Clinical, biochemical, and genetic features associated with VARS2-related mitochondrial disease.

In recent years, an increasing number of mitochondrial disorders have been associated with mutations in mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs), which are key enzymes of mitochondrial protein synthesis. Bi-allelic functional variants in VARS2, encoding the mitochondrial valyl tRNA-synthetase, were first reported in a patient with psychomotor delay and epilepsia partialis continua associated with an oxidative phosphorylation (OXPHOS) Complex I defect, before being described in a patient with a neonatal form of encephalocardiomyopathy. Here we provide a detailed genetic, clinical, and biochemical description of 13 patients, from nine unrelated families, harboring VARS2 mutations. All patients except one, who manifested with a less severe disease course, presented at birth exhibiting severe encephalomyopathy and cardiomyopathy. Features included hypotonia, psychomotor delay, seizures, feeding difficulty, abnormal cranial MRI, and elevated lactate. The biochemical phenotype comprised a combined Complex I and Complex IV OXPHOS defect in muscle, with patient fibroblasts displaying normal OXPHOS activity. Homology modeling supported the pathogenicity of VARS2 missense variants. The detailed description of this cohort further delineates our understanding of the clinical presentation associated with pathogenic VARS2 variants and we recommend that this gene should be considered in early-onset mitochondrial encephalomyopathies or encephalocardiomyopathies.

Oxidative stress in hypertensive children before and after 1 year of antihypertensive therapy.

BACKGROUND: The relation between primary hypertension (PH), target organ damage (TOD) and oxidative stress (SOX) is not known. METHODS: We assessed SOX in 86 children with PH before and after 12 months of standard non-pharmacological and pharmacological therapy based on renin-angiotensin system blockade. RESULTS: Patients with left ventricular hypertrophy (LVH) and with carotid intima-media thickness (cIMT) >2SDS had higher thiobarbituric acid reactive substances (TBARS) concentrations in comparison to patients without LVH or with normal cIMT. Patients with metabolic syndrome (MS) had lower activity of gluthatione peroxidase, higher asymmetric dimethyloarginine (ADMA) and oxidized LDL cholesterol (oxyLDL) in comparison to patients without MS. TBARS correlated with left ventricular concentric hypertrophy, cIMT, albuminuria and SBP/24 h. ADMA and oxyLDL correlated with CRP and TG/HDL ratio. After 1 year of antihypertensive treatment blood pressure, TOD and prevalence of MS decreased. TBARS decreased and glutathione concentrations increased. The decrease of TBARS concentration correlated with the decrease of body mass index (BMI). Decrease of oxyLDL and ADMA correlated with increased insulin sensitivity, however markers of SOX did not correlate with BP decrease. CONCLUSION: SOX in children with PH correlates with TOD, metabolic abnormalities, changes in fat amount and improvement of insulin sensitivity, but not with BP decrease.

Bone metabolism in cholestatic children before and after living-related liver transplantation--a long-term prospective study.

Bone disorders are common in children with end-stage liver diseases, especially those associated with cholestasis. Abnormal hepatocyte function, disordered vitamin D metabolism and calcium-phosphorous homeostasis, malnutrition, and immunosuppressive treatment are potential risk factors of bone tissue pathology before and after transplantation. The aim of the study was to analyze the long-term effect of successful living-related liver transplantation (LRLTx) on skeletal status and bone metabolism in cholestatic children. Eighteen cholestatic children (1.4±0.5yr old; 12 females [F]/6 males [M]) qualified for LRLTx were analyzed; 16 (5F/11M) of them participated in long-term observation (V4). Serum levels of osteocalcin (OC), procollagen type 1 N-terminal propeptide (P1NP), cross-linked telopeptide of type 1 collagen (CTx), insulin-like growth factor I (IGF-I), IGF-I binding protein 3 (IGFBP-3), parathyroid hormone (PTH), 25-hydroxyvitamin D (25(OH)D), and 1,25-dihydroxyvitamin D (1,25(OH)(2)D) were assayed before (V0) and 6mo (V1), 12mo (V2), 18mo (V3), and 4.4yr (V4) after LRLTx. Total body bone mineral content (TBBMC) and total body bone mineral density (TBBMD) were measured by dual-energy X-ray absorptiometry (DXA) at the same pattern. Before LRLTx, the OC, P1NP, CTx, IGF-I, and IGFBP-3 levels as well as TBBMC and TBBMD were decreased compared with age-matched control group. The mean serum levels of 25(OH)D and 1,25(OH)(2)D were within reference ranges from V0 to V4. After LRLTx, the OC, P1NP, CTx, IGF-I, and IGFBP-3 as well as TBBMC and TBBMD reached the age-matched reference values. At V4, the level of P1NP decreased below and the PTH increased above the reference range that coincided with reduced Z-scores of both TBBMC (-1.11±1.24) and TBBMD (-1.00±1.19). P1NP and CTx, both measured at V3, correlated with IGF-I at V2 (R=0.86, p=0.014 and R=0.78, p=0.021, respectively) and PTH at V3 for P1NP and V1 for CTx (R=0.64, p=0.048 and R=0.54, p=0.038, respectively). The TBBMC changes between V0 and V4 correlated with IGF-I (R=0.68, p=0.015) and 1,25(OH)(2)D (R=0.54, p=0.025), both assayed at V1. The change of TBBMC Z-scores between V0 and V4 correlated with P1NP at V1 (R=0.69, p=0.002). The TBBMD changes between V0 and V4 correlated with CTx at V1 (R=0.54, p=0.027) and P1NP change between V0 and V1 (R=0.51, p=0.038). In short-term observation, successful LRLTx led to bone metabolism normalization triggered by probable anabolic action of IGF-I and PTH and manifested by TBBMC and TBBMD increases. In long-term horizon, moderately impaired DXA assessed bone status coincided with disturbances in bone metabolism. Bone metabolism markers, especially P1NP and CTx, appeared to be good predictors of changes in bone status evaluated by DXA.

