Megalencephalic Leukoencephalopathy With Subcortical Cysts
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).
- 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 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, 2 | Proportion of MLC Attributed to Pathogenic Variants in This Gene | Proportion of Pathogenic Variants 3 Detectable by Method | |
|---|---|---|---|
| Sequence analysis 4 | Gene-targeted deletion/duplication analysis 5 | ||
| HEPACAM | 22% 6 | 100% | Unknown 7 |
| MLC1 | 76% | 97% | 3% 8 |
| Unknown 9 | ~2% | NA | |
- 1.
Genes are listed alphabetically.
- 2.
See Table A. Genes and Databases for chromosome locus and protein.
- 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 used may 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.
López-Hernández et al [2011]
- 7.
No data on detection rate of gene-targeted deletion/duplication analysis are available. See Molecular Genetics, MLC1.
- 8.
Leegwater et al [2002], Ilja Boor et al [2006]
- 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.
- 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].
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
| Disorder | Gene | MOI | Clinical Features of This Disorder | |
|---|---|---|---|---|
| Overlapping w/MLC | Distinguishing from MLC | |||
| Laminin alpha 2 deficiency | LAMA2 | AR | Similar cerebral WM disease w/swelling of the abnormal WM |
|
| Canavan disease | ASPA | AR | Similar cerebral WM disease w/swelling of the abnormal WM |
|
| Alexander disease | GFAP | AD | Similar WM disease w/swelling of the abnormal WM |
|
| L-2-hydroxyglutaric aciduria (OMIM 236792) | L2HGDH | AR | Similar WM disease w/swelling of the abnormal WM |
|
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; WM = white matter
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 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.