High frequency and founder effect of the CYP3A4*20 loss-of-function allele in the Spanish population classifies CYP3A4 as a polymorphic enzyme.

Cytochrome P450 3A4 (CYP3A4) is a key drug-metabolizing enzyme. Loss-of-function variants have been reported as rare events, and the first demonstration of a CYP3A4 protein lacking functional activity is caused by CYP3A4*20 allele. Here we characterized the world distribution and origin of CYP3A4*20 mutation. CYP3A4*20 was determined in more than 4000 individuals representing different populations, and haplotype analysis was performed using CYP3A polymorphisms and microsatellite markers. CYP3A4*20 allele was present in 1.2% of the Spanish population (up to 3.8% in specific regions), and all CYP3A4*20 carriers had a common haplotype. This is compatible with a Spanish founder effect and classifies CYP3A4 as a polymorphic enzyme. This constitutes the first description of a CYP3A4 loss-of-function variant with high frequency in a population. CYP3A4*20 results together with the key role of CYP3A4 in drug metabolism support screening for rare CYP3A4 functional alleles among subjects with adverse drug events in certain populations.

The brain-heart connection in mitochondrial respiratory chain diseases.

Mitochondrial respiratory chain disorders (MRCD) are a heterogeneous group of diseases leading to an inadequate production of ATP. Brain and heart are among the most affected organs. Thus far, no specific relationship has been found between specific affected areas in the central nervous system and cardiac involvement. This study investigated the relationship between specific brain involvement and heart disease in mitochondrial disorders. We hypothesize that specific areas of brain lesions in children with MRCD are more frequently correlated to heart disease than others. A retrospective evaluation of the clinical records of 63 children with a definite MRCD, was performed searching for heart disease, namely, dilated and hypertrophic cardiomyopathy and arrhythmia. Brain MR images were evaluated and characterized regarding specific areas of atrophy and involvement. These findings were correlated using the Fischer exact test whose strength was determined with the Phi coefficient. During the period analyzed, 13 children (20.6%) developed cardiac disease, of whom nine (14.3%) exhibited isolated cardiomyopathy, one (1.6%) exhibited arrhythmia and three both. The main MRI abnormalities observed were brain atrophy (65.1%) and among this group 17.5% of subjects had cerebellar involvement. In addition, supratentorial, cerebellar and brainstem white and grey matter lesions were also found. There was a statistically significant relationship between progression to cardiac disease and cerebellar atrophy (Fisher's Exact Test -0.005 and Phi 0.394) and lesions in the cerebral peduncles (0.035/0.358). Moreover, there was an additional correlation between thalamic lesions and progression to hypertrophic myocardiopathy (0.029/0.397). A statistical relationship between thalamic, mesencephalic and cerebellar involvement and cardiac disease in children with definite MRCD was observed. The true significance of this connection warrants further assessment.

Genetic basis of Alzheimer's dementia: role of mtDNA mutations.

Alzheimer's disease (AD) is the most common neurodegenerative disorder associated to dementia in late adulthood. Amyloid precursor protein, presenilin 1 and presenilin 2 genes have been identified as causative genes for familial AD, whereas apolipoprotein E epsilon4 allele has been associated to the risk for late onset AD. However, mutations on these genes do not explain the majority of cases. Mitochondrial respiratory chain (MRC) impairment has been detected in brain, muscle, fibroblasts and platelets of Alzheimer's patients, indicating a possible involvement of mitochondrial DNA (mtDNA) in the aetiology of the disease. Several reports have identified mtDNA mutations in Alzheimer's patients, suggesting the existence of related causal factors probably of mtDNA origin, thus pointing to the involvement of mtDNA in the risk contributing to dementia, but there is no consensual opinion in finding the cause for impairment. However, mtDNA mutations might modify age of onset, contributing to the neurodegenerative process, probably due to an impairment of MRC and/or translation mechanisms.

Mitochondrial dysfunction in autism spectrum disorders: a population-based study.

