intellectual disability (with or without autism) or normal cognitive function
  • No regression of mental or motor functions
  • Macrocephaly that may persist or may turn into normocephaly
  • On brain MRI:
    • Findings within the first year of life are similar to those seen in the classic phenotype, but cerebellar white matter is usually normal in signal.
    • Striking improvement occurs over time. The MRI may appear normal within a few years, or minor frontal and temporal subcortical white matter abnormalities and anterior temporal cysts may remain.

Establishing the Diagnosis

The diagnosis of MLC is established in a proband with the above Suggestive Findings. The characteristic abnormalities on brain MRI examination described in Suggestive Findings are diagnostic.

Identification of biallelic pathogenic variants in MLC1 or HEPACAM by molecular genetic testing (see Table 1) can confirm the diagnosis of classic MLC (MLC1 or MLC2A, respectively) if clinical features are inconclusive, and/or allow for family studies if the diagnosis has been established based on clinical and characteristic radiographic features.

Identification of a heterozygous HEPACAM pathogenic variant can confirm the diagnosis of MLC with improving phenotype (MLC2B) if clinical features are inconclusive, and/or allow for family studies if the diagnosis has been established based on clinical and characteristic radiographic features.

Molecular genetic testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Serial single-gene testing

A multigene panel that includes HEPACAM, MLC1, and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Megalencephalic Leukoencephalopathy with Subcortical Cysts

Gene 1, 2Proportion of MLC Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 3 Detectable by This Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
HEPACAM22% 6100%Unknown 7
MLC176%97%3% 8
Unknown 9~2%NA
1.

Genes are listed alphabetically.

2.
3.

See Molecular Genetics for information on allelic variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.
7.

No data on detection rate of gene-targeted deletion/duplication analysis are available. See Molecular Genetics, MLC1.

8.
9.

In some individuals with clinical features of MLC, pathogenic variants in HEPACAM or MLC1 have not been identified [Author, personal observation].

Neuropathologic examination. Brain biopsy shows the presence of numerous vacuoles between the outer lamellae of myelin sheaths, suggesting splitting of these lamellae along the intraperiod line or incomplete compaction [van der Knaap et al 1996]. In addition, small vacuoles are observed in astrocytic endfeet [Duarri et al 2011].

Clinical Characteristics

Clinical Description

The two phenotypes observed in individuals with megalencephalic leukoencephalopathy with subcortical cysts (MLC) include the classic phenotype and the improving phenotype. When associated with biallelic MLC1 pathogenic variants, the classic phenotype is known as MLC1; when caused by biallelic HEPACAM pathogenic variants, MLC is known as MLC2A. The improving phenotype associated with heterozygous HEPACAM pathogenic variants is known as MLC2B.

Classic Phenotype (MLC1 and MLC2A)

Macrocephaly. To date, macrocephaly has been observed in almost all individuals with MLC. Macrocephaly can be present at birth but more frequently develops during the first year of life. The degree of macrocephaly is variable; it may be as great as 4 to 6 SD above the mean in some affected individuals. After the first year of life, head growth rate normalizes and growth follows a line above and parallel to the 98th centile.

Motor development. Prior to age one year motor development is normal in most infants and mildly delayed in some. Apart from progressive macrocephaly, the first clinical sign is usually a delay in walking. Walking is often unstable, and the child falls frequently. However, most children achieve independent walking. Muscle tone tends to be low, apart from some ankle hypertonia.

After an interval of several years, slow deterioration of motor function occurs over years with development of ataxia of the trunk and extremities. Signs of pyramidal dysfunction are late and minor and are dominated by the signs of cerebellar ataxia. Speech becomes increasingly dysarthric and dysphagia may develop. Deep-tendon stretch reflexes become brisk and Babinski signs become apparent. Some individuals display extrapyramidal movement abnormalities with dystonia and athetosis. Some individuals develop tics [Sugiura et al 2006].

Gradually, the ability to walk independently is lost; many children become completely wheelchair dependent at the end of the first decade or in the second decade of life. Some children have a more severe clinical course and maintain their ability to walk independently for only a few years, or never achieve independent walking. Others maintain the ability to walk independently into the fifth decade.

