GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. Megalencephalic leukoencephalopathy with subcortical cysts (referred to as MLC in this Review) 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 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 the 98th percentile, usually several centimeters above it. Almost all individuals have epilepsy from an early age. Initial mental and motor development is normal in most cases. Walking is often unstable, followed by ataxia of the trunk and extremities, then minor signs of pyramidal dysfunction and brisk deep tendon stretch reflexes. Mental deterioration is late and mild. 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 forties.
Diagnosis/testing. The diagnosis of MLC is established in individuals with typical clinical findings and characteristic abnormalities observed on cranial MRI, including abnormal and swollen cerebral hemispheric white matter and presence of subcortical cysts in the anterior temporal region and often in the frontoparietal region. MLC1 is the only gene known to be associated with MLC. Sequence analysis detects mutations in approximately 60% to 70% of affected individuals. Such testing is clinically available.
Management. Treatment of manifestations: antiepileptic drugs to control epileptic seizures; physical therapy to improve motor function; special education.
Genetic counseling. MLC is 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. Once an at-risk sib is known to be unaffected, the chance of his/her being carrier is 2/3. Carrier testing for relatives at risk and prenatal diagnosis for pregnancies at increased risk are possible if both MLC1 disease-causing alleles have been identified in the family.
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].
Typical clinical findings
Macrocephaly 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 follows a line usually 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.
Figure 1A. The transverse T2-weighted image of a nine-year-old with MLC, showing diffusely abnormal and mildly swollen white matter.
Figure 1B. The sagittal T1-weighted image of the same child, showing subcortical cysts in the anterior-temporal and parietal areas (arrows).
Figure 2A, Figure 2B. The transverse T2-weighted and sagittal T1-weighted images, respectively, of a healthy child
Figure):
Cerebral hemispheric white matter is diffusely abnormal and mildly swollen; see Figure 1A (from an individual with MLC) as compared to Figure 2A (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 1B (from an individual with MLC) as compared to Figure 2B (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].
Routine 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].
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. MLC1 is currently the only gene known to be associated with MLC.
Other loci. Evidence exists for at least one other gene for MLC, but it has not been mapped or identified [Blattner et al 2003, Patrono et al 2003].
Clinical testing
Sequence analysis of the coding region of the MLC1 genomic DNA detects mutations in approximately 60% to 70% of individuals with clinical and MRI presentation of MLC. Affected individuals are homozygotes or compound heterozygotes for mutations within MLC1.
Sequence analysis of complementary DNA, if available, can be performed to:
Detect aberrant splice products that occur as a result of mutations outside the regions that are included in the standard analysis of exons and surrounding intronic regions, such as a genomic deletion of the region including exons 4 and 5 (p.Thr99fsX) [Ilja Boor et al 2006].
Determine the effect of mutations close to but not within the acceptor or donor sites, such as the mutation c.178-10T>A in IVS2. Theoretically, this change would not be predicted to affect splicing; however, cDNA analysis revealed a skipping of exon 2, which encodes amino acids 60 through 89 [S van der Knaap & GC Scheper, unpublished data].
Table 1 summarizes molecular genetic testing for this disorder.
| Gene Symbol | Proportion of MLC Attributed to Mutations in This Gene | Test Method | Mutation Detection Frequency by Test Method | Test Availability |
|---|---|---|---|---|
| MLC1 | 70% 1 | Sequence analysis | >95% 2 | Clinical
 |
1. Approximately 30% of affected individuals do not have an identifiable MLC1 mutation and most likely have a mutation in another as-yet-uncharacterized gene or genes.
2. 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. 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.
Interpretation of test results
For issues to consider in interpretation of sequence analysis results, click here.
Finding two-disease causing mutations in MLC1 confirms the diagnosis of MLC, but absence of MLC1 mutations does not exclude the diagnosis when the clinical and MRI findings are characteristic.
Establishing the diagnosis in a proband. 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.
Note: If the proband fulfills the clinical and MRI criteria, molecular genetic testing is mainly performed for genetic counseling purposes. If no mutations are found in the MLC1 gene, the diagnosis of MLC is unchanged.
Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.
Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing MLC.
Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.
Thus far, all individuals with mutations in MLC1 have a leukoencephalopathy; no other phenotypes have been observed.
It has been suggested that MLC1 could be involved in catatonic schizophrenia via a putative dominantly acting missense mutation, p.Leu309Met [Meyer et al 2001]. Meyer et al [2001] suggested that this mutation was cosegregating in a large pedigree with periodic catatonia. Subsequently, 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. More recently, Verma et al [2005] concluded that rare and common variants in MLC1 might 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 [2007] 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.” 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.
