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Background: Longitudinal trajectories of asthma and allergies from childhood to adulthood might be differentially associated with lung function and chronic obstructive pulmonary disease (COPD), but associations with extrapulmonary comorbidities have not been well investigated. We aimed to assess these trajectories and examine their associations with lung function outcomes and profiles of comorbidities. Method(s): In this prospective cohort study, data for asthma and related allergic conditions (ie, eczema, hay fever, and food allergy) were prospectively collected from the Tasmanian Longitudinal Health Study for participants aged 7-53 years originally recruited in Tasmania, Australia. All surviving individuals in the database with contact details were invited in the most recent follow-up (mean age 53 years). There were no exclusion criteria. With use of latent class analysis, we identified longitudinal trajectories of asthma and allergic conditions from 7-53 years, and profiles of self-reported extrapulmonary conditions recorded at 53 years. The associations between asthma and allergy trajectories and morbidity profiles and lung function at 53 years were investigated with regression models. Finding(s): Between Sept 3, 2012, and Nov 8, 2016, of 6128 individuals invited, 3609 (58.9%) individuals were enrolled. We identified five asthma and allergy trajectories: minimal and least asthma and allergies (n= 1767 [49.0%]); late-onset hay fever, no asthma (n=1065 [29.5%]); early-onset remitted asthma and allergies (n=236 [6.5%]); late-onset asthma and allergies (n=317 [8.8%]); and early-onset persistent asthma and allergies (n=224 [6.2%]); and four profiles of extrapulmonary morbidities: minimal or least disease (n=2206 [61.1%]); dominant mental health disorders (n=861 [23.9%]); dominant cardiovascular diseases or risks (n=424 [11.7%]); and multiple disorders (n=117 [3.2%]). The late-onset asthma and allergies trajectory was predominantly associated with the multiple disorde

Background: Longitudinal trajectories of asthma and allergies from childhood to adulthood might be differentially associated with lung function and chronic obstructive pulmonary disease (COPD), but associations with extrapulmonary comorbidities have not been well investigated. We aimed to assess these trajectories and examine their associations with lung function outcomes and profiles of comorbidities. Method(s): In this prospective cohort study, data for asthma and related allergic conditions (ie, eczema, hay fever, and food allergy) were prospectively collected from the Tasmanian Longitudinal Health Study for participants aged 7-53 years originally recruited in Tasmania, Australia. All surviving individuals in the database with contact details were invited in the most recent follow-up (mean age 53 years). There were no exclusion criteria. With use of latent class analysis, we identified longitudinal trajectories of asthma and allergic conditions from 7-53 years, and profiles of self-reported extrapulmonary conditions recorded at 53 years. The associations between asthma and allergy trajectories and morbidity profiles and lung function at 53 years were investigated with regression models. Finding(s): Between Sept 3, 2012, and Nov 8, 2016, of 6128 individuals invited, 3609 (58.9%) individuals were enrolled. We identified five asthma and allergy trajectories: minimal and least asthma and allergies (n= 1767 [49.0%]); late-onset hay fever, no asthma (n=1065 [29.5%]); early-onset remitted asthma and allergies (n=236 [6.5%]); late-onset asthma and allergies (n=317 [8.8%]); and early-onset persistent asthma and allergies (n=224 [6.2%]); and four profiles of extrapulmonary morbidities: minimal or least disease (n=2206 [61.1%]); dominant mental health disorders (n=861 [23.9%]); dominant cardiovascular diseases or risks (n=424 [11.7%]); and multiple disorders (n=117 [3.2%]). The late-onset asthma and allergies trajectory was predominantly associated with the multiple disorde

BACKGROUND: Untreated microangiopathic hemolytic anemia in pregnancy is associated with adverse maternal and perinatal outcomes. Accurate diagnosis is challenging owing to nonspecific clinical features and pathologic findings. Timely initiation of appropriate management is essential to optimize maternal and perinatal outcomes. CASE: A 26-year-old primiparous woman presented at 20 weeks of gestation with new-onset microangiopathic hemolytic anemia on a background of poorly controlled type 1 diabetes. She received eculizumab for presumed atypical hemolytic uremic syndrome. At 24 weeks of gestation, she developed superimposed early-onset preeclampsia; she delivered at 27 weeks of gestation after continuing eculizumab. CONCLUSION(S): Eculizumab may prolong pregnancy in early-onset preeclampsia. Additional research is needed to assess short-term and long-term maternal and newborn outcomes.Copyright © 2019 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.

Objectives:While early diagnosis of younger-onset dementia (YOD) is crucial in terms of accessing appropriate services and future planning, diagnostic delays are common. This study aims to identify predictors of delay to diagnosis in a large sample of people with YOD and to investigate the impact of a specialist YOD service on this time to diagnosis. Design(s):A retrospective cross-sectional study. Setting(s):The inpatient unit of a tertiary neuropsychiatry service in metropolitan Victoria, Australia. Participant(s):People diagnosed with a YOD.Measurements and methods:We investigated the following predictors using general linear modeling: demographics including sex and location, age at onset, dementia type, cognition, psychiatric diagnosis, and number of services consulted with prior to diagnosis. Result(s):A total of 242 inpatients were included. The mean time to diagnosis was 3.4 years. Significant predictors of delay included younger age at onset, dementia type other than Alzheimer's disease (AD) and behavioral-variant frontotemporal dementia (bvFTD), and increased number of services consulted. These predictors individually led to an increased diagnostic delay of approximately 19 days, 5 months, and 6 months, respectively. A specialized YOD service reduced time to diagnosis by 12 months. Conclusion(s):We found that younger age at onset, having a dementia which was not the most commonly occurring AD or bvFTD, and increasing number of services were significant predictors of diagnostic delay. A novel result was that a specialist YOD service may decrease diagnostic delay, highlighting the importance of such as service in reducing time to diagnosis as well as providing post-diagnostic support. Copyright © International Psychogeriatric Association 2020.