Cognitive development. Initial cognitive development is normal in most children and mildly delayed in some. Intellectual deterioration is late and mild. Decreasing school performance becomes evident during the later years of primary school. In a minority of children, intellectual capacities are mildly decreased in the early years. Some children develop behavior problems [Sugiura et al 2006].

Seizures. Approximately 75% of individuals with classic MLC experience at least one seizure before age 20 years [Dubey et al 2018; EMC Hamilton, personal communication]. Seizure onset is typically early, within a few years after birth [EMC Hamilton, personal communication]. Although the epilepsy is most often easily controlled with medication, 15%-20% of individuals experience one or more episodes of status epilepticus, the first of which typically occurs within a few years after seizure onset [Dubey et al 2018]. Seizures and status epilepticus are frequently precipitated by minor head trauma.

Minor head trauma may induce temporary deterioration in some individuals, most often observed as seizures or status epilepticus, prolonged unconsciousness, or acute motor deterioration with gradual improvement [Bugiani et al 2003, Dubey et al 2018].

Prognosis. Some children have a more benign clinical course and, even as teenagers, have macrocephaly only. Individuals who are ambulatory with or without support at age 15 years are most likely to remain ambulatory [EMC Hamilton, personal communication]. Because the disease has been known for a relatively short time, information regarding average life span is very limited. Some individuals have died in their teens or twenties; others are alive in their fifties.

Improving Phenotype (MLC2B)

In children diagnosed with MLC2B the initial disease course is the same as that in children with the classic phenotype: mental and motor development is normal in most and mildly delayed in some.

Macrocephaly is present at birth or (more commonly) develops within the first year of life in 90% of individuals. In individuals with the improving phenotype, head circumference is initially equally large. After the first year of life, growth of the head usually either decreases or follows a line above and parallel to the 98th centile. In 40%-50% of affected children, the head circumference normalizes [EMC Hamilton, personal communication].

Motor development. Apart from progressive macrocephaly, the first clinical sign is usually delay in walking. Walking is often unstable, and the child falls frequently. All children achieve independent walking. After the second or third year of life, motor function improves or normalizes in most. Neurologic examination may become normal, but some children have persistent hypotonia and clumsiness. Regression does not occur.

Cognitive function is normal in approximately 75% of individuals; 25% have mild intellectual disability [EMC Hamilton, personal communication]. Autism is observed in 25% of individuals. Regression has not been observed.

Seizures. Epilepsy and status epilepticus may occur, but 90% of individuals have no history of seizures [EMC Hamilton, personal communication].

Prognosis. Because the disease has been known for a relatively short time, information regarding average life span is very limited. Considering the normal health of parents heterozygous for a dominant HEPACAM pathogenic variant, it does not appear that MLC2B-related HEPACAM pathogenic variants shorten life span; however, no formal study has addressed this issue. One child died in status epilepticus at age three years [EMC Hamilton, personal communication].

In families with affected individuals from more than one generation, the proband is usually a child and the affected parent is subsequently diagnosed. Parents with the pathogenic variant often have macrocephaly but normal motor and cognitive function. Some parents have cognitive or behavioral problems or motor clumsiness.

Phenotype Correlations by Gene

Classic MLC. A review of 17 individuals with MLC2A (biallelic HEPACAM pathogenic variants) revealed no phenotypic differences from individuals with MLC1 who have identifiable biallelic pathogenic variants in MLC1 [Hamilton et al, unpublished].

Genotype-Phenotype Correlations

MLC1. A review of 187 individuals with biallelic MLC1 pathogenic variants revealed that in individuals from the same family, disease severity and clinical course can vary significantly [EMC Hamilton, personal communication]. There is no known genotype-phenotype correlation.

HEPACAM. All known MLC-related HEPACAM pathogenic variants affect the extracellular part of the protein and not its transmembrane and intracellular part, independent of whether they have dominant or recessive effects [López-Hernández et al 2011]. Recessive HEPACAM pathogenic variants are spread over the entire extracellular region of the protein; dominant pathogenic variants are clustered in the first immunoglobulin domain [López-Hernández et al 2011]. Dominant and recessive pathogenic variants do not overlap, although they may affect the same residue [López-Hernández et al 2011]. At present, it is unclear why some HEPACAM pathogenic variants have recessive inheritance and others dominant inheritance.

