Clinical and molecular characterization of genetically determined unclear white matter disorders
Zusammenfassung der Projektergebnisse
White matter disorders also known as leukoencephalopathies or leukodystrophies are a constantly growing heterogeneous group of genetic and acquired neurological disorders. The trilateral project brought together an internationally renowned group of clinician scientists with special expertise in the field of rare inborn leukoencephalopathies. The aim was an integrated coordinated approach to early diagnose affected children, learn about the initial symptoms and course of leukoencephalopathies in different ethnic groups, identify new disease genes and analyze their role in human myelin formation and brain development. The project started with the work-up of a consensus standard clinical protocol and the set-up of a web-based database. More than 200 patients from various ethnic groups with the suspected diagnosis of a white matter disorder were recruited. After thorough evaluation of patient data according to the consensus protocol 148 patients were included for molecular characterization. Within this patient cohort we diagnosed 56 cases with known classical leukoencephaolpathies and 92 cases with unclear leukoencephalopathies. For 37 patients we identified a new white matter disease gene and the underlying potential pathomechanisms. The identified genes and encoded proteins influence neurometabolic pathways and cellular regulatory functions that are related to white matter integrity. The information is mandatory to establishing neuroprotective and remyelinating therapies.
Projektbezogene Publikationen (Auswahl)
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Leukoencephalopathy with accumulated succinate is indicative of SDHAF1 related complex II deficiency. Orphanet J Rare Dis. 2012 Sep 20;7:69
Ohlenbusch A, Edvardson S, Skorpen J, Bjornstad A, Saada A, Elpeleg O, Gärtner J, Brockmann K
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Molecular and biochemical characterization of a unique mutation in CCS, the human copper chaperone to superoxide dismutase. Hum Mutat. 2012 Aug;33(8):1207-15
Huppke P, Brendel C, Korenke GC, Marquardt I, Donsante A, Yi L, Hicks JD, Steinbach PJ, Wilson C, Elpeleg O, Møller LB, Christodoulou J, Kaler SG, Gärtner J
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Mutations in SLC33A1 cause a lethal autosomal-recessive disorder with congenital cataracts, hearing loss, and low serum copper and ceruloplasmin. Am J Hum Genet. 2012 Jan 13;90(1):61-8
Huppke P, Brendel C, Kalscheuer V, Korenke GC, Marquardt I, Freisinger P, Christodoulou J, Hillebrand M, Pitelet G, Wilson C, Gruber-Sedlmayr U, Ullmann R, Haas S, Elpeleg O, Nürnberg G, Nürnberg P, Dad S, Møller LB, Kaler SG, Gärtner J
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West syndrome, microcephaly, grey matter heterotopia and hypoplasia of corpus callosum due to a novel ARFGEF2 mutation. J Med Genet. 2013 Nov;50(11):772-5
Banne E, Atawneh O, Henneke M, Brockmann K, Gärtner J, Elpeleg O, Edvardson S
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Diagnosis by whole exome sequencing of atypical infantile onset Alexander disease masquerading as a mitochondrial disorder. Eur J Paediatr Neurol. 2014 Jul;18(4): 495-501
Nishri D, Edvardson S, Lev D, Leshinsky-Silver E, Ben-Sira L, Henneke M, Lerman-Sagie T, Blumkin L
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Compound heterozygous variants in PGAP1 causing severe psychomotor retardation, brain atrophy, recurrent apneas and delayed myelination: a case report and literature review. BMC Neurol. 2016 May 21
Kettwig M, Elpeleg O, Wegener E, Dreha-Kulaczewski S, Henneke M, Gärtner J, Huppke P
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Leukoencephalopathy and early death associated with an Ashkenazi-Jewish founder mutation in the Hikeshi gene. J Med Genet. 2016 Feb;53(2):132-7
Edvardson S, Kose S, Jalas C, Fattal-Valevski A, Watanabe A, Ogawa Y, Mamada H, Fedick AM, Ben-Shachar S, Treff NR, Shaag A, Bale S, Gärtner J, Imamoto N, Elpeleg O
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Magnetic resonance imaging spectrum of succinate dehydrogenase-related infantile leukoencephalopathy. Ann Neurol. 2016 Mar;79(3):379-86
Helman G, Caldovic L, Whitehead MT, Simons C, Brockmann K, Edvardson S, Bai R, Moroni I, Taylor JM, Van Haren K; SDH Study Group., Taft RJ, Vanderver A, van der Knaap MS
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Microcephaly-dystonia due to mutated PLEKHG2 with impaired actin polymerization. Neurogenetics. 2016 Jan;17(1):25-30
Edvardson S, Wang H, Dor T, Atawneh O, Yaacov B, Gärtner J, Cinnamon Y, Chen S, Elpeleg O
