The diagnosis of megalencephalic leukoencephalopathy with subcortical cysts (MLC) can be made with confidence in individuals with typical clinical findings and characteristic abnormalities on cranial magnetic resonance imaging (MRI) [van der Knaap et al 1995, Singhal et al 1996, Topçu et al 1998]....
Diagnosis
Clinical DiagnosisThe diagnosis of megalencephalic leukoencephalopathy with subcortical cysts (MLC) can be made with confidence in individuals with typical clinical findings and characteristic abnormalities on cranial magnetic resonance imaging (MRI) [van der Knaap et al 1995, Singhal et al 1996, Topçu et al 1998].Typical Clinical FindingsClassic phenotypeMacrocephaly is present at birth or (more commonly) develops within the first year of life in all individuals. After the first year of life, head growth rate becomes normal; growth usually follows a line above and parallel to the 98th centile.Early development is normal or mildly delayed. Most (not all) children achieve independent walking.Slow deterioration of motor functions with cerebellar ataxia and mild spasticity usually starts in early childhood or later. The majority of affected children become wheelchair dependent in their teens.Speech can become increasingly dysarthric; dysphagia may develop.Some individuals have extrapyramidal movement abnormalities with dystonia and athetosis, usually as a late finding. Tics may occur.Mental decline occurs later and is much milder than motor decline.Some affected individuals develop behavioral problems.Most individuals have epileptic seizures that are usually easily controlled with medication; however, some experience status epilepticus.Minor head trauma may induce temporary deterioration in some individuals, most often observed as seizures, prolonged unconsciousness, or acute motor deterioration with gradual improvement.When associated with biallelic mutation of MLC1, the classic phenotype is known as MLC1; when caused by biallelic mutation of HEPACAM it is known as MLC2A.Improving phenotypeMacrocephaly is present at birth or (more commonly) develops within the first year of life in all individuals. After the first year of life, growth of the head usually follows a line above and parallel to the 98th centile. In a few children the head circumference normalizes. Early development is normal or mildly delayed. All children achieve independent walking.Motor function improves after first year of life; clumsiness and hypotonia persist in some. Some affected individuals have seizures that are usually easily controlled with medication; however, some experience status epilepticus.Some have a stable intellectual disability, with or without autism.Regression of mental and motor functions does not occur.The improving phenotype associated with heterozygous mutation of HEPACAM is known as MLC2B.MRI CriteriaMRI of the brain is diagnostic (see Figure 1): FigureFigure 1. Brain images of an individual with MLC (A, C) and an unaffected individual (B, D) A. Transverse T2-weighted image of a nine-year-old child with MLC, showing diffusely abnormal and mildly swollen white matter B. Transverse (more...)Cerebral hemispheric white matter is diffusely abnormal and mildly swollen; see Figure 1A (from an individual with MLC1) as compared to Figure 1B (from an unaffected child).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 as observed in Figure 1C (from an individual with MLC1) as compared to Figure 1D (from an unaffected child).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].In children with MLC2B, MRI early within the first year of life shows the same abnormalities as described above; however, striking improvement occurs on follow up. In some children the MRI becomes normal in a few years, whereas in others minor frontal and temporal subcortical white matter abnormalities and anterior temporal cysts remain.TestingRoutine laboratory tests, including cerebrospinal fluid analysis, are normal.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 end feet [Duarri et al 2011].Molecular Genetic TestingGenes. Megalencephalic leukoencephalopathy with subcortical cysts is caused by mutations in MLC1 or HEPACAM. Possible further locus heterogeneity. When the clinical and MRI findings are characteristic of MLC, the absence of identified MLC1 or HEPACAM mutations does not exclude the diagnosis of MLC because (1) the MLC1 or HEPACAM disease-causing mutations may not be identifiable with testing methods used or (2) the MLC phenotype may be the result of mutation(s) in another as-yet unidentified gene. Table 1. Summary of Molecular Genetic Testing Used in Megalencephalic Leukoencephalopathy with Subcortical CystsView in own windowGene SymbolProportion of MLC Attributed to Mutations in This GeneTest MethodMutations DetectedTest AvailabilityMLC175% 1
