Table 1.

Groups of disorders associated with secondary CoQ deficiency.

Group of Disorders	Gene	Function	Diagnosis	Clinical Phenotype Described in Humans	Refs.
G1: Disorders due to impairment of oxidative phosphorylation (OXPHOS) system	BSCL-1	Defective BSCL-1 generates a catalytically and structurally inactive complex III	Leigh syndrome	Neurological symptoms and lactic acidosis	[123]
	NDUFS4	Defects on assembly of functional complex I	Leigh syndrome	Progressive loss of mental and psychomotor regression	[124,125]
	PARL	Instability of TTC19 expression, which is required for complex III activity	Leigh-like syndrome due to impairment of CIII activity	Necrotizing encephalomyelopathy	[67]
G2: Defects on nuclear and mitochondrial DNA	nDNA and mtDNA deletions	OXPHOS dysfunction	Mitochondrial DNA depletion syndrome (MDS)	Clinically heterogeneous mitochondrial phenotypes	[126]
	POLG, MPV17, SUCLA2, FBXLA	mtDNA depletion			[127,128]
	EARS2	Defective mitochondrial aminoacyl-tRNA synthetase specific for glutamate	Combined OXPHOS deficiency	Leukoencephalopathy with high lactate	[129]
	MT-TL1	Translational defects by punctual mutations in tRNA encoded by mtDNA	MELAS disease	Encephalomyopathy and lactic acidosis	[130]
	MT-TK		MERFF disease	Clinically heterogeneous mitochondrial phenotypes	[131]
G3: Defects on other proteins involved in enzymatic reactions upstream of OXPHOS	ETFDH	Electron transfer defects from electron-transferring flavoprotein to ubiquinone	Multiple Acyl-CoA dehydrogenase deficiency (MADD)	Isolated myopathic phenotype	[132]
	BRAF	Disruption of signals controlling cell growth	Cardiofaciocutaneous syndrome (CFS)	Psychomotor development delayed, muscular hypotonia, and ataxia	[133]
	ACADVL	Defects of first step of the mitochondrial fatty acid beta-oxidation pathway	Very long-chain Acyl-CoA dehydrogenase deficiency	Encephalopathy and rhabdomyolysis	[134]
	TBC1D24	GTPase-activating protein for Rab family protein	Multifocal polymyoclorus	Multifocal polymyoclonus and neurodevelopmental delay	[135]
G4: Cholesterol metabolism impairment	PDZD8	Impairment of mitochondrial Ca2+ uptake	Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis with associated frontotemporal dementia	Typical symptoms in neurodegenerative diseases	[136,137]
	3-Hydroxy-3-Methylglutaryl-CoA Rase	Defects on mevalonate pathway and CoQ synthesis	Niemann-Pick Type C1-deficiency, steatohepatitis, Alzheimer’s disease		[138,139,140,141]
	StAR, MLN64, Aquaporin-8	Cholesterol metabolism impairment			[142,143]
	LDL-receptor and other proteins	Binding defects on LDL-cholesterol to plasma membrane receptor	Familial hypercholesterolemia	Early atherosclerosis and elevated serum cholesterol concentrations	[144]
G5: Diseases caused by defects on protein carrier	SLC25A11	Disruption of transport of 2-oxoglutarate to mitochondria	Liver cancer	Hepatocellular carcinoma	[145]
	ANO10	Putative calcium-activated chloride channels defects	Autosomal recessive spinocerebellar ataxia-10	Slowly progressive ataxia and dysarthria	[146]
	FXN	Defects in transport of iron to mitochondria	Friedreich’s ataxia	Ataxia, limn incoordination, dysarthria, dysphagia, eye movement defects, and muscle weakness	[122]
G6: Mitochondrial homeostasis dysregulation	LDL-receptor and other proteins	Autophagy flux impairment	Familial hypercholesterolemia	Early atherosclerosis and elevated serum cholesterol concentration	[144]
	Point mutations in mtDNA genes encoding tRNAs	Defective protein synthesis	MELAS disease	Lactic acidosis	[130]
	MFN2	Depletion of mitochondrial CoQ and respiratory chain dysfunction	n.d.	n.d.	[147]

n.d.: not determined.