Megalencephalic leukoencephalopathy with subcortical cysts
| Megalencephalic leukoencephalopathy with subcortical cysts | |
|---|---|
| Other names | Vacuolating megalencephalic leukoencephalopathy with subcortical cysts |
Megalencephalic leukoencephalopathy with subcortical cysts (MLC, or Van der Knaap disease) is a form of hereditary CNS demyelinating disease. It belongs to a group of disorders called leukodystrophies. It is characterized by early-onset enlargement of the head (macrocephaly) as well as delayed-onset neurological deterioration to include spasticity, epilepsy, and lack of muscular coordination.[1] MLC does not appear to be a disease that is fatal at birth or early in life despite its symptoms, although the number of patients throughout history known to have the disease is fairly limited.[1]
It belongs to a group of disorders called leukodystrophies. A series of cases with megalencephalic leukodystrophy were described by the Indian neurologist Bhim Sen Singhal (1933-) in 1991. However, it is sometimes referred to as Van der Knaap disease after the Dutch neurologist Marjo van der Knaap who described another series of cases with clinical and radiological features in 1995.[2]
There are three types of Megalencephalic leukoencephalopathy distinguished by the affected gene: Type 1 caused by autosomal recessive mutations on the MLC1 gene, Type 2A an autosomal recessive mutation on the HEPACAM gene, and Type 2B an autosomal dominant mutation on the HEPACAM gene.[1]
Signs and Symptoms
[edit]- Head
- Macrocephaly
- The disease is characterized by megalencephaly, the enlargement of the brain, which is followed by an increase in the size of the actual head.[3]
- Macrocephaly
- Central Nervous System
- Megalencephaly
- The M in MLC stands for “megalencephaly”, the enlargement of the brain
- Ataxia
- Slow, progressive and early-onset cerebellar ataxia has been noted in many patients
- Spasticity
- Patients with MLC often have muscle spasms
- Seizures
- Delay in motor development
- Mild mental retardation
- Diffuse swelling of cerebral white matter
- Large subcortical cysts in frontal and temporal lobes
- Patients develop cysts on the tips of the temporal and subcortical area
- Diffuse spongiform leukoencephalopathy
- Vacuolizing myelinopathy
- The protective myelin sheath on neurons pulls away from their cells forming small holes in nerve fibers – in turn affecting coordination and walking ability.[4]
- Megalencephaly
Genetics
[edit]It is associated with MLC1.[5][6] The MLC1 gene is located in chromosome 22q13.33 and is in the genomic coordinates 22:50,059,390 – 50,085874.[7] The gene contains 12 exons and that contain a start codon in exon 2 and an untranslated region in the 3’ end.[8] The MLC1 gene product is a 377 amino acid protein highly expressed in the brain.[9] The disease is caused by a homozygous or compound heterozygous mutation in the gene, MLC1. Previous research indicates that deficiency of cell surface protein expression of the MLC1 gene is the basis for the disorder.[10] The mutant protein is expressed in intracellular compartments reducing the membrane surface expression when compared to the wild type.[citation needed]
A developmental disorder of the gliovascular unit
[edit]Megalencephalic Leukoencephalopathy with Subcortical Cysts is a rare leukodystrophy caused by the absence of the astrocyte-specific membrane protein MLC1. This condition is characterized by early-onset macrocephaly and progressive vacuolation of the white matter, leading to ataxia, spasticity, and cognitive decline.
During postnatal development, from day 5 to day 15 in mice, MLC1 forms a membrane complex with GlialCAM, another astrocytic transmembrane protein, at the junctions of perivascular astrocytic processes. These processes, together with blood vessels, constitute the gliovascular unit.
MLC is a developmental disorder of the gliovascular unit. Using the Mlc1 knock-out mouse model of MLC it has been demonstrated that MLC1 regulates the postnatal development and organization of perivascular astrocytic processes. It also influences vascular smooth muscle cell contractility, neurovascular coupling, and the clearance of interstitial fluid within the brain parenchyma.[11]
Defects in the maturation of perivascular astrocytic processes and vascular smooth muscle cells are primary events in the pathogenesis of MLC, making them potential therapeutic targets for this disease.
Diagnosis
[edit]Diagnosis of Megalencephalic leukoencephalopathy with subcortical cysts is made with a combination of physical and clinical evaluations. The presence of frontal and temporal subcortical cysts is the main factor when diagnosing a patient with this disease.[12] In the late stages of the disease, patients have been noted to develop impaired coordination, overresponsive reflexes, and even seizures. MRI testing is used to study and diagnose patients with this disease. A study conducted on four patients with this disease yielded similar MRI results despite their slightly differing symptoms.[12] Genetic testing can show whether or not the individual has a mutation in the MLC1 gene, which accounts for 75% of all cases.[13]
Management
[edit]There currently is not a known cure for this disease. However, there are treatment options to mitigate the effects of symptoms that come with this disease. The drug Carbamazepine is an anticonvulsant drug commonly used to treat seizures and nerve pain. A case with a five-year-old girl indicated the ability of this drug to reduce the effects of seizures linked to this disease.[12]
Epidemiology
[edit]Most of the cases were studied in Turkish families who were part of consanguineous marriages (marrying relatives or the "same blood").[14] Nonetheless, Megalencephalic leukoencephalopathy with subcortical cysts does not show genetic heterogeneity which means that there are no mutations in other loci expressing similar phenotypes.[citation needed]
History
[edit]A series of cases with megalencephalic leukodystrophy were described by the Indian neurologist Bhim Sen Singhal (1933-)in 1991.[15][12][16] However, it is sometimes referred to as Van der Knaap disease after the Dutch neurologist Marjo van der Knaap who described another series of cases with clinical and radiological features in 1995.[17][2][18]
References
[edit]- ^ a b c "OMIM MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 1; MLC1". www.omim.org. Retrieved 2022-03-24.
