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Megalencephaly With Leukoencephalopathy and Cysts
Megalencephaly With Leukoencephalopathy and Cysts
Kevin R. Moore, MD; Susan I. Blaser, MD, FRCPC; Surjith Vattoth, MD, FRCR
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KEY FACTS

  • Terminology

    • Imaging

      • Pathology

        • Clinical Issues

          • Diagnostic Checklist

            TERMINOLOGY

            • Abbreviations

              • Megalencephaly with leukoencephalopathy and subcortical cysts (MLC)

            • Synonyms

              • Formerly
                • Vacuolating megaloencephalic leukoencephalopathy with benign, slowly progressive course
                • Infantile-onset leukoencephalopathy with swelling and discrepantly mild course
                • van der Knaap disease
                  • 1 of many disorders eponymously named after that author
                • Indian Agarwal megaloencephalic leukodystrophy

            • Definitions

              • Autosomal recessive disorder of astrocytic, volume-regulated anion currents
                • Characterized by macrocephaly, motor/cognitive decline, ataxia, spasticity

            IMAGING

            • General Features

              • CT Findings

                • MR Findings

                  • Imaging Recommendations

                    DIFFERENTIAL DIAGNOSIS

                      PATHOLOGY

                      • General Features

                        • Gross Pathologic & Surgical Features

                          • Microscopic Features

                            CLINICAL ISSUES

                            • Presentation

                              • Demographics

                                • Natural History & Prognosis

                                  • Treatment

                                    DIAGNOSTIC CHECKLIST

                                    • Consider

                                      • Image Interpretation Pearls

                                        • Reporting Tips

                                          Selected References

                                          1. Pérez-Rius C et al: Comparison of zebrafish and mice knockouts for megalencephalic leukoencephalopathy proteins indicates that GlialCAM/MLC1 forms a functional unit. Orphanet J Rare Dis. 14(1):268, 2019
                                          2. Endrakanti M et al: Macrocephaly, epilepsy and intracranial cysts: an image to remember. BMJ Case Rep, 2018
                                          3. Sun Y et al: Novel RNASET2 pathogenic variants in an east Asian child with delayed psychomotor development. Fetal Pediatr Pathol. 37(1):15-21, 2018
                                          4. Bugiani M et al: Megalencephalic leukoencephalopathy with cysts: the Glialcam-null mouse model. Ann Clin Transl Neurol. 4(7):450-65, 2017
                                          5. Abdel-Salam GM et al: Megalencephalic leukoencephalopathy with cysts in twelve Egyptian patients: novel mutations in MLC1 and HEPACAM and a founder effect. Metab Brain Dis. 31(5):1171-9, 2016
                                          6. Tonduti D et al: Clinical, radiological and possible pathological overlap of cystic leukoencephalopathy without megalencephaly and Aicardi-Goutières syndrome. Eur J Paediatr Neurol. 20(4):604-10, 2016
                                          7. Dash PK et al: Megalencephalic leucoencephalopathy with subcortical cysts: subcortical diffuse leucoencephalopathy associated with white matter cystic degeneration. BMJ Case Rep, 2015
                                          8. Dubey M et al: Mice with megalencephalic leukoencephalopathy with cysts: a developmental angle. Ann Neurol. 77(1):114-31, 2015
                                          9. Kariminejad A et al: Eight novel mutations in MLC1 from 18 Iranian patients with megalencephalic leukoencephalopathy with subcortical cysts. Eur J Med Genet. 58(2):71-4, 2015
                                          10. Reis F et al: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) - a case with clinical and magnetic resonance imaging (MRI) dissociation. Arq Neuropsiquiatr. 73(2):171-2, 2015
                                          11. Yamamoto T et al: Leukoencephalopathy associated with 11q24 deletion involving the gene encoding hepatic and glial cell adhesion molecule in two patients. Eur J Med Genet. 58(9):492-6, 2015
                                          12. Mahmoud IG et al: Clinical, neuroimaging, and genetic characteristics of megalencephalic leukoencephalopathy with subcortical cysts in Egyptian patients. Pediatr Neurol. 50(2):140-8, 2014
                                          13. Capdevila-Nortes X et al: Insights into MLC pathogenesis: GlialCAM is an MLC1 chaperone required for proper activation of volume-regulated anion currents. Hum Mol Genet. 22(21):4405-16, 2013
                                          14. Kocaman G et al: An unusually mild presentation of megalencephalic leukoencephalopathy with subcortical cysts. Clin Neurol Neurosurg. 115(8):1564-6, 2013
                                          15. Ramakers K et al: Macrocephaly in an 8-month-old infant. JBR-BTR. 96(6):392, 2013
                                          16. Rodriguez D: Leukodystrophies with astrocytic dysfunction. Handb Clin Neurol. 113:1619-28, 2013
                                          17. Renaud DL: Leukoencephalopathies associated with macrocephaly. Semin Neurol. 32(1):34-41, 2012
                                          18. van der Knaap MS et al: Megalencephalic leukoencephalopathy with subcortical cysts: chronic white matter oedema due to a defect in brain ion and water homoeostasis. Lancet Neurol. 11(11):973-85, 2012
                                          19. Batla A et al: Megalencephalic leukoencephalopathy with subcortical cysts: a report of four cases. J Pediatr Neurosci. 6(1):74-7, 2011
                                          20. Delmonaco AG et al: A child with macrocephaly: case report of a patient with megalencephalic leukoencephalopathy with subcortical cysts and a compound heterozygosity for two mutations in the MLC1 gene. Minerva Pediatr. 63(2):125-9, 2011
