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Multicenter Study
. 2020 Aug;88(2):251-263.
doi: 10.1002/ana.25751. Epub 2020 Jun 10.

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

Andreas Traschütz  1   2 , Tommaso Schirinzi  3   4 , Lucia Laugwitz  5   6 , Nathan H Murray  7   8 , Craig A Bingman  7   8 , Selina Reich  1   2 , Jan Kern  6 , Anna Heinzmann  9   10 , Gessica Vasco  3 , Enrico Bertini  11 , Ginevra Zanni  11 , Alexandra Durr  9   10 , Stefania Magri  12 , Franco Taroni  12 , Alessandro Malandrini  13 , Jonathan Baets  14   15   16 , Peter de Jonghe  14   15   16 , Willem de Ridder  14   15   16 , Matthieu Bereau  17   18 , Stephanie Demuth  19 , Christos Ganos  20 , A Nazli Basak  21 , Hasmet Hanagasi  22 , Semra Hiz Kurul  23 , Benjamin Bender  24 , Ludger Schöls  1   2 , Ute Grasshoff  5 , Thomas Klopstock  25   26   27 , Rita Horvath  28   29 , Bart van de Warrenburg  30 , Lydie Burglen  31   32   33 , Christelle Rougeot  31   34 , Claire Ewenczyk  9   10   35 , Michel Koenig  36 , Filippo M Santorelli  37 , Mathieu Anheim  38   39   40 , Renato P Munhoz  41 , Tobias Haack  5 , Felix Distelmaier  42 , David J Pagliarini  7   8 , Hélène Puccio  43   44   45   46 , Matthis Synofzik  1   2
Affiliations
Multicenter Study

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

Andreas Traschütz et al. Ann Neurol. 2020 Aug.

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.

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Conflict of interest statement

