Aktuelles zu den spinalen Muskelatrophien

Zusammenfassung

80 bis 90% aller spinalen Muskelatrophien (SMA) entfallen auf den autosomal-rezessiven Typ des Kindes- und Jugendalters, dessen Gen (SMN-Gen) auf Chromosom 5 identifiziert werden konnte. Auf Grund einer Duplikation dieses Chromosomenabschnittes liegt das Gen in zwei Kopien vor (SMN1 und SMN2), die sich lediglich in fünf Nukleotiden unterscheiden. Diese Unterschiede führen jedoch zu unterschiedlichem mRNA-Spleißen, indem nur das SMN1-Gen zu einem stabilen Genprodukt führt (SMN-Protein), während das Genprodukt von SMN2 instabil ist. Heterozygotes Fehlen von SMN1 führt zur SMA, während die Zahl der dennoch vorhandenen SMN2-Kopien den Schweregrad der Erkrankung bestimmt (SMA TypI bis III). Das SMN-Protein ist in allen Zellen an der Regulation der mRNA Synthese beteiligt. In den Motoneuronen scheint es zusätzlich eine besondere Rolle bei Wachstum und Differenzierung der Axone zu haben. Aktuelle experimentelle Therapieansätze zielen darauf ab, das Spleißverhalten des SMN2-Gens zu verbessern, sodass eine erhöhte Konzentration von funktionellem SMN-Protein resultiert. Erste klinische Studien sind in Vorbereitung.

Summary

80 to 90% of all spinal muscular atrophies (SMA) belong to the autosomal-recessive proximal SMA of childhood and adolescence. The gene of this disease (SMN-gene) has been identified on chromosome 5. The SMN-gene is located in a duplicated chromosomal area and exists in two copies, SMN1 and SMN2, which differ in only five nucleotides. However, this difference leads to different mRNA splicing. Only SMN1 results in a stable gene product (SMN-protein), whereas the product of SMN2 is unstable.A heterozygous loss of functional SMN1 leads to clinical SMA, whereas the number of existing SMN2 copies determines the severity of the disease (SMA types I, II and III). SMN protein playsa role in the regulation of mRNA synthesis of all cell types. In motor neurons it is additionally active in the regulation of axonal growth and differentiation. Experimental therapeutic research has been successful to elevate the SMN concentration by improving mRNA splicing of the SMN2 gene by different drugs. First clinical trials to investigate this effect in humans and its impact on strength and functioning are being prepared.

Schlüsselwörter

Spinale Muskelatrophie - Kindheit und Jugend - experimentelle Therapie

Keywords

Spinal muscular atrophy - childhood - adolescence - therapeutic research

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