                                          21. López-Hernández T et al: Mutant GlialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism. Am J Hum Genet. 88(4):422-32, 2011
                                          22. Miles L et al: Megalencephalic leukoencephalopathy with subcortical cysts: a third confirmed case with literature review. Pediatr Dev Pathol. 12(3):180-6, 2009
                                          23. Tinsa F et al: Megalencephalic leukoencephalopathy with subcortical cysts in a Tunisian boy. J Child Neurol. 24(1):87-9, 2009
                                          24. Duarri A et al: Molecular pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts: mutations in MLC1 cause folding defects. Hum Mol Genet. 17(23):3728-39, 2008
                                          25. Faria EC et al: Cystic leukoencephalopathy without megalencephaly. Arq Neuropsiquiatr. 66(2A):261-3, 2008
                                          26. Shukla P et al: Prenatal diagnosis of megalencephalic leukodystrophy. Prenat Diagn. 28(4):357-9, 2008
                                          27. Boor I et al: MLC1 is associated with the dystrophin-glycoprotein complex at astrocytic endfeet. Acta Neuropathol. 114(4):403-10, 2007
                                          28. Kiriyama T et al: SPECT revealed cortical dysfunction in a patient who had genetically definite megalencephalic leukoencephalopathy with subcortical cysts. Clin Neurol Neurosurg. 109(6):526-30, 2007
                                          29. Teijido O et al: Expression patterns of MLC1 protein in the central and peripheral nervous systems. Neurobiol Dis. 26(3):532-45, 2007
                                          30. Ilja Boor PK et al: Megalencephalic leukoencephalopathy with subcortical cysts: an update and extended mutation analysis of MLC1. Hum Mutat. 27(6):505-12, 2006
                                          31. Morita H et al: MR imaging and 1H-MR spectroscopy of a case of van der Knaap disease. Brain Dev. 28(7):466-9, 2006
                                          32. Henneke M et al: Cystic leukoencephalopathy without megalencephaly: a distinct disease entity in 15 children. Neurology. 64(8):1411-6, 2005
                                          33. Gorospe JR et al: Indian Agarwal megalencephalic leukodystrophy with cysts is caused by a common MLC1 mutation. Neurology. 62(6):878-82, 2004
                                          34. Marszał E et al: Leukoencephalopathy with macrocephaly and mild clinical course. Neurol Neurochir Pol. 38(1 Suppl 1):S25-30, 2004
                                          35. Schiffmann R et al: The latest on leukodystrophies. Curr Opin Neurol. 17(2):187-92, 2004
                                          36. Brockmann K et al: Megalencephalic leukoencephalopathy with subcortical cysts in an adult: quantitative proton MR spectroscopy and diffusion tensor MRI. Neuroradiology. 45(3):137-42, 2003
                                          37. Chandrashekar HS et al: Megalencephalic leukoencephalopathy with subcortical cysts: MRI and proton spectroscopic features. Neurol India. 51(4):525-7, 2003
                                          38. Singhal BS et al: Megalencephalic leukoencephalopathy with subcortical cysts. J Child Neurol. 18(9):646-52, 2003
                                          39. de Santos-Moreno MT et al: [Non specific leukodystrophy. A new case of vacuolizing leukoencephalopathy with megalencephaly.] Rev Neurol. 34(1):19-27, 2002
                                          40. De Stefano N et al: Severe metabolic abnormalities in the white matter of patients with vacuolating megalencephalic leukoencephalopathy with subcortical cysts. A proton MR spectroscopic imaging study. J Neurol. 248(5):403-9, 2001
                                          41. Leegwater PA et al: Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts. Am J Hum Genet. 68(4):831-8, 2001
                                          42. Gulati S et al: Infantile-onset leukoencephalopathy with discrepant mild clinical course. Indian J Pediatr. 67(10):769-73, 2000
                                          43. Topçu M et al: Vacuoliting megalencephalic leukoencephalopathy with subcortical cysts, mapped to chromosome 22qtel. Am J Hum Genet. 66(2):733-9, 2000
                                          44. Yalçinkaya C et al: Siblings with cystic leukoencephalopathy and megalencephaly. J Child Neurol. 15(10):690-3, 2000
                                          45. Thelle T et al: Van der Knaap's vacuolating leukoencephalopathy: two additional cases. Eur J Paediatr Neurol. 3(2):83-6, 1999
                                          46. van der Knaap MS et al: Defining and categorizing leukoencephalopathies of unknown origin: MR imaging approach. Radiology. 213(1):121-33, 1999
                                          47. Koeda T et al: Slowly progressive cystic leukoencephalopathy with megalencephaly in a Japanese boy. Brain Dev. 20(4):245-9, 1998
                                          48. Mejaski-Bosnjak V et al: Cystic leukoencephalopathy in a megalencephalic child: clinical and magnetic resonance imaging/magnetic resonance spectroscopy findings. Pediatr Neurol. 16(4):347-50, 1997
                                          49. van der Knaap MS et al: Histopathology of an infantile-onset spongiform leukoencephalopathy with a discrepantly mild clinical course. Acta Neuropathol. 92(2):206-12, 1996
                                          50. van der Knaap MS et al: Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children. Ann Neurol. 37(3):324-34, 1995
                                          Related Anatomy
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                                          Related Differential Diagnoses
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                                          References
                                          Tables