BACKGROUND: Untreated microangiopathic hemolytic anemia in pregnancy is associated with adverse maternal and perinatal outcomes. Accurate diagnosis is challenging owing to nonspecific clinical features and pathologic findings. Timely initiation of appropriate management is essential to optimize maternal and perinatal outcomes. CASE: A 26-year-old primiparous woman presented at 20 weeks of gestation with new-onset microangiopathic hemolytic anemia on a background of poorly controlled type 1 diabetes. She received eculizumab for presumed atypical hemolytic uremic syndrome. At 24 weeks of gestation, she developed superimposed early-onset preeclampsia; she delivered at 27 weeks of gestation after continuing eculizumab. CONCLUSION(S): Eculizumab may prolong pregnancy in early-onset preeclampsia. Additional research is needed to assess short-term and long-term maternal and newborn outcomes.Copyright © 2019 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.

Objectives:While early diagnosis of younger-onset dementia (YOD) is crucial in terms of accessing appropriate services and future planning, diagnostic delays are common. This study aims to identify predictors of delay to diagnosis in a large sample of people with YOD and to investigate the impact of a specialist YOD service on this time to diagnosis. Design(s):A retrospective cross-sectional study. Setting(s):The inpatient unit of a tertiary neuropsychiatry service in metropolitan Victoria, Australia. Participant(s):People diagnosed with a YOD.Measurements and methods:We investigated the following predictors using general linear modeling: demographics including sex and location, age at onset, dementia type, cognition, psychiatric diagnosis, and number of services consulted with prior to diagnosis. Result(s):A total of 242 inpatients were included. The mean time to diagnosis was 3.4 years. Significant predictors of delay included younger age at onset, dementia type other than Alzheimer's disease (AD) and behavioral-variant frontotemporal dementia (bvFTD), and increased number of services consulted. These predictors individually led to an increased diagnostic delay of approximately 19 days, 5 months, and 6 months, respectively. A specialized YOD service reduced time to diagnosis by 12 months. Conclusion(s):We found that younger age at onset, having a dementia which was not the most commonly occurring AD or bvFTD, and increasing number of services were significant predictors of diagnostic delay. A novel result was that a specialist YOD service may decrease diagnostic delay, highlighting the importance of such as service in reducing time to diagnosis as well as providing post-diagnostic support. Copyright © International Psychogeriatric Association 2020.

The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.Copyright © The Author(s) 2018.

Prevalence of skin sores and scabies in remote Australian Aboriginal communities remains unacceptably high, with Group A Streptococcus (GAS) the dominant pathogen. We aim to better understand the drivers of GAS transmission using mathematical models. To estimate the force of infection, we quantified the age of first skin sores and scabies infection by pooling historical data from three studies conducted across five remote Aboriginal communities for children born between 2001 and 2005. We estimated the age of the first infection using the Kaplan-Meier estimator; parametric exponential mixture model; and Cox proportional hazards. For skin sores, the mean age of the first infection was approximately 10 months and the median was 7 months, with some heterogeneity in median observed by the community. For scabies, the mean age of the first infection was approximately 9 months and the median was 8 months, with significant heterogeneity by the community and an enhanced risk for children born between October and December. The young age of the first infection with skin sores and scabies reflects the high disease burden in these communities.Copyright © Cambridge University Press 2018.

Background: Appropriate systems of stroke care are important to manage the increasing death and disability associated with stroke in Africa. Information on existing stroke services in African countries is limited. Aim(s): To describe the status of stroke care in Africa. Summary of review: We undertook a systematic search of the published literature to identify recent (1 January 2006-20 June 2017) publications that described stroke care in any African country. Our initial search yielded 838 potential papers, of which 38 publications were eligible representing 14/54 African countries. Across the publications included for our review, the proportion of stroke patients reported to arrive at hospital within 3 h from stroke onset varied between 10% and 43%. The median time interval between stroke onset and hospital admission was 31 h. Poor awareness of stroke signs and symptoms, shortages of medical transportation, health care personnel, and stroke units, and the high cost of brain imaging, thrombolysis, and outpatient physiotherapy rehabilitation services were reported as major barriers to providing best-practice stroke care in Africa. Conclusion(s): This review provides an overview of stroke care in Africa, and highlights the paucity of available data. Stroke care in Africa usually fell below the recommended standards with variations across countries and settings. Combined efforts from policy makers and health care professionals in Africa are needed to improve, and ensure access, to organized stroke care in as many settings as possible. Mechanisms to routinely monitor usual care (i.e., registries or audits) are also needed to inform policy and practice.Copyright © 2018 World Stroke Organization.

The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.Copyright © The Author(s) 2018.

Differential expression of neuregulin-1 (NRG1) mRNA isoforms and proteins has been reported in schizophrenia, primarily in post-mortem brain tissue. In this study, we examined 12 NRG1 SNPs, eight NRG1 mRNA isoforms (type I, type I(Ig2), type II, type III, type IV, EGFalpha, EGFbeta, pan-NRG1) in whole blood, and NRG1-beta1 protein in serum of clozapine-treated schizophrenia patients (N = 71) and healthy controls (N = 57). In addition, using cultured peripheral blood mononuclear cells (PBMC) from 15 healthy individuals, we examined the effect of clozapine on NRG1 mRNA isoform and protein expression. We found elevated levels of NRG1 mRNA, specifically the EGFalpha (P = 0.0175), EGFbeta (P = 0.002) and type I(Ig2) (P = 0.023) containing transcripts, but lower NRG1-beta1 serum protein levels (P = 0.019) in schizophrenia patients compared to healthy controls. However, adjusting for smoking status attenuated the difference in NRG1-beta1 serum levels (P = 0.050). Examination of clinical factors showed NRG1 EGFalpha (P = 0.02) and EGFbeta (P = 0.02) isoform expression was negatively correlated with age of onset. However, we found limited evidence that NRG1 mRNA isoform or protein expression was associated with current chlorpromazine equivalent dose or clozapine plasma levels, the latter corroborated by our PBMC clozapine exposure experiment. Our SNP analysis found no robust expression quantitative trait loci. Our results represent the first comprehensive investigation of NRG1 isoforms and protein expression in the blood of clozapine-treated schizophrenia patients and suggest levels of some NRG1 transcripts are upregulated in those with schizophrenia.Copyright © 2017 The Author(s).

