Spinal muscular atrophy: advances and challenges in treatment

Spinalna mišićna atrofija (SMA) je autosomno recesivni poremećaj karakteriziran degeneracijom motornih neurona kralježničke moždine, atrofijom skeletnih mišića i generaliziranom slabošću. Javlja se s učestalosti od otprilike 1/6000 do 1/11000 živih poroda. Bolest je uzrokovana štetnim mutacijama gena za preživljenje motoričkog neurona 1 (engl. survival of motor neuron 1 gene, SMN1) i posljedično sniženim razinama SMN proteina. Iako patogeneza nije razjašnjena, vrlo je vjerojatno kako smanjene razine SMN proteina dovode do poremećaja u prekrajanju brojnih gena. Pacijenti se klasificiraju u jedan od pet fenotipskih razreda (SMA 0, SMA I, SMA II, SMA III, SMA IV) na temelju dobi nastupa simptoma i postignutih ključnih točaka motoričkog razvoja. Unatoč klasifikaciji u diskretne razrede, SMA fenotipovi tvore kontinuirani spektar od najtežeg (SMA tip 0) do najlblažeg oblika (SMA tip IV), sa značajnim varijacijama unutar pojedinih razreda. Elektromiografija i biopsija mišića su nekada bili osnova za dijagnostiku SMA, međutim, genetsko testiranje na homozigotnu deleciju ili mutaciju SMN1 gena pokazalo se učinkovitijim i specifičnijim. SMA terapija je donedavno bila uglavnom suportivna i nije utjecala na tijek bolesti, unatoč značajnim naprecima u kvaliteti njege i skrbi za oboljele. Dvadeset godina nakon otkrića SMN1 gena i njegove uloge u SMA, veliki korak naprijed učinjen je je odobravanjem prvog lijeka za SMA od strane FDA i EMA, antisense oligonukleotida, nusinersena. Međutim, nusinersen je u isto vrijeme stvorio mnoge etičke, medicinske i financijske izazove koji se također odražavaju na nedavno odobrenu prvu gensku terapiju za SMA. U ovom radu dan je opsežanSpinal muscular atrophy (SMA) is autosomal recessive disorder characterized by degeneration of spinal cord motor neurons, atrophy of skeletal muscle and generalised weakness. Its incidence is approximately 1/6000 to 1/11000 live births. Disease is caused by deleterious mutations of survival of motor neuron 1 gene, SMN1 and subsequently decreased levels of SMN protein. Although pathogenesis isn`t clarified, it is very likely that reduced levels of SMN protein lead to disorders in splicing of numerous genes. Patients are classified into one of the five phenotypic classes (SMA 0, SMA I, SMA II, SMA III, SMA IV) based on the age at onset of symptoms onset and achieved motor milestones. Despite the classification in discrete classes, SMA phenotypes form a continuous spectrum from the most severe (SMA type 0) to the most mild form (SMA type IV), with significant variations within individual classes. Electromyography and muscle biopsy were once the basis for SMA diagnostics, however, genetic testing for homozygous deletion or mutation of the SMN1 gene has proven itself more effective and more specific. SMA therapy was, until recently, mainly supportive, and despite huge advances in medical technology and patient care, it didn`t have the power to influence natural history significantly. Twenty years after the discovery of the SMN1 gene and its role in SMA, a major step forward was made by approving the first drug for SMA by FDA and EMA, antisense oligonucleotide, nusinersen. However, despite the great enthusiasm within the SMA community, following approval, nusinersen has at the same time created many ethical, medical and financial challenges that are also reflected in th