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 anti-seizure 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; anti-seizure medication 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 testing for a pregnancy 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.

Suggestive Findings

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

• Classic phenotype (includes MLC1 and MLC2A)
  • MLC1, associated with MLC1 biallelic pathogenic variants
  • MLC2A, associated with HEPACAM biallelic pathogenic variants
• Improving phenotype (includes MLC2B)
  • MLC2B, associated with a HEPACAM heterozygous pathogenic variant

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.

Brain images of an individual with MLC (A, C) and an unaffected individual (B, D) A. Transverse T₂-weighted image of a child age nine years with MLC, showing diffusely abnormal and mildly swollen white matter

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

• Sequence analysis of MLC1 can be performed first in individuals with the classic phenotype, followed by sequence analysis of HEPACAM. Gene-targeted deletion/duplication analysis of MLC1 and HEPACAM can be considered next if no pathogenic variant is found.
• Sequence analysis of HEPACAM can be performed first in individuals with the improving phenotype. Gene-targeted deletion/duplication analysis of HEPACAM can be considered next if no pathogenic variant is found.

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 are likely to change 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 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.

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 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.

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.

• Almost all East Indian individuals with MLC1 belong to the Agrawal community; and all individuals within this community are biallelic for the same pathogenic variant (c.135dupC), providing evidence for a founder effect [Leegwater et al 2002, Singhal et al 2003, Gorospe et al 2004].
• MLC1 is also relatively common among Libyan Jews [Ben-Zeev et al 2001]. One common pathogenic variant (c.176G>A) was found in five unrelated Libyan Jewish families [Ben-Zeev et al 2002]. The same variant was identified in several affected individuals from a single Turkish Jewish family descended from the same ancestors. Screening of 200 normal Libyan Jewish individuals for this particular pathogenic variant revealed a carrier rate of one in 40, as compared with an expected carrier rate of one in 81. Non-Jewish Turkish individuals do not share a common pathogenic variant.
• The MLC1 pathogenic variant c.278C>T appears to be common in Japanese individuals [Shimada et al 2014] but has also been observed in Finland, Turkey [Leegwater et al 2001], and Italy [Montagna et al 2006].
• Among Egyptians with MLC, the MLC1 pathogenic variant c.908_918delinsGCA is common and affected individuals share a haplotype, indicating a founder effect [Abdel-Salam et al 2016].
• In Korea, c.824C>A accounted for 70% of alleles in affected individuals were [Choi et al 2017].

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
• Anti-seizure medication if epileptic seizures are present

Prevention of Secondary Complications

If patients have epilepsy, treatment with anti-seizure medication 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 anti-seizure medication 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 EU Clinical Trials Register 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.

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).

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

Parents of a proband

• The parents of an affected child are typically heterozygotes (i.e., carriers of one pathogenic variant); in rare cases, only one parent is heterozygous and a second pathogenic variant arose de novo in the proband [López-Hernández et al 2011].
• Heterozygotes (carriers) are asymptomatic. No clinical or MRI abnormalities have been found in individuals heterozygous for MLC1- or MLC2A-related pathogenic variants.

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.

Autosomal Dominant Inheritance (MLC2B) – Risk to Family Members

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

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.
• If the MLC2B-related pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the MLC2B-related pathogenic variant but are clinically unaffected, the sibs are still at increased risk for MLC2B because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.

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/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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 live
• 12 June 2003 (mvdk) Original submission

