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Megalencephalic leukoencephalopathy with subcortical cysts

Introduction

A novel leukoencephalopathy, now called 'megalencephalic leukoencpehalopathy with subcortical cysts' has been described by our group in 1995 (1). Since then it has been recognized in a growing number of patients (2-6). Recently, a gene for this disease was located (7) and identified (8).

Clinical Symptoms

Patients with MLC usually have normal or only mildly delayed early development. The first sign of the disease is almost always macrocephaly (an enlarged head). So far, all children with the disease develop a macrocephaly within the first year of life. Some already have it at birth. The macrocephaly is usually the reason to see a doctor and make a CT scan or MRI of the brain. These show extensive abnormalities of the white matter of the brain and lead to the diagnosis of  "a leukodystrophy". At that early stage in life, most children have no or very few neurological problems.

Diagnosis - MRI

In typical cases, MRI findings are sufficient for the diagnosis of MLC (1). Other laboratory tests are not helpful in establishing a diagnosis. Sometimes, these laboratory tests are used to exclude other diagnoses. The only disease, in which very similar MRI findings may be present, is merosin-deficient congenital muscular dystrophy (9). However, these children are also floppy and weak because of their muscle disorder. MLC patients are not.
The MRI in MLC shows that the white matter of the brain is diffusely abnormal in signal and mildly swollen, with the exception of some central white matter structures which are entirely or relatively spared (figure 1). These structures include the corpus callosum, internal capsule and brain stem. The cerebellar white matter is usually mildly abnormal in signal and not swollen. It is the swelling of the cerebral white matter that is responsible for the macrocephaly; there is no hydrocephalus. Very typical are the cysts in the white matter just below the cortex. They are always present in the anterior-temporal area and often in the frontoparietal area. They may become very large. In our experience, the cysts may be absent in very young children. With time, the cysts may increase in size and number. Another consistent finding is that over the years the white matter swelling becomes less prominent and some atrophy occurs. Our impression, based on our experience with patients, is that there is a relationship between the severity of the clinical problems and the MRI findings. The milder patients have less severe white matter swelling and more normal white matter.

 

Figure A is the transverse T2-weighted image of a 9-year-old MLC patient; figure B is the sagittal T1-weighted image of the patient. Figures C and D are the transverse T2-weighted and sagittal T1-weighted images of a healthy child. The T2-weighted image shows that the white matter is diffusely abnormal and mildly swollen in the MLC patient (figure A) as compared to the healthy child (figure C). The T1-weighted image shows the subcortical cysts in the anterior-temporal and parietal areas (figure B). 

 

The typical MRI findings are present from about 6 months, maybe even before that. However, the clinical problems lag behind. Usually, after several years of life, the gait becomes increasingly unstable. A slowly progressive cerebellar ataxia finally leads to inability to walk. Most patients become wheelchair dependent as a teenager, but some do so earlier and some later. Spasticity usually remains mild. Most patients have incidental epileptic seizures, but sometimes the epilepsy is more serious. Mental slowing usually sets in at the end of primary school, but the cognitive functions remain relatively well preserved.

We performed a brain biopsy in one patient with informed consent of the parents (10). Histopathology showed that the cortex was normal. In the white matter we found countless small bubbles, "vacuoles", within the myelin sheaths. Myelin sheaths were not lost.

Genetics

From the beginning it was evident that MLC is an inherited disease with apparently an autosomal recessive mode of inheritance (1). There may be multiple patients in one family. The disease is most common in Turkish (6) and Asian-Indian (2) populations. The Turkish parents are often related (1,6), but the Indian parents are not, although they do belong to one tribe (2).   

Knowing the mode of inheritance and having no clue for a biochemical defect, a search for the gene was started. A Turkish-French consortium was successful in locating a gene on chromosome 22qtel, one end of chromosome 22 (7). With data from a few highly informative families, we could narrow down the critical region of where the gene should be found to a small region containing only four genes. In one gene, with the code name KIAA0027, abnormalities (mutations) were found in many MLC patients. This means that this gene causes MLC. We renamed the gene MLC1 (8).

So far, we have found mutations in MLC1 in about 75% of the MLC families. The Indian families share one particular mutation, but the Turkish patients don't. As many as 26 different mutations have been found in 28 families (8,11). In the families with a known mutation, we can provide prenatal diagnosis.

Approximately 25% of the MLC patients lack mutations in MLC1 and genetic studies showed that in these families MLC1 could not be involved. Because we and other groups have been unable to find another gene for MLC, we thought that there could be several other genes that are involved in MLC. We therefore studied the clinical signs and MRIs of MLC patients without MLC1 mutations to see if there could be different sub-groups of patients. We found two distinct groups. The patients in the first group were indistinguishable from patients with MLC1 mutations, for both the clinical signs and the changes that are seen on MRI. Patients in the second group started with the typical clinical and MRI features of MLC in the first year of life. After that, the MRI abnormalities decreased over time and the MRI became normal or greatly improved. These patients lacked all signs of a loss of motor skills on prolonged follow-up. Some of the patients were intellectually normal; some were mentally retarded with or without signs of autism (12).