The authors declared no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Coenzyme COQ8A variants across protein domains. (A) Graphical overview of all variants in this study in relation to COQ8A protein structure and domains, including the mitochondrial targeting sequence (MTS), the transmembrane domain (TM), subdomains of the protein kinase‐like (PKL) and superfamily (PKL I‐IX), as well as the UbiB family‐specific N‐terminal extension (NTE), N lobe insert (NLI), and C lobe insert (CLI). Numbers indicate variant IDs specified in the Table S1, missense variants of unknown significance are marked in gray. (B) Missense variants in relation to specific sequence motifs. Bold titles and letters indicate functional motifs and conserved amino acids of the COQ8A active site, respectively. Variants cluster predominantly near structural or functional motifs, except for one cluster affecting a yet undefined region. [Color figure can be viewed at www.annalsofneurology.org]
FIGURE 2
FIGURE 2
Molecular effects of representative coenzyme COQ8A variants. (A) The 3D modeling of protein structure and function, revealing steric and electrostatic clashes or lost interactions for representative COQ8A variants. Missense variants cluster around the active size of COQ8A, except for three variants including E551K. (B) SDS‐PAGE analysis of purified wildtype (WT) and mutant COQ8ANΔ250. Protein stability and folding was severely impaired in R271C, leading to purification failure in two preparations. (C) Compared to WT, ATPase activity was impaired in variants affecting presumed noncatalytic (R301W) and catalytic regions (A338T and T487R) of the active site. Positive control: A339G, and negative control: D507N. (D) Decrease in melting temperature (Tm) of purified COQ8A indicating moderate protein destabilization in R301W and T487R. (E) ADP nucleotide binding, which increases Tm, is impaired in A338T and T487R, but not in R301W. Note that variants of uncertain significance (VUS) D326N is not predicted to lead to detrimental structural effects A and consistently yields results similar to WT in all experiments B to E. [Color figure can be viewed at www.annalsofneurology.org]
FIGURE 3
FIGURE 3
Phenotypic spectrum of coenzyme COQ8A‐ataxia. (A) Prevalence of signs and symptoms in patients with COQ8A mutations (n = 59). Numerator and denominator in brackets indicate the number of affected patients and the number of patients assessed for this feature, respectively. (B) Frequency of initial features at disease onset. Thirteen of 59 patients had more than one feature at onset. Note that cerebellar ataxia was only present in 68% at disease onset. (C) Age of onset of disease features. Number of affected patients in brackets. Box‐whisker plots representing median, interquartile range, and 95% confidence interval (CI). (D) Frequency of the most prevalent features in five clusters identified by a two‐step cluster analysis. Note cluster 1 comprising of 14 patients (24%) with a cerebellar ataxia phenotype, but none of the other 4 prevalent features (“ataxia simplex” cluster), and cluster 4 comprising of 12 patients (20%) with ataxia and only myoclonus or dystonia. (E, F) Genotype–phenotype associations. Frequency of clinical features stratified by the number of loss of function (LOF) alleles (E), and by clusters of missense variants in specific COQ8A motifs (F). The p values represent results from Fisher’s exact tests. [Color figure can be viewed at www.annalsofneurology.org]
FIGURE 4
FIGURE 4
Magnetic resonance imaging (MRI) features of coenzyme COQ8A‐ataxia. (A) Reported MRI findings. Numerator and denominator in brackets indicate the number of patients with a feature and the number of patients assessed for this feature, respectively. (B) Centralized analysis of original MRI images of 18 patients by 2 independent raters. Vermal cerebellar atrophy was universally present. Representative images highlighting cerebellar atrophy (C), cerebral atrophy (D), and stroke‐like abnormalities (E), and infratentorial T2 hyperintensities of the dorsal pons, and dentate nuclei (F) as a novel imaging features of COQ8‐ataxia. (G) Diffusion tensor imaging (DTI) analysis. The z‐map of three individual COQ8A patients (P36, P35, and P38) superimposed on the mean FA map of all controls, depicting voxels with a z‐score less than −2.5 and a cluster size of 30. In all three patients, FA values are reduced in the periphery of the anterior and posterior lobe, the superior cerebellar peduncle and pontine crossing tracts, and diffusely in supratentorial clusters. [Color figure can be viewed at www.annalsofneurology.org]
FIGURE 5
FIGURE 5
Disease progression of coenzyme COQ8A‐ataxia. (A) Both overall disease and ataxia start early in life in COQ8A‐ataxia, with 50% of patients affected before age 6 years. (B) Kaplan–Meier analysis of disease milestones. Because of the limited number of subjects aged >60 years, estimates above age 60 years should be interpreted with caution. (C) Cross‐sectional functional disease progression as indicated by the Spinocerebellar Degeneration Functional Score (SDFS) relative to age. SDFS 3 reflects moderate ataxia with the inability to run, and SDFS 6 reflects wheelchair dependence. Mean and 95% confidence interval based on 10‐year bins. (D) Cross‐sectional ataxia progression as indicated by the individual Scale for the Assessment and Rating of Ataxia (SARA) score at the last assessment relative to disease duration. (E) Prospective longitudinal progression of ataxia. Relative progression of each patient quantified by the slope of a linear regression through all available SARA scores. Solid and dashed lines indicate mean and 95% confidence interval. Note that variation in disease course/SARA ratings can appear as “improvements” even in the natural course of COQ8A disease. (F) Sample size estimation based on longitudinal progression of SARA scores during the first assessment interval (0.59 ± 0.51 per year) for a trial to detect a treatment effect with a power of 0.8 and a significance level of 0.05. [Color figure can be viewed at www.annalsofneurology.org]
FIGURE 6
FIGURE 6
Effect of coenzyme Q10 (CoQ10) treatment. (A) Treatment response by clinical reports, suggesting improvements under CoQ10 in 43% of patients. (B) Treatment response by longitudinal assessment. Longitudinal changes in individual subjects’ Scale for the Assessment and Rating of Ataxia (SARA) scores (slope of a linear regression through all available SARA scores) after initiation of CoQ10 treatment. Solid and dashed lines indicate mean and 95% confidence interval of annualized change in SARA. (C) Trajectory of ataxia severity in two exemplary individual patients with longitudinal SARA scores both on and off treatment with CoQ10. A similar rate of each deterioration and improvement can be seen in these two patients, with a possible rebound after discontinuation of treatment in patient P6. [Color figure can be viewed at www.annalsofneurology.org]
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