Aim: Childhood stroke disrupts brain development and emerging neural networks. Motor, cognitive, and language deficits are well recognized, yet little is known about psychosocial function after childhood stroke. This study aims to describe psychosocial function within the first year after childhood stroke, and to identify factors associated with outcome. Method(s): Thirty-seven children were involved in a prospective, longitudinal study investigating recovery over the first year after childhood stroke. Children's social functioning was assessed at 6-months and 12-months poststroke and psychological function at 12-months poststroke, using standardized measures. Result(s): Mean social function was poorer at both 6-months and 12-months poststroke, compared to prestroke. Psychological problems were more common than expected, with emotional difficulties and hyperactivity-inattention most significantly affected. Poorer social function was associated with older age at onset, acute neurological impairment, and prestroke social impairment. Social and psychological problems were associated with parent mental health. Interpretation(s): While not all children are affected, psychosocial impairment affects a significant minority after childhood stroke. Older age at onset, acute neurological impairment, prestroke social problems, and poorer parent mental health were associated with deficits. Identifying early predictors of poorer outcome will facilitate early intervention. Of particular importance is parent mental health, suggesting support for families may improve child outcome.Copyright © 2017 Mac Keith Press

Differential expression of neuregulin-1 (NRG1) mRNA isoforms and proteins has been reported in schizophrenia, primarily in post-mortem brain tissue. In this study, we examined 12 NRG1 SNPs, eight NRG1 mRNA isoforms (type I, type I(Ig2), type II, type III, type IV, EGFalpha, EGFbeta, pan-NRG1) in whole blood, and NRG1-beta1 protein in serum of clozapine-treated schizophrenia patients (N = 71) and healthy controls (N = 57). In addition, using cultured peripheral blood mononuclear cells (PBMC) from 15 healthy individuals, we examined the effect of clozapine on NRG1 mRNA isoform and protein expression. We found elevated levels of NRG1 mRNA, specifically the EGFalpha (P = 0.0175), EGFbeta (P = 0.002) and type I(Ig2) (P = 0.023) containing transcripts, but lower NRG1-beta1 serum protein levels (P = 0.019) in schizophrenia patients compared to healthy controls. However, adjusting for smoking status attenuated the difference in NRG1-beta1 serum levels (P = 0.050). Examination of clinical factors showed NRG1 EGFalpha (P = 0.02) and EGFbeta (P = 0.02) isoform expression was negatively correlated with age of onset. However, we found limited evidence that NRG1 mRNA isoform or protein expression was associated with current chlorpromazine equivalent dose or clozapine plasma levels, the latter corroborated by our PBMC clozapine exposure experiment. Our SNP analysis found no robust expression quantitative trait loci. Our results represent the first comprehensive investigation of NRG1 isoforms and protein expression in the blood of clozapine-treated schizophrenia patients and suggest levels of some NRG1 transcripts are upregulated in those with schizophrenia.Copyright © 2017 The Author(s).

Aim: Childhood stroke disrupts brain development and emerging neural networks. Motor, cognitive, and language deficits are well recognized, yet little is known about psychosocial function after childhood stroke. This study aims to describe psychosocial function within the first year after childhood stroke, and to identify factors associated with outcome. Method(s): Thirty-seven children were involved in a prospective, longitudinal study investigating recovery over the first year after childhood stroke. Children's social functioning was assessed at 6-months and 12-months poststroke and psychological function at 12-months poststroke, using standardized measures. Result(s): Mean social function was poorer at both 6-months and 12-months poststroke, compared to prestroke. Psychological problems were more common than expected, with emotional difficulties and hyperactivity-inattention most significantly affected. Poorer social function was associated with older age at onset, acute neurological impairment, and prestroke social impairment. Social and psychological problems were associated with parent mental health. Interpretation(s): While not all children are affected, psychosocial impairment affects a significant minority after childhood stroke. Older age at onset, acute neurological impairment, prestroke social problems, and poorer parent mental health were associated with deficits. Identifying early predictors of poorer outcome will facilitate early intervention. Of particular importance is parent mental health, suggesting support for families may improve child outcome.Copyright © 2017 Mac Keith Press

Background: Pediatric stroke outcome studies are often cross sectional in design. Prospective information regarding the clinical course following diagnosis is lacking, but may inform clinical management beyond the acute period. Aim(s): To describe the outcome of arterial ischemic stroke in infants, children and adolescents at one-month and six-months post-stroke across health domains, and explore the relationship between lesion characteristics and early outcome with six-month adaptive behavior. Method(s): A single center prospective longitudinal study at a tertiary level children's hospital. Recruitment was undertaken from December 2007 to January 2012. Participants were children aged birth to 18 years presenting acutely with first diagnosed arterial ischemic stroke. Lesion characteristics on brain imaging were classified. Children were grouped according to age at diagnosis for analysis (neonates vs. those aged >30 days). Result(s): In 50 children with a median age of 47 months at diagnosis, sensorimotor impairments were most evident upon neurological examination acutely, especially in the older children. At both one-month and six-months motor functioning was significantly impaired in the older age group but no significant cognitive or language sequelae were identified. Lesion characteristics alone were not associated with six-month adaptive behavior outcomes. Conclusion(s): For patients surviving arterial ischemic stroke, the most significant clinical consequences both acutely and at six-months, are sensorimotor impairments, particularly evident in the older children. In contrast cognitive or language sequelae were not identified. Long-term surveillance is required to describe clinical course and rehabilitation needs, particularly for neonates and infants.Copyright © 2015 World Stroke Organization.

Objective: To explore the progression of Friedreich ataxia by analysing the change in scores of four clinical measures (the Friedreich Ataxia Rating Scale (FARS), the International Cooperative Ataxia Rating Scale (ICARS), the Functional Independence Measure (FIM) and the Modified Barthel Index (MBI)) over a period of up to 12 years, to ascertain the effects of clinical variables on performance of these measures, and to determine the most sensitive rating scale for measuring disease progression. Method(s): We measured the disease progression of up to 147 individuals against disease duration grouped into 5-year intervals. Additional subgroups were created to study the effects of the size of the smaller FXN intron 1 GAA repeat size (GAA1) and onset age on rating scale performance. Result(s): Both the FARS and ICARS demonstrated greater change in the first 20 years post disease onset than in the subsequent 20 years during which there was little change in the mean score. While the FIM and MBI continued to deteriorate beyond 20 years post disease onset, floor effects were noted. As measured by the FARS, individuals with a larger GAA1 repeat were found to progress more quickly in the first 20 years of disease. Conclusion(s): Individuals with larger GAA1 repeat sizes and earlier ages of disease onset were shown to deteriorate at a faster rate and were associated with greater FARS and ICARS scores and lower FIM and MBI scores, which are indicative of greater disease severity.

