Seltene paroxysmale Störungen in der Neurologie

Zusammenfassung

Seltene paroxysmale neurologische Erkrankungen umfassen seltene monogenetische Epilepsien, episodische Ataxien, seltene Formen der Migräne, primäre Hyperekplexieformen, angeborene paroxysmale Schmerzsyndrome sowie paroxysmale Dyskinesien. Die Weiterentwicklungen in der genetischen Technologie führten zur Entdeckung zahlreicher Gendefekte, die Ursache paroxysmaler Störungen sind. Zudem konnten in der Aufklärung der Pathophysiologie dieser Erkrankungen große Fortschritte erzielt werden. Bestimmte Syndrome sind bereits neben ihrer typischen klinischen Manifestation sowohl über den Stoffwechseldefekt als auch über ihren genetischen Defekt definiert (z. B. GLUT1-Defizienz-Syndrom) und können durch die Kenntnis der spezifischen Funktionsänderung zielgerichtet behandelt werden. Die Art der Funktionsveränderung durch die Mutationen ist bei Ionenkanalerkrankungen von erheblicher Relevanz (wie Funktionsverlust gegenüber -gewinn). Epilepsien, die auf einer SCN2A-Mutation mit einem Funktionsgewinn beruhen, sprechen z. B. gut auf Natriumkanalblocker an. Bei Mutationen in Natriumkanalgenen mit einem Funktionsverlust hingegen sollten Natriumkanalblocker vermieden werden. Solche Beispiele werden durch die fortlaufende Entdeckung weiterer Krankheitsgene und der zugrunde liegenden Mechanismen immer häufiger, sodass langfristig Betroffenen weitere zielgerichtete Therapien angeboten werden können.

Summary

Rare paroxysmal neurological disorders comprise rare forms of epilepsy, episodic ataxias, rare forms of migraine, primary hyperekplexia, congenital paroxysmal pain disorders and paroxysmal dyskinesias. The progression of genetic technologies in the last decades revealed numerous gene mutations which are responsible for paroxysmal disorders. Further investigations lead to substantial advances in the pathophysiological understanding of these diseases. Apart from their classical clinical manifestation, certain syndromes are already defined by their metabolic or genetic defect (i.e. GLUT1-Deficiency Syndrome). As a result, sometimes specific treatment concepts can be offered. In patients with ion channel diseases, the type of functional alteration due to the mutation is highly relevant (for example Loss of Function vs Gain of Function). For example, patients who suffer from SCN2A mutations, which lead to a Gain of Function, show a good response to sodium channel blockers, whereas mutations in different types of sodium channels leading to a Loss of Function should not be treated with sodium channel blockers. Due to ongoing discoveries of further disease-causing mutations and investigation of their basic mechanisms, such examples become steadily more frequent. On the long term, it will be possible to offer an increasing number of individualized therapy concepts to our patients.

Schlüsselwörter

Paroxysmale Erkrankungen - hereditäre Epilepsien - episodische Ataxien - hemiplegische Migräne - primäre Hyperekplexie - angeborene paroxysmale Schmerzsyndrome und paroxysmale Dyskinesien - precision medicine

Keywords

Paroxysmal disorders - monogenetic epilepsies - episodic ataxia - hemiplegic migraine - primary hyperekplexia - congenital paroxysmal pain disorders - parosysmal dyskinesias - precision medicine