Literature Cited

• Abdel-Salam GM, Abdel-Hamid MS, Ismail SI, Hosny H, Omar T, Effat L, Aglan MS, Temtamy SA, Zaki MS. Megalencephalic leukoencephalopathy with cysts in twelve Egyptian patients: novel mutations in MLC1 and HEPACAM and a founder effect. Metab Brain Dis. 2016;31:1171–9. [PubMed: 27389245]
• Arnedo T, López-Hernández T, Jeworutzki E, Capdevila-Nortes X, Sirisi S, Pusch M, Estévez R. Functional analyses of mutations in HEPACAM causing megalencephalic leukoencephalopathy. Hum Mutat. 2014;35:1175–8. [PubMed: 25044933]
• Balestri M, Crisafulli C, Donato L, Giegling I, Calati R, Antypa N, Schneider B, Marusic D, Tarozzi ME, Marusic D, Paragi M, Hartmann AM, Konte B, Marsano A, Serretti A, Rujescu D. Nine differentially expressed genes from a post mortem study and their association with suicidal status in a sample of suicide completers, attempters and controls. J Psychiatr Res. 2017;91:98–104. [PubMed: 28327445]
• Ben-Zeev B, Gross V, Kushnir T, Shalev R, Hoffman C, Shinar Y, Pras E, Brand N. Vacuolating megalencephalic leukoencephalopathy in 12 Israeli patients. J Child Neurol. 2001;16:93–9. [PubMed: 11292232]
• Ben-Zeev B, Levy-Nissenbaum E, Lahat H, Anikster Y, Shinar Y, Brand N, Gross-Tzur V, MacGregor D, Sidi R, Kleta R, Frydman M, Pras E. Megalencephalic leukoencephalopathy with subcortical cysts; a founder effect in Israeli patients and a higher than expected carrier rate among Libyan Jews. Hum Genet. 2002;111:214–8. [PubMed: 12189496]
• Boor I, Nagtegaal M, Kamphorst W, van der Valk P, Pronk JC, van Horssen J, Dinopoulos A, Bove KE, Pascual-Castroviejo I, Muntoni F, Estévez R, Scheper GC, van der Knaap MS. MLC1 is associated with the dystrophin-glycoprotein complex at astrocytic endfeet. Acta Neuropathol. 2007;114:403–10. [PMC free article: PMC2039857] [PubMed: 17628813]
• Brignone MS, Lanciotti A, Camerini S, De Nuccio C, Petrucci TC, Visentin S, Ambrosini E. MLC1 protein: a likely link between leukodystrophies and brain channelopathies. Front Cell Neurosci. 2015;9:66. [PMC free article: PMC4381631] [PubMed: 25883547]
• Bugiani M, Dubey M, Breur M, Postma NL, Dekker MP, Ter Braak T, Boschert U, Abbink TEM, Mansvelder HD, Min R, van Weering JRT, van der Knaap MS. Megalencephalic leukoencephalopathy with cysts: the Glialcam-null mouse model. Ann Clin Transl Neurol. 2017;4:450–65. [PMC free article: PMC5497535] [PubMed: 28695146]
• Bugiani M, Moroni I, Bizzi A, Nardocci N, Bettecken T, Gärtner J, Uziel G. Consciousness disturbances in megalencephalic leukoencephalopathy with subcortical cysts. Neuropediatrics. 2003;34:211–4. [PubMed: 12973663]
• Cao B, Yan H, Guo M, Xie H, Wu Y, Gu Q, Xiao J, Shang J, Yang Y, Xiong H, Niu Z, Wu X, Jiang Y, Wang J. Ten novel mutations in Chinese patients with megalencephalic leukoencephalopathy with subcortical cysts and a long-term follow-up research. PLoS One. 2016;11:e0157258. [PMC free article: PMC4913951] [PubMed: 27322623]
• Capdevila-Nortes X, López-Hernández T, Apaja PM, López de Heredia M, Sirisi S, Callejo G, Arnedo T, Nunes V, Lukacs GL, Gasull X, Estévez R. Insights into MLC pathogenesis: GlialCAM is an MLC1 chaperone required for proper activation of volume-regulated anion currents. Hum Mol Genet. 2013;22:4405–16. [PubMed: 23793458]
• Choi SA, Kim SY, Yoon J, Choi J, Park SS, Seong MW, Kim H, Hwang H, Choi JE, Chae JH, Kim KJ, Kim S, Lee YJ, Nam SO, Lim BC. A unique mutational spectrum of MLC1 in Korean patients with megalencephalic leukoencephalopathy with subcortical cysts. Ann Lab Med. 2017;37:516–21. [PMC free article: PMC5587825] [PubMed: 28840990]
• Chung Moh M, Hoon Lee L, Shen S. Cloning and characterization of hepaCAM, a novel Ig-like cell adhesion molecule suppressed in human hepatocellular carcinoma. J Hepatol. 2005;42:833–41. [PubMed: 15885354]
• Devaney JM, Donarum EA, Brown KM, Meyer J, Stöber G, Lesch KP, Nestadt G, Stephan DA, Pulver AE. No missense mutation of WKL1 in a subgroup of probands with schizophrenia. Mol Psychiatry. 2002;7:419–23. [PubMed: 11986987]