Healthy Food Pyramid as Well as Physical and Mental Activity in the Prevention of Alzheimer's Disease.

The ageing of the population is resulting in neurodegenerative diseases, including Alzheimer's disease (AD), which are an increasing social, economic and medical problem. Diet and physical activity are now considered as important modifiable factors that help prevent or delay the development of AD and other dementia-related diseases. The pyramid of healthy nutrition and lifestyle is a way of presenting the principles, the implementation of which gives a chance for proper development and a long healthy life. The basis of the pyramid, in the first place, is physical activity. Our review of the literature in the PubMed database supports the hypothesis that complementary factors, such as proper diet, physical exercise and mental activity, have a positive impact on the prevention of neurodegenerative diseases. The nutritional recommendations for healthy adults primarily include the consumption of vegetables, fruits, cereals, legumes, vegetable oils and fishes. Therefore, the introduction of Mediterranean and Asian diets may reduce the risk of the neurodegenerative diseases associated with dementia, whereas dairy products and meat-the main sources of L-carnitine-should be consumed in moderate amounts. The aim of our work is to provide up-to-date knowledge about the appropriate dietary model and healthy lifestyle elements and their impact on good health and the long life of people.

Potential Role of L-Carnitine in Autism Spectrum Disorder.

L-carnitine plays an important role in the functioning of the central nervous system, and especially in the mitochondrial metabolism of fatty acids. Altered carnitine metabolism, abnormal fatty acid metabolism in patients with autism spectrum disorder (ASD) has been documented. ASD is a complex heterogeneous neurodevelopmental condition that is usually diagnosed in early childhood. Patients with ASD require careful classification as this heterogeneous clinical category may include patients with an intellectual disability or high functioning, epilepsy, language impairments, or associated Mendelian genetic conditions. L-carnitine participates in the long-chain oxidation of fatty acids in the brain, stimulates acetylcholine synthesis (donor of the acyl groups), stimulates expression of growth-associated protein-43, prevents cell apoptosis and neuron damage and stimulates neurotransmission. Determination of L-carnitine in serum/plasma and analysis of acylcarnitines in a dried blood spot may be useful in ASD diagnosis and treatment. Changes in the acylcarnitine profiles may indicate potential mitochondrial dysfunctions and abnormal fatty acid metabolism in ASD children. L-carnitine deficiency or deregulation of L-carnitine metabolism in ASD is accompanied by disturbances of other metabolic pathways, e.g., Krebs cycle, the activity of respiratory chain complexes, indicative of mitochondrial dysfunction. Supplementation of L-carnitine may be beneficial to alleviate behavioral and cognitive symptoms in ASD patients.

beta-Carotene deficiency in cholestatic liver disease of childhood is caused by beta-carotene malabsorption.

BACKGROUND: : Depletion of beta-carotene (b-c) has not been extensively studied in children with chronic cholestatic liver disease. PATIENTS AND METHODS: : We assessed b-c serum concentration in 53 children with cholestatic liver disease: 19 patients operated on for biliary atresia, 12 with Alagille syndrome, and 22 with progressive familial intrahepatic cholestasis. To test b-c absorption, 6 children with chronic cholestasis received a load of 10 mg b-c/kg body weight. RESULTS: : We found decreased b-c concentrations in 45 patients. The absorption of b-c was not detectable in 5 of 6 children studied. CONCLUSIONS: : b-c depletion is a common problem of chronic cholestatic liver disease in childhood that can be attributed to disturbed intestinal absorption.

Preventive Role of L-Carnitine and Balanced Diet in Alzheimer's Disease.