- ^ a b van der Knaap, M. S.; Barth, P. G.; Stroink, H.; van Nieuwenhuizen, O.; Arts, W. F.; Hoogenraad, F.; Valk, J. (1995). "Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children". Annals of Neurology. 37 (3): 324–334. doi:10.1002/ana.410370308. ISSN 0364-5134. PMID 7695231. S2CID 29580717.
- ^ "Megalencephalic leukoencephalopathy with subcortical cysts: MedlinePlus Genetics". medlineplus.gov. Retrieved 2022-03-24.
- ^ "Vacuolar Myelopathy | NIH". clinicalinfo.hiv.gov. Retrieved 2022-03-24.
- ^ Ilja Boor PK, de Groot K, Mejaski-Bosnjak V, et al. (June 2006). "Megalencephalic leukoencephalopathy with subcortical cysts: an update and extended mutation analysis of MLC1". Hum. Mutat. 27 (6): 505–12. doi:10.1002/humu.20332. PMID 16652334. S2CID 3174994.
- ^ "Megalencephalic leukoencephalopathy with subcortical cysts - Genetics Home Reference". Retrieved 2009-03-11.
- ^ "MLC1 modulator of VRAC current 1 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-03-17.
- ^ Leegwater, Peter A. J.; Yuan, Bao Qiang; van der Steen, Jeffrey; Mulders, Joyce; Könst, Andrea A. M.; Boor, P. K. Ilja; Mejaski-Bosnjak, Vlatka; van der Maarel, Silvère M.; Frants, Rune R.; Oudejans, Cees B. M.; Schutgens, Ruud B. H. (2001-04-01). "Mutations of MLC1 (KIAA0027), Encoding a Putative Membrane Protein, Cause Megalencephalic Leukoencephalopathy with Subcortical Cysts". The American Journal of Human Genetics. 68 (4): 831–838. doi:10.1086/319519. ISSN 0002-9297. PMC 1275636. PMID 11254442.
- ^ "Megalencephalic leukoencephalopathy with subcortical cysts protein 1 functionally cooperates with the TRPV4 cation channel to activate the response of astrocytes to osmotic stress: dysregulation by pathological mutations". Retrieved 2022-03-17.
- ^ "Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts". academic.oup.com. Retrieved 2022-03-17.
- ^ Gilbert, Alice; Elorza-Vidal, Xabier; Rancillac, Armelle; Chagnot, Audrey; Yetim, Mervé; Hingot, Vincent; Deffieux, Thomas; Boulay, Anne-Cécile; Alvear-Perez, Rodrigo; Cisternino, Salvatore; Martin, Sabrina; Taïb, Sonia; Gelot, Aontoinette; Mignon, Virginie; Favier, Maryline (2021-11-01). "Megalencephalic leukoencephalopathy with subcortical cysts is a developmental disorder of the gliovascular unit". eLife. 10. doi:10.7554/eLife.71379. ISSN 2050-084X. PMC 8598235. PMID 34723793.
- ^ a b c d Batla, Amit; Pandey, Sanjay; Nehru, Ravi (2011). "Megalencephalic leukoencephalopathy with subcortical cysts: A report of four cases". Journal of Pediatric Neurosciences. 6 (1): 74–77. doi:10.4103/1817-1745.84416. PMC 3173924. PMID 21977097.
- ^ "Megalencephalic leukoencephalopathy with subcortical cysts | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2022-03-24.
- ^ Topçu, Meral; Gartioux, Corine; Ribierre, Florence; Yalçinkaya, Cengiz; Tokus, Erem; Öztekin, Nese; Beckmann, Jacques S.; Ozguc, Meral; Seboun, Eric (February 1, 2000). "Vacuoliting Megalencephalic Leukoencephalopathy with Subcortical Cysts, Mapped to Chromosome 22qtel". The American Journal of Human Genetics. 66 (2): 733–739. doi:10.1086/302758. PMC 1288127. PMID 10677334.
- ^ Singhal, BS; Gursahani, RD; Udani, VP; Biniwale, AA (May 1996). "Megalencephalic leukodystrophy in an Asian Indian ethnic group". Pediatric Neurology. 14 (4): 291–6. doi:10.1016/0887-8994(96)00048-3. PMID 8805171.
- ^ Singhal BS, Gursahani RD, Biniwale AA, Udani VP. Tokyo, Japan: In Proceedings of the 8th Asian and Oceanian Congress of Neurology; 1991. Megalencephalic leukodystrophy in India; p. 72.
- ^ van der Knaap, Marjo S.; Wevers, Ron A.; Kure, Shigeo; Gabreëls, Fons J. M.; Verhoeven, Nanda M.; van Raaij-Selten, Bertie; Jaeken, Jaak (2 July 2016). "Increased Cerebrospinal Fluid Glycine: A Biochemical Marker for a Leukoencephalopathy With Vanishing White Matter". Journal of Child Neurology. 14 (11): 728–731. doi:10.1177/088307389901401108. PMID 10593550. S2CID 25535446.
- ^ van der Knaap, Marjo S; Boor, Ilja; Estévez, Raúl (November 2012). "Megalencephalic leukoencephalopathy with subcortical cysts: chronic white matter oedema due to a defect in brain ion and water homoeostasis". The Lancet Neurology. 11 (11): 973–985. doi:10.1016/S1474-4422(12)70192-8. PMID 23079554. S2CID 31690619.