Primary coenzyme Q10 deficiency-7: expanded phenotypic spectrum and a founder mutation in southern Chinese

Abstract

Primary coenzyme Q10 deficiency-7 (COQ10D7) is a rare mitochondrial disease caused by biallelic mutations in COQ4. Here we report the largest cohort of COQ10D7 to date, with 11 southern Chinese patients confirmed with biallelic COQ4 mutations. Five of them have the classical neonatal-onset encephalo-cardiomyopathy, while the others have infantile onset with more heterogeneous clinical presentations. We also identify a founder mutation COQ4 (NM_016035.5): c.370G>A, p.(Gly124Ser) for COQ10D7, suggesting a higher chance of occurrence in the southern Chinese. This study helps improve understanding of the clinical spectrum of this disorder.

Keywords: Disease genetics; Diseases.

Fig. 1

Cerebral magnetic resonance (MR) findings. a Axial T1W, b axial FLAIR, c DWI from Patient 1 at neonatal stage, and d axial T2W at follow-up; e axial T1W and f MR spectroscopy (MRS) at basal ganglia at neonate and g axial T1W at infant stages from Patient 4; h coronal T2W, i sagittal T1W, j axial T2W, k axial T1W from Patient 11. MR features include cerebellar atrophy (white arrows) (h, i) with progression (e, g); cerebral atrophy with frontal and anterior temporal lobar predominance (i–k); thinning of the corpus callosum (i); white matter loss and cystic change with frontal predominance (asterisks) (j, k); basal ganglia involvement with restricted diffusion and cystic change on follow-up (curved arrows) (a–d); lactate peak at around 1.3 ppm on MRS (arrowheads) (f)

Fig. 2

Pedigrees of 9 families with 11 subjects described in our study

Fig. 3

Founder mutation analysis. Shared haplotypes among homozygous COQ4:c.370G>A. Red square indicates the location of homozygous COQ4:c.370G>A, while black square indicates the nearest heterozygous single-nucleotide polymorphism. The length of the haplotype for each subject is at the right panel. The maximum shared length is approximately 577 kb

Fig. 4

Phenotypic spectrum of neonatal, infantile, and childhood onset of COQ10D7 from all the reported cases including this study. †Lactic acidosis is not mentioned in the childhood-onset cases. (The color intensity representing the percentage of patients having that clinical presentation in arbitrary form)