Background: Pediatric stroke outcome studies are often cross sectional in design. Prospective information regarding the clinical course following diagnosis is lacking, but may inform clinical management beyond the acute period. Aim(s): To describe the outcome of arterial ischemic stroke in infants, children and adolescents at one-month and six-months post-stroke across health domains, and explore the relationship between lesion characteristics and early outcome with six-month adaptive behavior. Method(s): A single center prospective longitudinal study at a tertiary level children's hospital. Recruitment was undertaken from December 2007 to January 2012. Participants were children aged birth to 18 years presenting acutely with first diagnosed arterial ischemic stroke. Lesion characteristics on brain imaging were classified. Children were grouped according to age at diagnosis for analysis (neonates vs. those aged >30 days). Result(s): In 50 children with a median age of 47 months at diagnosis, sensorimotor impairments were most evident upon neurological examination acutely, especially in the older children. At both one-month and six-months motor functioning was significantly impaired in the older age group but no significant cognitive or language sequelae were identified. Lesion characteristics alone were not associated with six-month adaptive behavior outcomes. Conclusion(s): For patients surviving arterial ischemic stroke, the most significant clinical consequences both acutely and at six-months, are sensorimotor impairments, particularly evident in the older children. In contrast cognitive or language sequelae were not identified. Long-term surveillance is required to describe clinical course and rehabilitation needs, particularly for neonates and infants.Copyright © 2015 World Stroke Organization.

Objective: To explore the progression of Friedreich ataxia by analysing the change in scores of four clinical measures (the Friedreich Ataxia Rating Scale (FARS), the International Cooperative Ataxia Rating Scale (ICARS), the Functional Independence Measure (FIM) and the Modified Barthel Index (MBI)) over a period of up to 12 years, to ascertain the effects of clinical variables on performance of these measures, and to determine the most sensitive rating scale for measuring disease progression. Method(s): We measured the disease progression of up to 147 individuals against disease duration grouped into 5-year intervals. Additional subgroups were created to study the effects of the size of the smaller FXN intron 1 GAA repeat size (GAA1) and onset age on rating scale performance. Result(s): Both the FARS and ICARS demonstrated greater change in the first 20 years post disease onset than in the subsequent 20 years during which there was little change in the mean score. While the FIM and MBI continued to deteriorate beyond 20 years post disease onset, floor effects were noted. As measured by the FARS, individuals with a larger GAA1 repeat were found to progress more quickly in the first 20 years of disease. Conclusion(s): Individuals with larger GAA1 repeat sizes and earlier ages of disease onset were shown to deteriorate at a faster rate and were associated with greater FARS and ICARS scores and lower FIM and MBI scores, which are indicative of greater disease severity.

Although epileptic photosensitivity is well known, its genetics and syndromic associations are incompletely understood. Seizures triggered by photic stimulation are usually a manifestation of the idiopathic generalized epilepsies, especially juvenile myoclonic epilepsy (JME), or of the occipital epilepsies. Idiopathic photosensitive occipital epilepsy (IPOE) is a focal epilepsy with colourful elementary visual auras, often with conscious tonic head and eye version; myoclonus is not a feature. All seizures are induced by photic stimuli. We describe four families with phenotypic overlap between JME and IPOE. Families were identified if two or more affected individuals had visual auras and electro-clinical features of an idiopathic epilepsy. Family members underwent detailed electro-clinical assessment. In addition, 40 unrelated JME probands were investigated systematically for unrecognized features of IPOE (visual aura and conscious head version). There were 12 affected individuals in four families; 11 were female. Clinical onset was at 8-21 years of age. Of 10 patients with visual auras, six had conscious head version and five also experienced myoclonic jerks; eight had non-photic induced tonic-clonic seizures (TCS). Of the remaining individuals, one had myoclonic jerks and occipital spikes; the other had TCS without visual aura or myoclonic jerks. Of 10 patients with EEG studies, eight had generalized spike and wave (GSW) and six had occipital spikes. All had photosensitivity with GSW and four had additional occipital spikes. Of the 40 JME probands, six had visual aura and/or conscious head version; five of these were photosensitive. There is overlap between the clusters of clinical features used to diagnose IPOE and JME. Half of the affected individuals in our families with visual aura had myoclonic jerks; the former is characteristic of IPOE and the latter of JME. Importantly, visual aura is not regarded as part of JME, nor myoclonus part of IPOE, but our data emp

Lateral biases in visual perception have been demonstrated in normal individuals and in patients with unilateral brain lesions. It has been suggested that the absence of structural and functional asymmetries in schizophrenia could be due to a failure in lateralisation that may be most pronounced in those patients whose illness onset is at an early age. Here we examined lateral biases in patients with schizophrenia of an early onset (N = 21) and a late onset (N = 19), and their respective age-matched control groups, using the greyscales task, a sensitive measure of asymmetries in visual processing. The stimuli consisted of two rectangles, one above the other, shaded in opposite directions and matched overall for darkness. Participants judged which of the two rectangles looked darker overall. Previous studies using this task in healthy participants have reported a reliable bias, such that the rectangle with the darker end on the left is selected preferentially. Whereas the late-onset patients in this study exhibited a perceptual bias of similar direction and magnitude to that of controls, this was not the case for the early-onset patients, who exhibited significantly less bias than their control group. The reduced perceptual bias seen in the early-onset group, but not the late-onset group, suggests an attenuation of right hemisphere mechanisms dedicated to processing visuospatial information. The attenuated perceptual asymmetry in the early-onset group only may be consistent with the view that (i) an earlier illness onset reflects a greater loss of hemispheric differentiation and (ii) reduced functional asymmetries in the early-onset group are a manifestation of a failure to allocate functions to one or the other hemisphere.