Penetrance

MLC2B. The penetrance of dominant HEPACAM pathogenic variants is reduced. The proportion of individuals with a pathogenic HEPACAM variant who exhibit or have exhibited clinical manifestations of MLC2B is not known. There is no evidence of a difference in penetrance based on sex.

Nomenclature

Names previously used for MLC:

  • Leukoencephalopathy with swelling and a discrepantly mild course
  • Leukoencephalopathy with swelling and cysts
  • Infantile leukoencephalopathy and megalencephaly
  • Vacuolating leukoencephalopathy

Prevalence

Megalencephalic leukoencephalopathy with subcortical cysts is a rare disorder with a low carrier rate in the general population. Consequently, the disease is rarer in communities with a low rate of consanguinity and higher in communities with a high rate of consanguinity (e.g., see Topçu et al [1998]). The parents of many individuals with classic megalencephalic leukoencephalopathy with subcortical cysts are consanguineous.

Differential Diagnosis

The differential diagnosis of macrocephaly and a diffuse leukoencephalopathy is limited; it includes Canavan disease, Alexander disease, infantile-onset GM2 gangliosidosis, and, on occasion, infantile-onset GM1 gangliosidosis and L-2-hydroxyglutaric aciduria. Some children with congenital muscular dystrophy caused by laminin alpha-2 (merosin) deficiency (also known as MDC1A) have macrocephaly. The clinical features and course of these disorders are usually different from those of MLC. If the head circumference is well within the normal limits at age one year, it is highly unlikely that the infant has MLC. None of these disorders shares all the MRI characteristics of megalencephalic leukoencephalopathy with subcortical cysts (MLC).

Table 2.

Disorders to Consider in the Differential Diagnosis of MLC

DisorderGeneMOIClinical Features of This Disorder
Overlapping with MLCDistinguishing from MLC
Laminin alpha 2 deficiency (see Congenital Muscular Dystrophy)LAMA2ARSimilar cerebral WM disease w/swelling of the abnormal WM
  • Usually lacking the typical subcortical cysts seen in MLC
  • Prominent weakness & hypotonia (not seen in MLC)
Canavan diseaseASPAARSimilar cerebral WM disease w/swelling of the abnormal WM
  • In some cases: WM abnormalities limited to the directly subcortical WM
  • Typically on MRI: involvement of the thalamus & globus pallidus w/relative sparing of a bilateral crescent formed by the putamen & caudate nucleus (The globus pallidus & thalamus are not involved in MLC.)
  • Lacking the typical subcortical cysts seen in MLC
Alexander diseaseGFAPADSimilar WM disease w/swelling of the abnormal WM
  • Frontal predominance of MRI abnormalities (Predilection for the anterior parts of the brain is less clear in MLC.)
  • Mild signal abnormalities of basal ganglia & thalami (not seen in MLC)
  • Contrast enhancement of particular brain structures almost invariably seen (not seen in MLC)
  • Cysts usually located in deep frontal WM (different from MLC)
  • Typical involvement of brain stem structures (signal abnormalities, tumor-like structures, atrophy) (not seen in MLC)
L-2-hydroxyglutaric aciduria (OMIM 236792)L2HGDHARSimilar WM disease w/swelling of the abnormal WM
  • Cerebral WM abnormalities in some cases limited to the directly subcortical WM
  • Cerebral WM abnormalities multifocal in some cases (invariably diffuse in MLC)
  • Typicially on MRI: involvement of the basal nuclei (not seen in MLC)
  • Dentate nucleus typically prominently affected (not in MLC)

See OMIM Phenotypic Series: Leukoencephalopathy, megalencephalic to view genes associated with this phenotype in OMIM.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with megalencephalic leukoencephalopathy with subcortical cysts (MLC) the following evaluations are recommended if they have not already been completed:

  • Neurologic examination
  • Brain MRI examination
  • Physical therapy / occupational therapy assessment
  • Assessment of cognitive function (neuropsychological testing)
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Supportive therapy includes the following:

  • Physical therapy to improve motor function
  • Speech therapy as needed
  • Special education
  • Antiepileptic drugs if epileptic seizures are present

Prevention of Secondary Complications

If patients have epilepsy, treatment with antiepileptic drugs should be considered.