The prevention or alleviation of neurodegenerative diseases, including Alzheimer's disease (AD), is a challenge for contemporary health services. The aim of this study was to review the literature on the prevention or alleviation of AD by introducing an appropriate carnitine-rich diet, dietary carnitine supplements and the MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet, which contains elements of the Mediterranean diet and the Dietary Approaches to Stop Hypertension (DASH) diet. L-carnitine (LC) plays a crucial role in the energetic metabolism of the cell. A properly balanced diet contains a substantial amount of LC as well as essential amino acids and microelements taking part in endogenous carnitine synthesis. In healthy people, carnitine biosynthesis is sufficient to prevent the symptoms of carnitine deficiency. In persons with dysfunction of mitochondria, e.g., with AD connected with extensive degeneration of the brain structures, there are often serious disturbances in the functioning of the whole organism. The Mediterranean diet is characterized by a high consumption of fruits and vegetables, cereals, nuts, olive oil, and seeds as the major source of fats, moderate consumption of fish and poultry, low to moderate consumption of dairy products and alcohol, and low intake of red and processed meat. The introduction of foodstuffs rich in carnitine and the MIND diet or carnitine supplementation of the AD patients may improve their functioning in everyday life.

Relation of plasma carnitine and aminotransferases to alcohol dose and time of dependence.

BACKGROUND: Serum aspartate, alanine aminotransferases (AST, ALT), and plasma carnitine are all indirect biomarkers of alcohol abuse. Carnitine transfers long-chain fatty acids from cytoplasm to mitochondria for ß-oxidation. The aim of the study was to determine the relationship between daily alcohol intake, time of alcohol dependence, plasma carnitine, and serum aminotransferases. PATIENTS: We studied 26 men who were addicted for 2-30 years, consuming ethanol from 75 to 700 g/day (alcoholic group), as well as 17 healthy men (control group). RESULTS: In alcoholics, compared to the controls, we found: a significant increase in serum: AST (p = 0.0014), ALT (p = 0.0071), AST/ALT ratio (p < 0.000); significantly lower plasma free carnitine (FC) (p = 0.0316) and total carnitine (TC) (p = 0.0349); and a significant negative correlation between FC (r = -0.6200; R2 = 0.3844; p = 0.0007), TC (r = -0.4365; R2 = 0.1905; p = 0.0258), and time of alcohol dependence, suggesting carnitine as an indirect marker of alcohol abuse. We did not find any significant correlation between FC, TC, and levels of alcohol or aminotransferase activity. CONCLUSION: In the alcoholic group, there was an increase in serum activity of AST, ALT, and AST/ALT ratio that confirms liver injury. In addition, we found low plasma FC and TC, which may indicate damage to mitochondrial ß-oxidation caused by alcohol metabolites. The significantly higher plasma FC and TC in patients consuming the most, compared to patients consuming smaller doses of alcohol, may be caused by a lower carnitine demand of injured liver cells, decreased urinary carnitine excretion by impaired renal tubules, and leakage of carnitine into the blood from damaged muscles by the higher quantities of alcohol. The negative correlation between carnitine concentration and time of alcohol dependence may suggest the potential use of carnitine for treatment of alcohol abuse.

[Oxidative stress and hypertensive arteriopathy in children with primary hypertension--preliminary results]. / Stres oksydacyjny a uszkodzenie tetnic u dzieci z nadcisnieniem tetniczym pierwotnym--wyniki wstepne.

UNLABELLED: Hypertensive arteriopathy and intima-media (IMT) thickening is observed already in adolescents with primary hypertension (PH) at diagnosis. The injury of arterial wall may cause also generation of free radicals and free radicals may by itself perpetuate arterial wall injury. The aim of the study was to verify the hypothesis that children with PH are exposed to oxidative injury (Sox) due to impaired antioxidant barrier, and that markers of Sox correlate with IMT and metabolic risk factors of arteriosclerosis. STUDY DESIGN: controlled, cross-sectional. PATIENTS: 76 children with untreated PH, aged 14.7 yrs (5-20): 23 girls, 53 boys. CONTROLS: 83 healthy children aged 13.4 yrs (4-23): 44 girls, 39 boys. METHODS: Sono-graphic assessment of IMT in common carotid (cIMT) and superficial femoral arteries (cIMT). Sox was assessed as thiobarbituric acid reactive substances plasma concentration (TBARS), glutathione plasma concentration (GSH) as well as, glutathione peroxidase activity (GPX) were tested to demonstrate free radical scavenger activity. RESULTS: PH pts had greater cIMT (p<0.0001), carotid wall cross sectional area (WCSA) (p<0.0001), fIMT (p<0.0001), lower HDL-cholesterol, apoA1/apoB than control group (p<0.05). GSH and GPX did not differ between groups but TBARS was significantly greater in PH pts (p <0.05). In control group fIMT significantly correlated with hCRP (r=0.30, p<0.01), homocysteine (r=0.3, p< 0.05), apoA1 (r=-0.2417, p<0.05), TBARS (r=0.329, p<0.01), GPX (r=-0.241, p<0.05) and with GSH (r=-0.22, p=0.05). In pts group, there were similar correlations between fIMT and hCRP (r=0.29, p<0.05), apoA1/apoB (r=-0.28, p<0.05). CONCLUSIONS: PH pts are exposed to significantly higher Sox than controls. The significant correlations between markers of Sox and biochemical parameters suggest that hypertensive arteriopathy is an effect of complex interplay between Sox, metabolic and hemodynamic insults.