Sequence analysisSequence variants 2ClinicalDeletion / duplication analysis 3Deletion / duplication of one or more exons or the whole gene 4HEPACAM20% 5 Sequence analysisSequence variants 2Clinical1. Sequence analysis of the coding region of MLC1 genomic DNA detects homozygotes or compound heterozygous mutations in approximately 65% to 70% of individuals with clinical and MRI presentation of MLC. Large deletions and some deep intronic mutations in MLC1 are not detected and require deletion/duplication analysis or cDNA sequencing. If extensive analysis of genomic DNA and cDNA does not reveal any mutations in MLC1, it is assumed that the individual has mutations in another gene, most likely HEPACAM. Complementary DNA is not always available so it is possible that some mutations in MLC1 are missed by the standard genomic DNA sequencing of exons and surrounding intronic regions.2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment. 4. Leegwater et al [2002], Ilja Boor et al [2006]5. Sequence analysis of the coding region of HEPACAM genomic DNA detects mutations in approximately 75% of persons with MLC with no identifiable MLC1 mutation: two thirds have heterozygous HEPACAM mutations (i.e., MLC2B), one third have biallelic HEPACAM mutations (i.e., MLC2A) [López-Hernández et al 2011].Interpretation of test resultsFinding two disease-causing mutations in MLC1 or HEPACAM confirms the diagnosis of MLC1 and MLC2A, respectively, and the classic phenotype of MLC. Finding one disease-causing mutation in HEPACAM in combination with improvement of MRI on follow-up confirms the diagnosis of autosomal dominant MLC2B, the improving phenotype of MLC.When the clinical and MRI findings are characteristic of MLC, the absence of identified MLC1 or HEPACAM mutations does not exclude the diagnosis of MLC because (1) the MLC1 or HEPACAM disease-causing mutations may not be identifiable with testing methods used or (2) the MLC phenotype may be the result of mutation(s) in another gene as yet unidentified gene. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a probandWhen diagnostic criteria including brain MRI findings are met, the diagnosis of MLC is established. Note: If the proband fulfills the clinical and MRI criteria, molecular genetic testing is mainly performed to identify the family-specific mutations for genetic counseling purposes. If no mutations are found in MLC1 or HEPACAM, the diagnosis of MLC is unchanged.If the proband does not fulfill diagnostic criteria and, for example, lacks the typical macrocephaly or has equivocal MRI findings, the definitive diagnosis of MLC depends on the results of molecular genetic testing.For probands with findings consistent with the classic phenotype, molecular genetic testing of MLC1 is recommended first, followed by molecular genetic testing of HEPACAM if no MLC1 mutations are identified.For probands with findings consistent with the improving phenotype, molecular genetic testing of HEPACAM is recommended first.Carrier testing for relatives at risk for the autosomal recessive disorders MLC1 and MLC2A requires prior identification of the disease-causing mutations in the family. Heterozygotes (carriers) of an MLC1 or HEPACAM mutation associated with the phenotypes MLC1 and MLC2A, respectively, are not at risk of developing MLC. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation(s) in the family.Genetically Related (Allelic) DisordersIn addition to the phenotypes discussed in this GeneReview, mutations in MLC1 could be involved in catatonic schizophrenia.Meyer et al [2001] suggested that a putative dominantly acting missense mutation, p.Leu309Met was cosegregating in a large pedigree with periodic catatonia. Rubie et al [2003] screened MLC1 in 140 index cases with periodic catatonia and five individuals with MLC; their findings and those of Devaney et al [2002] and Kaganovich et al [2004] seemed to exclude MLC1 as a susceptibility locus for schizophrenia. Verma et al [2005] concluded that rare and common variants in MLC1 could contribute to schizophrenia and bipolar disorder. Selch et al [2007] replicated the data from Verma et al [2005] and narrowed the association of MLC1 genetic variation to periodic catatonia. Selch et al also stated that “a further possible alternative explanation might be that associated SNPs in MLC1 are in linkage disequilibrium with a potential ‘true’ disease-causing variant in a gene nearby” [Selch et al 2007]. Elucidation of the function of MLC1 and determination of the effects of variants that appear to be associated with a subgroup of schizophrenia are needed to resolve this ongoing debate.