                                          Tables

                                          KEY FACTS

                                          • Terminology

                                            • Imaging

                                              • Pathology

                                                • Clinical Issues

                                                  • Diagnostic Checklist

                                                    TERMINOLOGY

                                                    • Abbreviations

                                                      • Megalencephaly with leukoencephalopathy and subcortical cysts (MLC)

                                                    • Synonyms

                                                      • Formerly
                                                        • Vacuolating megaloencephalic leukoencephalopathy with benign, slowly progressive course
                                                        • Infantile-onset leukoencephalopathy with swelling and discrepantly mild course
                                                        • van der Knaap disease
                                                          • 1 of many disorders eponymously named after that author
                                                        • Indian Agarwal megaloencephalic leukodystrophy

                                                    • Definitions

                                                      • Autosomal recessive disorder of astrocytic, volume-regulated anion currents
                                                        • Characterized by macrocephaly, motor/cognitive decline, ataxia, spasticity

                                                    IMAGING

                                                    • General Features

                                                      • CT Findings

                                                        • MR Findings

                                                          • Imaging Recommendations

                                                            DIFFERENTIAL DIAGNOSIS

                                                              PATHOLOGY

                                                              • General Features

                                                                • Gross Pathologic & Surgical Features

                                                                  • Microscopic Features

                                                                    CLINICAL ISSUES

                                                                    • Presentation

                                                                      • Demographics

                                                                        • Natural History & Prognosis

                                                                          • Treatment

                                                                            DIAGNOSTIC CHECKLIST

                                                                            • Consider

                                                                              • Image Interpretation Pearls

                                                                                • Reporting Tips

                                                                                  Selected References

                                                                                  1. Pérez-Rius C et al: Comparison of zebrafish and mice knockouts for megalencephalic leukoencephalopathy proteins indicates that GlialCAM/MLC1 forms a functional unit. Orphanet J Rare Dis. 14(1):268, 2019
                                                                                  2. Endrakanti M et al: Macrocephaly, epilepsy and intracranial cysts: an image to remember. BMJ Case Rep, 2018
                                                                                  3. Sun Y et al: Novel RNASET2 pathogenic variants in an east Asian child with delayed psychomotor development. Fetal Pediatr Pathol. 37(1):15-21, 2018
                                                                                  4. Bugiani M et al: Megalencephalic leukoencephalopathy with cysts: the Glialcam-null mouse model. Ann Clin Transl Neurol. 4(7):450-65, 2017
                                                                                  5. Abdel-Salam GM et al: Megalencephalic leukoencephalopathy with cysts in twelve Egyptian patients: novel mutations in MLC1 and HEPACAM and a founder effect. Metab Brain Dis. 31(5):1171-9, 2016
                                                                                  6. Tonduti D et al: Clinical, radiological and possible pathological overlap of cystic leukoencephalopathy without megalencephaly and Aicardi-Goutières syndrome. Eur J Paediatr Neurol. 20(4):604-10, 2016
