Successful treatment of neonatal COQ2 deficiency with 4-hydroxybenzoic acid

Primary coenzyme Q10 (CoQ10) deficiency encompasses a group of mitochondrial diseases with variable clinical spectrum.1 Some of the affected individuals manifest shortly after birth with severe multiple organ involvement. One of these diseases is COQ2 deficiency, which is caused by the defect of a key enzyme (4-hydroxybenzoate polyprenyltransferase; EC 2.5.1.39) that catalyses the fusion of the benzoquinone ring (head group) with the isoprenoid side chain (tail group).2 The clinical phenotype of COQ2 deficiency ranges from very severe neonatal-onset forms to childhood-onset Leigh-like syndrome up to an adult-onset multiple system atrophy (MSA) phenotype (OMIM # 607426). Neonatal cases typically feature severe lactic acidosis, encephalopathy and renal failure with nephrotic syndrome. This severest form of COQ2 deficiency presents with a rapidly fatal course, which cannot be prevented by oral CoQ10 supplementation.1,2 Writing in Brain, we recently described a novel treatment approach for COQ2 deficiency using the compound 4-hydroxybenzoic acid (4-HBA).3 This small molecule is the substrate of the COQ2 enzyme. We showed that pathogenic COQ2 variants likely impair substrate availability at the catalytic side (possibly due to disrupted substrate transport).2 Increasing 4-HBA concentrations can overcome this problem. In a compassionate use trial in an affected 3-year-old male with COQ2 deficiency (childhood-onset Leigh-like syndrome with nephrotic syndrome) we demonstrated feasibility and efficiency of 4-HBA treatment with rapid recovery of renal function and marked improvement of neurodevelopment. However, this study was based on a single case and, in addition, it remained unknown whether 4-HBA treatment can be similarly beneficial for the severe neonatal-onset phenotype of COQ2 deficiency.