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DOI: 10.1055/a-0621-9139
Spinale Muskelatrophien: Klinik und Therapie
Spinal muscular atrophy – clinical spectrum and therapyPublication History
eingereicht 05 March 2018
akzeptiert 23 April 2018
Publication Date:
24 September 2018 (online)
Zusammenfassung
Die spinale Muskelatrophie (SMA) ist eine fortschreitende autosomal rezessive Motoneuronerkrankung mit einer Inzidenz von 1 in 10.000 Lebendgeburten, die durch den Verlust des Survial Motor Neuron 1 Gens (SMN1) verursacht wird, und stellt die häufigste neurodegenerative Erkrankung im Kindesalter dar. Mit besserem Verständnis der molekularen Basis der SMA in den letzten beiden Jahrzehnten verdichtete sich der Fokus therapeutischer Entwicklungen auf eine Erhöhung des Anteils an funktionsfähigem SMN Protein, entweder durch Einschluss von Exon 7 in SNM2 Transkripte, Erhöhung der SMN2 Genexpression, oder durch direkten Genersatz von SMN1. Auch wenn sich die therapeutischen Möglichkeiten bei SMA mit den zahlreichen neuen Therapieansätzen deutlich verbessert haben, bleiben dennoch zahlreiche Fragen wie der richtige Zeitpunkt für eine optimale therapeutische Intervention ungeklärt. Bestimmend für den Therapieerfolg wird die frühzeitige Erkennung der Erkrankung sein – es ist davon auszugehen, dass ein früher, nach Möglichkeit präsymptomatischer Therapiebeginn das Outcome im Vergleich zu einem späteren Therapiebeginn entscheidend verbessert. Ziel muss daher die präsymptomatische Diagnosestellung durch ein molekulargenetisches Neugeborenenscreening auf SMA sein, um eine Behandlung vor dem Untergang der Motoneurone einleiten zu können.
Abstract
Spinal muscular atrophy (SMA) is a progressive autosomal recessive motor neuron disease with an incidence of 1:10,000 live births, caused by loss of the survival motor neuron 1 gene (SMN1), and represents the most frequent neurodegenerative disorder in children. With greater understanding of the molecular basis of SMA in the past two decades, a major focus of therapeutic developments has been on increasing the fulllength SMN protein by increasing the inclusion of exon 7 in SMN2 transcripts, enhancing SMN2 gene expression, stabilizing the SMN protein or replacing the SMN1 gene. Although the SMA research field is rapidly expanding with new therapeutic opportunities, there are still several issues that remain unsolved. The timing of an optimal intervention is not clear, in particular the point at which there is irreversible pathology precluding any meaningful therapeutic response. Early diagnosis will be crucial for therapeutic success; presumably, the clinical outcome will be much better if treatment already starts presymptomatically. Therefore, presymptomatic diagnosis of SMA via a nationwide genetic newborn screening will be key for an efficient therapy prior to motor neuron death.
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