                                                                                  7. Dash PK et al: Megalencephalic leucoencephalopathy with subcortical cysts: subcortical diffuse leucoencephalopathy associated with white matter cystic degeneration. BMJ Case Rep, 2015
                                                                                  8. Dubey M et al: Mice with megalencephalic leukoencephalopathy with cysts: a developmental angle. Ann Neurol. 77(1):114-31, 2015
                                                                                  9. Kariminejad A et al: Eight novel mutations in MLC1 from 18 Iranian patients with megalencephalic leukoencephalopathy with subcortical cysts. Eur J Med Genet. 58(2):71-4, 2015
                                                                                  10. Reis F et al: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) - a case with clinical and magnetic resonance imaging (MRI) dissociation. Arq Neuropsiquiatr. 73(2):171-2, 2015
                                                                                  11. Yamamoto T et al: Leukoencephalopathy associated with 11q24 deletion involving the gene encoding hepatic and glial cell adhesion molecule in two patients. Eur J Med Genet. 58(9):492-6, 2015
                                                                                  12. Mahmoud IG et al: Clinical, neuroimaging, and genetic characteristics of megalencephalic leukoencephalopathy with subcortical cysts in Egyptian patients. Pediatr Neurol. 50(2):140-8, 2014
                                                                                  13. Capdevila-Nortes X et al: Insights into MLC pathogenesis: GlialCAM is an MLC1 chaperone required for proper activation of volume-regulated anion currents. Hum Mol Genet. 22(21):4405-16, 2013
                                                                                  14. Kocaman G et al: An unusually mild presentation of megalencephalic leukoencephalopathy with subcortical cysts. Clin Neurol Neurosurg. 115(8):1564-6, 2013
                                                                                  15. Ramakers K et al: Macrocephaly in an 8-month-old infant. JBR-BTR. 96(6):392, 2013
                                                                                  16. Rodriguez D: Leukodystrophies with astrocytic dysfunction. Handb Clin Neurol. 113:1619-28, 2013
                                                                                  17. Renaud DL: Leukoencephalopathies associated with macrocephaly. Semin Neurol. 32(1):34-41, 2012
                                                                                  18. van der Knaap MS et al: Megalencephalic leukoencephalopathy with subcortical cysts: chronic white matter oedema due to a defect in brain ion and water homoeostasis. Lancet Neurol. 11(11):973-85, 2012
                                                                                  19. Batla A et al: Megalencephalic leukoencephalopathy with subcortical cysts: a report of four cases. J Pediatr Neurosci. 6(1):74-7, 2011
                                                                                  20. Delmonaco AG et al: A child with macrocephaly: case report of a patient with megalencephalic leukoencephalopathy with subcortical cysts and a compound heterozygosity for two mutations in the MLC1 gene. Minerva Pediatr. 63(2):125-9, 2011
                                                                                  21. López-Hernández T et al: Mutant GlialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism. Am J Hum Genet. 88(4):422-32, 2011
                                                                                  22. Miles L et al: Megalencephalic leukoencephalopathy with subcortical cysts: a third confirmed case with literature review. Pediatr Dev Pathol. 12(3):180-6, 2009
                                                                                  23. Tinsa F et al: Megalencephalic leukoencephalopathy with subcortical cysts in a Tunisian boy. J Child Neurol. 24(1):87-9, 2009
                                                                                  24. Duarri A et al: Molecular pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts: mutations in MLC1 cause folding defects. Hum Mol Genet. 17(23):3728-39, 2008
                                                                                  25. Faria EC et al: Cystic leukoencephalopathy without megalencephaly. Arq Neuropsiquiatr. 66(2A):261-3, 2008
                                                                                  26. Shukla P et al: Prenatal diagnosis of megalencephalic leukodystrophy. Prenat Diagn. 28(4):357-9, 2008
                                                                                  27. Boor I et al: MLC1 is associated with the dystrophin-glycoprotein complex at astrocytic endfeet. Acta Neuropathol. 114(4):403-10, 2007
                                                                                  28. Kiriyama T et al: SPECT revealed cortical dysfunction in a patient who had genetically definite megalencephalic leukoencephalopathy with subcortical cysts. Clin Neurol Neurosurg. 109(6):526-30, 2007
