Clinical Features, Biochemistry, Imaging, and Treatment Response in a Single-Center Cohort With Coenzyme Q10 Biosynthesis Disorders

Abstract

Background and objectives: Disorders of coenzyme Q₁₀ (CoQ₁₀) biosynthesis comprise a group of 11 clinically and genetically heterogeneous rare primary mitochondrial diseases. We sought to delineate clinical, biochemical, and neuroimaging features of these disorders, together with outcomes after oral CoQ₁₀ supplementation and the utility of peripheral blood mononuclear cell (PBMNC) CoQ₁₀ levels in monitoring therapy.

Methods: This was a retrospective cohort study, registered as an audit at a specialist pediatric hospital (Registration Number: 3318) of 14 patients with genetically confirmed CoQ₁₀ biosynthesis deficiency, including 13 previously unreported cases.

Results: We show that oral doses of CoQ₁₀ up to 70 mg/kg/d were needed to ameliorate neurologic features. Additional idebenone was required to control seizures in some cases, and 3 children with neonatal-onset neurologic disease died in early childhood despite receiving high-dose oral CoQ₁₀ from birth. We also demonstrate that early diagnosis and treatment of CoQ₁₀ deficiency with oral supplementation (30 mg/kg/d) can reverse renal manifestations and can completely prevent kidney disease over 10 years of follow-up. PBMNC CoQ₁₀ levels increased after oral CoQ₁₀ supplementation, demonstrating absorption of exogenous CoQ₁₀ into the bloodstream.

Discussion: An early genome-wide diagnostic approach is needed for expeditious diagnosis of CoQ₁₀ biosynthesis disorder because our study demonstrates that there are no pathognomonic blood, muscle, or imaging biomarkers of these diseases. Our findings indicate that earlier diagnosis and treatment with high-dose CoQ₁₀ is key in halting progression of kidney disease or preventing it altogether. This study uses serial PBMNC CoQ₁₀ levels to monitor therapy. Patients with genetically confirmed CoQ₁₀ biosynthesis disorder should receive high-dose oral CoQ₁₀ as soon as possible after presentation, regardless of genetic cause, to prevent disease progression, but parents of children with neonatal or infantile neurologic presentations should be counseled about the poor prognosis.

Figure 1. Scheme of CoQ₁₀ Biosynthesis

Components of the CoQ₁₀ biosynthesis complex and enzymes known to be involved are indicated. Regulatory enzymes such as COQ8 and COQ9 are indicated at the steps in which they are involved. Enzymes outlined in a black box indicate those in which variant(s) in the COQ gene(s) are found in our cohort. 4HB = 4-hydroxybenzoate; DPHB = decaprenyl hydroxybenzoic acid; DHHB = 3-hexaprenyl-4,5-dihydroxybenzoic acid; DPVA = decaprenyl-vanillic acid; DDMQ₁₀H₂ = demethyl-demethoxy-hydroquinone; DDMQ₁₀ = demethoxy-demethyl-coenzyme Q₁₀; DMQ₁₀ = demethoxy-coenzyme Q₁₀; DMeQ₁₀ = demethyl-coenzyme Q₁₀.

Figure 2. Frequency of Clinical Features for Each COQ Gene Involved in Our Cohort of Patients With Primary CoQ₁₀ Deficiency

In this heatmap, colors indicate the frequency of each symptom in our cohort normalized to the number of patients with variants in 1 of the 6 genes. The most prevalent symptom (deep red) was seizures, observed in 100% of the patients with pathogenic variants in COQ4 and COQ9. Seizures were observed with all gene defects except COQ8A.

Figure 3. Representative Brain Images of Selected Patients Selected Patients From Our Cohort

MRI images for patient 7 (COQ4) at 2 years (A, B) and at 4 years (C, D) show dentate hilus hyperintensity (arrow in A) and thalamic laminar hyperintensity (arrow in C) occipital volume loss and gliosis as well as deep parietal white matter hyperintensity (arrows in D). MRI images for patient 4 (COQ4) at 14 years show pronounced cerebral volume loss, small thalamus with laminar hyperintensity (arrows in E), and cerebellar atrophy and parenchymal gliosis with inferior predominance (arrows in F, G). MR spectroscopy for patient 1 (COQ2) at 26 days shows intermediate TE showing large inverted lactate peak at 1.3 ppm (arrow in H). MRI images for patient 8 at 9 years shows diffuse cerebral atrophy, small thalamus (arrows in I), as well as diffuse cerebellar atrophy (arrow in J). MRI images for patient 13 (COQ9) at 4 weeks show simplified gyral pattern, poor operculization, small thalami (white arrows in L), and cystic foci along striatum (black arrow in L). CT of the brain for patient 12 (COQ9) at 12 months shows pronounced cerebellar and cerebral atrophy (arrows in M, N) with ex vacuo ventricular dilatation. MRI of the brain for patient 9 (COQ8A) at 14 years shows mild diffuse cerebellar atrophy (arrow in O) and normal supratentorial appearances (P).

Figure 4. Serial Peripheral Blood Mononuclear Cell CoQ₁₀ Levels in 5 Patients

(A) Patient 2; (B) patient 7; (C) patient 13; (D) patient 10; (E) patient 11. The horizontal blue bar indicates supplementation with oral CoQ₁₀ and the red bar indicates idebenone supplementation. Doses are indicated on the bar. The gradient blue bar above D indicates inconsistent supplementation after initial initiation of oral CoQ₁₀ because of noncompliance. WCCoQ₁₀ = white cell CoQ₁₀. Reference range: 37–133 pmol/mg.