Primary coenzyme Q10 deficiency presenting as fatal neonatal multiorgan failure

Abstract

Coenzyme Q10 deficiency is a clinically and genetically heterogeneous disorder, with manifestations that may range from fatal neonatal multisystem failure, to adult-onset encephalopathy. We report a patient who presented at birth with severe lactic acidosis, proteinuria, dicarboxylic aciduria, and hepatic insufficiency. She also had dilation of left ventricle on echocardiography. Her neurological condition rapidly worsened and despite aggressive care she died at 23 h of life. Muscle histology displayed lipid accumulation. Electron microscopy showed markedly swollen mitochondria with fragmented cristae. Respiratory-chain enzymatic assays showed a reduction of combined activities of complex I+III and II+III with normal activities of isolated complexes. The defect was confirmed in fibroblasts, where it could be rescued by supplementing the culture medium with 10 μM coenzyme Q10. Coenzyme Q10 levels were reduced (28% of controls) in these cells. We performed exome sequencing and focused the analysis on genes involved in coenzyme Q10 biosynthesis. The patient harbored a homozygous c.545T>G, p.(Met182Arg) alteration in COQ2, which was validated by functional complementation in yeast. In this case the biochemical and morphological features were essential to direct the genetic diagnosis. The parents had another pregnancy after the biochemical diagnosis was established, but before the identification of the genetic defect. Because of the potentially high recurrence risk, and given the importance of early CoQ10 supplementation, we decided to treat with CoQ10 the newborn child pending the results of the biochemical assays. Clinicians should consider a similar management in siblings of patients with CoQ10 deficiency without a genetic diagnosis.

Biochemistry of Mitochondrial Coenzyme Q Biosynthesis

“…Primary CoQ deficiencies—genetic diseases due to mutations in genes encoding CoQ biosynthesis proteins—are known to be caused by nuclear DNA mutations in COQ2 [145–148], COQ4 [149, 150], COQ6 [151, 152], COQ7 [153], COQ8A ( ADCK3 ) [136, 154–158], COQ8B ( ADCK4 ) [118, 159], COQ9 [160, 161], PDSS1 [162], or PDSS2 [163, 164] (Figure IA). These diseases variably disrupt multiple organ systems.…”

“…Therapy should be initiated as soon as possible to limit irreversible tissue damage [173]. The urgency is such that prior to diagnostic tests, newborn siblings of affected individuals have been treated [148]. …”

Mitochondrial dysfunction in inherited renal disease and acute kidney injury

“…Renal symptoms are rarely isolated and commonly form part of a multisystemic disorder. Exceptions include some mtDNA mutations and some cases of CoQ 10 deficiency in which renal dysfunction might be the only clinical manifestation at presentation 24 . In general, the coexistence of neuromuscular symptoms and renal defects should raise suspicion of a mitochondrial defect 25 .…”

Coenzyme Q10 in the Treatment of Mitochondrial Disease

“…37 In order to exploit the "window of opportunity" whereby organ dysfunction may be amenable to CoQ 10 treatment, supplementation at birth has been suggested for siblings of CoQ 10 -deficient patients. 38 In vitro studies have indicated that the use of modified precursors of the quinone ring of CoQ 10 to bypass the enzymatic defect may be effective in treating specific mutations of the COQ6 and COQ7 genes. 39 Studies in yeast harboring the mutant COQ6 gene revealed that treatment with vanillic acid as well as 3-4-hydroxybenzoic acid could restore respiratory growth.…”