Minor head trauma may lead to temporary motor deterioration, seizures, or (rarely) coma. Wearing of a helmet should be considered for situations involving increased risk of head trauma.

Surveillance

There are no published guidelines for surveillance. Most affected individuals are reevaluated in neurology clinics annually to document disease progression and determine if other interventions are necessary. For some patients more frequent visits are needed to treat the epilepsy.

Initially, annual MRI may be considered to monitor disease development, while eventually one MRI every five years should suffice because of the slow disease course.

Agents/Circumstances to Avoid

Minor head trauma may lead to temporary motor deterioration, seizures, or (rarely) to coma. For this reason, contact sports and other activities with a high risk of head trauma should be avoided.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Potential teratogenic effects of antiepileptic drugs should be discussed with affected women of childbearing age, ideally prior to conception.

See MotherToBaby for more information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Unsuccessful therapies have included diuretics, acetazolamide, and creatine monohydrate.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The classic phenotype of megalencephalic leukoencephalopathy with subcortical cysts (MLC) caused by biallelic pathogenic variants in MLC1 (known as MLC1) or by biallelic pathogenic variants HEPACAM (known as MLC2A) is inherited in an autosomal recessive manner.

The improving phenotype of MLC caused by heterozygous pathogenic variants in HEPACAM (known as MLC2B) is inherited in an autosomal dominant manner.

Note: HEPACAM pathogenic variants associated with dominant inheritance do not overlap with HEPACAM pathogenic variants associated with recessive inheritance (see Phenotype Correlations by Gene).

Risk to Family Members – Autosomal Recessive Inheritance (MLC1 and MLC2A)

Parents of a proband

Sibs of a proband

  • If both parents are carriers, at conception, each sib of an individual with MLC1 or MLC2A has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Intrafamilial variability has been observed in MLC1.
  • If only one parent is a carrier for an MLC1- or MLC2A-related pathogenic variant, at conception, each sib has a 50% chance of being an asymptomatic carrier and a 50% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. No clinical or MRI abnormalities have been found in individuals heterozygous for an MLC1- or MLC2A-related pathogenic variant.

Offspring of a proband. The offspring of an affected individual are obligate heterozygotes (carriers) for a pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the MLC1- or MLC2A-related pathogenic variants in the family.

Risk to Family Members – Autosomal Dominant Inheritance (MLC2B)

Parents of a proband

  • Many individuals with MLC2B have a parent with macrocephaly. Given the neurologic improvement that is observed in this phenotype, the parent is not at risk of neurologic regression. Whether having a heterozygous HEPACAM pathogenic variant leads to other symptoms late in life has not been investigated; however, to date no evidence suggests disease progression later in life.
  • A proband with MLC2B may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants is approximately 20%.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of germline mosaicism have been reported.
  • The family history of some individuals diagnosed with MLC2B may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, or milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband

Offspring of a proband. Each child of an individual with MLC2B has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the MLC2B-related pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for MLC are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • European Leukodystrophy Association (ELA)
    2, rue Mi-les-Vignes
    B.P. 61024
    Laxou Cedex 54521
    France
    Phone: 03833093 34
    Fax: 03833000 68
    Email: ela@ela-asso.com
  • Leukodystrophy Australia
    P O Box 2550
    Mount Waverley Victoria 3149
    Australia
    Phone: 1800-141-400 (toll free)
    Email: info@leuko.org.au
  • United Leukodystrophy Foundation (ULF)
    224 North Second Street
    Suite 2
    DeKalb IL 60115
    Phone: 800-728-5483 (toll-free); 815-748-3211
    Fax: 815-748-0844
    Email: office@ulf.org
  • Myelin Disorders Bioregistry Project
    Email: myelindisorders@cnmc.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Megalencephalic Leukoencephalopathy with Subcortical Cysts: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Megalencephalic Leukoencephalopathy with Subcortical Cysts (View All in OMIM)

604004MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 1; MLC1
605908MLC1 GENE; MLC1
611642HEPATOCYTE CELL ADHESION MOLECULE; HEPACAM
613925MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 2A; MLC2A
613926MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 2B, REMITTING, WITH OR WITHOUT MENTAL RETARDATION; MLC2B

