TY - JOUR
T1 - The movement disorder spectrum of SCA21 (ATX-TMEM240)
T2 - 3 novel families and systematic review of the literature
AU - Traschuetz, Andreas
AU - van Gaalen, Judith
AU - Oosterloo, Mayke
AU - Vreeburg, Maaike
AU - Kamsteeg, Erik-Jan
AU - Deininger, Natalie
AU - Riess, Olaf
AU - Reimold, Matthias
AU - Haack, Tobias
AU - Schoels, Ludger
AU - van de Warrenburg, Bart P.
AU - Synofzik, Matthis
N1 - Funding Information:
Dr. van de Warrenburg received research support from Bioblast Pharma, unrelated to this manuscript.Dr. Synofzik received speakers' honoraria and research support from Actelion Pharmaceuticals, unrelated to this manuscript.This work was supported via the European Union's Horizon 2020 research and innovation program under the ERA-NET Cofund action N° 643578. It was supported by the BMBF (01GM1607 under the frame of the E-Rare-3 network PREPARE (to M. S and B. vdW.). M.S. received additional support by the Else Kröner-Fresenius-Stiftung (2015_EKMS.018). B .vdW. receives additional research support from ZonMw, Hersenstichting, and Radboud university medical centre. This study was supported by the German Bundesministerium für Bildung und Forschung (BMBF) through the Juniorverbund in der Systemmedizin “mitOmics” (FKZ 01ZX1405C to TBH).
Funding Information:
This work was supported via the European Union’s Horizon 2020 research and innovation program under the ERA-NET Cofund action N° 643578 . It was supported by the BMBF ( 01GM1607 under the frame of the E-Rare-3 network PREPARE (to M. S and B. vdW.). M.S. received additional support by the Else Kröner-Fresenius-Stiftung ( 2015_EKMS.018 ). B .vdW. receives additional research support from ZonMw, Hersenstichting, and Radboud university medical centre . This study was supported by the German Bundesministerium für Bildung und Forschung (BMBF) through the Juniorverbund in der Systemmedizin “mitOmics” ( FKZ 01ZX1405C to TBH).
Funding Information:
This work was supported via the European Union's Horizon 2020 research and innovation program under the ERA-NET Cofund action N° 643578. It was supported by the BMBF (01GM1607 under the frame of the E-Rare-3 network PREPARE (to M. S and B. vdW.). M.S. received additional support by the Else Kröner-Fresenius-Stiftung (2015_EKMS.018). B.vdW. receives additional research support from ZonMw, Hersenstichting, and Radboud university medical centre. This study was supported by the German Bundesministerium für Bildung und Forschung (BMBF) through the Juniorverbund in der Systemmedizin “mitOmics” (FKZ 01ZX1405C to TBH).
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2019/5
Y1 - 2019/5
N2 - Spinocerebellar ataxia type 21 (SCA21/ATX-TMEM240) was recently found to be caused by mutations in TMEM240, with still limited knowledge on the phenotypic spectrum and disease course. Here we present five subjects from three novel SCA21 families from different parts of the world (including a novel c.196G > A, p.G66R TMEM240 variant from Colombia), demonstrating that, in addition to cerebellar ataxia, not only hypokinetic features (hypomimia, bradykinesia), but also hyperkinetic movement disorders (poly-mini-myoclonus, proximal myoclonus) are a recurrent part of the phenotypic spectrum of SCA21. Presenting first prospective longitudinal data, our results provide examples of two different disease trajectories: while it was inherently progressive in adult-onset cases, a dramatically improving trajectory was observed in an infantile-onset case. A systematic review of all previously reported SCA21 patients (n = 42) demonstrates that SCA21 is a relatively early-onset SCA (median onset age 18 years; range 1-61 years) with frequent non-cerebellar involvement, including hyporeflexia (69%), bradykinesia (65%), slow saccades (38%) and pyramidal signs (17%). Our results characterize SCA21 as a multisystem disorder with substantial extra-cerebellar involvement, including a wide spectrum of hypo- as well as hyperkinetic movement disorders as well as damage to the midbrain, corticospinal tract and peripheral nerves. However, in contrast to the current perspective on SCA21 disease, cognitive impairment is not an obligatory feature of the disease. The disease course is inherently progressive in adult-onset subjects, but might also be characterized by improvement in infantile-onset cases. These findings have important consequences of the work-up and counseling of SCA21/ATX-TMEM240 patients.
AB - Spinocerebellar ataxia type 21 (SCA21/ATX-TMEM240) was recently found to be caused by mutations in TMEM240, with still limited knowledge on the phenotypic spectrum and disease course. Here we present five subjects from three novel SCA21 families from different parts of the world (including a novel c.196G > A, p.G66R TMEM240 variant from Colombia), demonstrating that, in addition to cerebellar ataxia, not only hypokinetic features (hypomimia, bradykinesia), but also hyperkinetic movement disorders (poly-mini-myoclonus, proximal myoclonus) are a recurrent part of the phenotypic spectrum of SCA21. Presenting first prospective longitudinal data, our results provide examples of two different disease trajectories: while it was inherently progressive in adult-onset cases, a dramatically improving trajectory was observed in an infantile-onset case. A systematic review of all previously reported SCA21 patients (n = 42) demonstrates that SCA21 is a relatively early-onset SCA (median onset age 18 years; range 1-61 years) with frequent non-cerebellar involvement, including hyporeflexia (69%), bradykinesia (65%), slow saccades (38%) and pyramidal signs (17%). Our results characterize SCA21 as a multisystem disorder with substantial extra-cerebellar involvement, including a wide spectrum of hypo- as well as hyperkinetic movement disorders as well as damage to the midbrain, corticospinal tract and peripheral nerves. However, in contrast to the current perspective on SCA21 disease, cognitive impairment is not an obligatory feature of the disease. The disease course is inherently progressive in adult-onset subjects, but might also be characterized by improvement in infantile-onset cases. These findings have important consequences of the work-up and counseling of SCA21/ATX-TMEM240 patients.
KW - Spinocerebellar ataxia type 21
KW - Spinocerebellar ataxia
KW - TMEM240
KW - Genetics
KW - Ataxia
KW - Parkinsonism
KW - Bradykinesia
KW - Hyperkinetic
KW - Myoclonus
U2 - 10.1016/j.parkreldis.2018.11.027
DO - 10.1016/j.parkreldis.2018.11.027
M3 - (Systematic) Review article
C2 - 30522958
SN - 1353-8020
VL - 62
SP - 215
EP - 220
JO - Parkinsonism & Related Disorders
JF - Parkinsonism & Related Disorders
ER -