The two phenotypes observed in megalencephalic leukoencephalopathy with subcortical cysts (MLC) are the classic phenotype and the atypical improving phenotype. When associated with biallelic mutation of MLC1, the classic phenotype is known as MLC1; when caused by biallelic mutation of HEPACAM it is known as MLC2A. The improving phenotype associated with heterozygous mutation of HEPACAM is known as MLC2B....
Natural History
The two phenotypes observed in megalencephalic leukoencephalopathy with subcortical cysts (MLC) are the classic phenotype and the atypical improving phenotype. When associated with biallelic mutation of MLC1, the classic phenotype is known as MLC1; when caused by biallelic mutation of HEPACAM it is known as MLC2A. The improving phenotype associated with heterozygous mutation of HEPACAM is known as MLC2B.To date, macrocephaly has been observed in all individuals with MLC [van der Knaap et al 1995, Goutières et al 1996, Singhal et al 1996, Topçu et al 1998, Ben-Zeev et al 2001]. It can 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 parallel to the 98th percentile. In individuals with the atypical improving phenotype, head circumference is initially equally large, but may normalize.Classic megalencephalic leukoencephalopathy with subcortical cysts phenotype (MLC1 and MLC2A). Initial mental and motor development is normal in most children and mildly delayed in some. Apart from progressive macrocephaly, the first clinical sign is usually delay in walking. Walking is often unstable, and the child falls frequently. Subsequently, slow deterioration of motor function is noted over the 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. Muscle tone tends to be low, apart from some ankle hypertonia. Deep-tendon stretch reflexes become brisk, and Babinski signs become apparent. Gradually, the ability to walk independently is lost; and many children become completely wheelchair dependent at the end of the first decade or in the second decade of life.Almost all children have epilepsy from early on [Yalcinkaya et al 2003], usually easily controlled with medication.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]. Speech becomes increasingly dysarthric, and dysphagia may develop. Some individuals display extrapyramidal movement abnormalities with dystonia and athetosis. Some develop tics [Sugiura et al 2006].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].Some children have a more severe clinical course and maintain their ability to walk independently only for a few years, or never achieve independent walking.Some children have a more benign clinical course and, even as teenagers, only have macrocephaly. Some individuals maintain the ability to walk independently into their forties.Because the disease has been known for a relatively short time, little information is available about average life span. Some individuals have died in their teens or twenties; others are alive in their fifties.Improving megalencephalic leukoencephalopathy with subcortical cysts 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. Apart from progressive macrocephaly, the first clinical sign is usually delay in walking. Walking is often unstable, and the child falls frequently. 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 can be normal, but some children have intellectual disability with or without autism. Regression has not been observed. Epilepsy and status epilepticus may occur. Most children remain macrocephalic; however, some become normocephalic. Because the disease has been known for a relatively short time, little information is available about average life span. One child died in status epilepticus at age four years [Authors, unpublished data].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 mutation often have macrocephaly but normal function. Some have cognitive or behavioral problems or motor clumsiness. Considering the normal health of parents heterozygous for a HEPACAM mutation, it does not appear that a heterozygous HEPACAM mutation shortens life span; however, no formal study has addressed this issue.
Classic MLC. No phenotypic difference is evident between individuals with MLC who have identifiable mutations in MLC1 (MLC1) and those who have MLC associated with identifiable mutations in HEPACAM (MLC2A)....
Genotype-Phenotype Correlations
Classic MLC. No phenotypic difference is evident between individuals with MLC who have identifiable mutations in MLC1 (MLC1) and those who have MLC associated with identifiable mutations in HEPACAM (MLC2A).Severity of the phenotype in individuals with MLC1 and MLC2A does not correlate with the specific mutations found.In individuals from the same family disease severity and clinical course can vary significantly.Improving MLC. In individuals from the same family disease severity and clinical course can vary significantly. Parents and sibs who have the same mutation as the proband can be normal with or without macrocephaly.
