Leigh-like syndrome with the T8993G mutation in the mitochondrial ATPase 6 gene: long-term follow-up discloses a slowly progressive course

We describe the long-term clinical outcome of a patient with Leigh-like syndrome presenting as an early onset encephalopathy and peripheral neuropathy caused by the T8993G mutation in the mitochondrial DNA (mtDNA). Clinical follow-up for 20 years revealed a peculiar pattern of slow disease progression, characterized by the addition of new minor deficits, while worsening of previous symptoms was mild. Brain MRI revealed cerebellar atrophy, diffuse demyelination of corona radiata and parietal white matter, and bilateral and symmetrical putaminal lesions. The proportion of mutant mtDNAs in blood was 72% (+/- 0.02%) and in skeletal muscle was 81% (+/- 0.4%). Leigh-like syndrome caused by the T8993G mtDNA mutation is a progressive disease, although not necessarily associated with an aggressive clinical course. (C) 2009 Elsevier B.V. All rights reserved.

Characterizing the phenotypic manifestations of MFN2 R104W mutation in Charcot-Marie-Tooth type 2

Mutations of the mitofusin 2 (MFN2) gene have been reported to be the most common cause of the axonal form of Charcot Marie Tooth disease (CMT). The aim of this study was to describe a de novo MFN2 p.R104W mutation and characterize the associated phenotype. We screened the entire coding region of MFN2 gene and characterized its clinical phenotype, nerve conduction studies and sural nerve biopsy. Neuropsychological tests and brain MRI were also performed. A de nova mutation was found in exon 4 (c.310C > T; p.R104W). In addition to a severe and early onset axonal neuropathy, the patient presented learning problems, obesity, glucose intolerance, leukoencephalopathy, brain atrophy and evidence of myelin involvement and mitochondrial structural changes on sural nerve biopsy. These results suggest that MFN2 p.R104W mutation is as a hot-spot for MFN2 gene associated to a large and complex range of phenotypes. (C) 2011 Elsevier B.V. All rights reserved.

Functional deficiencies of sulfite oxidase: Differential diagnoses in neonates presenting with intractable seizures and cystic encephalomalacia

Sulfite oxidase is a mitochondrial enzyme encoded by the SUOX gene and essential for the detoxification of sulfite which results mainly from the catabolism of sulfur-containing amino acids. Decreased activity of this enzyme can either be due to mutations in the SUOX gene or secondary to defects in the synthesis of its cofactor, the molybdenum cofactor. Defects in the synthesis of the molybdenum cofactor are caused by mutations in one of the genes MOCS1, MOCS2, MOCS3 and GEPH and result in combined deficiencies of the enzymes sulfite oxidase, xanthine dehydrogenase and aldehyde oxidase. Although present in many ethnic groups, isolated sulfite oxidase deficiency and molybdenum cofactor deficiency are rare inborn errors of metabolism, which makes awareness of key clinical and laboratory features of affected individuals crucial for early diagnosis. We report clinical, radiologic, biochemical and genetic data on a Brazilian and on a Turkish child with sulfite oxidase deficiency due to the isolated defect and impaired synthesis of the molybdenum cofactor, respectively. Both patients presented with early onset seizures and neurological deterioration. They showed no sulfite oxidase activity in fibroblasts and were homozygous for the mutations c.1136A>G in the SUOX gene and c.667insCGA in the MOCS1 gene, respectively. Widely available routine laboratory tests such as assessment of total homocysteine and uric acid are indicated in children with a clinical presentation resembling that of hypoxic ischemic encephalopathy and may help in obtaining a tentative diagnosis locally, which requires confirmation by specialized laboratories. (C) 2009 Published by Elsevier B.V.

