The past 20 years have resulted in unprecedented progress in understanding brain energy metabolism and its role in health and disease. In this review, which was initiated at the 14th International Society for Neurochemistry Advanced School, we address the basic concepts of brain energy metabolism and approach the question of why the brain has high energy expenditure. Our review illustrates that the vertebrate brain has a high need for energy because of the high number of neurons and the need to maintain a delicate interplay between energy metabolism, neurotransmission, and plasticity. Disturbances to the energetic balance, to mitochondria quality control or to glia–neuron metabolic interaction may lead to brain circuit malfunction or even severe disorders of the CNS. We cover neuronal energy consumption in neural transmission and basic (‘housekeeping’) cellular processes. Additionally, we describe the most common (glucose) and alternative sources of energy namely glutamate, lactate, ketone bodies, and medium chain fatty acids. We discuss the multifaceted role of non‐neuronal cells in the transport of energy substrates from circulation (pericytes and astrocytes) and in the supply (astrocytes and microglia) and usage of different energy fuels. Finally, we address pathological consequences of disrupted energy homeostasis in the CNS.
Attention deficit hyperactivity disorder (ADHD) is the most frequently diagnosed behavioral disorder in children with a high frequency of co-morbid conditions like conduct disorder (CD) and oppositional defiant disorder (ODD). These traits are controlled by neurotransmitters like dopamine, serotonin and norepinephrine. Monoamine oxidase A (MAOA), a mitochondrial enzyme involved in the degradation of amines, has been reported to be associated with aggression, impulsivity, depression, and mood changes. We hypothesized that MAOA can have a potential role in ADHD associated CD/ODD and analyzed 24 markers in a group of Indo-Caucasoid subjects. ADHD probands and controls (N = 150 each) matched for ethnicity and gender were recruited following the Diagnostic and Statistical Manual for Mental Disorders-IV. Appropriate scales were used for measuring CD and ODD traits. Markers were genotyped by PCR-based methods and data obtained analyzed using the Cocaphase program under UNPHASED. Only eight markers were found to be polymorphic. rs6323 "G" allele showed higher frequencies in ADHD (P = 0.0023), ADHD + CD (P = 0.03) and ADHD + ODD (P = 0.01) as compared to controls. Haplotype analysis revealed statistically significant difference for three haplotypes in ADHD cases (P < 0.02). Statistically significant differences were also noticed for haplotypes in ADHD + CD and ADHD + ODD cases (P < 0.01). LD analysis showed significant variation in different groups. Multidimensionality reduction analysis showed independent as well as interactive effects of markers. Genotypes showed correlation with behavioral problems in ADHD and ADHD + CD. We interpret that MAOA gene variants may contribute to the etiology of ADHD as well as associated co-morbid CD and ODD in this ethnic group.
Background: Attention deficit hyperactivity disorder (ADHD) is characterized by symptoms of inattention, excessive motor activity and impulsivity detected mostly during childhood. These traits are known to be controlled by monoamine neurotransmitters, chiefly dopamine, serotonin and norepinephrine. Monoamine oxidase A (MAOA) and B (MAOB), two isoenzymes bound to the outer membrane of mitochondria, are involved in the degradation of monoamines and were explored for association with ADHD in different ethnic groups. In the present study, few exonic as well as intronic MAOB variants were analyzed in ADHD probands (N = 150) and ethnically matched controls (N = 150) recruited following the Diagnostic and Statistical Manual for Mental Disorders-4 th edition (DSM-IV). Appropriate scales were used for measuring the behavioural attributes. Gene variants were analyzed by amplification of target sites followed by DNA sequencing and data obtained were analyzed by population based statistical methods. Results: Out of 34 variants present in the analyzed sites, only seven functional variants, rs4824562, rs56220155, rs2283728, rs2283727, rs3027441, rs6324 and rs3027440, were found to be polymorphic. rs2283728 'C' (P = 3.45e-006) and rs3027440 'T' (P = 0.02) alleles showed higher frequencies in ADHD probands as compared to controls. rs56220155 ' A' (P = 0.04) allele and 'GA' (P = 0.04) genotype showed higher frequencies in the male and female ADHD probands respectively as compared to sex-matched controls. Analysis of pairwise linkage disequilibrium revealed striking differences between probands and controls. Haplotype analysis revealed significantly higher occurrence of different haplotypes in the ADHD probands while some haplotypes were detected in the controls only. Higher scores for conduct problems were found to be associated with rs56220155 ' A' (P = 0.05) allele in the male ADHD probands. Multifactor dimensionality reduction analysis showed independent as well as interactive effects of polymorphic variants which were more robust in the male probands. Conclusions: Since all the polymorphic variants analyzed were functional, it may be inferred that MAOB gene variants are contributing to the etiology of ADHD in the Indo-Caucasoid population from eastern India which merits further in depth analysis.
