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Identifying diseases displaying chronic low plasma Coenzyme Q 10 (CoQ) values may be important to prevent possible cardiovascular dysfunction. The aim of this study was to retrospectively evaluate plasma CoQ concentrations in a large cohort of pediatric and young adult patients. We evaluated plasma CoQ values in 597 individuals (age range 1 month to 43 years, average 11 years), studied during the period 2005–2016. Patients were classified into 6 different groups: control group of healthy participants, phenylketonuric patients (PKU), patients with mucopolysaccharidoses (MPS), patients with other inborn errors of metabolism (IEM), patients with neurogenetic diseases, and individuals with neurological diseases with no genetic diagnosis. Plasma total CoQ was measured by reverse-phase high-performance liquid chromatography with electrochemical detection and ultraviolet detection at 275 nm. ANOVA with Bonferroni correction showed that plasma CoQ values were significantly lower in the PKU and MPS groups than in controls and neurological patients. The IEM group showed intermediate values that were not significantly different from those of the controls. In PKU patients, the Chi-Square test showed a significant association between having low plasma CoQ values and being classic PKU patients. The percentage of neurogenetic and other neurological patients with low CoQ values was low (below 8%). In conclusión, plasma CoQ monitoring in selected groups of patients with different IEM (especially in PKU and MPS patients, but also in IEM under protein-restricted diets) seems advisable to prevent the possibility of a chronic blood CoQ suboptimal status in such groups of patients.

‘Developmental programming’, as a consequence of suboptimal in-utero and early environments can be associated with metabolic dysfunction in later life, including increased incidence of cardiovascular disease and type 2 diabetes and predisposition of older men to sarcopenia. However, the molecular mechanisms underpinning these associations are poorly understood. Many conditions associated with ‘developmental programming’ are also known to be associated with the aging process. We therefore utilized our well-established rat model of low-birth weight and accelerated postnatal catch-up growth (termed ‘recuperated’) in this study to establish the effects of suboptimal maternal nutrition on age-associated factors in skeletal muscle. We demonstrated accelerated telomere shortening (a robust marker of cellular aging) as evidenced by reduced frequency of long telomeres (48.5-8.6kb) and increased frequency of short telomeres (4.2-1.3kb) in vastus-lateralis muscle from aged recuperated offspring compared to controls. This was associated with increased protein expression of the DNA damage repair marker 8-oxoguanine-glycosylase (OGG1) in recuperated offspring. Recuperated animals also demonstrated an oxidative stress phenotype, with decreased citrate synthase activity, increased electron-transport complex activities of complex I, complex II-III and complex IV (all markers of functional mitochondria), increased xanthine oxidase (XO), p67phox and Nuclear-factor kappa-light-chain-enhancer of activated B-cells (NF-κB). Recuperated offspring also demonstrated increased antioxidant defense capacity with increased protein expression of manganese superoxide dismutase (MnSOD), copper-zinc superoxide dismutase (CuZnSOD), Catalase and heme oxygenase-1 (HO1), all of which are known targets of NF-κB and may be upregulated as a consequence of oxidative stress. Recuperated offspring also had a pro-inflammatory phenotype as evidenced by increased tumor necrosis factor-α (TNFα) and interleukin-1β (IL1β) protein levels. Taken together, we demonstrate for the first time, to our knowledge, an accelerated aging phenotype in skeletal muscle in the context of developmental programming. These findings may pave the way for suitable interventions in at-risk populations.

The objective of this study was to evaluate whether the levels of coenzyme Q10 (CoQ10) in brain tissue of multiple system atrophy (MSA) patients differ from those in elderly controls and in patients with other neurodegenerative diseases. Flash frozen brain tissue of a series of 20 pathologically confirmed MSA patients [9 olivopontocerebellar atrophy (OPCA) type, 6 striatonigral degeneration (SND) type, and 5 mixed type] was used for this study. Elderly controls (n = 37) as well as idiopathic Parkinson's disease (n = 7), dementia with Lewy bodies (n = 20), corticobasal degeneration (n = 15) and cerebellar ataxia (n = 18) patients were used as comparison groups. CoQ10 was measured in cerebellar and frontal cortex tissue by high performance liquid chromatography. We detected a statistically significant decrease (by 3-5%) in the level of CoQ10 in the cerebellum of MSA cases (P = 0.001), specifically in OPCA (P = 0.001) and mixed cases (P = 0.005), when compared to controls as well as to other neurodegenerative diseases [dementia with Lewy bodies (P<0.001), idiopathic Parkinson's disease (P<0.001), corticobasal degeneration (P<0.001), and cerebellar ataxia (P = 0.001)]. Our results suggest that a perturbation in the CoQ10 biosynthetic pathway is associated with the pathogenesis of MSA but the mechanism behind this finding remains to be elucidated.