Cannabis use before age 15 and subsequent executive functioning

Background Many studies have suggested that adolescence is a period of particular vulnerability to neurocognitive effects associated with substance misuse. However, few large studies have measured differences in cognitive performance between chronic cannabis users who started in early adolescence (before age 15) with those who started later. Aims To examine the executive functioning of individuals who started chronic cannabis use before age 15 compared with those who started chronic cannabis use after 15 and controls. Method We evaluated the performance of 104 chronic cannabis users (49 early-onset users and 55 late-onset users) and 44 controls who undertook neuropsychological tasks, with a focus on executive functioning. Comparisons involving neuropsychological measures were performed using generalised linear model analysis of variance (ANOVA). Results The early-onset group showed significantly poorer performance compared with the controls and the late-onset group on tasks assessing sustained attention, impulse control and executive functioning. Conclusions Early-onset chronic cannabis users exhibited poorer cognitive performance than controls and late-onset users in executive functioning. Chronic cannabis use, when started before age 15, may have more deleterious effects on neurocognitive functioning.

Could sudden death syndrome (SDS) in chickens (Gallus gallus) be a valid animal model for sudden unexpected death in epilepsy (SUDEP)?

Epilepsy is the most common serious neurological disorder and approximately 1% of the population worldwide has epilepsy. Moreover, sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. Information concerning fisk factors for SUDEP is conflicting, but potential risk factors include: young age, early onset of epilepsy, duration of epilepsy, uncontrolled seizures, seizure frequency, AED number and winter temperatures. Additionally, the cause of SUDEP is still unknown; however, the most commonly suggested mechanisms are cardiac abnormalities during and between seizures. Similarly, sudden death syndrome (SDS) is a disease characterized by an acute death of well-nourished and seeming healthy Gallus gallus after abrupt and brief flapping of their wings and incidence of SDS these animals has recently increased worldwide. Moreover, the exactly cause of SDS in Gallus gallus is unknown, but is very probable that cardiac abnormalities play a potential role. Due the similarities between SUDEP and SDS and as Gallus gallus behavioral manifestation during SDS phenomenon is close of a tonic-clonic seizure, in this paper we suggest that epilepsy could be a new possible causal factor for SDS. (C) 2009 Elsevier Ltd. All rights reserved.

Hematopoietic response of rats exposed to the impact of an acute psychophysiological stressor on responsiveness to an in vivo challenge with Listeria monocytogenes: Modulation by Chlorella vulgaris prophylactic treatment

In this study, we investigated the hematopoietic response of rats pretreated with CV and exposed to the impact of acute escapable, inescapable or psychogenical stress on responsiveness to an in vivo challenge with Listeria monocytogenes. No consistent changes were observed after exposure to escapable footshock. Conversely, the impact of uncontrollable stress (inescapable and psychogenical) was manifested by an early onset and increased severity and duration of myrelossuppression produced by the infection. Small size CFU-CM colonies and increased numbers of clusters were observed, concurrently to a greater expansion in the more mature population of bone marrow granulocytes. No differences were observed between the responses of both uncontrollable stress regimens. CV prevented the myelossuppression caused by stress/infection due to increased numbers of CFU-GM in the bone marrow. Colonies of cells tightly packed, with a very condensed nucleus; in association with a greater expansion in the more immature population of bone marrow granulocytes were observed. Investigation of the production of colony-stimulating factors revealed increased colony-stimulating activity (CSA) in the serum of normal and infected/stressed rats treated with the algae. CV treatment restored/enhanced the changes produced by stress/infection in total and differential bone marrow and peripheral cells counts. Further studies demonstrated that INF-gamma is significantly reduced, whereas IL-10 is significantly increased after exposure to Uncontrollable stress. Treatment with CV significantly increased INF-gamma levels and diminished the levels of IL-10. Uncontrollable stress reduced the protection afforded by CV to a lethal dose of L. monocytogenes, with survival rates being reduced from (50%) in infected rats to 20% in infected/stressed rats. All together, our results suggest Chlorella treatment as an effective tool for the prophylaxis of post-stress myelossupression, including the detrimental effect of stress on the course and outcome of infections. (C) 2008 Elsevier Inc. All rights reserved.