To investigate the relationships between age, the advanced clinical stages of Parkinson's disease and neuropathology, we surveyed 129 case records from donors with pathologically proven Parkinson's disease at the Queen Square Brain Bank for Neurological Disorders. Cases were separated into five groups according to age at death, thus comparing patients who reached the advanced stage of the disease at different ages. Four milestones of advanced disease (frequent falls, visual hallucinations, dementia and need for residential care) occurred at a similar time from death in each group. There were no significant differences in disease duration across these age groupings, nor were there differences in the severity and distribution of Lewy body and other pathologies. The milestones of dementia (P < 0.0005) and visual hallucinations (P = 0.02) as well as the accumulation of multiple milestones (P < 0.0005) were associated with high cortical Lewy body scores. Demented cases also had significantly more Alzheimer neurofibrillary and amyloid-beta plaque pathology. Correlation analysis showed that the time intervals between disease onset and recording of milestones were strongly influenced by age at onset (P < 0.0001) and by total disease duration (P < 0.0001). The advanced disease phase plays out in a similar fashion at whatever age it occurs, with a common pathological endpoint. The clinico-pathological comparisons for the final stage of Parkinson's disease do support a staging system based on the rostral extent and severity of Lewy body pathology, although other pathologies may play a synergistic role in causing cognitive disability. The chief effects of age on the rate of progression are seen over the early-middle part of the disease. An exponential curve for clinical progression provides the best explanation for these observations about age and the disease course. © The Author (2010).

Background: There is little information available on the features of initial presentation of bronchiectasis and documentation of the onset and progress of symptoms leading up to this. Therefore a study was performed on a large cohort of adult patients presenting to Monash Medical Centre (MMC) to survey the course of their disease up to the time of diagnosis. Objective(s): To characterise the onset and presenting clinical features of bronchiectasis in adults. Method(s): A cross-sectional study of 103 adults presenting to a tertiary referral hospital with newly diagnosed bronchiectasis. Clinical features of bronchiectasis and results of spirometry, sputum microbiology and radiology were assessed and correlated. Result(s): Most patients had idiopathic bronchiectasis (74%) and did not have other significant disease. The dominant symptom was chronic productive cough present in 98% of patients with other important symptoms being chronic rhinosinusitis (70%), dyspnoea (62%), and fatigue (74%). Most patients had had a chronic productive cough for over 30 years prior to diagnosis and over 80% of patients had chronic respiratory symptoms from childhood. The dominant finding on physical examination was the presence of crackles which were generally bi-basal. Spirometry showed mild airway obstruction with an average forced expiratory volume in 1 s of the cohort of 76% predicted. Radiologic imaging generally showed multilobar disease (80%). Conclusion(s): The typical profile of bronchiectasis in this group of patients was of longstanding productive cough, rhinosinusitis and fatigue in non-smokers with crackles on chest auscultation. © 2006 Elsevier Ltd. All rights reserved.

The menopause, defined as the permanent cessation of menstruation resulting from the loss of ovarian follicular activity, marks the end of natural female reproductive life. It is preceded by a period of menstrual cycle irregularity, the menopausal transition, which usually begins in the mid-40s and is conventionally divided into early and late phases. The endocrine changes, which underlie the transition, are predominantly the consequence of a marked decline in ovarian follicle numbers. The most significant changes include a decrease in early cycle inhibin B and in anti-Mullerian hormone (AMH) levels. The decline in inhibin B results in an increase in FSH, which appears to be an important factor in the maintenance of estradiol (E2) concentrations until late in reproductive life. In the post-menopause, FSH levels are markedly raised, E2 levels are low, whereas inhibin B and AMH are undetectable. The menopausal transition is a time of marked hormonal instability. The Melbourne Women's Midlife Health Project has been an extremely productive study in which it has been possible to describe longitudinal changes in hormone levels throughout the menopause transition and to separate the effects of hormone change from the effects of ageing on a number of endpoints. This review provides the background for an accompanying manuscript in which a novel approach to modelling the hormonal changes during the transition is described. © The Author 2007. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

Aims: New onset of the clinical symptoms of immunoglobulin A (IgA) nephropathy (IgAN) manifests with proliferative glomerular lesions in children, whereas adults exhibit mesangial matrix expansion and interstitial fibrosis. Alternatively, activated (M2) macrophages have been implicated in promoting tissue fibrosis in some settings. Therefore, the aim of this study was to investigate whether M2 macrophages are present in new-onset IgAN and if they are related to pathological differences between paediatric and adult disease. Methods and Results: Biopsy specimens from paediatric (<10years, n=14; >12years, n=15) and adult (n=27) IgAN showed a significant infiltrate of CD68+ macrophages. M2 macrophages, identified by CD163 or CD204 expression, were detected in glomeruli and the interstitium, being more prominent in adults versus young children. CD163+ and CD204+ macrophages were present in areas of fibrosis containing myofibroblasts, and double staining showed that CD163+ cells produced the profibrotic molecule, connective tissue growth factor. In young children, total CD68+ macrophages, but not M2 macrophages, correlated with glomerular hypercellularity. In contrast, in adults and older children, mesangial matrix expansion correlated with M2 macrophages but not with the total CD68+ macrophage infiltrate. Conclusion(s): Alternatively activated M2 macrophages are present in new-onset paediatric and adult IgAN, and this population may promote the development of fibrotic lesions. © 2011 Blackwell Publishing Limited.

Background: X chromosome inactivation, which silences gene expression from one of the two X chromosomes in females, is usually random. Skewed X inactivation has been implicated in both the expression and the suppression of X-linked disease phenotypes and has been reported to occur more frequently in breast and ovarian cancer patients, including BRCA1 or BRCA2 mutation carriers, than in control subjects. Method(s): We assessed the pattern of X chromosome inactivation using methylation-specific polymerase chain reaction amplification of the exon 1 microsatellite region of the X-linked androgen receptor (AR) gene in DNA from blood samples obtained from control subjects without a personal history of breast or ovarian cancer (n = 735), ovarian cancer patients (n = 313), familial breast cancer patients who did not carry mutations in BRCA1 or BRCA2 (n = 235), and affected and unaffected carriers of mutations in BRCA1 (n = 260) or BRCA2 (n = 63). We defined the pattern of X chromosome inactivation as skewed when the same X chromosome was active in at least 90% of cells. The association between skewed X inactivation and disease and/or BRCA mutation status was assessed by logistic regression analysis. The association between skewed X inactivation and age at cancer diagnosis was assessed by Cox proportional hazards regression analysis. All statistical tests were two-sided. Result(s): The age-adjusted frequency of skewed X inactivation was not statistically significantly higher in ovarian cancer or familial breast cancer case subjects compared with control subjects. Skewed X inactivation was higher in BRCA1 mutation carriers than in control subjects (odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.1 to 6.2; P =. 02), particularly among unaffected women (OR = 6.1, 95% CI = 1.5 to 31.8; P =. 005). Among BRCA1 mutation carriers, those with skewed X inactivation were older at diagnosis of breast or ovarian cancer than those without skewed X inactivation (hazard ratio [HR] o

