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Objective: The objective was to confirm whether a homozygous genotype for the C957 allele of the C957T DRD2 gene single nucleotide polymorphism (SNP) is associated with schizophrenia in an independent study population. Method: We examined the genotypic distribution of this SNP in a set of clinically ascertained schizophrenic patients ( n = 131) and age-matched control subjects ( n = 364). Individuals were genotyped using automated analysis of fluorescently labeled PCR products. Results: The distribution of grouped genotypes for the C957T DRD2 SNP (CC vs. CT, TT) showed that C homozygote genotype was over-represented in our patient sample when compared with control subjects. This difference reaches the statistical significance ( χ2 = 7.0; df = 1; P = 0.008; OR = 2.05; % CI 1.2–3.4). Conclusion: The findings of this study provide additional evidence that genetic variation at the DRD2 gene plays an important role in the vulnerability to schizophrenia. [ABSTRACT FROM AUTHOR]

Introduction: Previous studies have associated a decreased striatal D2 dopamine receptor (DRD2) binding with impaired performance in cognitive tasks. In vivo studies have found a lower DRD2 binding associated with the CC genotype of the C957T single nucleotide polymorphism (SNP) of the DRD2 gene. Objective: The aim of this study was to investigate the relationship between executive functions and the C957T DRD2 SNP. We hypothesized that the CC genotype would be associated with a poorer executive functioning. Methods: Our sample consisted of 83 healthy volunteers (28 males and 55 females; mean age 25.2, SD 1.7 years). To assess executive functions, the Wisconsin Card Sorting Test was used, considering the variables perseverative errors, perseverative responses, and number of categories achieved. The genotype distribution was 13 CC, 41 CT, and29 TT, satisfying Hardy-Weinberg equilibrium. Results: Carriers of the CC genotype, compared with carriers of the CT/TT genotypes, achieved significantly fewer categories (5.00 vs. 5.81; p = 0.004), made a greater number of perseverative errors (13.46 vs. 8.39; p = 0.018), and had a greater number of perseverative responses (14.92 vs. 8.94; p = 0.014). Conclusions: Our results support the hypothesis that the C957T DRD2 SNP may influence cognitive performance through its repercussions on central dopaminergic function. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The endocannabinoid system is known to regulate the dopaminergic system through CB1 presynaptic receptors. The CB1 receptor is further encoded by CNR1 gene, which is known to carry a nine-allele microsatellite polymorphism. There is a quantitative relationship between largest-sized alleles of CNR1 gene and the presence of attention deficit- hyperactivity disorder (ADHD), during childhood in Spanish male alcoholic patients. In comparison with non-ADHD patients and control individuals, those alcoholic patients who suffered from ADHD during childhood were found to carry the longer forms of alleles. Therefore, the cannabinoid system is known to affect dopaminergic transmission and is regarded as a potential physiopathological cause of ADHD.