Non-invasive detection of aortic and coronary atherosclerosis in homozygous familial hypercholesterolemia by 64 slice multi-detector row computed tomography angiography

Homozygous familial hypercholesterolemia (HoFH) is a rare disorder characterized by the early onset of atherosclerosis, often at the ostia of coronary arteries. In this study we document for the first time that aortic and coronary atherosclerosis can be detected using 64 slice multiple detector row computed tomographic coronary angiography (CTCA). We studied five HoFH patients (three females, two males, mean age 19.8 +/- 2.9 years, age range 15-23 years, with a mean low density lipoprotein (LDL) cholesterol 618 +/- 211 mg/dL) using 64 slice CTCA. None of the patients showed evidence of ischemia with standard exercise testing. Calcified and mixed atherosclerotic plaques adjacent to or compromising the coronary artery ostia were found in all study subjects. Coronary plaques causing significant obstruction were found in one patient, who had previously undergone coronary artery bypass surgery and aortic valve replacement. Two other patients were noted to have non-obstructive calcified, mixed and non-calcified coronary artery plaques. Our data suggest that CTCA could be a useful non-invasive method for detection of early aortic and coronary atherosclerosis specifically affecting the coronary ostia in HoFH subjects. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

Towards a molecular epidemiology of alcohol dependence analysing the interplay of genetic and environmental risk factors

Background Progress in identifying genetic factors protective against alcohol dependence (AlcD) requires a paradigm shift in psychiatric epidemiology. Aims To integrate analysis of research into the genetics of alcoholism. Method Data from prospective questionnaire and interview surveys of the Australian twin panel, and from a subsample who underwent alcohol challenge, were analysed. Results In men, effects of alcohol dehydrogenase ADH2*1/*2 genotype or high alcohol sensitivity (risk-decreasing), and of history of childhood conduct disorder, or having monozygotic co-twin or twin sister with AlcD (risk-increasing) were significant and comparable in magnitude. Religious affiliation (Anglican versus other) was associated with the ADH2 genotype, but did not explain the associations with AlcD symptoms. No protective effect of the ADH2*1/*2 genotype was observed in women. Conclusions The early onset and strong familial aggregation of AlcD, and opportunity for within-family tests of genetic association to avoid confounding effects, make epidemiological family studies of adolescents and young adults and their families a priority.

Estimating Two-Stage Models for Genetic Influences on Alcohol, Tobacco or Drug Use Initiation and Dependence Vulnerability in Twin and Family Data

Genetic research on risk of alcohol, tobacco or drug dependence must make allowance for the partial overlap of risk-factors for initiation of use, and risk-factors for dependence or other outcomes in users. Except in the extreme cases where genetic and environmental risk-factors for initiation and dependence overlap completely or are uncorrelated, there is no consensus about how best to estimate the magnitude of genetic or environmental correlations between Initiation and Dependence in twin and family data. We explore by computer simulation the biases to estimates of genetic and environmental parameters caused by model misspecification when Initiation can only be defined as a binary variable. For plausible simulated parameter values, the two-stage genetic models that we consider yield estimates of genetic and environmental variances for Dependence that, although biased, are not very discrepant from the true values. However, estimates of genetic (or environmental) correlations between Initiation and Dependence may be seriously biased, and may differ markedly under different two-stage models. Such estimates may have little credibility unless external data favor selection of one particular model. These problems can be avoided if Initiation can be assessed as a multiple-category variable (e.g. never versus early-onset versus later onset user), with at least two categories measurable in users at risk for dependence. Under these conditions, under certain distributional assumptions., recovery of simulated genetic and environmental correlations becomes possible, Illustrative application of the model to Australian twin data on smoking confirmed substantial heritability of smoking persistence (42%) with minimal overlap with genetic influences on initiation.