The relationship between severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome) and the related syndrome SMEI-borderland (SMEB) with mutations in the sodium channel alpha 1 subunit gene SCN1A is well established. To explore the phenotypic variability associated with SCN1A mutations, 188 patients with a range of epileptic encephalopathies were examined for SCN1A sequence variations by denaturing high performance liquid chromatography and sequencing. All patients had seizure onset within the first 2 years of life. A higher proportion of mutations were identified in patients with SMEI (52/66; 79%) compared to patients with SMEB (25/36; 69%). By studying a broader spectrum of infantile epileptic encephalopathies, we identified mutations in other syndromes including cryptogenic generalized epilepsy (24%) and cryptogenic focal epilepsy (22%). Within the latter group, a distinctive subgroup designated as severe infantile multifocal epilepsy had SCN1A mutations in three of five cases. This phenotype is characterized by early onset multifocal seizures and later cognitive decline. Knowledge of an expanded spectrum of epileptic encephalopathies associated with SCN1A mutations allows earlier diagnostic confirmation for children with these devastating disorders. © The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

Although epileptic photosensitivity is well known, its genetics and syndromic associations are incompletely understood. Seizures triggered by photic stimulation are usually a manifestation of the idiopathic generalized epilepsies, especially juvenile myoclonic epilepsy (JME), or of the occipital epilepsies. Idiopathic photosensitive occipital epilepsy (IPOE) is a focal epilepsy with colourful elementary visual auras, often with conscious tonic head and eye version; myoclonus is not a feature. All seizures are induced by photic stimuli. We describe four families with phenotypic overlap between JME and IPOE. Families were identified if two or more affected individuals had visual auras and electro-clinical features of an idiopathic epilepsy. Family members underwent detailed electro-clinical assessment. In addition, 40 unrelated JME probands were investigated systematically for unrecognized features of IPOE (visual aura and conscious head version). There were 12 affected individuals in four families; 11 were female. Clinical onset was at 8-21 years of age. Of 10 patients with visual auras, six had conscious head version and five also experienced myoclonic jerks; eight had non-photic induced tonic-clonic seizures (TCS). Of the remaining individuals, one had myoclonic jerks and occipital spikes; the other had TCS without visual aura or myoclonic jerks. Of 10 patients with EEG studies, eight had generalized spike and wave (GSW) and six had occipital spikes. All had photosensitivity with GSW and four had additional occipital spikes. Of the 40 JME probands, six had visual aura and/or conscious head version; five of these were photosensitive. There is overlap between the clusters of clinical features used to diagnose IPOE and JME. Half of the affected individuals in our families with visual aura had myoclonic jerks; the former is characteristic of IPOE and the latter of JME. Importantly, visual aura is not regarded as part of JME, nor myoclonus part of IPOE, but our data emp

The aim of this study was to examine the impact of Friedreich ataxia (FRDA) on quality of life (QOL) using a generic tool to explore factors potentially associated with health status. Sixty-three individuals with genetically confirmed FRDA, self completed the Medical Outcomes Study 36 item Short Form Health Survey Version 2 (SF-36V2) and were assessed using the FRDA Rating Scale. Disease-specific, demographic, and social characteristics were also recorded. SF-36V2 results were compared with Australian population norms. Sample subgroups of disease severity and age at disease onset were reviewed. Physical and mental component summaries were examined in relation to clinical and social characteristics using multiple linear regression. QOL is significantly worse in individuals with FRDA compared with population norms. Those with severe disease did not perceive a lower QOL than those with mild or moderate disease except in their physical functioning. A later age of onset and increased disease severity were negatively associated with physical QOL, whilst, increased disease duration was positively associated with mental QOL. There were limitations associated with the use of SF-36V2 in the FRDA population. Further exploration of health-related QOL and FRDA may benefit from the use of a more appropriate generic tool. © 2007 EFNS.

Lateral biases in visual perception have been demonstrated in normal individuals and in patients with unilateral brain lesions. It has been suggested that the absence of structural and functional asymmetries in schizophrenia could be due to a failure in lateralisation that may be most pronounced in those patients whose illness onset is at an early age. Here we examined lateral biases in patients with schizophrenia of an early onset (N = 21) and a late onset (N = 19), and their respective age-matched control groups, using the greyscales task, a sensitive measure of asymmetries in visual processing. The stimuli consisted of two rectangles, one above the other, shaded in opposite directions and matched overall for darkness. Participants judged which of the two rectangles looked darker overall. Previous studies using this task in healthy participants have reported a reliable bias, such that the rectangle with the darker end on the left is selected preferentially. Whereas the late-onset patients in this study exhibited a perceptual bias of similar direction and magnitude to that of controls, this was not the case for the early-onset patients, who exhibited significantly less bias than their control group. The reduced perceptual bias seen in the early-onset group, but not the late-onset group, suggests an attenuation of right hemisphere mechanisms dedicated to processing visuospatial information. The attenuated perceptual asymmetry in the early-onset group only may be consistent with the view that (i) an earlier illness onset reflects a greater loss of hemispheric differentiation and (ii) reduced functional asymmetries in the early-onset group are a manifestation of a failure to allocate functions to one or the other hemisphere.