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic neuropathies, with more than 90 associated genes. While the majority of individuals with genetic diagnosis have demyelinating CMT, a significant proportion of individuals with axonal CMT remain genetically unsolved. Aminoacyl-tRNA synthetases (aaRS) have been implicated in various neurological disorders, including CMT. Here, we hypothesize that hypomorphic variations of DARS2 , which encodes the mitochondrial aspartyl-tRNA synthetase, are associated with axonal CMT. We investigated four individuals from two unrelated families with axonal CMT. We conducted clinical assessments, genetic testing, and functional studies in fibroblasts from two affected individuals. Two pairs of siblings, now adults, presented with progressive distal muscle weakness with onset during childhood, absent lower limb reflexes and normal cognitive function. Brain MRI scans showed no abnormalities. Electrophysiological studies revealed positive waves and fibrillations and was consistent with a diagnosis of axonal motor and sensory neuropathy. Genetic testing identified compound heterozygous variants in DARS2 in both families (c.713C>T; p.Ser238Phe and c.1006C>T; p.Arg336Cys in Family 1; and c.74del; p.Ile25Thrfs*38 and c.1006C>T; p.Arg336Cys in Family 2). The four individuals share the variant DARS2 : c.1006C>T, p.Arg336Cys, located in the insertion subdomain of DARS2, where very few variants have been previously reported. In Family 1, this variant is in trans with another missense variant (c.713C>T; p.Ser238Phe) located in the dimerization domain of DARS2, which is an essential region for the correct functionality of the protein, as in other aaRS. In Family 2, it is combined with a truncating variant. Functional analyses in fibroblasts revealed reduced DARS2 protein levels and altered mitochondrial localization. Additionally, we observed a decrease in both mitochondrial mass and fragmentation, consistent with a disrupted mitochondrial network morphology, suggesting the involvement of DARS2 in the disease pathophysiology. The identification of fully penetrant variants (p.Ser238Phe and p.Ile25Thrfs*38) combined with a hypomorphic variant (p.Arg336Cys) expands the phenotypic spectrum of DARS2-related disorders, establishing a novel association between DARS2 and axonal CMT. The combination of penetrant variants and hypomorphic variants distinguishes these cases from previously reported with DARS2-related leukoencephalopathy. We propose that the genotypic combination of a hypomorphic and a penetrating allele for DARS2 explains the symptoms in these two families with a pure axonal CMT. These findings underscore the importance of mitochondrial aspartyl-tRNA synthetase in peripheral nerve function and highlight potential targets for therapeutic intervention in CMT. [ABSTRACT FROM AUTHOR]

Next-generation sequencing has enhanced the rate of genetic diagnosis in neuromuscular diseases. Nevertheless, half of the patients remain without a molecular diagnosis. One factor that can impede the acquisition of a genetic diagnosis is the presence of mosaicism: the coexistence of at least two different genetic cell populations within an organism. We present two cases of neuromuscular pediatric patients in which a phenotype-driven analysis guided the careful interrogation of candidate genes. Patient A showed a phenotype of congenital myopathy (CM). Trio genome sequencing detected a heterozygous likely pathogenic variant in RYR1 (c.14566G>A; p.Ala4856Thr), inherited from his unaffected mother. It was considered the potential existence of a missing second variant in trans in the proband, but also hypothesized that the variant might be mosaic in the mother. The comparison between alternative allele frequencies (AAF) showed that, while the affected child had an AAF of 0.60, the mother had an AAF of only 0.23. A quantification through ddPCR from blood-derived DNA revealed a 17% of the alternative allele in the mother's sample, whereas in the individual's sample, 49% was observed. Patient B was born with congenital hip dislocation, hypotonia and distal hyperlaxity. Upon clinical examination of the parents, it was detected a left hemicorporal hypotrophy and hand retractions in the father. A neuromuscular gene panel in patient B and his father was inconclusive. RNAseq performed on the muscle sample of the father revealed an exon 9 skipping of COL6A1 in 15% of the transcripts. In genome sequencing it was detected an exon 9 deletion of COL6A1 in 10% of the reads in the father and 50% in patient B (p.Gly269_Pro286del), which was validated through a custom MLPA. Our study highlights the importance of phenotype-driven analysis and careful interrogation of the likely relevant genes and variants and illustrates the genetic mosaicism as a possible explanation behind genetically unsolved affected individuals. [ABSTRACT FROM AUTHOR]

