Biallelic variants in COQ7 cause distal hereditary motor neuropathy with upper motor neuron signs.

COQ7 encodes a hydroxylase responsible for the penultimate step of coenzyme Q10 (CoQ10) biosynthesis in mitochondria. CoQ10 is essential for multiple cellular functions, including mitochondrial oxidative phosphorylation, lipid metabolism, and reactive oxygen species homeostasis. Mutations in COQ7 have been previously associated with primary CoQ10 deficiency, a clinically heterogeneous multisystemic mitochondrial disorder. We identified COQ7 biallelic variants in nine families diagnosed with distal hereditary motor neuropathy with upper neuron involvement, expending the clinical phenotype associated with defects in this gene. A recurrent p.Met1? change was identified in five families from Brazil with evidence of a founder effect. Fibroblasts isolated from patients revealed a substantial depletion of COQ7 protein levels, indicating protein instability leading to loss of enzyme function. High-performance liquid chromatography assay showed that fibroblasts from patients had reduced levels of CoQ10, and abnormal accumulation of the biosynthetic precursor DMQ10. Accordingly, fibroblasts from patients displayed significantly decreased oxygen consumption rates in patients, suggesting mitochondrial respiration deficiency. Induced pluripotent stem cell-derived motor neurons from patient fibroblasts showed significantly increased levels of extracellular neurofilament light protein, indicating axonal degeneration. Our findings indicate a molecular pathway involving CoQ10 biosynthesis deficiency and mitochondrial dysfunction in patients with distal hereditary motor neuropathy. Further studies will be important to evaluate the potential benefits of CoQ10 supplementation in the clinical outcome of the disease.

Learning and retention of associations between auditory icons and denotative referents: implications for the design of auditory warnings.

OBJECTIVE: This study examined the way in which the type and preexisting strength of association between an auditory icon and a warning event affects the ease with which the icon/event pairing can be learned and retained. BACKGROUND: To be effective, an auditory warning must be audible, identifiable, interpretable, and heeded. Warnings consisting of familiar environmental sounds, or auditory icons, have potential to facilitate identification and interpretation. The ease with which pairings between auditory icons and warning events can be learned and retained is likely to depend on the type and strength of the preexisting icon/event association. METHOD: Sixty-three participants each learned eight auditory-icon/denotative-referent pairings and attempted to recall them 4 weeks later. Three icon/denotative-referent association types (direct, related, and unrelated) were employed. Participants rated the strength of the association for each pairing on a 7-point scale. RESULTS: The number of errors made while learning pairings was greater for unrelated than for either related or direct associations, whereas the number of errors made while attempting to recall pairings 4 weeks later was greater for unrelated than for related associations and for related than for direct associations. Irrespective of association type, both learning and retention performance remained at very high levels, provided the strength of the association was rated greater than 5. CONCLUSION: This suggests that strong preexisting associations are used to facilitate learning and retention of icon/denotative-referent pairings. APPLICATION: The practical implication of this study is that auditory icons having either direct or strong, indirect associations with warning events should be preferred.