                                                                                  29. Teijido O et al: Expression patterns of MLC1 protein in the central and peripheral nervous systems. Neurobiol Dis. 26(3):532-45, 2007
                                                                                  30. Ilja Boor PK et al: Megalencephalic leukoencephalopathy with subcortical cysts: an update and extended mutation analysis of MLC1. Hum Mutat. 27(6):505-12, 2006
                                                                                  31. Morita H et al: MR imaging and 1H-MR spectroscopy of a case of van der Knaap disease. Brain Dev. 28(7):466-9, 2006
                                                                                  32. Henneke M et al: Cystic leukoencephalopathy without megalencephaly: a distinct disease entity in 15 children. Neurology. 64(8):1411-6, 2005
                                                                                  33. Gorospe JR et al: Indian Agarwal megalencephalic leukodystrophy with cysts is caused by a common MLC1 mutation. Neurology. 62(6):878-82, 2004
                                                                                  34. Marszał E et al: Leukoencephalopathy with macrocephaly and mild clinical course. Neurol Neurochir Pol. 38(1 Suppl 1):S25-30, 2004
                                                                                  35. Schiffmann R et al: The latest on leukodystrophies. Curr Opin Neurol. 17(2):187-92, 2004
                                                                                  36. Brockmann K et al: Megalencephalic leukoencephalopathy with subcortical cysts in an adult: quantitative proton MR spectroscopy and diffusion tensor MRI. Neuroradiology. 45(3):137-42, 2003
                                                                                  37. Chandrashekar HS et al: Megalencephalic leukoencephalopathy with subcortical cysts: MRI and proton spectroscopic features. Neurol India. 51(4):525-7, 2003
                                                                                  38. Singhal BS et al: Megalencephalic leukoencephalopathy with subcortical cysts. J Child Neurol. 18(9):646-52, 2003
                                                                                  39. de Santos-Moreno MT et al: [Non specific leukodystrophy. A new case of vacuolizing leukoencephalopathy with megalencephaly.] Rev Neurol. 34(1):19-27, 2002
                                                                                  40. De Stefano N et al: Severe metabolic abnormalities in the white matter of patients with vacuolating megalencephalic leukoencephalopathy with subcortical cysts. A proton MR spectroscopic imaging study. J Neurol. 248(5):403-9, 2001
                                                                                  41. Leegwater PA et al: Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts. Am J Hum Genet. 68(4):831-8, 2001
                                                                                  42. Gulati S et al: Infantile-onset leukoencephalopathy with discrepant mild clinical course. Indian J Pediatr. 67(10):769-73, 2000
                                                                                  43. Topçu M et al: Vacuoliting megalencephalic leukoencephalopathy with subcortical cysts, mapped to chromosome 22qtel. Am J Hum Genet. 66(2):733-9, 2000
                                                                                  44. Yalçinkaya C et al: Siblings with cystic leukoencephalopathy and megalencephaly. J Child Neurol. 15(10):690-3, 2000
                                                                                  45. Thelle T et al: Van der Knaap's vacuolating leukoencephalopathy: two additional cases. Eur J Paediatr Neurol. 3(2):83-6, 1999
                                                                                  46. van der Knaap MS et al: Defining and categorizing leukoencephalopathies of unknown origin: MR imaging approach. Radiology. 213(1):121-33, 1999
                                                                                  47. Koeda T et al: Slowly progressive cystic leukoencephalopathy with megalencephaly in a Japanese boy. Brain Dev. 20(4):245-9, 1998
                                                                                  48. Mejaski-Bosnjak V et al: Cystic leukoencephalopathy in a megalencephalic child: clinical and magnetic resonance imaging/magnetic resonance spectroscopy findings. Pediatr Neurol. 16(4):347-50, 1997
                                                                                  49. van der Knaap MS et al: Histopathology of an infantile-onset spongiform leukoencephalopathy with a discrepantly mild clinical course. Acta Neuropathol. 92(2):206-12, 1996
                                                                                  50. van der Knaap MS et al: Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children. Ann Neurol. 37(3):324-34, 1995