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]
| Megalencephalic leukoencephalopathy with subcortical cysts | |
|---|---|
| Other names | Vacuolating megalencephalic leukoencephalopathy with subcortical cysts |
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
editThe disease presents with various signs and symptoms affecting different parts of the body.
In the head, patients exhibit macrocephaly. This is characterized by megalencephaly, which is the enlargement of the brain leading to an increase in the size of the actual head.[3]
In the central nervous system, several symptoms are observed. Megalencephaly, the enlargement of the brain, is notable as it represents the "M" in MLC. Ataxia, particularly slow, progressive, and early-onset cerebellar ataxia, is common among many patients. Spasticity, characterized by muscle spasms, is frequently reported in individuals with MLC. Seizures and delays in motor development are also prevalent. Additionally, mild mental retardation can be observed. Patients often exhibit diffuse swelling of the cerebral white matter and large subcortical cysts in the frontal and temporal lobes, with cysts developing on the tips of the temporal and subcortical areas.
Other significant central nervous system symptoms include diffuse spongiform leukoencephalopathy and vacuolizing myelinopathy. In vacuolizing myelinopathy, the protective myelin sheath on neurons pulls away from their cells, forming small holes in nerve fibers. This condition adversely affects coordination and walking ability.[4]
Genetics
editIt 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]
Diagnosis
editDiagnosis 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.[11] 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.[11] Genetic testing can show whether or not the individual has a mutation in the MLC1 gene, which accounts for 75% of all cases.[12]
Management
editThere 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.[11]
Epidemiology
editMost of the cases were studied in Turkish families who were part of consanguineous marriages (marrying relatives or the "same blood").[13] 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
editA series of cases with megalencephalic leukodystrophy were described by the Indian neurologist Bhim Sen Singhal (1933-)in 1991.[14][11][15] 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.[16][2][17]
References
edit- ^ a b c "Megalencephalic leukoencephalopathy with subcortical cysts; MLC1". Online Mendelian Inheritance in Man (OMIM). Retrieved 2022-03-24.
- ^ a b van der Knaap MS, Barth PG, Stroink H, van Nieuwenhuizen O, Arts WF, Hoogenraad F, et al. (March 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. PMID 7695231. S2CID 29580717.
- ^ "Megalencephalic leukoencephalopathy with subcortical cysts". MedlinePlus Genetics. U.S. National Library of Medicine. Retrieved 2022-03-24.
- ^ "Vacuolar Myelopathy". Clinicalinfo.HIV.gov. U.S. National Institutes of Health. Retrieved 2022-03-24.
- ^ Ilja Boor PK, de Groot K, Mejaski-Bosnjak V, Brenner C, van der Knaap MS, Scheper GC, et al. (June 2006). "Megalencephalic leukoencephalopathy with subcortical cysts: an update and extended mutation analysis of MLC1". Human Mutation. 27 (6): 505–512. doi:10.1002/humu.20332. PMID 16652334. S2CID 3174994.
- ^ "Megalencephalic leukoencephalopathy with subcortical cysts". Genetics Home Reference. U.S. National Library of Medicine. Retrieved 2009-03-11.
- ^ "MLC1 modulator of VRAC current 1 [Homo sapiens (human)] - Gene". National Center for Biotechnology Information (NCBI). U.S. National Library of Medicine. Retrieved 2022-03-17.
- ^ Leegwater PA, Yuan BQ, van der Steen J, Mulders J, Könst AA, Boor PK, et al. (April 2001). "Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts". American Journal of Human Genetics. 68 (4): 831–838. doi:10.1086/319519. PMC 1275636. PMID 11254442.
- ^ Lanciotti A, Brignone MS, Molinari P, Visentin S, De Nuccio C, Macchia G, et al. (May 2012). "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". Human Molecular Genetics. 21 (10): 2166–80. doi:10.1093/hmg/dds032. PMID 22328087.
- ^ López-Hernández T, Sirisi S, Capdevila-Nortes X, Montolio M, Fernández-Dueñas V, Scheper GC, et al. (August 2011). "Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts". Human Molecular Genetics. 20 (16): 3266–77. doi:10.1093/hmg/ddr238. PMID 21624973.
- ^ a b c d Batla A, Pandey S, Nehru R (January 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. U.S. National Institutes of Health. Retrieved 2022-03-24.
- ^ Topçu M, Gartioux C, Ribierre F, Yalçinkaya C, Tokus E, Oztekin N, et al. (February 2000). "Vacuoliting megalencephalic leukoencephalopathy with subcortical cysts, mapped to chromosome 22qtel". 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): 291–296. 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 MS, Wevers RA, Kure S, Gabreëls FJ, Verhoeven NM, van Raaij-Selten B, et al. (November 1999). "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 MS, Boor I, Estévez R (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.