• Literatur

• 1 Bakker MJ, van Dijk JG, van den Maagdenberg AM, Tijssen MA. Startle syndromes. Lancet Neurol 2006; 05: 513-524.
• 2 Barcia G, Fleming MR, Deligniere A. et al. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet 2012; 44: 1255-1259.
• 3 Bearden D, Strong A, Ehnot J. et al. Targeted treatment of migrating partial seizures of infancy with quinidine. Ann Neurol 2014; 76: 457-461.
• 4 Bennett DLH, Woods CG. Painful and painless channelopathies. Lancet Neurol 2014; 13: 587-599.
• 5 Berg AT, Berkovic SF, Brodie MJ. et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 2010; 51: 676-685.
• 6 Berkovic SF. Paroxysmal movement disorders and epilepsy Links across the channel. Neurology 2000; 55: 169-170.
• 7 Bhatia KP. Familial (idiopathic) paroxysmal dyskinesias: an update. Semin Neurol 2001; 21: 69-74.
• 8 Bode A, Lynch JW. The impact of human hyperekplexia mutations on glycine receptor structure and function. Mol Brain 2014; 07: 2.
• 9 Borck G, Kubisch C. Ausgewählte Ionenkanalerkrankungen des peripheren Nervensystems. Med Genet 2013; 25: 448-453.
• 10 Brunklaus A, Ellis R, Reavey E. et al. Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome. Brain 2012; 135: 2329-2336.
• 11 Brunklaus A, Ellis R, Reavey E. et al. Genotype phenotype associations across the voltage-gated sodium channel family. J Med Genet 2014; 51: 650-658.
• 12 Choi K-D, Choi J-H. Episodic Ataxias: Clinical and Genetic Features. J Mov Disord 2016; 09: 129-135.
• 13 Deprez L, Weckhuysen S, Holmgren P. et al. Clinical spectrum of early-onset epileptic encephalopathies associated with STXBP1 mutations. Neurology 2010; 75: 1159-1165.
• 14 Faber CG, Lauria G, Merkies ISJ. et al. Gain-offunction Nav1.8 mutations in painful neuropathy. Proc Natl Acad Sci USA 2012; 109: 19444-19449.
• 15 Fischer TZ, Waxman SG. Familial pain syndromes from mutations of the Nav1.7 sodium channel. Ann N Y Acad Sci 2010; 1184: 196-207.
• 16 Freilinger T. Ionenkanalerkrankungen des Gehirns – monogene Migräneformen. Med. Genet 2013; 25.
• 17 Hedrich UBS, Maljevic S. Pathophysiologische Mechanismen genetischer EpilepsienPathophysiological mechanisms of genetic epilepsies. Z Für Epileptol 2016; 29: 77-83.
• 18 Ihsclassification 1.2.3 Hemiplegic migraine – ICHD-3 Beta The International Classification of Headache Disorders 3rd edition (Beta version). ICHD-3 Beta Int. Classif. Headache Disord. 3rd Ed. Beta Version.
• 19 Jen JC, Graves TD, Hess EJ. et al. Primary episodic ataxias: diagnosis, pathogenesis and treatment. Brain 2007; 130: 2484-2493.
• 20 Kegele J, Weber Y. Relevante genetische Befunde für die Praxis. Z Für Epileptol 2016; 29: 87-90.
• 21 Klein K-M, Kluger G, Lemke J, Neubauer B, von Spiczak S, Weber Y. Empfehlungen der Arbeitsgemeinschaft Genetik der DGFE. 2017
• 22 Kovermann P, Hessel M, Kortzak D. et al. Impaired K+ binding to glial glutamate transporter EAAT1 in migraine. Sci Rep. 2017 doi: 10.1038/s41598–017–14176–4.
• 23 Kremeyer B, Lopera F, Cox JJ. et al. A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome. Neuron 2010; 66: 671-680.
• 24 Larsen J, Carvill GL, Gardella E. et al. The phenotypic spectrum of SCN8A encephalopathy. Neurology 2015; 84: 480-489.
• 25 Lerche H, Shah M, Beck H. et al. Ion channels in genetic and acquired forms of epilepsy. J Physiol 2013; 591: 753-764.
• 26 Lim CX, Ricos MG, Dibbens LM, Heron SE. KCNT1 mutations in seizure disorders: the phenotypic spectrum and functional effects. J Med Genet 2016; 53: 217-225.
• 27 Mikati MA, Jiang Y, Carboni M. et al. Quinidine in the treatment of KCNT1-positive Epilepsies. Ann Neurol 2015; 78: 995-999.
• 28 Milligan CJ, Li M, Gazina EV. et al. KCNT1 gainof-function in two epilepsy phenotypes is reversed by quinidine. Ann Neurol 2014; 75: 581-590.
• 29 Mulley JC, Scheffer IE, Petrou S. et al. SCN1A mutations and epilepsy. Hum Mutat 2005; 25: 535-542.
• 30 Nakamura K, Kato M, Osaka H. et al. Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. Neurology 2013; 81: 992-998.
• 31 Nishimaru H, Kakizaki M. The role of inhibitory neurotransmission in locomotor circuits of the developing mammalian spinal cord. Acta Physiol 2009; 197: 83-97.
• 32 Pierson TM, Yuan H, Marsh ED. et al. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol 2014; 01: 190-198.
• 33 Pisano T, Numis AL, Heavin SB. et al. Early and effective treatment of KCNQ2 encephalopathy. Epilepsia 2015; 56: 685-691.
• 34 Rees MI, Harvey K, Pearce BR. et al. Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease. Nat Genet 2006; 38: 801-806.
• 35 Rees MI, Lewis TM, Kwok JBJ. et al. Hyperekplexia associated with compound heterozygote mutations in the beta-subunit of the human inhibitory glycine receptor (GLRB). Hum Mol Genet 2002; 11: 853-860.
• 36 Riant F, Roze E, Barbance C. et al. PRRT2 mutations cause hemiplegic migraine. Neurology 2012; 79: 2122-2124.
• 37 Saitsu H, Fukai R, Ben-Zeev B. et al. Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay. Eur J Hum Genet EJHG 2016; 24: 129-134.
• 38 Scheffer IE, Berkovic S, Capovilla G. et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017; 58: 512-521.
• 39 Strømme P, Mangelsdorf ME, Shaw MA. et al. Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. Nat Genet 2002; 30: 441-445.
• 40 Strupp M, Kalla R, Claassen J. et al. A randomized trial of 4-aminopyridine in EA2 and related familial episodic ataxias. Neurology 2011; 77: 269-275.
• 41 Weber YG, Lerche H. Genetics of paroxysmal dyskinesias. Curr Neurol Neurosci Rep 2009; 09: 206-211.
• 42 Gardiner AR. et al. The clinical and genetic heterogeneity of paroxysmal dyskinesias. Brain 2015; 138: 3567-3580.
• 43 Gardella E. et al. Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation. Ann Neurol 2016; 79: 428-436.
• 44 Wolff M, Johannesen KM, Hedrich UBS. et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain 2017; 140: 1316-1336.
• 45 Wolking S, Spiczak S, von Weber YG. Genetik epileptischer Enzephalopathien. Z Für Epileptol 2016; 29: 70-77.
• 46 Zhang XY, Wen J, Yang W. et al. Gain-of-function mutations in SCN11A cause familial episodic pain. Am J Hum Genet 2013; 93: 957-966.