DTNA encodes for α-dystrobrevin, a component of the macromolecular dystrophin-glycoprotein complex that binds to dystrophin/utrophin and α-syntrophin. Absence of α-dystrobrevin causes muscular dystrophy in mice but variants in DTNA in humans have not been associated with muscle disease. Here, we present nine individuals from two unrelated families with dominantly inherited DTNA variants. Affected individuals of family A showed a phenotype characterized by hyperCKaemia, myalgias and exercise intolerance, without weakness, that started in the second decade of life in most cases. One patient had an episode of rhabdomyolysis at 12 years old. The WBMRI performed in one patient was normal. All 4 affected individuals from family B had hyperCKaemia. The index case in family B showed also a progressive proximal weakness in lower limbs with onset at the age of 5. Muscle biopsies in five affected individuals showed a combination of myopathic and dystrophic pattern, characterized by variation in fiber size, increased internal nuclei, and slightly increased extracellular connective tissue. A patchy endomysial and perimysial inflammation was observed in one patient of family B. Immunohistochemical analysis of the four biopsies of affected individuals of family A showed a reduction in α-dystrobrevin as well as a variable reduction of several other proteins of the dystrophin-associated protein complex, including dystrophin, sarcoglycans and dystroglycans. The five affected individuals from family A harbored the heterozygous variant c.1585G>A; p.Glu529Lys while the four affected individuals from family B had a c.1567-1587del; p.Gln523_Glu529del. Both variants are located in the coiled-coil domain of α-dystrobrevin that mediates the interaction with dystrophin and utrophin, are absent from population databases, affect highly conserved residues, and have a pahogenic in silico prediction. This is the first description of variants in DTNA causing muscle disease. Our findings show variable expressivity of this new condition ranging from hyperCKemia to proximal muscle weakness making family studies very important for diagnosis. [ABSTRACT FROM AUTHOR]

ANXA11 mutations have been associated with two different adult-onset conditions: amyotrophic lateral sclerosis and inclusion body myopathy/multisystem proteinopathy. The pathogenic variant p.Asp40Gly has been identified in individuals with ALS and, more recently, p.Asp40Tyr in patients with multisystem proteinopathy. The pathophysiological mechanism by which the myopathy occurs has not been elucidated until now. Here we describe a patient who carries the new variant of ANXA11 p.Asp40Ile and shows a severe and rapidly progressive childhood-onset oculopharyngeal muscular dystrophy, mainly characterized by ptosis, ophthalmoplegia, dysphagia, respiratory failure and progressive muscle weakness. The patient's unique early-onset oculopharyngeal muscular dystrophy phenotype is strikingly similar to that recently described in children with frameshift variants of HNRNPA2B1 , which encodes a ribonucleoprotein involved in dynamic stress granule regulation. Muscle biopsy was characterized by a myopathic pattern that included ANXA11 aggregate and lower levels of both soluble ANXA11 and HNRNPA2B1. Mechanistically, in vitro studies using recombinant ANXA11 p.Asp40Ile revealed defects of the protein function, being the peptide more prone to aggregation. Of note, the impact of p.Asp40Ile was more deleterious on ANXA11 ability to undergo liquid-liquid phase separation than other mutations affecting the Asp40 residue and associated with other clinical phenotypes. Moreover, ANXA11 and HNRNPA2B1 expression in the patient´s fibroblasts was decreased and showed defects in the dynamics of the stress granules. Our findings extend the phenotypic spectrum of ANXA11-related conditions to childhood progressive myopathies and help understand the pleiotropism associated with changes in the aspartic acid in position 40 of ANXA11. [ABSTRACT FROM AUTHOR]