To date, macrocephaly has been observed in all individuals with genetically confirmed megalencephalic leukoencephalopathy with subcortical cysts (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.
Initial mental and motor development is normal in most cases 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.
Mental deterioration is late and mild. Decreasing school performance becomes evident during the later years of primary school. In a minority of individuals, intellectual capacities are mildly decreased in the early years. Some individuals develop behavioral problems [Sugiura et al 2006]. Speech becomes increasingly dysarthric, and dysphagia may develop. Some individuals display extrapyramidal movement abnormalities with dystonia and athetosis. Some individuals 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 individuals have a more severe clinical course and maintain their ability to walk independently only for a few years or never achieve independent walking.
Some individuals have a more benign clinical course and, even as teenagers, only have macrocephaly. Some 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 forties.
No genotype-phenotype correlation has been described [Leegwater et al 2001, Leegwater et al 2002]:
Severity of the phenotype does not correlate with the specific mutation found.
Individuals from the same family can show significant variability in symptom severity and clinical course.
No difference is evident between individuals with MLC who have identifiable mutations in MLC1 and those who do not.
Names previously used for MLC:
Leukoencephalopathy with swelling and a discrepantly mild course
Leukoencephalopathy with swelling and cysts
Infantile leukoencephalopathy and megalencephaly
van der Knaap disease
Vacuolating leukoencephalopathy
MLC is a rare disease with a low carrier rate in the general population. The disease is rare in communities with a low rate of consanguinity. In many individuals with MLC, the parents are consanguineous.
The disease has a higher than expected incidence in populations in which consanguinity is common, such as in Turkey [Topçu et al 1998]. Almost all East-Indian individuals with MLC belong to the Agrawal community; and all individuals within this community share the same mutation (c.135insC, p.Cys46LeufsX34), providing evidence for a founder effect [Leegwater et al 2002, Singhal et al 2003, Gorospe et al 2004].
MLC is also relatively common among Libyan Jews [Ben-Zeev et al 2001]. One common mutation (c.176G>A, p.Gly59Glu) was found in five unrelated Libyan Jewish families [Ben-Zeev et al 2002]. The same mutation was identified in several affected individuals from a single Jewish Turkish family descended from the same ancestors. Screening of 200 normal Libyan Jewish individuals for this particular mutation 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 mutation.
The mutation c.278C>T, p.SerS93Leu appears to be fairly common in Japanese individuals [Saijo et al 2003, Tsujino et al 2003] but has also been observed in Finland, Turkey [Leegwater et al 2001], and Italy [Montagna et al 2006].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
The differential diagnosis of macrocephaly and a diffuse leukoencephalopathy is limited; it includes Canavan disease, Alexander disease, infantile-onset GM2 gangliosidosis, and, on occasion, individuals with infantile-onset GM1 gangliosidosis and L-2-hydroxyglutaric aciduria (see Organic Acidemias Overview). Some children with merosin-deficient congenital muscular dystrophy have macrocephaly. None of the mentioned disorders shares all the MRI characteristics of megalencephalic leukoencephalopathy with subcortical cysts (MLC). Usually, the clinical features and disease course are also different. If the head circumference is well within the normal limits at age one year, it is highly unlikely that the infant has MLC.
The white matter disease in merosin-deficient congenital muscular dystrophy most clearly resembles that observed in MLC, but the typical subcortical cysts are generally lacking [van der Knaap et al 1997]. In addition, individuals with merosin-deficient congenital muscular dystrophy have prominent weakness and hypotonia, not shared by individuals with MLC. The diagnosis can be confirmed using muscle biopsy and staining for merosin.
In 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. In Canavan disease, N-acetyl aspartate is elevated in urine and blood and a deficiency of the enzyme aspartoacylase can be demonstrated in cultured fibroblasts.
Alexander disease leads to a megalencephaly and leukoencephalopathy with frontal predominance of MRI abnormalities [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 analysis of the GFAP gene.
MRI in infantile GM2 gangliosidosis 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.
MRI features in infantile GM1 gangliosidosis 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.
To establish the extent of disease in an individual diagnosed with megalencephalic leukoencephalopathy with subcortical cysts (MLC), the following evaluations are recommended:
Neurologic examination
Brain MRI
Physical therapy/occupational therapy assessment
Assessment of cognitive dysfunction (neuropsychological testing)
Supportive therapy includes the following:
Anti-epileptic drugs (AED) if epileptic seizures are present
Physical therapy to improve motor function
Special education
Speech therapy as needed
Minor 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.