ERICA: patterns of alcohol consumption in Brazilian adolescents

ABSTRACT OBJECTIVE To describe the patterns of alcohol consumption in Brazilian adolescents. METHODS We investigated adolescents who participated in the Study of Cardiovascular Risks in Adolescents (ERICA). This is a cross-sectional, national and school-based study, which surveyed adolescents of 1,247 schools from 124 Brazilian municipalities. Participants answered a self-administered questionnaire with a section on alcoholic beverages consumption. Measures of relative frequency (prevalence), and their 95% confidence intervals, were estimated for the following variables: use of alcohol beverages in the last 30 days, frequency of use, number of glasses or doses consumed in the period, age of the first use of alcohol, and most consumed type of drink. Data were estimated for country and macro-region, sex, and age group. The module survey of the Stata program was used for data analysis of complex sample. RESULTS We evaluated 74,589 adolescents, who accounted for 72.9% of eligible students. About 1/5 of adolescents consumed alcohol at least once in the last 30 days and about 2/3 in one or two occasions during this period. Among the adolescents who consumed alcoholic beverages, 24.1% drank it for the first time before being 12 years old, and the most common type of alcoholic beverages consumed by them were drinks based on vodka, rum or tequila, and beer. CONCLUSIONS There is a high prevalence of alcohol consumption among adolescents, as well as their early onset of alcohol use. We also identified a possible change in the preferred type of alcoholic beverages compared with previous research.

Tuberculosis in renal transplant patients

Tuberculosis (TB) was diagnosed in 25 of 466 patients who underwent renal transplant over a period of 15 years. TB developed from 1 month to 9 years post-transplant. In 56% of the cases the onset was within the first post-transplant year. TB affected several isolated or combined organs. Pulmonary involvement was present in 76% of cases, either as isolated pleuro-pulmonary (56%) or associated with other sites (20%). The non-pulmonary sites were: skin, joints, tests, urinary tract, central nervous system and lymphonodules. The diagnosis was confirmed by biopsy in 64% of the cases, by identification of tubercle bacilli in 24% and only at necropsy in 12% Biopsy specimens could be classified in three histological forms: exudative, that occurred in early onset and more severe cases granulomatous in late onset and benign cases; and mixed in intermediate cases. Azathioprine dosages were similar along post-transplant time periods in TB patients and in the control groups; and in TB patients who were cured and who died. The number of steroid treated rejection crises was greater in TB than in the control group. Prednisone doses were higher and the number of rejection crises was greater in TB patients who died than in those who were cured. Fifteen patients were cured and ten died, two of them of causes unrelated to TB. Six of the eight TB-related deaths occurred in the first 6 post-transplant months. The outcome was poor in patients in whom TB arose early in post-transplant period and where the exudative or mixed forms were present; whereas the prognosis was good in patients with late onset and granulomatous form of TB. In one patient TB was transmitted by the allograft.

Group B streptococcal neonatal infections in Rio Grande do Sul, Brazil

Group B Streptococcus is the most common pathogen found in neonatal sepsis in North America. OBJECTIVES: We describe 15 cases of neonatal infections by Group B Streptococcus (Streptococcus agalactiae) at a Neonatal Intensive Care Unit of a public and teaching hospital. METHODS: We conducted a study at Hospital de Clínicas de Porto Alegre, from January 1st, 1996 to June 30, 1999. Diagnosis of neonatal infection was established according to the findings of Group B Streptococcus in blood culture associated with alterations resembling sepsis on the basis of clinical picture and laboratory findings. RESULTS: Fifteen cases of neonatal infections by Group B Streptococcus were detected. Eleven cases consisted of early-onset sepsis, 2 cases of occult bacteremia and 2 cases of late-onset sepsis. Eight cases had septic shock (53%), 8 cases had pneumonia (53%), and 4 cases had meningitis (27%). Fourteen cases were diagnosed from a positive blood culture, and 1 case from evidence of these bacteria in pulmonary anatomopathological examination. Thirteen cases (87%) were diagnosed before 72 hours of life. We had 3 deaths (20%), and 3 cases of meningitis developing neurological deficits. CONCLUSIONS: Streptococcus Group B is one of the most important pathogens in the etiology of early-onset neonatal sepsis at our hospital, with high mortality and morbidity. However, we do not know the incidence of GBS neonatal infections at other hospitals. More data are needed to establish a basis for trials of different strategies to reduce these infections.