A minority of cases of autism has been associated with several different organic conditions, including bioenergetic metabolism deficiency. In a population-based study, we screened associated medical conditions in a group of 120 children with autism (current age range 11y 5mo to 14y 4mo, mean age 12y 11mo [SD 9.6mo], male:female ratio 2.9:1). Children were diagnosed using Diagnostic and Statistical Manual of Mental Disorders criteria, the Autism Diagnostic Interview--Revised, and the Childhood Autism Rating Scale; 76% were diagnosed with typical autism and 24% with atypical autism. Cognitive functional level was assessed with the Griffiths scale and the Wechsler Intelligence Scale for Children and was in the normal range in 17%. Epilepsy was present in 19 patients. Plasma lactate levels were measured in 69 patients, and in 14 we found hyperlactacidemia. Five of 11 patients studied were classified with definite mitochondrial respiratory chain disorder, suggesting that this might be one of the most common disorders associated with autism (5 of 69; 7.2%) and warranting further investigation.

Influence of apolipoprotein E genotype on blood redox status of Alzheimer's disease patients.

The blood redox status of probable Alzheimer's Disease (AD) patients and control subjects with distinct Apo E genotypes was investigated. It was assessed by measuring the levels of hydroperoxides (MDA) in plasma and erythrocytes, the levels of the antioxidant defense system (enzymatic and non-enzymatic) in plasma, erythrocytes, platelets and leukocytes, the activities of catechol-O-methyltransferase (COMT) in erythrocytes and monoamine oxidase-B (MAO-B) in platelets and also the activity of the mitochondrial respiratory chain in leukocytes. No significant differences were found between the Apo E genotype and MDA, uric acid, vitamin E and reduced-glutathione (GSH) levels in plasma; MDA, vitamin E, GSH, superoxide-dismutase (SOD), glutathione-peroxidase (GSH-Px) and COMT levels in erythrocytes; vitamin E levels in the platelets of AD patients and control subjects. However, the uric acid levels in plasma and the COMT levels in erythrocytes of AD patients and control subjects with the epsilon4 allele were significantly lower than those observed in control subjects without the epsilon4 allele. Moreover, the duraquinol oxidation level in leukocytes of AD patients with the epsilon4 allele was significantly higher than that in AD patients without the epsilon4 allele and control subjects with and without the epsilon4 allele. The meaning of these results is discussed in terms of involvement of oxidative stress in the etiopathogenesis of AD.

[Dopaminergic system genes in Mexican schizophrenics]. / Evaluación de genes del sistema dopaminérgico en esquizofrénicos mexicanos.

This investigation reports an association study with alleles of the dopaminergic system genes (tyrosine hydroxylase (TH), D2 and D4 receptors) in schizophrenic patients and non-schizophrenic subjects. The genotypes were typed using a polymerase chain reactions PCR-based CA repeat polymorphisms. There were no significant associations between the studied alleles and schizophrenia. Also, a linkage analysis was performed using the same genes (TH, D2 and D4) in two multiple affected schizophrenic families. There was no linkage among any of three genes and schizophrenia. The maximum lod score (Z = 0.43, theta = 0.10 penetrance 100%) was for the tyrosine hydroxylase gene. Linkage analysis significantly excluded the D2 receptor gene (Z = 5.6, theta = 0.01), assuming an autosomal dominant pattern and complete penetrance, However, when the lod scores were calculated with other penetrance values, they lost significance.

A study of the electrochemical oxidation of Navelbine.

The search for drugs with cytostatic activity and with better pharmacokinetic features led to the synthesis of Navelbine (5'-noranhydrovinblastine) which is a structural modification of antitumour Vinca alkaloids. The new drug Navelbine has high liposolubility, a lower toxicity and increased antitumour activity. The electrochemical oxidation of Navelbine was studied over a wide pH range (1.2-12.8) at a glassy carbon disc electrode in buffered aqueous media using differential pulse and cyclic voltammetry. The anodic oxidation mechanism is a very complex, pH dependent, multistep electron transfer process with coupled homogeneous chemical reactions.