Mutations in COQ8A gene can result in primary CoQ10 deficiency type 4 that patients typically present with clinical features including ataxia or a more subtle gait instability. Other neurological abnormalities have been reported include adolescence onset exercise intolerance due to fatigability, seizures, stroke-like episodes, intellectual disability, spasticity, ophthalmic involvement, decreased visual acuity, sensorineural hearing loss, depression ( Traschütz and et al. 2020; Rahman and et al.2012).
Juvenile onset was characterized by a variable combination of writing difficulties clumsiness and tremor with ataxia, unsteady gait, myoclonus or dystonia. Clinical severity in reported juvenile onset (11–18 years) was classified mild: slow progression, less severe symptoms and absence of cognitive impairment] to severe (presence of severe epilepsy and/or regression, association with poor cognitive and/or motor outcome such that subjects are reliant upon caretakers for all activities of daily living). The clinical, laboratory and treatment response characteristics of juvenile onset COQ10D4 patients reported to date are summarized in Table 1.
Our patient showed a less severe course and as in literature cerebellar symptoms were mild, writing difficulties were obvious. Although the origin of hand clumsiness may in part be cerebellar, particularly when associated with gait ataxia, the dystonic nature of hand clumsiness and neck tremor has been demonstrated in COQ10D4 patients through electromyographic recordings CoQ10 levels are reduced in skeletal muscle and less frequently in fibroblasts, but their correlation with disease severity is still debated (Galosia and et al.2019).
It has been reported that there was no difference in patterns of clinical presentation between subjects with missense and nonsense mutations or for mutations distributed throughout specific regions of the protein (Blumkin and et al.2014).
Cognitive impairment is often observed in primary coenzyme Q10 deficiency cases with epileptic encephalopathy. Our patient exhibited relative normal cognitive state. The absence of seizures, exercise intolerance or ocular dismotility confirms the heterogeneity of this disorder and the lack of correlation between CoQ10 residual levels and disease severity This case emphasizes the importance of an early molecular diagnosis for suspected inherited ataxias, particularly given the availability of approved treatments for some subtypes similar to our patient.
The additional compelling evidence for the CoQ10 deficiency in our patient comes from clinical responses to CoQ10 supplementation, including the improvement in exercise intolerance and unsteady gait, a response similar to that found in the majority of cases of primary CoQ10 deficiency (Barca and et al.2019; Mignot and et al.2013) Dosage and course of CoQ10 supplement have not been standardized and results have been variable. The dose of oral CoQ10 (ubiquinone, ubiquinol, idebenone and ubidecarenone) ranged from 5 mg/kg/day to 3000 mg/day in treatment of CoQ10 deficiencies. Most COQ10D4 patients experienced symptomatic improvement (Jacobsen and et al.2018; Chang and et al.2018). Early and sustained CoQ10 supplementation appears to be important for a favorable outcome, suggesting that persistent ongoing damage to target tissues and irreversibility of established damages are determinants of therapeutic efficacy (Blumkin and et al.2014; Quinzii and et al.2010).
We administered oral ubidecarenone 100 mg, two times a day for 2 weeks to our patient, with an initial subjective improvement of fatigue followed by a remarkable improvement of tremor with a substantially lower (by five points) total SARA score. Regarding previous reported juvenile onset cases, ubiquinone therapy did not lead to significant improvement of the neurological status in most patients (Mignot and et al.2013; Gerards and et al.2010; Lagier-Tourenne and et al.2018). Severe forms seem to be less responsive to CoQ10 supplementation while patients with ataxia tend to have a better response.
CoQ10 is frequently reduced in muscle of patients with mitochondrial myopathy. It is unfortunate that the patient declined muscle biopsy since the HPLC assay for the CoQ10 level in skeletal muscle is the golden standard for CoQ10 deficiency.
Our aim is to highlight the clinical and genetic heterogeneity of CoQ10 deficiency and also to report a novel mutation of COQ8A gene that has not been previously reported in the literature. Gait ataxia, suggesting that cerebellar syndrome may be the common feature of juvenile onset patients. The atypical presentation with prominent writing deterioration, possibly representing the initial manifestation of cerebellar disease, is an example of the extreme phenotypic variability of CoQ10 deficiency.