To investigate the relationships between age, the advanced clinical stages of Parkinson's disease and neuropathology, we surveyed 129 case records from donors with pathologically proven Parkinson's disease at the Queen Square Brain Bank for Neurological Disorders. Cases were separated into five groups according to age at death, thus comparing patients who reached the advanced stage of the disease at different ages. Four milestones of advanced disease (frequent falls, visual hallucinations, dementia and need for residential care) occurred at a similar time from death in each group. There were no significant differences in disease duration across these age groupings, nor were there differences in the severity and distribution of Lewy body and other pathologies. The milestones of dementia (P < 0.0005) and visual hallucinations (P = 0.02) as well as the accumulation of multiple milestones (P < 0.0005) were associated with high cortical Lewy body scores. Demented cases also had significantly more Alzheimer neurofibrillary and amyloid-beta plaque pathology. Correlation analysis showed that the time intervals between disease onset and recording of milestones were strongly influenced by age at onset (P < 0.0001) and by total disease duration (P < 0.0001). The advanced disease phase plays out in a similar fashion at whatever age it occurs, with a common pathological endpoint. The clinico-pathological comparisons for the final stage of Parkinson's disease do support a staging system based on the rostral extent and severity of Lewy body pathology, although other pathologies may play a synergistic role in causing cognitive disability. The chief effects of age on the rate of progression are seen over the early-middle part of the disease. An exponential curve for clinical progression provides the best explanation for these observations about age and the disease course. © The Author (2010).

Background: There is little information available on the features of initial presentation of bronchiectasis and documentation of the onset and progress of symptoms leading up to this. Therefore a study was performed on a large cohort of adult patients presenting to Monash Medical Centre (MMC) to survey the course of their disease up to the time of diagnosis. Objective(s): To characterise the onset and presenting clinical features of bronchiectasis in adults. Method(s): A cross-sectional study of 103 adults presenting to a tertiary referral hospital with newly diagnosed bronchiectasis. Clinical features of bronchiectasis and results of spirometry, sputum microbiology and radiology were assessed and correlated. Result(s): Most patients had idiopathic bronchiectasis (74%) and did not have other significant disease. The dominant symptom was chronic productive cough present in 98% of patients with other important symptoms being chronic rhinosinusitis (70%), dyspnoea (62%), and fatigue (74%). Most patients had had a chronic productive cough for over 30 years prior to diagnosis and over 80% of patients had chronic respiratory symptoms from childhood. The dominant finding on physical examination was the presence of crackles which were generally bi-basal. Spirometry showed mild airway obstruction with an average forced expiratory volume in 1 s of the cohort of 76% predicted. Radiologic imaging generally showed multilobar disease (80%). Conclusion(s): The typical profile of bronchiectasis in this group of patients was of longstanding productive cough, rhinosinusitis and fatigue in non-smokers with crackles on chest auscultation. © 2006 Elsevier Ltd. All rights reserved.

The menopause, defined as the permanent cessation of menstruation resulting from the loss of ovarian follicular activity, marks the end of natural female reproductive life. It is preceded by a period of menstrual cycle irregularity, the menopausal transition, which usually begins in the mid-40s and is conventionally divided into early and late phases. The endocrine changes, which underlie the transition, are predominantly the consequence of a marked decline in ovarian follicle numbers. The most significant changes include a decrease in early cycle inhibin B and in anti-Mullerian hormone (AMH) levels. The decline in inhibin B results in an increase in FSH, which appears to be an important factor in the maintenance of estradiol (E2) concentrations until late in reproductive life. In the post-menopause, FSH levels are markedly raised, E2 levels are low, whereas inhibin B and AMH are undetectable. The menopausal transition is a time of marked hormonal instability. The Melbourne Women's Midlife Health Project has been an extremely productive study in which it has been possible to describe longitudinal changes in hormone levels throughout the menopause transition and to separate the effects of hormone change from the effects of ageing on a number of endpoints. This review provides the background for an accompanying manuscript in which a novel approach to modelling the hormonal changes during the transition is described. © The Author 2007. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

Aims: New onset of the clinical symptoms of immunoglobulin A (IgA) nephropathy (IgAN) manifests with proliferative glomerular lesions in children, whereas adults exhibit mesangial matrix expansion and interstitial fibrosis. Alternatively, activated (M2) macrophages have been implicated in promoting tissue fibrosis in some settings. Therefore, the aim of this study was to investigate whether M2 macrophages are present in new-onset IgAN and if they are related to pathological differences between paediatric and adult disease. Methods and Results: Biopsy specimens from paediatric (<10years, n=14; >12years, n=15) and adult (n=27) IgAN showed a significant infiltrate of CD68+ macrophages. M2 macrophages, identified by CD163 or CD204 expression, were detected in glomeruli and the interstitium, being more prominent in adults versus young children. CD163+ and CD204+ macrophages were present in areas of fibrosis containing myofibroblasts, and double staining showed that CD163+ cells produced the profibrotic molecule, connective tissue growth factor. In young children, total CD68+ macrophages, but not M2 macrophages, correlated with glomerular hypercellularity. In contrast, in adults and older children, mesangial matrix expansion correlated with M2 macrophages but not with the total CD68+ macrophage infiltrate. Conclusion(s): Alternatively activated M2 macrophages are present in new-onset paediatric and adult IgAN, and this population may promote the development of fibrotic lesions. © 2011 Blackwell Publishing Limited.

Background: X chromosome inactivation, which silences gene expression from one of the two X chromosomes in females, is usually random. Skewed X inactivation has been implicated in both the expression and the suppression of X-linked disease phenotypes and has been reported to occur more frequently in breast and ovarian cancer patients, including BRCA1 or BRCA2 mutation carriers, than in control subjects. Method(s): We assessed the pattern of X chromosome inactivation using methylation-specific polymerase chain reaction amplification of the exon 1 microsatellite region of the X-linked androgen receptor (AR) gene in DNA from blood samples obtained from control subjects without a personal history of breast or ovarian cancer (n = 735), ovarian cancer patients (n = 313), familial breast cancer patients who did not carry mutations in BRCA1 or BRCA2 (n = 235), and affected and unaffected carriers of mutations in BRCA1 (n = 260) or BRCA2 (n = 63). We defined the pattern of X chromosome inactivation as skewed when the same X chromosome was active in at least 90% of cells. The association between skewed X inactivation and disease and/or BRCA mutation status was assessed by logistic regression analysis. The association between skewed X inactivation and age at cancer diagnosis was assessed by Cox proportional hazards regression analysis. All statistical tests were two-sided. Result(s): The age-adjusted frequency of skewed X inactivation was not statistically significantly higher in ovarian cancer or familial breast cancer case subjects compared with control subjects. Skewed X inactivation was higher in BRCA1 mutation carriers than in control subjects (odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.1 to 6.2; P =. 02), particularly among unaffected women (OR = 6.1, 95% CI = 1.5 to 31.8; P =. 005). Among BRCA1 mutation carriers, those with skewed X inactivation were older at diagnosis of breast or ovarian cancer than those without skewed X inactivation (hazard ratio [HR] o