MLC1

Gene structure. MLC1 comprises 26,214 bases and 13 exons; the cDNA has 3,435 base pairs. MLC1 is mainly expressed in the brain but also in all types of leukocytes. Within the brain, MLC1 is exclusively expressed in astrocytic endfeet. The highest levels have been found within the brain in the caudate nucleus, thalamus, and hippocampus. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 100 variants in MLC1 have been associated with disease. Approximately 50% of MLC1 pathogenic variants are missense, 28% are frameshifts caused by deletion or insertion, 22% are in a splice junction, and one (out of 50) is a nonsense variant [Ilja Boor et al 2006, van der Knaap et al 2012, Kariminejad et al 2015, Cao et al 2016]. (For more information, see Table A.) Deep intronic pathogenic variants as well as multiexon deletions have been detected by analysis (Table 3, footnotes 2 and 3).

Table 3.

MLC1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.135dupC 1p.Cys46LeufsTer34NM_015166​.3
NP_055981​.1
c.176G>A 1p.Gly59Glu
c.178-10T>A 2p.Ser60_Ser89del
c.278C>T 1p.Ser93Leu
c.298_423+108del 3p.Thr99fsTer
c.824C>A 1p.Ala275Asp
c.908_918delinsGCA 1p.V303GfsTer96

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.
2.

Causes complete skipping exon 3 [Ilja Boor et al 2006, van der Knaap et al 2012]

3.

Describes the deletion of 126 nucleotides in an exon and deletion of 108 additional nucleotides after base 423, which is at a splice donor site. The total deletion of exon and intron sequences is 234 nucleotides [Ilja Boor et al 2006].

Normal gene product. The MLC1 protein is 377 amino acids; its predicted molecular weight is 41 kd. MLC1 is an integral membrane protein [HUGE Protein Database] of unknown function. The protein is localized mainly in the endfeet of astrocytes in the perivascular, subependymal, and subpial regions. The localization of the protein, combined with the clinical phenotype of MLC, suggests a role for MLC1 in brain ion and water homeostasis [van der Knaap et al 2012]. The MLC1 protein shares its endfeet localization with members of the dystrophin glycoprotein-associated complex [Boor et al 2007] and has been shown to interact with a variety of proteins potentially involved in brain ion and water homeostasis. These include, among others, the Na+/K+-ATPase, TRPV4, caveolin-1, and Kir4.1 [Brignone et al 2015].

Abnormal gene product. Teijido et al [2004] and Montagna et al [2006] examined MLC1 pathogenic variants by measuring the protein expression and the amount of protein at the plasma membrane. All tested MLC1 pathogenic variants showed a low steady-state expression of MLC1 with a consequent reduction in surface expression. Electrophysiologic experiments reveal a reduction of volume-regulated anion channel (VRAC) activity in lymphoblasts from individuals with biallelic MLC1 pathogenic variants. This results in impaired regulatory volume decrease (RVD) upon hypotonic cell swelling [Ridder et al 2011]. Cell lines overexpressing normal MLC1 show enhanced VRAC activity, which is absent upon overexpression of mutated MLC1 in an affected individual [Ridder et al 2011]. This is in line with a role for MLC1 in VRAC regulation.

Animal models. Mlc1-null mice recapitulate important disease features including increased brain water content and progressive white matter vacuolization [Hoegg-Beiler et al 2014, Dubey et al 2015]. Study of these mice reveals that swelling of perivascular astrocyte endfeet occurs early in the disease, before widespread myelin vacuolization. Disrupted VRAC activity and disturbed RVD are observed in isolated astrocytes prepared from Mlc1-null mice [Dubey et al 2015]. In rat primary astrocytes, reduction of MLC1 expression resulted in the appearance of intracellular vacuoles [Duarri et al 2011].

HEPACAM

Gene structure. HEPACAM comprises 17,076 bases and seven exons. The cDNA has 3,563 base pairs. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. HEPACAM pathogenic variants leading to the classic phenotype (MLC2A) are mostly missense (e.g., c.292C>T); however, nonsense and frameshift variants have also been observed. In the case of the improving phenotype (MLC2B), only missense variants in HEPACAM have been reported [López-Hernández et al 2011, van der Knaap et al 2012].

