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Androgen modulation of neurotrophic factor action: A possible mechanism for sexually dimorphic neural developmentXu, Jun 01 January 1999 (has links)
Motoneurons of the spinal nucleus of the bulbocavernosus (SNB) reside in the lower lumbar spinal cord and innervate the bulbocavernosus (BC) and levator ani (LA) muscles. Adult males have larger BC and LA muscles and many more SNB motoneurons than do females. This sex difference comes about as a result of androgen-regulated cell death. How is androgen stimulation of the BC/LA muscles translated into a live-or-die decision by the SNB motoneurons? Neurotrophic factors such as ciliary neurotrophic factor (CNTF) may play such a role. The experiments described in this dissertation are designed to (1) identify potential direct sites of CNTF action in the SNB neuromuscular system, (2) examine androgen regulation of CNTFRα gene expression in BC/LA muscle and lumbosacral spinal cord, and (3) to test whether endogenously produced neurotrophic factors normally influence SNB cell survival. To determine whether CNTFRα is expressed in the developing SNB system, I first performed Northern blotting. The perineal muscles and motoneurons are potential sites of direct CNTF action. Androgen regulation of CNTFRα expression was examined in prenatal animals by administering the androgen receptor blocker hydroxyflutamide from embryonic day 18 (E18) through E21. Expression of the CNTFRα, gene in BC/LA muscle is modulated by androgen. Transient up-regulation of CNTFRα following castration or androgen receptor blockade may represent a protective response designed to counteract the muscle atrophy normally induced by androgen withdrawal. To detect CNTFRα, protein specifically in SNB motoneurons, two immunocytochemical experiments were performed. In the first experiment, CNTFRα immunoreactivity (CNTFRα-IR) was detected from E20 through postnatal day 14 (P14), which spans the cell death period for the SNB. There was no sex difference in CNTFRα-IR during this period. In the second experiment, CNTFRα-IR was compared in newborn (P3), prepubertal (P26) and adult rats (P54). CNTFRα-IR in the SNB remained relatively stable across the three ages examined in males, but declined significantly in females between P26 and P54. To test whether endogenously produced trophic factors acting through CNTFRα, and/or trkB modulate SNB survival, I administered the antagonists, AADH-CNTF (blocking CNTFRα, trkB-IgG (blocking trkB) or PBS (as a control) to testosterone propionate (TP) treated neonatal female rats. SNB motoneuron numbers in females receiving TP plus AADH-CNTF or TP plus trkB-IgG were significantly lower than that of the TP plus PBS treated ones. This finding demonstrates an in vivo requirement for endogenous ligands of CNTFRα, and trkB in SNB motoneuron survival and sexual differentiation of the SNB system. A working model is proposed for how androgens and neurotrophic factors may collaborate to cause a sex difference in the SNB. (Abstract shortened by UMI.)
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Cocaine-sensitive monoamine transporters in rat placenta labeled with (iodine-125)RTI-55 and tritiated nisoxetineShearman, Lauren Patricia 01 January 1996 (has links)
Some of the adverse effects of prenatal cocaine exposure have been associated with uteroplacental vasculature, and (3H) cocaine binding sites were previously reported in human placental villus tissue (Ahmed et al., 1990). Specific uptake systems for serotonin (5-HT) and norepinephrine (NE) are present in human placental syncytiotrophoblastic cells and may be substrates for cocaine action (Cool et al.. 1990; Ramamoorthy et al., 1993b). To investigate whether monoamine transporters are present in rat placenta, I studied the characteristics of placental cocaine recognition sites, and the influence of maternal cocaine treatment on placental and fetal brain monoamine transporter binding. First, saturation analyses were performed with (125I) RTI-55, a potent cocaine congener, on membrane fractions from gestational day (GD) 20 rat placenta. Results yielded curvilinear Scatchard plots that were resolved by non-linear curve-fitting into high- and low-affinity components. Mean Kd values were 0.29 nM and 7.9 nM for high- and low-affinity binding sites respectively, and resembled those found in adult rat brain. Drug displacement studies with