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Hereditäre Ataxien

Aktuelle Übersicht und diagnostische Strategien

Hereditary ataxias

Current overview and diagnostic strategies

Zusammenfassung

Hereditäre Ataxien stellen aufgrund der Vielfalt der möglichen genetischen Ursachen eine große diagnostische Herausforderung für die medizinische Genetik dar. Dieses Problem wird dadurch verstärkt, dass zwar die Zahl der neu identifizierten Gene in den letzten 3 Jahren durch neue Sequenziertechnologien rasant zugenommen hat, häufig jedoch nur wenige Familien weltweit Mutationen in diesen Genen aufweisen, d. h. sie extrem selten sind. Der vorliegende Artikel gibt eine Übersicht über dominante und rezessive Ataxien und berücksichtigt dabei auch die neu identifizierten Ataxie-Gene. Um den Anforderungen einer praktisch-orientierten genetischen Diagnostik gerecht zu werden, versuchen wir dabei auch, Häufigkeitseinschätzungen der betroffenen Genorte zu geben und – sofern möglich – phänotypische Eigenschaften und Biomarker zu definieren, die eine genetische Diagnostik erfolgversprechend leiten können, insbesondere bei rezessiven Ataxien. Diese diagnostischen Indikatoren werden in Form von diagnostischen Pfaden zusammengefasst, die eine Orientierung bei der mehrstufigen genetischen Diagnostik dominanter und rezessiver Ataxien geben sollen. Aufgrund der Vielzahl der Genkandidaten und des großen phänotypischen Überlappungsbereichs wird es in den meisten Fällen jedoch am zeiteffizientesten und kostengünstigsten sein, Panel-Untersuchungen mittels Next-Generation-Sequencing-Technologien durchzuführen.

Abstract

Hereditary ataxias represent a major diagnostic challenge in medical genetics due to the large number of possible genetic causes. This problem has been intensified during the past 3 years by the identification of a large number of novel genes by modern sequencing technologies. However, the newly identified genes are often extremely rare, occurring at only very low frequencies in ataxia families worldwide. We provide an up-to-date overview of dominant and recessive ataxia genes, including those recently identified. We offer practical guidance for genetic diagnosis by providing frequency estimates and—where possible—defining phenotypic features and biomarkers, particularly for recessive ataxias. These diagnostic indicators are summarized by diagnostic pathways that aim to provide orientation within the multiple genetic diagnostic levels of dominant and recessive ataxia. However, given the high number of candidate genes and the large phenotypic overlap, gene panel approaches based on next-generation sequencing technologies will be most time- and cost-efficient for the majority of ataxia cases in the future.

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Interessenkonflikt

M. Synofzik erhielt eine Forschungsförderung der Volkswagen-Stiftung, Reisekostenerstattung von Ataxia UK/Ataxia Ireland und Beratungshonorare von Actelion Pharmaceuticals Ltd. Dr. Schöls erhielt Forschungsförderung durch die Deutsche Forschungsgemeinschaft (SCHO754/4-1 und SCHO754/5-1), Fördergelder vom Bundesministerium für Bildung und Forschung (BMBF) für Leukonet (01GM0644) und mitoNET (01GM0864) sowie E-RARE-Fördermittel für EUROSPA (01GM0807) und RISCA (01GM0820). Er erhielt außerdem Fördergelder von der HSP-Selbsthilfegruppe Deutschland e. V. Die Arbeitsgruppe von O. Riess wurde durch die E-RARE-Förderung RISCA (01GM0820) unterstützt.

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Synofzik, M., Schöls, L. & Riess, O. Hereditäre Ataxien. medgen 25, 235–248 (2013). https://doi.org/10.1007/s11825-013-0383-y

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Schlüsselwörter

  • Ataxie
  • Autosomal-dominante Ataxien
  • Autosomal-rezessive Ataxien
  • Friedreich-Ataxie
  • Mitochondriale Proteine

Keywords

  • Ataxia
  • Autosomal dominant ataxias
  • Autosomal recessive ataxias
  • Friedreich’s ataxia
  • Mitochondrial proteins