The most common pathogenic variant in MLC2B (6 of 16 cases in López-Hernández et al [2011]) is the pathogenic missense variant p.Gly89Ser. Another common variant is p.Arg92Trp [López-Hernández et al 2011], which occurs in the same codon as the MLC2A-associated p.Arg92Gln. See Table 4.

Table 4.

HEPACAM Pathogenic Variants Discussed in This GeneReview

MLC TypeDNA Nucleotide ChangePredicted Protein ChangeReference Sequences
MLC2Ac.275G>Ap.Arg92GlnNM_152722​.4
NP_689935​.2
c.292C>Tp.Arg98Cys
MLC2Bc.265G>Ap.Gly89Ser
c.274C>Tp.Arg92Trp

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The size of the protein encoded by HEPACAM, the hepatic and glial cell adhesion molecule (called either HepaCAM or GlialCAM) [Chung Moh et al 2005, Favre-Kontula et al 2008], is 417 amino acids; its predicted molecular weight is 46 kd. GlialCAM is a single transmembrane protein with two extracellular immunoglobulin domains. Although originally identified in hepatocellular carcinoma cell lines (hence its name HepaCAM), it is predominantly expressed in the brain. GlialCAM colocalizes with MLC1 in astrocyte endfeet. However, GlialCAM expression is not restricted to astrocytes; it is also present in axons, on the outside of myelin sheaths, and in oligodendrocytes [Favre-Kontula et al 2008, López-Hernández et al 2011]. GlialCAM acts as a chaperone for MLC1, ensuring the localization of both proteins at astrocyte-astrocyte junctions in endfeet and in cultured astrocytes [López-Hernández et al 2011, Capdevila-Nortes et al 2013]. In addition, GlialCAM acts as an auxiliary subunit for the chloride channel ClC-2. It increases ClC-2 mediated currents, changes their functional properties, and is necessary for ClC-2 localization to astrocyte-astroycte junctions [Jeworutzki et al 2012, Hoegg-Beiler et al 2014]. GlialCAM also interacts with the gap junction subunit connexin 43 [Wu et al 2016].

Abnormal gene product. All MLC-causing variants in HEPACAM affect the extracellular region of GlialCAM. In cultured rat primary astrocytes, mutated GlialCAM with either a dominant or a recessive pathogenic variant disrupts localization of MLC1 and GlialCAM at astrocyte-astrocyte junctions. Coexpression of wild type GlialCAM rescues the detrimental effect of GlialCAM with a recessive variant on MLC1 localization, but it does not rescue the effect of the dominant variant of GlialCAM [López-Hernández et al 2011]. Biochemical analysis shows that some dominant and recessive pathogenic variants disrupt the ability of GlialCAM to homo-oligomerize [Arnedo et al 2014]. However, what causes a HEPACAM variant to be dominant versus recessive is still unclear.

Animal models. Similar to Mlc1-null mice, Glialcam-null mice as well as mice homozygous for a dominant Glialcam pathogenic variant recapitulate important features of MLC such as increased brain water content, astrocyte swelling, and progressive myelin vacuolization [Hoegg-Beiler et al 2014, Bugiani et al 2017]. In rat primary astrocytes, reduction of GlialCAM expression results in the appearance of intracellular vacuoles and disrupts VRAC activity [Capdevila-Nortes et al 2013].

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Suggested Reading

  • Kazusa Human cDNA Project. Database of human unidentified gene-encoded (HUGE) large proteins analyzed.

Chapter Notes

Author History

Truus EM Abbink, PhD (2018-present)
Rogier Min, PhD (2018-present)
JC Pronk, PhD; Vrije Universiteit Medical Center, Amsterdam (2003-2008)
Gert C Scheper, PhD; Vrije Universiteit Medical Center, Amsterdam (2008-2018)
Marjo S van der Knaap, MD, PhD (2003-present)

Revision History

  • 29 March 2018 (sw) Comprehensive update posted live
  • 3 November 2011 (me) Comprehensive update posted live
  • 29 July 2008 (me) Comprehensive update posted live
  • 29 November 2005 (me) Comprehensive update posted live
  • 11 August 2003 (me) Review posted to live Web site
  • 12 June 2003 (mvdk) Original submission
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