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 (see Organic Acidemias Overview). 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). ...
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 (see Organic Acidemias Overview). 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). Laminin alpha 2 deficiency. The white matter disease in laminin alpha-2 deficiency most closely resembles that observed in MLC; however, the typical subcortical cysts are generally lacking [van der Knaap et al 1997]. In addition, individuals with laminin alpha-2 deficiency have prominent weakness and hypotonia, not shared by individuals with MLC. The diagnosis can be confirmed with molecular genetic testing. (See Congenital Muscular Dystrophy).Canavan disease. The MRI typically shows involvement of the thalamus and globus pallidus with relative sparing of a bilateral crescent formed by the putamen and caudate nucleus. The globus pallidus and thalamus are not involved in MLC. The white matter may be cystic in Canavan disease, but the typical subcortical cysts seen in MLC are lacking. The diagnosis of neonatal/infantile Canavan disease relies on demonstration of very high concentration of N-acetylaspartic acid (NAA) in the urine and/or molecular genetic testing of ASPA.Alexander disease. Megalencephaly and leukoencephalopathy with frontal predominance of MRI abnormalities are observed [van der Knaap et al 2001]. This predilection for the anterior parts of the brain is not shared by MLC. In Alexander disease, contrast enhancement of particular brain structures is almost invariably observed [van der Knaap et al 2001], whereas contrast enhancement is not a feature of MLC. Cystic degeneration may occur in Alexander disease, but the location of the cysts is different: the deep frontal white matter is mainly affected. The diagnosis of Alexander disease can be confirmed by molecular genetic testing of GFAP.Infantile GM2 gangliosidosis. The MRI is characterized by prominent involvement of the basal ganglia and thalami in addition to the white matter abnormalities. A definitive diagnosis is established by assaying hexosaminidase A and B in serum, leukocytes, or cultured skin fibroblasts.Infantile GM1 gangliosidosis. MRI findings are very similar to those of GM2 gangliosidosis [Chen et al 1998]. Demonstration of deficiency of beta-galactosidase activity in leukocytes or cultured fibroblasts confirms the diagnosis.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with megalencephalic leukoencephalopathy with subcortical cysts (MLC) the following evaluations are recommended:...
Management
Evaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with megalencephalic leukoencephalopathy with subcortical cysts (MLC) the following evaluations are recommended:Neurologic examinationBrain MRIPhysical therapy/occupational therapy assessmentAssessment of cognitive dysfunction (neuropsychological testing)Treatment of ManifestationsSupportive therapy includes the following:Antiepileptic drugs (AED) if epileptic seizures are presentPhysical therapy to improve motor functionSpecial educationSpeech therapy as neededPrevention of Secondary ComplicationsMinor head trauma may lead to temporary motor deterioration or (rarely) to coma. Wearing a helmet should be considered for situations involving increased risk of head trauma.Agents/Circumstances to AvoidMinor head trauma may lead to temporary motor deterioration 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 RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherUnsuccessful therapies have included diuretics, acetazolamide, and creatine monohydrate.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDMLC122q13.33
Membrane protein MLC1MLC1 homepage - Mendelian genesMLC1HEPACAM11q24.2Hepatocyte cell adhesion molecule HEPACAMData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Megalencephalic Leukoencephalopathy with Subcortical Cysts (View All in OMIM) View in own window 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; MLC2BMLC1Normal allelic variants. MLC1 comprises 26,214 bases and 13 exons; the cDNA has 3435 base pairs. MLC1 is mainly expressed in the brain but also in all types of leukocytes. The highest levels have been found within the brain in the caudate nucleus, thalamus, and hippocampus.Pathologic allelic variants. According to the most recent MLC1 mutation update [Ilja Boor et al 2006], approximately 50% of mutations are missense, 28% are frameshifts