• Duarri A, Lopez de Heredia M, Capdevila-Nortes X, Ridder MC, Montolio M, López-Hernández T, Boor I, Lien CF, Hagemann T, Messing A, Gorecki DC, Scheper GC, Martínez A, Nunes V, van der Knaap MS, Estévez R. Knockdown of MLC1 in primary astrocytes causes cell vacuolation: A MLC disease cell model. Neurobiol Dis. 2011;43:228–38. [PMC free article: PMC3885813] [PubMed: 21440627]
• Dubey M, Brouwers E, Hamilton EMC, Stiedl O, Bugiani M, Koch H, Kole MHP, Boschert U, Wykes RC, Mansvelder HD, van der Knaap MS, Min R. Seizures and disturbed brain potassium dynamics in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts. Ann Neurol. 2018;83:636–49. [PMC free article: PMC5900999] [PubMed: 29466841]
• Dubey M, Bugiani M, Ridder MC, Postma NL, Brouwers E, Polder E, Jacobs JG, Baayen JC, Klooster J, Kamermans M, Aardse R, de Kock CP, Dekker MP, van Weering JR, Heine VM, Abbink TE, Scheper GC, Boor I, Lodder JC, Mansvelder HD, van der Knaap MS. Mice with megalencephalic leukoencephalopathy with cysts: a developmental angle. Ann Neurol. 2015;77:114–31. [PubMed: 25382142]
• Favre-Kontula L, Rolland A, Bernasconi L, Karmirantzou M, Power C, Antonsson B, Boschert U. GlialCAM, an immunoglobulin-like cell adhesion molecule is expressed in glial cells of the central nervous system. Glia. 2008;56:633–45. [PubMed: 18293412]
• Gorospe JR, Singhal BS, Kainu T, Wu F, Stephan D, Trent J, Hoffman EP, Naidu S. Indian Agarwal megalencephalic leukodystrophy with cysts is caused by a common MLC1 mutation. Neurology. 2004;62:878–82. [PubMed: 15037685]
• Hoegg-Beiler MB, Sirisi S, Orozco IJ, Ferrer I, Hohensee S, Auberson M, Gödde K, Vilches C, de Heredia ML, Nunes V, Estévez R, Jentsch TJ. Disrupting MLC1 and GlialCAM and ClC-2 interactions in leukodystrophy entails glial chloride channel dysfunction. Nat Commun. 2014;5:3475. [PubMed: 24647135]
• Ilja Boor PK, de Groot K, Mejaski-Bosnjak V, Brenner C, van der Knaap MS, Scheper GC, Pronk JC. Megalencephalic leukoencephalopathy with subcortical cysts: an update and extended mutation analysis of MLC1. Hum Mutat. 2006;27:505–12. [PubMed: 16652334]
• Itoh N, Maeda M, Naito Y, Narita Y, Kuzuhara S. An adult case of megalencephalic leukoencephalopathy with subcortical cysts with S93L mutation in MLC1 gene: a case report and diffusion MRI. Eur Neurol. 2006;56:243–5. [PubMed: 17077634]
• Jeworutzki E, López-Hernández T, Capdevila-Nortes X, Sirisi S, Bengtsson L, Montolio M, Zifarelli G, Arnedo T, Müller CS, Schulte U, Nunes V, Martínez A, Jentsch TJ, Gasull X, Pusch M, Estévez R. GlialCAM, a protein defective in a leukodystrophy, serves as a ClC-2 Cl(-) channel auxiliary subunit. Neuron. 2012;73:951–61. [PMC free article: PMC3334819] [PubMed: 22405205]
• Kaganovich M, Peretz A, Ritsner M, Bening Abu-Shach U, Attali B, Navon R. Is the WKL1 gene associated with schizophrenia? Am J Med Genet B Neuropsychiatr Genet. 2004;125B:31–7. [PubMed: 14755440]
• Kariminejad A, Rajaee A, Ashrafi MR, Alizadeh H, Tonekaboni SH, Malamiri RA, Ghofrani M, Karimzadeh P, Mohammadi MM, Baghalshooshtari A, Bozorgmehr B, Kariminejad MH, Postma N, Abbink TE, van der Knaap MS. Eight novel mutations in MLC1 from 18 Iranian patients with megalencephalic leukoencephalopathy with subcortical cysts. Eur J Med Genet. 2015;58:71–4. [PubMed: 25497041]
• Leegwater PA, Boor PK, Yuan BQ, van der Steen J, Visser A, Konst AA, Oudejans CB, Schutgens RB, Pronk JC, van der Knaap MS. Identification of novel mutations in MLC1 responsible for megalencephalic leukoencephalopathy with subcortical cysts. Hum Genet. 2002;110:279–83. [PubMed: 11935341]
• Leegwater PA, Yuan BQ, van der Steen J, Mulders J, Konst AA, Boor PK, Mejaski-Bosnjak V, van der Maarel SM, Frants RR, Oudejans CB, Schutgens RB, Pronk JC, van der Knaap MS. Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts. Am J Hum Genet. 2001;68:831–8. [PMC free article: PMC1275636] [PubMed: 11254442]
• López-Hernández T, Ridder MC, Montolio M, Capdevila-Nortes X, Polder E, Sirisi S, Duarri A, Schulte U, Fakler B, Nunes V, Scheper GC, Martínez A, Estévez R, van der Knaap MS. Mutant GlialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism. Am J Hum Genet. 2011;88:422–32. [PMC free article: PMC3071909] [PubMed: 21419380]