Parkinsonism and attention deficit hyperactivity disorder (ADHD) are widespread brain disorders that involve disturbances of dopaminergic signaling. The sodium-coupled dopamine transporter (DAT) controls dopamine homeostasis, but its contribution to disease remains poorly understood. Here, we analyzed a cohort of patients with atypical movement disorder and identified 2 DAT coding variants, DAT-Ile312Phe and a presumed de novo mutant DAT-Asp421Asn, in an adult male with early-onset parkinsonism and ADHD. According to DAT single-photon emission computed tomography (DAT-SPECT) scans and a fluoro-deoxy-glucose-PET/MRI (FDG-PET/MRI) scan, the patient suffered from progressive dopaminergic neurodegeneration. In heterologous cells, both DAT variants exhibited markedly reduced dopamine uptake capacity but preserved membrane targeting, consistent with impaired catalytic activity. Computational simulations and uptake experiments suggested that the disrupted function of the DAT-Asp421Asn mutant is the result of compromised sodium binding, in agreement with Asp421 coordinating sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine, and electrophysiological analyses identified a large cation leak that might further perturb dopaminergic neurotransmission. Our results link specific DAT missense mutations to neurodegenerative early-onset parkinsonism. Moreover, the neuropsychiatric comorbidity provides additional support for the idea that DAT missense mutations are an ADHD risk factor and suggests that complex DAT genotype and phenotype correlations contribute to different dopaminergic pathologies.

Vitamin B 6 dependent seizure disorders are an important and treatable cause of childhood epilepsy. The molecular and biochemical basis for some of these disorders has only recently been elucidated and it is likely that inborn errors affecting other parts of this complex metabolic pathway are yet to be described. In man vitamin B 6 ingested from the diet exists as six different vitamers, pyridoxal (PL), pyridoxamine (PM), pyridoxine (PN), pyridoxal 5’‐phosphate (PLP), pyridoxamine 5’‐ phosphate (PMP) and pyridoxine 5’‐phosphate (PNP). Its breakdown product, 4‐pyridoxic acid (PA), is excreted in urine. Here we describe an analytical LC‐MS/MS method to measure all vitameric B 6 forms in plasma and have subsequently applied this methodology to investigate children with vitamin B 6 responsive seizure disorders. We show that patients with inborn errors of B 6 metabolism such as pyridox(am)ine 5’‐phosphate oxidase (PNPO) deficiency have characteristic B 6 profiles which allow them to be differentiated from each other and control populations, even when on treatment with B 6 . Regardless of diagnosis, patients on treatment doses of pyridoxine hydrochloride and pyridoxal phosphate have markedly elevated levels of some vitameric forms (PLP, PL and PA). Such mega doses of B 6 treatment are known to be associated with neurotoxicity. This LC‐MS/MS method will be a useful tool for treatment monitoring and may help further our understanding of mechanisms of neurotoxicity in patient groups.

Vitamin B 6 dependent seizure disorders are an important and treatable cause of childhood epilepsy. The molecular and biochemical basis for some of these disorders has only recently been elucidated and it is likely that inborn errors affecting other parts of this complex metabolic pathway are yet to be described. In man vitamin B 6 ingested from the diet exists as six different vitamers, pyridoxal (PL), pyridoxamine (PM), pyridoxine (PN), pyridoxal 5’-phosphate (PLP), pyridoxamine 5’- phosphate (PMP) and pyridoxine 5’-phosphate (PNP). Its breakdown product, 4-pyridoxic acid (PA), is excreted in urine. Here we describe an analytical LC-MS/MS method to measure all vitameric B 6 forms in plasma and have subsequently applied this methodology to investigate children with vitamin B 6 responsive seizure disorders. We show that patients with inborn errors of B 6 metabolism such as pyridox(am)ine 5’-phosphate oxidase (PNPO) deficiency have characteristic B 6 profiles which allow them to be differentiated from each other and control populations, even when on treatment with B 6 . Regardless of diagnosis, patients on treatment doses of pyridoxine hydrochloride and pyridoxal phosphate have markedly elevated levels of some vitameric forms (PLP, PL and PA). Such mega doses of B 6 treatment are known to be associated with neurotoxicity. This LC-MS/MS method will be a useful tool for treatment monitoring and may help further our understanding of mechanisms of neurotoxicity in patient groups.