Platelet hyperserotonemia in a subset of Autism Spectrum Disorder (ASD) probands, efficacy of selective serotonin reuptake inhibitors (SSRIs) in reducing behavioral deficits and gender-bias in normal serotonin (5-hydroxy tryptamine or 5-HT) synthesis suggest disruption in stringent regulation of serotonin metabolism in ASD. Therefore, we investigated the changes in 5-HT and 5-hydroxy indole acetic acid (5-HIAA) in ASD probands to assess its effect on the behavior of male and female probands. ASD cases (n = 215) were examined using childhood autism rating scale (CARS). Platelet 5-HT (104 cases and 26 controls) and platelet/plasma 5-HIAA (73 cases and 17 controls) were estimated using high performance liquid chromatography coupled with electrochemical detector (HPLC-ECD). In male probands, we observed increase in platelet 5-HT content in association with increase in the score for adaptive responses and increase in platelet 5-HIAA levels with concomitant decline in the score for intellectual response. Age did not influence the neurochemical parameters, but imitation, listening responses and nonverbal communication scores decreased with age. Conversely in female probands, plasma 5-HIAA level significantly attenuated with age, when platelet 5-HT content remained unchanged. Interestingly, platelet/plasma 5-HT and plasma 5-HIAA were higher in female controls. Female probands displayed severe autism-associated behaviors. Overall results indicate gender-bias in 5-HT and 5-HIAA regulation, which probably increases the threshold level of ASD phenotypes in the females, thereby affecting ASD prevalence in a sex-specific manner.
Autism spectrum disorder (ASD) is a male predominance, behaviorally defined neurodevelopmental disorder which is characterized by impairment in social communication and restricted and repetitive activities. Abnormalities in serotoninergic function play a major role in ASD pathophysiology. Monoamine oxidases, encoded by two X-chromosomal genes MAOA and MAOB regulate the serotonergic function by the degradation of serotonin and other biological amines. Therefore, the objective of present study is to investigate genetic correlation of MAOB markers with the severity of specific behavioral traits as scored by Childhood Autism Rating Scale (CARS) has been examined as quantitative trait (QT) analysis using IBM-SPSS program. A total of 225 ASD patients (190 male and 35 female) were recruited after psychometric evaluation done by DSM-IV-TR/DSM-5 criteria and assessment by CARS. Genotyping carried by PCR/RFLP/sequencing methods, and population were found in Hardy-Weinberg equilibrium. The outcome of the QT analysis indicating the increased score in overall CARS were associated with G and C allele of MAOB marker rs3027449 (p-value: 0.03) and rs1040399 (p-value: 0.01), respectively in male ASD children. In addition to this, major alleles of studied polymorphisms of gene were found to be statistically associated with the higher impairment in social communication domain only in male ASD children. Overall outcome of the study suggests likely involvement of MAOB with ASD in a gender-specific manner with the severity in behavior phenotypes. Considering the cumulative impact of these markers in regulating the severity of the behavioral symptoms of ASD, it is likely that MAOB gene is associated with the disorder.