Minor 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.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Search 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.
Unsuccessful therapies have included diuretics, acetazolamide, and creatine monohydrate.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is inherited in an autosomal recessive manner.
Parents of a proband
The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
Heterozygotes (carriers) are asymptomatic. No clinical or MRI abnormalities have been found in heterozygotes (carriers) for a MLC1 mutation.
Sibs of a proband
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.
Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic. No clinical or MRI abnormalities have been found in heterozygotes (carriers) for an MLC1 mutation.
Offspring of a proband. The offspring of an individual with MLC are obligate heterozygotes (carriers) for a disease-causing mutation in MLC1.
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier testing for relatives of the proband is available on a clinical basis once the mutation(s) has/have been identified in the family.
Family planning
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at-risk of being carriers.
Testing of at-risk asymptomatic individuals. So far, all individuals homozygous or compound heterozygous for two pathogenic mutations in MLC1 have borderline macrocephaly or, more often, prominent macrocephaly. So far, individuals with a normal head circumference have never been found to have two mutations in MLC1. Thus, only very young infants can be at risk and asymptomatic. Testing of such infants for MLC is available using the same techniques described in Molecular Genetic Testing. Such testing is not useful in predicting the severity of the neurologic disease. When testing at-risk individuals for MLC, an affected family member should be tested first to confirm the presence of mutations in MLC1. If no mutations are found in the individual, molecular genetic testing of the at-risk infant is not possible. An MRI in the second half year of life can distinguish between healthy and affected infants, more or less at the same time that the macrocephaly becomes evident.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to12 weeks' gestation. Both MLC1 disease-causing alleles must be identified in an affected relative before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| MLC1 | 22q13.3 | Membrane protein MLC1 |
Data are compiled from the following standard references: gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
Table B. OMIM Entries for Megalencephalic Leukoencephalopathy with Subcortical Cysts
| 604004 | MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS; MLC |
| 605908 | MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS GENE 1; MLC1 |
| Gene Symbol | Entrez Gene | HGMD |
|---|---|---|
| MLC1 | 23209 (MIM No. 605908) | MLC1 |
For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
Normal allelic variants: The gene comprises 26,214 bases. The gene contains 13 exons; the cDNA has 3435 base pairs. The gene 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 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 only one out of 50 is a nonsense mutation. (For more information, see Genomic Databases table.) More recently, Montagna et al [2006] reported nine additional novel mutations.
| Class of Variant Allele | DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequence |
|---|---|---|---|
| Normal | c.512G>T 1 | p.Cys171Phe | NM_015166.3NP_055981.1 |
| c.654C>A 1 | p.Asn218Lys | ||
| c.925C>A 1 | p.Leu309Met | ||
| c.1031A>G 1 | p.Asn344Ser | ||
| Pathologic | c.135insC | p.Cys46LeufsX34 | |
| c.176G>A | p.Gly59Glu | ||
| c.178-10T>A | -- | ||
| c.298_423del126+108del 2 | p.Thr99fsX | ||
| c.278C>T | p.Ser93Leu |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (http://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%)
Normal gene product: The protein size is 377 amino acids; its predicted molecular weight is 41 kd. It 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: Not known. 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.
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
Australian Leukodystrophy Support Group
10 Mitchell Street
Mentone VIC 3194
Victoria Australia
Phone: (+61)3 9584 7070; 1800-141-400 (toll free)
Fax: (+61)3 9583 4379
Email: mail@alds.org.au
www.alds.org.au
European Leukodystrophy Association (ELA)
Email: ela@ela-asso.com
http://www.ela-asso.com/
United Leukodystrophy Foundation (ULF)
2304 Highland Drive
Sycamore, IL 60178
Phone: 800-728-5483; 815-895-3211
Fax: 815-895-2432
Email: office@ulf.org
www.ulf.org
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
JC Pronk, PhD; Vrije Universiteit Medical Center, Amsterdam (2003-2008)
Gert C Scheper, PhD (2008-present)
Marjo S Van der Knaap, MD, PhD (2003-present)
29 July 2008 (me) Comprehensive update posted live
29 November 2005 (me) Comprehensive update posted live
11 August 2003 (me) Review posted to live Web site
12 June 2003 (MVDK) Original submission