The TaqIA single-nucleotide polymorphism (SNP), which is the most widely studied genetic polymorphism in addictions, is located at the gene that encodes the RIP kinase ANKK1 near the gene for dopamine receptor D2. The TaqIA SNP is in strong linkage disequilibrium with the SNP rs7118900, which changes the alanine at position 239 to threonine in the ANKK1 protein (Ala239/A2; Thr239/A1). In silico analysis has predicted that this polymorphic substitution creates an additional phosphorylation site in the kinase domain of ANKK1. To investigate the contribution of ANKK1 to the pathophysiology of TaqIA-associated phenotypes, we analyzed transfected HEK293T cells with the human ANKK1-kinase and ANKK1-kinase variants tagged with GFP. We observed that the ANKK1-kinase is located in both the nucleus and the cytoplasm, suggesting that there is nucleocytoplasmic shuttling of this putative signal transducer. In addition, we found that the Ala239Thr ANKK1-kinase polymorphism exhibited strong expression differences in both the nucleus and the cytoplasm at basal level and when stimulated with the dopamine agonist apomorphine. Specifically, the ANKK1-kinase variant showed the highest level of basal protein expression, while ANKK1-kinase was 0.64-fold lower. After treatment with apomorphine, ANKK1-kinase showed a 2.4-fold increment in protein levels, whereas a 0.67-fold reduction was observed in ANKK1-kinase. Thus, here we provide the first evidence of functional ANKK1 differences that are marked by TaqIA and could be associated with vulnerability to addiction. [ABSTRACT FROM AUTHOR]

A number of findings suggest that inflammation plays a role in the pathophysiology of schizophrenia. Taking into account a physiological balance between pro- and anti-inflammatory mediators, we measured the plasma levels of cyclooxygenase-derived mediators and other key pro- and anti-inflammatory transcription factors in peripheral blood mononuclear cells (PBMC). Forty healthy subjects and 46 treated chronic schizophrenic patients with an acutely exacerbated condition who met DSM-IV criteria were included. COX by-products prostaglandin E2 (PGE2) and 15d-prostaglandin J2 (15d-PGJ2) plasma levels were measured by EIA. Peroxisome proliferator-activated receptor gamma (PPARγ) as well as nuclear factor kappaB (NFκB) activity in nuclear extracts from PBMC and expression of its inhibitory subunit IκBα in cytosolic extracts were determined using ELISA-based kits. Schizophrenic patients showed higher plasma levels of pro-inflammatory PGE2 than age-matched controls (p=0.043). On the contrary, levels of anti-inflammatory 15-d-PGJ2 were lower (p=0.004), correlating with a lower expression of its nuclear target, PPARγ in nuclear extracts from PBMC (p=0.001). Although no changes in NFκB activity were observed between patients and healthy controls, the expression of its inhibitory protein IκBα was lower in the patients compared to the controls (p=0.027). These findings suggest that schizophrenia is associated with a systemic imbalance in the plasma levels of pro-inflammatory/anti-inflammatory prostaglandins in favor of the former. Furthermore, the expression and activity of anti-inflammatory PPARγ are diminished in PBMC, which indicates a state of inflammation and blunted anti-inflammatory counterbalancing mechanisms at systemic level in these patients. [ABSTRACT FROM AUTHOR]

Polymorphisms of DRD2 and A NKK1 have been associated with psychiatric syndromes where there is believed to be an underlying learning process deficit such as addiction, post-traumatic stress disorder and psychopathy. We investigated the effects of the DRD2 C957T and ANKK1 TaqIA single nucleotide polymorphism (SNP), which have been associated with psychopathic traits in alcoholic patients, on fear conditioning and aversive priming in healthy volunteers. We found that the DRD2 C957T SNP, but not the ANKK1 TaqIA SNP, was associated with both differential conditioning of the skin conductance response and the aversive priming effect. There were no differences between the genotype groups with respect to the extinction of the skin-conductance conditioned response. These results suggest that the C957T SNP could be related to learning differences associated with the risk of developing psychiatric disorders in individuals that are carriers of the C homozygous genotype. Our genetic data raise the possibility that the dopaminergic system functional variations determined by this SNP could affect fear learning. [ABSTRACT FROM AUTHOR]