monoamine uptake inhibitors indicated that the majority of high-affinity (125I) RTI-55 binding was to the 5-HT transporter. The selective ligands (3H) GBR 12935 and (3H) nisoxetine were used to ascertain whether the rat placenta also possessed dopamine (DA) and/or NE transporters. No saturable binding was detected with (3H) GBR 12935. In contrast, the NE transporter-selective ligand (3H) nisoxetine labeled a single population of binding sites with a Kd of 1.0 nM and a Bmax of 1.2 pmol/mg protein. Drug competition studies confirmed that (3H) nisoxetine labeled NE transporters in rat placenta. Additionally, monoamine transporter binding was localized in GD 20 placenta using in vitro film and dry emulsion autoradiography. (3H) Nisoxetine-labeled NE transporters were visible throughout the placenta, with high densities in giant trophoblastic cells and moderate labeling in the labyrinth. Cocaine-like binding sites labeled with (125I) RTI-55 were mainly distributed in the labyrinth and decidua. To verify the presence of 5-HT transporters in rat placenta, 5-HT immunocytochemistry was carried out. The distribution of 5-HT-immunoreactive cells paralleled sites of (125I) RTI-55 binding in the rat placenta. In the final experiment, pregnant dams received cocaine continuously via s.c. Silastic implants from GD 17 to GD 20, and changes in fetal brain and placental (125I) RTI-55 and (3H) nisoxetine binding were assessed. Cocaine treatment did not alter (125I) RTI-55 binding in the placenta. No effect was found in fetal brain, whereas cocaine produced a marked upregulation of NE transporter density in the placenta at GD 20. These studies demonstrate that rat placenta, a noninnervated tissue, possesses cocaine-like binding sites and 5-HT and NE transporters. Placenta is thus a potential target for mediating some effects of cocaine on fetal development.
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The role of brainstem noradrenergic neurons in communicating steroid hormone signals to luteinizing hormone -releasing hormone neuronsCurran, Meredith Ames 01 January 2001 (has links)
The author examined the role of brainstem noradrenergic (NA) neurons in communicating steroid hormone signals to luteinizing hormone-releasing hormone (LBRH) neurons. To this end, the author tested whether NA neurons contained steroid hormone receptors, whether steroid hormone influenced the activity of NA neurons, whether LHRH neurons or gamma-amino butyric acid (GABA) neurons could receive direct input from NA neurons, and how the GABA system may be influenced by the NA system. Experiment 1 found that progestin receptors were found in numerous nuclei and regions throughout the brainstem, especially in regions containing NA cell groups. Experiment 2 found that estrogen receptor-alpha, estrogen receptor-beta and progestin receptors were found in subpopulations of NA neurons in the ventrolateral medulla (A1 NA neurons) and the nucleus of the solitary tract (A2 NA neurons), as well as in NA neurons in the locus coeruleus (A6 NA neurons). In addition, the author found that a significant number of estrogen receptor-alpha containing neurons in the ventrolateral medulla were GABA neurons. These results suggest that steroid hormones may directly and indirectly regulate NA neurons in the brainstem. Experiment 3 evaluated steroid hormone effects on tyrosine hydroxylase (rate-limiting enzyme for NA synthesis) mRNA levels in A1, A2 and A6 NA neurons. The results demonstrated that subpopulations of NA neurons are activated at different time points on the day of the luteinizing hormone surge. Experiment 4 determined whether alpha1B-, alpha2A- or beta1-adrenergic receptors were found in LHRH neurons or in GABA neurons in the preoptic area. Less than twenty percent of LHRH neurons expressed each adrenergic receptor, whereas 50–80% of GABA neurons expressed each adrenergic receptor. Experiment 5 demonstrated that glutamic acid decarboxylase (GAD) 65 and 67 (synthetic enzymes for GABA) mRNA levels were altered by steroid hormones in the rostral preoptic area/organum vasculosum of the lamina terminalis and the anteroventral periventricular nucleus/media preoptic nucleus. In addition, the changes in GAD 65 mRNA levels parallel changes in tyrosine hydroxylase mRNA levels. Collectively, the results of Experiments 1 to 5 demonstrate the NA communicates steriod hormone signals directly and indirectly to LHRH neurons.
