Neues zur Huntington-Krankheit

Zusammmenfassung

Als im Jahr 1993 das krankheitsverursachende Gen der Huntington-Krankheit (HK) entdeckt wurde, schienen ein rasches Verständnis der Pathogenese dieser hereditären neurodegenerativen Erkrankung und eine kausale Therapie in greifbare Nähe gerückt zu sein. Allerdings gestaltet sich die Entwicklung einer wirksamen und früh im Krankheitsprozess einsetzbaren Behandlung durch die komplexe Pathophysiologie der HK schwierig. Die volle Penetranz dieser monogenetischen Erkrankung ermöglicht es jedoch, modellhaft neurodegenerative Prozesse mit gestörter Proteinhomöostase und RNA-Toxizität sowie rationale Ansatzpunkte für kausal angreifende Therapien zu erforschen und Mutationsträger vor der Entwicklung klinisch erkennbarer Auffälligkeiten in Verlaufsstudien zu untersuchen. Diese Studien (TRACK-HD, PREDICT-HD) haben zur Identifika­tion von MRT-basierten Indikatoren der Neurodegeneration im prämanifesten Stadium geführt, die mit messbaren, aber subtilen funktionellen Veränderungen korrelieren. Standardisierte Untersuchungen im Rahmen von Beobachtungsstudien wie REGISTRY und Fortschritte in den Methoden der Genetik erlauben darüber hinaus eine breitgefächerte Suche nach krankheitsmodifizierenden Einflussfaktoren. Die Therapie der HK ist zur Zeit noch auf symptomatische Maßnahmen beschränkt, aber eine kontinuierliche ärztliche Begleitung und eine an die unterschiedlichen Symptome der verschiedenen Krankheitsphasen angepasste Behandlung verbessern die Lebensqualität der Betroffenen und ihrer Familien messbar. Neue Ansatzpunkte für mechanismenbasierte therapeutische Interventionen geben konkreten Anlass zur Hoffnung, in absehbarer Zukunft den Krankheitsverlauf günstig beeinflussen zu können. Dieser Artikel gibt eine Übersicht über den aktuellen Stand derzeitiger und zukünftiger Behandlungsstrategien sowie Fortschritte in der Biomarkerentwicklung.

Abstract

The discovery of the gene mutation causing Huntington’s disease (HD) 20 years ago raised high hopes for a better understanding of its pathogenesis from primary cause to all of its down-stream ramifications. A rapid development of targeted treatments for this monogenetic disorder appeared to be within reach. Despite concerted efforts there is still no cure and establishing disease modifying treatments continues to remain an elusive goal; the pathophysiology of this slowly progressive disorder proved to be more complex than anticipated. However, research in HD has offered unique insights into a disrupted protein homeostasis and RNA toxicity due to structural RNA alterations as key features in most neurodegenerative disorders. The full penetrance of the HD expansion mutation greatly facilitated the identification of biomarkers for stages of the disease process prior to the emergence of diagnostic clinical symptoms and signs. Large observational studies like TRACK-HD and PREDICT-HD involving pre-manifest muta­tion carriers and patients in early disease stages allowed the identification of imaging markers for neurodegeneration, correlating with subtle functional changes. Standardised assessments in large observational studies like REGISTRY and advances in genetic techniques allow for a comprehensive search for genetic and environmental modifiers of the features and of the course of HD. Treatment is currently restricted to symptomatic relief, but competent care provided by health-care professionals knowledgeable about HD has a measurable impact on the life of people affected by HD. While a disease-modifying therapy for HD has yet to be established, observations in model systems for HD suggest a rational basis for future clinical trials and raise hopes that efficient interventions will be developed which can improve the life of HD affected people and their families.

Schlüsselwörter

Huntington-Krankheit - Pathogenese - Biomarker - Behandlung - Krankheitsmodifikation

Keywords

Huntington’s disease - pathogenesis - biomarker - treatment - disease modification

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