Perinatal Bacterial Infection: Screenning of Vertical Transmitted Infections

Perinatal bacterial infection may be caused by any microorganism colonizing the vaginal tract. Neonatologists and paediatricians are especially concerned about group B Stretpococcus (GBS). However, Enterobactereacea, mainly E.coli and Proteus, are also responsible for infection. GBS screening may be accomplished in over 90% of pregnant women. In our maternity in 2007-2008, 85% of the mothers had been screened. Screening and prophylaxis were responsible for a decreasing incidence of neonatal infection - from 0.6/1000 to 0.15/1000 live births in Portugal, from 2002 to 2007. However there are some difficulties related to screening. In the second Portuguese study 16/57 NB with early-onset infection (28%) were born to “negative” mothers. Several factors illustrate how difficult is to draw national screening policies: a wide range of carrier’s state rate throughout a country - in Portugal from 12% to 30%. The success of any screening policy may also be affected by additional technical and organizational problems. In countries where home delivery is a tradition or a trend intrapartum GBS prophylaxis requires a very well organized assistance.. Moreover factors usually accepted as protective are not so effective. In the Portuguese study 24/57 infected newborns (42%) were delivery by caesarean section. Another subject deals with the workload in the postnatal ward generated by deficient compliance to the guidelines a problem not confirm by a study of our group. Decreasing the importance of GBS, highlight the importance of E. coli in perinatal infection. From the 16 340 registrations of the National Registry 1676 were newborns with mother-related infection. Applying the same reasoning to E.coli as to GBS and Listeria monocytogenes – that is considering all of them are of maternal origin - 6.7% of these infections were due to E. coli, 4.6% to SGB and 0.5% to Listeria monocytogenes. In conclusion screening and prophylaxis may be not the best way to prevent all GBS neonatal infections but by now it is the only available procedure. The other bacteria continue to demand a high suspicion level and immediate intervention.

Cerebrospinal Fluid Synaptic Proteins as Useful Biomarkers in Tyrosine Hydroxylase Deficiency

Tyrosine hydroxylase (TH) deficiency is an inborn error of dopamine biosynthesis and a cause of early parkinsonism. Two clinical phenotypes have been described. Type “B”: early onset severe encephalopathy; type “A”: later onset, less severe and better response to L-dopa. We aimed to study the expression of several key dopaminergic and gabaergic synaptic proteins in the cerebrospinal fluid (CSF) of a series of patients with TH deficiency and their possible relation with the clinical phenotype and response to L-DOPA. Dopamine transporter (DAT), D2-receptor and vesicularmonoamine transporter (VMAT2)weremeasured in the CSF of 10 subjectswith THdeficiency byWestern blot analysis. In 3 patients, data of pre- and post-treatmentwith L-DOPA were available, and in one of them, GABA vesicular transporter was determined. Results were compared to an age-matched control population. The concentration of D2-receptors in CSFwas significantly higher in patients with TH deficiency than in controls. Similarly, DAT and vesicular monoamine transporter type 2 were up-regulated. Studies performed before LDOPA, and on L-DOPA therapy showed a paradoxical response with D2 receptor expression increase as L-Dopa doses and homovanillic concentration gradually raised in a B phenotype patient. The opposite results were found in two patients with A phenotype. However, this is a very small sample, and further studies are needed to conclude robust differences between phenotypes. Synaptic proteins are detectable in the CSF and their quantification can be useful for understanding the pathophysiology of neurotransmitter defects and potentially to adjust and personalize treatments in the future.