Pathological gambling (PG) has been associated to both impulsiveness and attention deficit/hyperactivity disorder (ADHD) in different studies. Our objective was to compare different impulsivity and sustained attention variables, using both behavioural tasks and self-administered questionnaires, in a group of pathological gamblers with a history of childhood ADHD (PG-ADHD; n = 16), a group of pathological gamblers without this history (PG-non-ADHD; n = 39), and a control group (n = 40). As instruments of measure, we used the stop signal task (to evaluate inhibitory control/impulsivity), the differential reinforcement of Low Rate Responding Task (delay of gratification/impulsivity) and the Continuous Performance Test (sustained attention). The Barratt Impulsivity Scale (BIS-11) was used as a self-administered questionnaire to measure impulsiveness. Our results show that patients in the PG-ADHD group exhibit a significantly lower capacity to delay gratification than those in the PG-non-ADHD and control groups, and less inhibitory control than patients in the PG-non-ADHD group. On self-administered questionnaires such as the BIS-11 the PG-ADHD group obtained higher scores than the PG-non-ADHD and control groups. However, no differences were found with respect to sustained attention using the CPT. Our results suggest a possible selective implication of the prefrontal cortex in PG, which would be especially evident in those with a childhood history of ADHD. [ABSTRACT FROM AUTHOR]

Abstract: The TaqIA polymorphism linked to the DRD2 gene has been associated with alcoholism. The aim of this work is to study attention and inhibitory control as per the continuous performance test and the stop task in a sample of 50 Spanish male alcoholic patients split into two groups according to the presence of the TaqIA1 allele in their genotype. Our results show that alcoholics carrying the TaqIA1 allele present lower sustained attention and less inhibitory control than those patients without such allele. [Copyright &y& Elsevier]

Aims: To determine the clinically ascertained variables that are related to satisfactory response to naltrexone (NTX) treatment of alcohol dependence after detoxification. Methods: The use of intake and outcome variables were measured in a randomized 3-month open-controlled trial comparing the effects of naltrexone plus psychotherapy treatment versus psychotherapy treatment alone on the maintenance of abstinence in the final 28 days (n = 336, all male). Results: Predictors of a positive response to NTX treatment were family history of alcoholism (P = 0.010), early age at onset of drinking problems (P = 0.014) and comorbid use of other drugs of abuse (P < 0.001). Among the subjects not treated with NTX, the greater the number of predictor variables, the lower the final 28 days abstinence rates (P = 0.00003), but this was not the case in patients treated with NTX (P = 0.844). Conclusions: Patients with these features, suggesting biological vulnerability overall have poorer outcomes, but this can be reduced with NTX treatment. The type of alcoholism should be considered before deciding on the pharmacological strategy. [ABSTRACT FROM AUTHOR]

Depression is a common symptom in Parkinson's disease (PD) and it is present in up to 40%of the patients. The cause of depression in PD is thought to be related to disturbance of monoamine neurotransmission. The endogenous cannabinoid system mediates different brain processes that play a role in the control of behaviour and emotions. Cannabinoid function may be altered in neuropsychiatry diseases, directly or through interactions with monoamine, GABA and glutamate systems. For this reason, we have investigated whether there is a genetic risk factor for depression in PD linked to the polymorphisms of CB1 receptor gene. Depression was more frequent in patients with PD than in controls with osteoarthritis. The presence of depression did not correlate with the stage of the disease but it was more frequent in patients with pure akinetic syndrome than in those with tremoric or mixed type PD. The CB1 receptor gene polymorphism (AAT)n is considered to modify the transcription of the gene and, therefore, it may have functional relevance. We analysed the length of the polymorphic triplet (AAT)n of the gene that encodes CB1 (CNR1) receptor in 89 subjects (48 PD patients and 41 controls). In patients with PD, the presence of two long alleles, with more than 16 repeated AAT trinucleotides in the CNR1 gene, was associated with a reduced prevalence of depression (Fisher's exact test: P=0.003). This association did not reach significant differences in the control group, but the number of control individuals with depression was too small to allow for statistical analysis. Since the alleles with long expansions may have functional impact in cannabinoid neurotransmission, our data suggest that the pharmacological manipulation of cannabinoid neurotransmission could open a new therapeutic approach for the treatment of depression in PD and possibly in other conditions.The Pharmacogenomics Journal (2005) 5, 135-141. doi:10.1038/sj.tpj.6500301 Published online 25 January 2005 [ABSTRACT FROM AUTHOR]