Vitamin B6 dependent seizure disorders are an important and treatable cause of childhood epilepsy. The molecular and biochemical basis for some of these disorders has only recently been elucidated and it is likely that inborn errors affecting other parts of this complex metabolic pathway are yet to be described. In man vitamin B6 ingested from the diet exists as six different vitamers, pyridoxal (PL), pyridoxamine (PM), pyridoxine (PN), pyridoxal 5'-phosphate (PLP), pyridoxamine 5'- phosphate (PMP) and pyridoxine 5'-phosphate (PNP). Its breakdown product, 4-pyridoxic acid (PA), is excreted in urine. Here we describe an analytical LC-MS/MS method to measure all vitameric B6 forms in plasma and have subsequently applied this methodology to investigate children with vitamin B6 responsive seizure disorders. We show that patients with inborn errors of B6 metabolism such as pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency have characteristic B6 profiles which allow them to be differentiated from each other and control populations, even when on treatment with B6. Regardless of diagnosis, patients on treatment doses of pyridoxine hydrochloride and pyridoxal phosphate have markedly elevated levels of some vitameric forms (PLP, PL and PA). Such mega doses of B6 treatment are known to be associated with neurotoxicity. This LC-MS/MS method will be a useful tool for treatment monitoring and may help further our understanding of mechanisms of neurotoxicity in patient groups.

Identifying diseases displaying chronic low plasma Coenzyme Q (CoQ) values may be important to prevent possible cardiovascular dysfunction. The aim of this study was to retrospectively evaluate plasma CoQ concentrations in a large cohort of pediatric and young adult patients. We evaluated plasma CoQ values in 597 individuals (age range 1 month to 43 years, average 11 years), studied during the period 2005-2016. Patients were classified into 6 different groups: control group of healthy participants, phenylketonuric patients (PKU), patients with mucopolysaccharidoses (MPS), patients with other inborn errors of metabolism (IEM), patients with neurogenetic diseases, and individuals with neurological diseases with no genetic diagnosis. Plasma total CoQ was measured by reverse-phase high-performance liquid chromatography with electrochemical detection and ultraviolet detection at 275 nm. ANOVA with Bonferroni correction showed that plasma CoQ values were significantly lower in the PKU and MPS groups than in controls and neurological patients. The IEM group showed intermediate values that were not significantly different from those of the controls. In PKU patients, the Chi-Square test showed a significant association between having low plasma CoQ values and being classic PKU patients. The percentage of neurogenetic and other neurological patients with low CoQ values was low (below 8%). In conclusión, plasma CoQ monitoring in selected groups of patients with different IEM (especially in PKU and MPS patients, but also in IEM under protein-restricted diets) seems advisable to prevent the possibility of a chronic blood CoQ suboptimal status in such groups of patients.

Background The objective of this study was to evaluate whether the levels of coenzyme Q10 (CoQ10) in brain tissue of multiple system atrophy (MSA) patients differ from those in elderly controls and in patients with other neurodegenerative diseases. Methods Flash frozen brain tissue of a series of 20 pathologically confirmed MSA patients [9 olivopontocerebellar atrophy (OPCA) type, 6 striatonigral degeneration (SND) type, and 5 mixed type] was used for this study. Elderly controls (n = 37) as well as idiopathic Parkinson's disease (n = 7), dementia with Lewy bodies (n = 20), corticobasal degeneration (n = 15) and cerebellar ataxia (n = 18) patients were used as comparison groups. CoQ10 was measured in cerebellar and frontal cortex tissue by high performance liquid chromatography. Results We detected a statistically significant decrease (by 3-5%) in the level of CoQ10 in the cerebellum of MSA cases (P = 0.001), specifically in OPCA (P = 0.001) and mixed cases (P = 0.005), when compared to controls as well as to other neurodegenerative diseases [dementia with Lewy bodies (P<0.001), idiopathic Parkinson's disease (P<0.001), corticobasal degeneration (P<0.001), and cerebellar ataxia (P = 0.001)]. Conclusion Our results suggest that a perturbation in the CoQ10 biosynthetic pathway is associated with the pathogenesis of MSA but the mechanism behind this finding remains to be elucidated.

This chapter focuses on two pharmacotherapies, statins and fibrates, which are used in the treatment of dyslipidemia, highlighting the putative mechanisms responsible for their contrasting effects on mitochondrial function. Impairment of oxidative phosphorylation has been associated with adverse side effects of statin treatment, with the lipophilicity of the statin being an important determinant of the mitochondrial toxicity. The mitochondrial respiratory chain (MRC) is located in the inner mitochondrial membrane and plays a central role in cellular energy generation. In view of the invasiveness of a muscle biopsy, investigators have used other cell types to evaluate the effect of statin therapy on endogenous CoQ 10 status. In vitro studies have indicated that the mitochondrial toxicity associated with fibrate treatment may be caused by their prodrug ester forms rather than by the active fibric acid moiety. The antiepileptics and the antioxidant drug idebenone may exhibit the dichotomy toward mitochondrial function.