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Dystonian patofysiologia ja hoito

Dystonia on krooninen neurologinen liikehäiriösairaus, johon liittyy lisääntyneen lihasten aktiivisuuden aiheuttamia tahdosta riippumattomia, vääntäviä tai nykiviä liikkeitä ja pysyviä virheasentoja. Oireet voivat alkaa lapsuudessa tai aikuisiässä ja painottua paikallisesti yksittäiselle kehon alueelle (fokaalinen ja segmentaalinen dystonia) tai esiintyä laaja-alaisesti kehon eri lihaksissa (hemidystonia, multifokaalinen ja yleistynyt dystonia). Aikuisiässä alkanut dystonia on useimmiten etiologialtaan idiopaattinen, mutta dystonia voi kehittyä myös esimerkiksi keskushermostovaurion seurauksena. Dystonian neurobiologista mekanismia ei toistaiseksi tunneta, mutta sen ajatellaan olevan aivojen laaja-alainen sensoristen ja motoristen hermoverkostojen toimintahäiriö. Aikuisiän dystonian diagnoosi on kliininen ja kuuluu neurologian erikoisalalle. Dystonian hoito on oireenmukaista ja hoitovaihtoehtoja ovat botuliiniruiskeet, lääkehoito ja syväaivostimulaatio.</p

ATPase-deficient mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia

De novo mutations in ATAD3A (ATPase family AAA-domain containing protein 3A) were recently found to cause a neurological syndrome with developmental delay, hypotonia, spasticity, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. Using whole-exome sequencing, we identified a dominantly inherited heterozygous variant c.1064G > A (p.G355D) in ATAD3A in a mother presenting with hereditary spastic paraplegia (HSP) and axonal neuropathy and her son with dyskinetic cerebral palsy, both with disease onset in childhood. HSP is a clinically and genetically heterogeneous disorder of the upper motor neurons. Symptoms beginning in early childhood may resemble spastic cerebral palsy. The function of ATAD3A, a mitochondrial inner membrane AAA ATPase, is yet undefined. AAA ATPases form hexameric rings, which are catalytically dependent on the co-operation of the subunits. The dominant-negative patient mutation affects the Walker A motif, which is responsible for ATP binding in the AAA module of ATAD3A, and we show that the recombinant mutant ATAD3A protein has a markedly reduced ATPase activity. We further show that overexpression of the mutant ATAD3A fragments the mitochondrial network and induces lysosome mass. Similarly, we observed altered dynamics of the mitochondrial network and increased lysosomes in patient fibroblasts and neurons derived through differentiation of patient-specific induced pluripotent stem cells. These alterations were verified in patient fibroblasts to associate with upregulated basal autophagy through mTOR inactivation, resembling starvation. Mutations in ATAD3A can thus be dominantly inherited and underlie variable neurological phenotypes, including HSP, with intrafamiliar variability. This finding extends the group of mitochondrial inner membrane AAA proteins associated with spasticity.Peer reviewe

SNCA mutation p.Ala53Glu is derived from a common founder in the Finnish population

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