The relationship between severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome) and the related syndrome SMEI-borderland (SMEB) with mutations in the sodium channel alpha 1 subunit gene SCN1A is well established. To explore the phenotypic variability associated with SCN1A mutations, 188 patients with a range of epileptic encephalopathies were examined for SCN1A sequence variations by denaturing high performance liquid chromatography and sequencing. All patients had seizure onset within the first 2 years of life. A higher proportion of mutations were identified in patients with SMEI (52/66; 79%) compared to patients with SMEB (25/36; 69%). By studying a broader spectrum of infantile epileptic encephalopathies, we identified mutations in other syndromes including cryptogenic generalized epilepsy (24%) and cryptogenic focal epilepsy (22%). Within the latter group, a distinctive subgroup designated as severe infantile multifocal epilepsy had SCN1A mutations in three of five cases. This phenotype is characterized by early onset multifocal seizures and later cognitive decline. Knowledge of an expanded spectrum of epileptic encephalopathies associated with SCN1A mutations allows earlier diagnostic confirmation for children with these devastating disorders. © The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

Aim: The corpus callosum (CC) can be affected by childhood traumatic brain injury (TBI), through focal lesions, reductions in size and arrested development. Little is known, however, about what constitutes normal CC shape and appearance and how it may be affected in the long-term after early TBI. Method(s): In this study, the appearance of the CC was investigated in individuals with TBI assessed 10 years post-injury (n = 52, mean age = 16.82 years, SD = 3.55 years, 24 male) and compared to age-matched healthy controls (n = 44, mean age = 15.77 years, SD = 1.21 years, 18 male). A simple visual analysis technique was used to code the appearance of the CC according to location of focal thinning and severity of thinning and results between groups were compared using Chi-square analysis. Result(s): A significantly higher proportion of patients with childhood TBI had focal posterior thinning of the CC than age-matched controls (p = 0.001). Conclusion(s): The findings call into question previous conclusions that focal posterior thinning is a normal variant of development. Instead, attenuations of the posterior portion of the CC in the long-term may reflect altered cortical and callosal development as a result of early brain injury, although the functional significance of this remains to be determined. © 2011 Informa UK Ltd All rights reserved.

Aim: The corpus callosum (CC) can be affected by childhood traumatic brain injury (TBI), through focal lesions, reductions in size and arrested development. Little is known, however, about what constitutes normal CC shape and appearance and how it may be affected in the long-term after early TBI. Method(s): In this study, the appearance of the CC was investigated in individuals with TBI assessed 10 years post-injury (n = 52, mean age = 16.82 years, SD = 3.55 years, 24 male) and compared to age-matched healthy controls (n = 44, mean age = 15.77 years, SD = 1.21 years, 18 male). A simple visual analysis technique was used to code the appearance of the CC according to location of focal thinning and severity of thinning and results between groups were compared using Chi-square analysis. Result(s): A significantly higher proportion of patients with childhood TBI had focal posterior thinning of the CC than age-matched controls (p = 0.001). Conclusion(s): The findings call into question previous conclusions that focal posterior thinning is a normal variant of development. Instead, attenuations of the posterior portion of the CC in the long-term may reflect altered cortical and callosal development as a result of early brain injury, although the functional significance of this remains to be determined. © 2011 Informa UK Ltd All rights reserved.

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease, caused by the expansion of a trinucleotide repeat (TNR) in exon 1 of the androgen receptor (AR) gene. This disorder is characterized by degeneration of motor and sensory neurons, proximal muscular atrophy, and endocrine abnormalities, such as gynecomastia and reduced fertility. We describe the development of a transgenic model of SBMA expressing a full-length human AR (hAR) cDNA carrying 65 (AR65) or 120 CAG repeats (AR120), with widespread expression driven by the cytomegalovirus promoter. Mice carrying the AR120 transgene displayed behavioral and motor dysfunction, while mice carrying 65 CAG repeats showed a mild phenotype. Progressive muscle weakness and atrophy was observed in AR120 mice and was associated with the loss of alpha-motor neurons in the spinal cord. There was no evidence of neurodegeneration in other brain structures. Motor dysfunction was observed in both male and female animals, showing that in SBMA the polyglutamine repeat expansion causes a dominant gain-of-function mutation in the AR. The male mice displayed a progressive reduction in sperm production consistent with testis defects reported in human patients. These mice represent the first model to reproduce the key features of SBMA, making them a useful resource for characterizing disease progression, and for testing therapeutic strategies for both polyglutamine and motor neuron diseases.

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease, caused by the expansion of a trinucleotide repeat (TNR) in exon 1 of the androgen receptor (AR) gene. This disorder is characterized by degeneration of motor and sensory neurons, proximal muscular atrophy, and endocrine abnormalities, such as gynecomastia and reduced fertility. We describe the development of a transgenic model of SBMA expressing a full-length human AR (hAR) cDNA carrying 65 (AR65) or 120 CAG repeats (AR120), with widespread expression driven by the cytomegalovirus promoter. Mice carrying the AR120 transgene displayed behavioral and motor dysfunction, while mice carrying 65 CAG repeats showed a mild phenotype. Progressive muscle weakness and atrophy was observed in AR120 mice and was associated with the loss of alpha-motor neurons in the spinal cord. There was no evidence of neurodegeneration in other brain structures. Motor dysfunction was observed in both male and female animals, showing that in SBMA the polyglutamine repeat expansion causes a dominant gain-of-function mutation in the AR. The male mice displayed a progressive reduction in sperm production consistent with testis defects reported in human patients. These mice represent the first model to reproduce the key features of SBMA, making them a useful resource for characterizing disease progression, and for testing therapeutic strategies for both polyglutamine and motor neuron diseases.