5303 The state of West Bengal in the eastern part of India has a high prevalence of the carrier states of beta thalassemia and Hb E. Analysis of Hb HPLC screening data from 200 individuals, including adults and children from urban areas around Kolkata in West Bengal, carried out in our institution1, reveals a prevalence 6.5% for beta trait and 5.5% for HbE trait. (unpublished data) It may be possible to reduce births of beta thalassemia major and E beta thalassemia by preventive strategies, including mass screening and awareness campaigns. The best preventive method is debatable, because of the highly variable prevalence of the haemoglobin disorders within defined geographic regions (Weatherall DJ, Blood.2010), the economic factors involved and most importantly the question of acceptance of prevention methods. Because of the social stigma attached to the diagnosis of a genetic disease, families of young men and women diagnosed as thalassemia carriers in community screening programs often suppress this information when marriages are arranged, according to prevalent social practice. Therefore pre-marital screening, in our experience, is unlikely to be effective in reducing the number of beta thalassemia major and E-Beta thalassemia births in eastern India. Antenatal screening on the other hand has the potential for greater acceptability. Concern for the welfare of the unborn child are likely to make prospective parents more amenable to counselling and getting themselves tested for the thalassemia carrier state. We analysed data of 1000 antenatal mothers (Table 1), who had undergone screening for the thalassemia carrier state by red cell indices and Hb HPLC, as part of a government funded screening programme conducted in our institution1 in Kolkata city of West Bengal, India, in order to determine whether red cell indices, which is more economical than Hb HPLC, was an effective screening tool. Results of Hb HPLC screening data of 1000 antenatal women (Table 1) Result Beta Trait (HbA2% 3.6-6.6) Hb E trait (A2+E% 22.8-42.8) E Beta E Disease Sickle trait Sickle Beta D Trait D disease No of cases (%) 58(5.8%) 48(4.8%) 3(0.2%) 2(0.2%) 2(0.2%) 1(0.1%) 1 1 Where both partners were carriers, mutations were confirmed by complementary reverse dot blot hybridisation or DNA sequencing. Red Cell Indices in Thalassemia Carrier States (Table 2) Thalassemia Carrier State (1000 Antenatal Women) MCV (fl) MCH (pg) Mean Range (±95%CI) (±2SD) Mean Range (±95%CI) (±2SD) Beta Trait (n= 58) 68.6±1.70 55.4–81.8 21.80±0.64 16.6–26.8 E Trait(n=48) 78.8±1.42 67.8–89.8 26.4±0.62 22.0–30.8 Most antenatal women received iron and folic acid supplements, therefore iron status was not separately examined. To exclude the possibility of the effect of pregnancy on red cell indices, evaluation of MCV and MCH in 50 HbE trait individuals and 250 beta trait drawn from community screening data, comprising non-pregnant females and males, with normal serum ferritin values, mean MCV was 76.6fl (range 66.3–86.8fl), mean MCH 25.6pg (range 21.5–29.7pg) for E trait. For beta trait mean MCV was 67.0 fl (range 50–84 fl), mean MCH 21 pg (range 15–26 pg). There was no statistically significant difference from antenatal cases (Student's t-test ). MCV of <80fl and MCH < 27pg were previously reported to predict most beta thalassemia in pregnancy (Weatherall and Clegg Eds, The Thalassemia Syndromes, Part 4. UK: Blackwell Science Ltd, 2001 ). We tested whether these values could reliably predict beta trait and E trait taken together, in 1000 antenatal women in the present study (Table 3) Red Cell Indices as Predictor of Beta Trait and HbE Trait (Table 3) Sensitivity (%) Specificity (%) Positive Predictive Value (%) Negative Predictive Value (%) No of Beta Trait Missed on Screening (%) n=58 No of E Trait Missed on Screening (%) n=48 MCV <80fl 88 85 42 98 6 (10.3) 15 (31.3) MCH <27pg 84 82 35.2 98 9 (15.5) 17 (35.4) Conclusion –MCH and MCV tend to be higher in E trait compared to beta trait. We recommend that in high prevalence areas, Hb HPLC should be performed in all antenatal women irrespective of red cell indices, to avoid missing thalassemia carriers and facilities for genetic diagnosis and counselling be made available to couples at risk of beta thalessemia major and E beta thalessemia births. Disclosures: No relevant conflicts of interest to declare.
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