Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients

Andreas Traschütz; Tommaso Schirinzi; Lucia Laugwitz; Nathan H. Murray; Craig A. Bingman; Selina Reich; Jan Kern; Anna Heinzmann; Gessica Vasco; Enrico Bertini; Ginevra Zanni; Alexandra Durr; Stefania Magri; Franco Taroni; Alessandro Malandrini; Jonathan Baets; Peter de Jonghe; Willem de Ridder; Matthieu Bereau; Stephanie Demuth; Christos Ganos; A. Nazli Basak; Hasmet Hanagasi; Semra Hiz Kurul; Benjamin Bender; Ludger Schöls; Ute Grasshoff; Thomas Klopstock; Rita Horvath; Bart van de Warrenburg; Lydie Burglen; Christelle Rougeot; Claire Ewenczyk; Michel Koenig; Filippo M. Santorelli; Mathieu Anheim; Renato P. Munhoz; Tobias Haack; Felix Distelmaier; David J. Pagliarini; Hélène Puccio; Matthis Synofzik

doi:10.1002/ana.25751

Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients

Andreas Traschütz, Tommaso Schirinzi, Lucia Laugwitz, Nathan H. Murray, Craig A. Bingman, Selina Reich, Jan Kern, Anna Heinzmann, Gessica Vasco, Enrico Bertini, Ginevra Zanni, Alexandra Durr, Stefania Magri, Franco Taroni, Alessandro Malandrini, Jonathan Baets, Peter de Jonghe, Willem de Ridder, Matthieu Bereau, Stephanie DemuthChristos Ganos, A. Nazli Basak, Hasmet Hanagasi, Semra Hiz Kurul, Benjamin Bender, Ludger Schöls, Ute Grasshoff, Thomas Klopstock, Rita Horvath, Bart van de Warrenburg, Lydie Burglen, Christelle Rougeot, Claire Ewenczyk, Michel Koenig, Filippo M. Santorelli, Mathieu Anheim, Renato P. Munhoz, Tobias Haack, Felix Distelmaier, David J. Pagliarini, Hélène Puccio, Matthis Synofzik

Research output: Contribution to journal › Article

1 Scopus citations

Abstract

Objective: To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). Methods: Cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype–phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. Results: Fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82–93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: −0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. Interpretation: This study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia. ANN NEUROL 2020;88:251–263.

Original language	English
Pages (from-to)	251-263
Number of pages	13
Journal	Annals of neurology
Volume	88
Issue number	2
DOIs	https://doi.org/10.1002/ana.25751
State	Published - Aug 1 2020
Externally published	Yes

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Traschütz, A., Schirinzi, T., Laugwitz, L., Murray, N. H., Bingman, C. A., Reich, S., Kern, J., Heinzmann, A., Vasco, G., Bertini, E., Zanni, G., Durr, A., Magri, S., Taroni, F., Malandrini, A., Baets, J., de Jonghe, P., de Ridder, W., Bereau, M., ... Synofzik, M. (2020). Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients. Annals of neurology, 88(2), 251-263. https://doi.org/10.1002/ana.25751

Traschütz, Andreas ; Schirinzi, Tommaso ; Laugwitz, Lucia ; Murray, Nathan H. ; Bingman, Craig A. ; Reich, Selina ; Kern, Jan ; Heinzmann, Anna ; Vasco, Gessica ; Bertini, Enrico ; Zanni, Ginevra ; Durr, Alexandra ; Magri, Stefania ; Taroni, Franco ; Malandrini, Alessandro ; Baets, Jonathan ; de Jonghe, Peter ; de Ridder, Willem ; Bereau, Matthieu ; Demuth, Stephanie ; Ganos, Christos ; Basak, A. Nazli ; Hanagasi, Hasmet ; Kurul, Semra Hiz ; Bender, Benjamin ; Schöls, Ludger ; Grasshoff, Ute ; Klopstock, Thomas ; Horvath, Rita ; van de Warrenburg, Bart ; Burglen, Lydie ; Rougeot, Christelle ; Ewenczyk, Claire ; Koenig, Michel ; Santorelli, Filippo M. ; Anheim, Mathieu ; Munhoz, Renato P. ; Haack, Tobias ; Distelmaier, Felix ; Pagliarini, David J. ; Puccio, Hélène ; Synofzik, Matthis. / Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia : A Multicenter Study of 59 Patients. In: Annals of neurology. 2020 ; Vol. 88, No. 2. pp. 251-263.

@article{9de50aa2336542f5833cb0043d8480eb,

title = "Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients",

abstract = "Objective: To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). Methods: Cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype–phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. Results: Fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82–93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: −0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. Interpretation: This study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia. ANN NEUROL 2020;88:251–263.",