Background. – Presence of A1 allele of the DRD2 gene has been associated with a predisposition for alcoholism although there are limited data about its phenotypic expression in alcoholism.Objectives. – To determine the importance of the A1 allele in clinical variables of alcohol dependence.Methodology. – A sample of 103 alcohol-dependent males was studied. All patients were recruited consecutively from the general hospital and community settings. The diagnostics were made with the structured clinical interview for DSM-III-R (SCID); and the International Personality Disorder Examination (IPDE). Diagnosis of family alcoholism was made by direct interview or with the Research Diagnostic Criteria-Family History (RDC-FH). The Addiction Severity Index (ASI) and the Severity of Alcohol Dependence Scale (SADS) were used to assess alcohol dependence severity. Genotyping was done by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods.Results. – Approximately 39% of the sample carried the A1 allele (A1+ group). This group had higher prevalences of antisocial personality disorder (60% vs. 15.9%); and alcoholism family history (72.5% vs. 52.4%). Also A1+ had early onset alcohol abuse and more drinking problems. The presence of A1+ was the main factor to explain the diagnosis of antisocial personality disorder, but the weight of this factor was not sufficient to explain the complications assessed by the ASI.Conclusions. – Our results support the existence of an association between the A1 allele and factors resulting from dopaminergic deficiency, otherwise denominated reward deficiency syndrome. [Copyright &y& Elsevier]

Mutations in the DYT1 gene cause idiopathic torsion dystonia (ITD) transmitted in families as an autosomal dominant trait with incomplete penetrance. The most common mutation, 946delGAG, has been observed in populations with different ethnic and geographic origins. We have investigated 40 individuals from 22 unrelated families with ITD originating from the Land of Valencia, Spain, for the presence of this mutation and we found 5 patients and 6 unaffected subjects from 4 families who were carriers of the mutation. This finding indicates that 18% of families may be diagnosed as DYT1 and that penetrance is reduced. We detected two different geographic and linguistic origins of the Valencian families. However, by haplotype analysis using D9S1260 , D9S1261 , D9S63 and D9S1262 as flanking markers, we demonstrated that all affected and unaffected carriers shared a common chromosome confirming identical origin of the mutation in the four families. We postulate a unique origin for the 946delGAG mutation in the Land of Valencia and, based on linguistic criterion, we propose that the mutation might have occurred at the beginning of the second millennium. Genetic analysis of another family from Castilla-La Mancha showed a different haplotype segregating with the disease, suggesting that at least two distinct mutational events for the 946delGAG mutation have occurred in Spain. [ABSTRACT FROM AUTHOR]

Unlabelled: We report a 5-year-old boy with propionic acidaemia who developed a rapidly fatal necrosis of the basal ganglia after an episode of clinical deterioration. Neither metabolic acidosis nor hyperammonaemia were present. Organic acid analysis in both urine and CSF showed increased levels of methylcitric and 3-hydroxypropionic acids. Propionic acidaemia was confirmed by demonstrating a propionyl-CoA carboxylase deficiency (11% of control value) in skin fibroblasts. DNA analysis revealed that the patient was a compound heterozygote for two mutations in the PCCB gene.Conclusion: Propionic acidaemia can present as a sudden and fatal neurological disease and not only as an organic aciduria with severe biochemical dis-turbances and progressive neurological deterioration. [ABSTRACT FROM AUTHOR]

Abstract: Fibromyalgia and ADHD share some clinical features, and a reduced dopamine function has been proposed for both disorders. Here we found, in a large sample of fibromyalgia female patients, a higher frequency of childhood ADHD antecedent when compared with healthy women. Our data suggest that Fibromyalgia and ADHD have some common etiopathological mechanism. [Copyright &y& Elsevier]