caused by deletion or insertion, 22% are mutations in a splice junction, and one (out of 50) is a nonsense mutation. (For more information, see Table A.) Montagna et al [2006] reported nine additional novel mutations.Mutated nucleotides deep within the intron are often best detected by analysis of cDNA, if available, which will reveal the alternative transcripts resulting from aberrant splicing. Examples include c.298_423del126+108del, a deletion of exons 4 and 5 and intronic regions [Ilja Boor et al 2006] and c.178-10T>A in intron 1. Theoretically, this change would not be predicted to affect splicing; however, cDNA analysis revealed skipping of exon 2, which encodes amino acids 60 through 89 [MS van der Knaap & GC Scheper, unpublished data].Table 2. Selected MLC1 Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference SequencesNormalc.512G>T 1p.Cys171PheNM_015166.3 NP_055981.1c.654C>A 1p.Asn218Lys c.925C>A 1p.Leu309Metc.1031A>G 1p.Asn344Ser Pathologicc.135insCp.Cys46Leufs*34c.176G>Ap.Gly59Gluc.178-10T>A --c.298_423del126+108del 2p.Thr99fs*c.278C>Tp.Ser93LeuSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Frequency of normal variants: c.512G>T (9%); c.654C>A (1.5%); c.925C>A (0.7%); c.1031A>G (11%)2. 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 exonic and intronic sequences is 234 nucleotides.Normal gene product. The MLC1 protein size 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 suggests a role for MLC1 in the transport process across the blood-brain barrier and brain-cerebrospinal fluid barrier [Boor et al 2005, Teijido et al 2007]. Teijido et al [2004] reported that in the adult mouse brain MLC1 is expressed in subsets of neurons, where it localizes primarily in fibers and axonal tracts. In human tissue, the MLC1 protein colocalizes with members of the dystrophin glycoprotein-associated complex [Boor et al 2007].Abnormal gene product. Teijido et al [2004] and Montagna et al [2006] examined MLC1 mutations by measuring the protein expression and the amount of protein at the plasma membrane. All tested MLC1 mutations showed a low steady-state expression of MLC1 with a consequent reduction in surface expression. In rat primary astrocytes, reduction of MLC1 expression resulted in the appearance of intracellular vacuoles [Duarri et al 2011]. HEPACAMNormal allelic variants. HEPACAM comprises 17,076 bases and seven exons. The cDNA has 3563 base pairs. Pathologic allelic variants. HEPACAM mutations leading to the classic phenotype (MLC2A) are mostly missense mutations; however, nonsense and frame-shift mutations have also been observed. In the case of the improving phenotype (MLC2B), only missense mutations in HEPACAM have been reported [López-Hernández et al 2011].Table 3. Selected HEPACAM Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference SequencesPathologic (MLC2A)c.275G>A 1p.Arg92GlnNM_152722.4 NP_689935.2Pathologic (MLC2B)c.265G>A 2p.Gly89Serc.274C>Tp.Arg92TrpSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (http://www.hgvs.org).1. The missense mutation c.274C>T, p.Arg92Trp, which involves this same amino acid, is among the most common mutations in MLC2B.2. Most common mutation in MLC2B (6 of 16 cases in López-Hernández et al [2011])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. HEPACAM is mainly expressed in the brain, with the highest expression in white matter tracts of the central nervous system, in ependymal cells of the brain ventricular zones, and in the central canal of the spinal cord [Favre-Kontula et al 2008]. 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, where it is present in astrocytes, oligodendrocytes, and neurons. A role for GlialCAM in myelination is supported by its upregulation during postnatal mouse brain development, where it is concomitantly expressed with myelin basic protein (MBP). In addition, in vitro, GlialCAM is observed in various developmental stages of oligodendrocytes and in astrocytic processes and at cell contact sites [Favre-Kontula et al 2008].Abnormal gene product. Mutant GlialCAM is not properly localized at the cell membrane in cell-cell contacts. In cultured rat primary astrocytes, mutant GlialCAM with either a dominant or a recessive mutation causes mislocalization of MLC1. Coexpression of wild type GlialCAM rescues the detrimental effect of GlialCAM with a recessive mutation on MLC1 localization, but it does not rescue the effect of the dominant variant of GlialCAM [López-Hernández et al 2011].