RT Journal Article
SR Electronic
T1 Human COQ4 deficiency: delineating the clinical, metabolic and neuroimaging phenotypes
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 878
OP 887
DO 10.1136/jmedgenet-2021-107729
VO 59
IS 9
A1 Lucia Laugwitz
A1 Annette Seibt
A1 Diran Herebian
A1 Susana Peralta
A1 Imke Kienzle
A1 Rebecca Buchert
A1 Ruth Falb
A1 Darja Gauck
A1 Amelie Müller
A1 Mona Grimmel
A1 Stefanie Beck-Woedel
A1 Jan Kern
A1 Karim Daliri
A1 Pegah Katibeh
A1 Katharina Danhauser
A1 Steffen Leiz
A1 Viola Alesi
A1 Fabian Baertling
A1 Gessica Vasco
A1 Robert Steinfeld
A1 Matias Wagner
A1 Ahmet Okay Caglayan
A1 Hakan Gumus
A1 Margit Burmeister
A1 Ertan Mayatepek
A1 Diego Martinelli
A1 Parag Mohan Tamhankar
A1 Vasundhara Tamhankar
A1 Pascal Joset
A1 Katharina Steindl
A1 Anita Rauch
A1 Penelope E Bonnen
A1 Tawfiq Froukh
A1 Samuel Groeschel
A1 Ingeborg Krägeloh-Mann
A1 Tobias B Haack
A1 Felix Distelmaier
YR 2022
UL http://jmg.bmj.com/content/59/9/878.abstract
AB Background Human coenzyme Q4 (COQ4) is essential for coenzyme Q10 (CoQ10) biosynthesis. Pathogenic variants in COQ4 cause childhood-onset neurodegeneration. We aimed to delineate the clinical spectrum and the cellular consequences of COQ4 deficiency.Methods Clinical course and neuroradiological findings in a large cohort of paediatric patients with COQ4 deficiency were analysed. Functional studies in patient-derived cell lines were performed.Results We characterised 44 individuals from 36 families with COQ4 deficiency (16 newly described). A total of 23 different variants were identified, including four novel variants in COQ4. Correlation analyses of clinical and neuroimaging findings revealed three disease patterns: type 1: early-onset phenotype with neonatal brain anomalies and epileptic encephalopathy; type 2: intermediate phenotype with distinct stroke-like lesions; and type 3: moderate phenotype with non-specific brain pathology and a stable disease course. The functional relevance of COQ4 variants was supported by in vitro studies using patient-derived fibroblast lines. Experiments revealed significantly decreased COQ4 protein levels, reduced levels of cellular CoQ10 and elevated levels of the metabolic intermediate 6-demethoxyubiquinone.Conclusion Our study describes the heterogeneous clinical presentation of COQ4 deficiency and identifies phenotypic subtypes. Cell-based studies support the pathogenic characteristics of COQ4 variants. Due to the insufficient clinical response to oral CoQ10 supplementation, alternative treatment strategies are warranted.Data are available in a public, open access repository. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.