• Meyer J, Huberth A, Ortega G, Syagailo YV, Jatzke S, Mossner R, Strom TM, Ulzheimer-Teuber I, Stober G, Schmitt A, Lesch KP. A missense mutation in a novel gene encoding a putative cation channel is associated with catatonic schizophrenia in a large pedigree. Mol Psychiatry. 2001;6:302–6. [PubMed: 11326298]
• Montagna G, Teijido O, Eymard-Pierre E, Muraki K, Cohen B, Loizzo A, Grosso P, Tedeschi G, Palacín M, Boespflug-Tanguy O, Bertini E, Santorelli FM, Estévez R. Vacuolating megalencephalic leukoencephalopathy with subcortical cysts: functional studies of novel variants in MLC1. Hum Mutat. 2006;27:292. [PubMed: 16470554]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Ridder MC, Boor I, Lodder JC, Postma NL, Capdevila-Nortes X, Duarri A, Brussaard AB, Estévez R, Scheper GC, Mansvelder HD, van der Knaap MS. Megalencephalic leucoencephalopathy with cysts: defect in chloride currents and cell volume regulation. Brain. 2011;134:3342–54. [PubMed: 22006981]
• Rubie C, Lichtner P, Gartner J, Siekiera M, Uziel G, Kohlmann B, Kohlschutter A, Meitinger T, Stober G, Bettecken T. Sequence diversity of KIAA0027/MLC1: are megalencephalic leukoencephalopathy and schizophrenia allelic disorders? Hum Mutat. 2003;21:45–52. [PubMed: 12497630]
• Selch S, Strobel A, Haderlein J, Meyer J, Jacob CP, Schmitt A, Lesch KP, Reif A. MLC1 polymorphisms are specifically associated with periodic catatonia, a subgroup of chronic schizophrenia. Biol Psychiatry. 2007;61:1211–4. [PubMed: 17210142]
• Shimada S, Shimojima K, Masuda T, Nakayama Y, Kohji T, Tsukamoto H, Matsubasa T, Oka A, Yamamoto T. MLC1 mutations in Japanese patients with megalencephalic leukoencephalopathy with subcortical cysts. Hum Genome Var. 2014;1:14019. [PMC free article: PMC4785519] [PubMed: 27081509]
• Singhal BS, Gorospe JR, Naidu S. Megalencephalic leukoencephalopathy with subcortical cysts. J Child Neurol. 2003;18:646–52. [PubMed: 14572144]
• Spijker S, Van Zanten JS, De Jong S, Penninx BW, van Dyck R, Zitman FG, Smit JH, Ylstra B, Smit AB, Hoogendijk WJ. Stimulated gene expression profiles as a blood marker of major depressive disorder. Biol Psychiatry. 2010;68:179–86. [PubMed: 20471630]
• Sugiura C, Shiota M, Maegaki Y, Yoshida K, Koeda T, Kitahara T, Ohno K. Late-onset neuropsychological symptoms in a Japanese patient with megalencephalic leukoencephalopathy with subcortical cysts. Neuropediatrics. 2006;37:286–90. [PubMed: 17236107]
• Teijido O, Martínez A, Pusch M, Zorzano A, Soriano E, Del Río JA, Palacín M, Estévez R. Localization and functional analyses of the MLC1 protein involved in megalencephalic leukoencephalopathy with subcortical cysts. Hum Mol Genet. 2004;13:2581–94. [PubMed: 15367490]
• Topçu M, Saatci I, Topcuoglu MA, Kose G, Kunak B. Megalencephaly and leukodystrophy with mild clinical course: a report on 12 new cases. Brain Dev. 1998;20:142–53. [PubMed: 9628190]
• van der Knaap MS, Barth PG, Vrensen GF, Valk J. Histopathology of an infantile-onset spongiform leukoencephalopathy with a discrepantly mild clinical course. Acta Neuropathol (Berl). 1996;92:206–12. [PubMed: 8841668]
• van der Knaap MS, Boor I, Estévez R. Megalencephalic leukoencephalopathy with subcortical cysts: chronic white matter oedema due to a defect in brain ion and water homoeostasis. Lancet Neurol. 2012;11:973–85. [PubMed: 23079554]
• van der Voorn JP, Pouwels PJW, Hart AA, Serrarens J, Willemsen MA, Kremer HP, Barkhof F, van der Knaap MS. Childhood white matter disorders: quantitative MR imaging and spectroscopy. Radiology. 2006;241:510–7. [PubMed: 17057071]
• Verma R, Mukerji M, Grover D. B-Rao C, Das SK, Kubendran S, Jain S, Brahmachari SK. MLC1 gene is associated with schizophrenia and bipolar disorder in Southern India. Biol Psychiatry. 2005;58:16–22. [PubMed: 15992519]
• Wu M, Moh MC, Schwarz H. HepaCAM associates with connexin 43 and enhances its localization in cellular junctions. Sci Rep. 2016;6:36218. [PMC free article: PMC5098153] [PubMed: 27819278]