author = "Andreas Trasch{\"u}tz and Tommaso Schirinzi and Lucia Laugwitz and Murray, {Nathan H.} and Bingman, {Craig A.} and Selina Reich and Jan Kern and Anna Heinzmann and Gessica Vasco and Enrico Bertini and Ginevra Zanni and Alexandra Durr and Stefania Magri and Franco Taroni and Alessandro Malandrini and Jonathan Baets and {de Jonghe}, Peter and {de Ridder}, Willem and Matthieu Bereau and Stephanie Demuth and Christos Ganos and Basak, {A. Nazli} and Hasmet Hanagasi and Kurul, {Semra Hiz} and Benjamin Bender and Ludger Sch{\"o}ls and Ute Grasshoff and Thomas Klopstock and Rita Horvath and {van de Warrenburg}, Bart and Lydie Burglen and Christelle Rougeot and Claire Ewenczyk and Michel Koenig and Santorelli, {Filippo M.} and Mathieu Anheim and Munhoz, {Renato P.} and Tobias Haack and Felix Distelmaier and Pagliarini, {David J.} and H{\'e}l{\`e}ne Puccio and Matthis Synofzik",

year = "2020",

month = aug,

day = "1",

doi = "10.1002/ana.25751",

language = "English",

volume = "88",

pages = "251--263",

journal = "Annals of Neurology",

issn = "0364-5134",

number = "2",

}

Traschütz, A, Schirinzi, T, Laugwitz, L, Murray, NH, Bingman, CA, Reich, S, Kern, J, Heinzmann, A, Vasco, G, Bertini, E, Zanni, G, Durr, A, Magri, S, Taroni, F, Malandrini, A, Baets, J, de Jonghe, P, de Ridder, W, Bereau, M, Demuth, S, Ganos, C, Basak, AN, Hanagasi, H, Kurul, SH, Bender, B, Schöls, L, Grasshoff, U, Klopstock, T, Horvath, R, van de Warrenburg, B, Burglen, L, Rougeot, C, Ewenczyk, C, Koenig, M, Santorelli, FM, Anheim, M, Munhoz, RP, Haack, T, Distelmaier, F, Pagliarini, DJ, Puccio, H & Synofzik, M 2020, 'Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients', Annals of neurology, vol. 88, no. 2, pp. 251-263. https://doi.org/10.1002/ana.25751

Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia : A Multicenter Study of 59 Patients. / Traschütz, Andreas; Schirinzi, Tommaso; Laugwitz, Lucia; Murray, Nathan H.; Bingman, Craig A.; Reich, Selina; Kern, Jan; Heinzmann, Anna; Vasco, Gessica; Bertini, Enrico; Zanni, Ginevra; Durr, Alexandra; Magri, Stefania; Taroni, Franco; Malandrini, Alessandro; Baets, Jonathan; de Jonghe, Peter; de Ridder, Willem; Bereau, Matthieu; Demuth, Stephanie; Ganos, Christos; Basak, A. Nazli; Hanagasi, Hasmet; Kurul, Semra Hiz; Bender, Benjamin; Schöls, Ludger; Grasshoff, Ute; Klopstock, Thomas; Horvath, Rita; van de Warrenburg, Bart; Burglen, Lydie; Rougeot, Christelle; Ewenczyk, Claire; Koenig, Michel; Santorelli, Filippo M.; Anheim, Mathieu; Munhoz, Renato P.; Haack, Tobias; Distelmaier, Felix; Pagliarini, David J.; Puccio, Hélène; Synofzik, Matthis.

In: Annals of neurology, Vol. 88, No. 2, 01.08.2020, p. 251-263.

Research output: Contribution to journal › Article

TY - JOUR

T1 - Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia

T2 - A Multicenter Study of 59 Patients

AU - Traschütz, Andreas

AU - Schirinzi, Tommaso

AU - Laugwitz, Lucia

AU - Murray, Nathan H.

AU - Bingman, Craig A.

AU - Reich, Selina

AU - Kern, Jan

AU - Heinzmann, Anna

AU - Vasco, Gessica

AU - Bertini, Enrico

AU - Zanni, Ginevra

AU - Durr, Alexandra

AU - Magri, Stefania

AU - Taroni, Franco

AU - Malandrini, Alessandro

AU - Baets, Jonathan

AU - de Jonghe, Peter

AU - de Ridder, Willem

AU - Bereau, Matthieu

AU - Demuth, Stephanie

AU - Ganos, Christos

AU - Basak, A. Nazli

AU - Hanagasi, Hasmet

AU - Kurul, Semra Hiz

AU - Bender, Benjamin

AU - Schöls, Ludger

AU - Grasshoff, Ute

AU - Klopstock, Thomas

AU - Horvath, Rita

AU - van de Warrenburg, Bart

AU - Burglen, Lydie

AU - Rougeot, Christelle

AU - Ewenczyk, Claire

AU - Koenig, Michel

AU - Santorelli, Filippo M.

AU - Anheim, Mathieu

AU - Munhoz, Renato P.

AU - Haack, Tobias

AU - Distelmaier, Felix

AU - Pagliarini, David J.

AU - Puccio, Hélène

AU - Synofzik, Matthis

PY - 2020/8/1

Y1 - 2020/8/1

N2 - Objective: To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). Methods: Cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype–phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. Results: Fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82–93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: −0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. Interpretation: This study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia. ANN NEUROL 2020;88:251–263.

AB - Objective: To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). Methods: Cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype–phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. Results: Fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82–93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: −0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. Interpretation: This study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia. ANN NEUROL 2020;88:251–263.

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U2 - 10.1002/ana.25751

DO - 10.1002/ana.25751

M3 - Article

C2 - 32337771

AN - SCOPUS:85086169325

VL - 88

SP - 251

EP - 263

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 2

ER -