In collaboration with Prof. Raul Estevez and his group in Barcelona, we have found that the MLC1 protein binds to another protein called GlialCAM. This 'hepatocyte and glial cell adhesion molecule' is encoded by the gene GLIALCAM / HEPACAM. Analysis of GLIALCAM in MLC patients show that mutations in this gene can cause the classical phenotype with autosomal recessive inheritance, in which the children have two mutations, one from each parent. Interestingly, the more benign phenotype has an autosomal dominant mode of inheritance. The children have only one mutation and it comes from one of the parents. In this latter group, the parent with the mutation very often has a large head. This indicates that GLIALCAM is a gene that can be involved in benign familial macrocephaly and macrocephaly with retardation wit or without autism Studies on the interaction between MLC1 and GlialCAM show that MLC1 is not localized properly in the membrane of the cells if GlialCAM is mutated (13).

Finding the second gene for MLC allows us to provide prenatal diagnosis for families with mutations in GLIALCAM.

 

The function of MLC1

A very important question is what the function is of the proteins that the genes MLC1 and  GLIALCAM code for, and what can be done about a defect in one of these proteins. There is no clear answer yet. MLC1 codes for a protein of unknown function, probably a membrane protein. The protein is mainly present in the brain and in white blood cells but in low concentrations. We have started a study to elucidate the function of the MLC1-protein. Mutations in MLC1 result in a reduced amount of MLC1 in the plasma membrane and mutations in GLIALCAM cause mislocalization of GlialCAM and the associated MLC1 (13-15).

Important for the patient

We cannot (yet) cure the disease. We cannot (yet) stop the disease. We can give general support and care. Patients often need anti-epileptic drugs to control the epilepsy. They need physical therapy and special education. Drugs to reduce the white matter swelling appear not to be effective. Some doctors think that creatine monohydrate may be helpful. We have tried this in several patients and followed them clinically and with MRI. Our impression is that creatine monohydrate may increase the energy of the patient, which may lead to some temporary improvement. Personally, we never saw lasting beneficial effects. MRIs did not change. The results of our studies concerning the function of the MLC-protein may tell us more about which way to go.

References

1. Van der Knaap MS, Barth PG, Stroink H,  van Nieuwenhuizen O, Arts WFM, Hoogenraad F, Valk J. Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children. Ann Neurol 1995; 37: 324-334
2. Singhal BS, Gursahani RD, Udani VP, Biniwale AA. Megalencephalic leukodystrophy in an Asian Indian ethnic group. Pediatr Neurol 1996; 14: 291-296
3. Goutičres F, Boulloche J, Bourgeois M, Aicardi J. Leukoencephalopathy, megalencephaly, and mild clinical course. A recently individualized familial leukodystrophy. Report on five new cases. J Child Neurol 1996; 11: 439-444
4. Mejaski-Bosnjak V, Besenski N, Brockmann K, Pouwels PJW, Frahm J, Hanefeld FA. Cystic leukoencephalopathy in a megalencephalic child: clinial and magnetic resonance imaging/magnetic resonance spectroscopy findings. Pediatr Neurol 1997; 16: 347-350
5. Besenski N, Bosnjak V, Cop S, Pavic D, Mikulic D, Orsolic K. Neuroimaging and clinically distinctive features in van der Knaap megalencephalic leukoencephalopathy. Int J Neuroradiol 1997; 3: 244-249
6. Topçu M, Saatic I, Topcuoglu MA, Kose G, Kunak B. Megalencephaly and leukodystrophy with mild clinical course: a report on 12 new cases. Brain Dev 1998; 20: 142-153
7. Topçu M, Gartioux C, Ribierre F, Yalçinkaya C, Tokus E, Öztekin N, Beckmann JS, Ozguc M, Seboun E. Vacuolating leukoencephalopathy with subcortical cysts, mapped to chromosome 22qtel. Am J Hum Genet 2000; 66: 733-739
8. Leegwater PAJ, Yuan BQ, van der Steen J, Mulders J, Konst AAM, 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: 831-838
9. Van der Knaap MS, Smit LME, Barth PG, Catsman-Berrevoets CE, Brouwer OF, Begeer JH, de Coo IFM, Valk J. Magnetic resonance imaging in classification of congenital muscular dystrophies with brain abnormalities. Ann Neurol 1997; 42: 50-59.
10. Van der Knaap MS, Barth PG, Vrensen GFJM, Valk J. Histopathology of an infantile-onset spongiform leukoencephalopathy with a discrepantly mild clinical course. Acta Neuropathol 1996; 92: 206-212
11. Leegwater PAJ, Boor PKI, Yuan BQ, van der Steen J, Visser A, Könst AAM, Oudejans CBM, Schutgens RBH, Pronk JC, van der Knaap MS. Identification of novel mutations in MLC1 responsible for Megalencephalic Leukoencephalopathy with Subcortical Cysts. Hum Genet 2002; 110: 279-283 
12. van der Knaap MS, Lai V, Köhler W, Salih MA, Fonseca MJ, Benke TA, Wilson C, Jayakar P, Aine MR, Dom L, Lynch B, Kálmánchey R, Pietsch P, Errami A, Scheper GC. Megalencephalic leukoencephalopathy with cysts without MLC1 defect. Ann Neurol 2010; 67: 834-837
13. 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: 422-432
14. 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: 2581-2594
15. Duarri A, Teijido O, López-Hernández T, Scheper GC, Barriere H, Boor I, Aguado F, Zorzano A, Palacín M, Martínez A, Lukacs GL, van der Knaap MS, Nunes V, Estévez R. Molecular pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts: mutations in MLC1 cause folding defects. Hum Mol Genet 2008; 17: 3728-3739

 

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