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Sexual differentiation of arginine vasopressin expression in the rat brainHan, Tina M 01 January 2002 (has links)
Perhaps nothing defines an individual more strongly than sex. Along with one's designation as male or female are a slew of differences relating to anatomy, physiology, and behavior. In the laboratory rat, one such dimorphic characteristic in the brain is the expression of arginine vasopressin (AVP). Male rats have twice as many cells expressing AVP in the bed nucleus of the stria terminalis (BST) and the medial amygdala (MA) as do female rats. In rats and mice, AVP in the lateral septum, modulates social behaviors such as social recognition and aggression. Because of its striking dimorphism and its role in social behaviors, sexually dimorphic expression of AVP in the BST can serve as an interesting model system in which to study the differentiation of neuropeptide expression in a behavioral circuit. The work presented here addresses three primary issues. First, to study the development of AVP expression, a developmental marker is needed to identify cells that may be induced to express AVP in adulthood. Based on birthdating studies, I have found that galaninergic neurons represent a pool of cells from which AVP expression may be derived; the majority of galaninergic neuron cell birth overlaps with neurogenesis of AVP cells and there is no sexually dimorphic pattern of BrdU-labeling in galaninergic cells. Secondly, in order to understand cellular mechanisms of neuropeptide induction more precisely, I determined the extent to which male and female brains are bipotential with respect to AVP expression. Using neonatal hormone manipulations and later in situ hybridization, I found that female rats may be completely masculinized with post-natal hormone treatment. Finally, knowing that post-natal testosterone alone can completely masculinize AVP expression, I used similar techniques to determine the form of testosterone that is active in masculinization of AVP expression. I not only found that neonatal treatment with estradiol benzoate is sufficient for masculinizing AVP expression but that neonatal treatment with dihydrotestosterone propionate can also increase AVP expression in the BST, but only to a level intermediate that produced by estradiol benzoate and oil treatment.
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An in vivo investigation of the role of the 5-HT(1A) receptor in brain developmentMcReynolds, Alison Michelle 01 January 2002 (has links)
A growing body of work suggests that the 5-HT1A receptor plays a critical role in both serotonergic development and in the development of target regions to which 5-HT fibers project. Serotonin has been shown to autoregulate its own development and this process appears to involve the stimulation of 5-HT1A receptors. However, much of the work to date has been done in vitro and only a few studies have investigated the effects of altered 5-HT1A receptor function during development in vivo. The goals of the work presented here were to (1) create and validate an in vivo model of 5-HT1A receptor blockade during development using the selective 5-HT 1A antagonist WAY 100635, and (2) to investigate whether developmental exposure to WAY 100635 produces lasting deficits in the maturation of the serotonergic system and of target regions to which 5-HT fibers project. Prenatal blockade of the 5-HT1A receptor produced a transient decrease in 5-HT1A receptor density at GD 20, but no long lasting changes in 5-HT1A or SERT density. Furthermore, continued treatment with WAY 100635 until PD 14 also failed to produce any changes in 5-HT1A receptor density. Thus, prenatal exposure may cause a transient downregulation of the 5-HT1A receptor, but does not appear to result in lasting changes in the maturation of the serotonergic system and 5-HT target areas detected by the methods described here.
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Myasthenia Gravis mimics: An audit of cases identified at Groote Schuur Hospital over 20 yearsNeshuku, Saara Ndinelago 13 February 2020 (has links)
Background: Myasthenia gravis (MG) is characterised by fatigable muscle weakness. The diagnosis is made clinically and supported by ancillary tests such as electrophysiological studies, autoantibodies and pharmacological responses. Autoimmune MG will respond to immune therapy. Although there are several case reports of patients who were incorrectly diagnosed as MG, this study describes the MG mimics encountered at Groote Schuur Hospital, Cape Town, over a period of 20 years. Aims & Methods: To describe the MG mimics captured in the MG database (1996 to 2017) by final diagnosis, the age at symptom onset, the time delay and clues which led to the final diagnosis. Results: There were 31 cases identified; 10 were probable congenital myasthenic syndromes (CMS), 6 functional neurological symptoms (FNS), 6 motor neuron disease (MND) variants, 3 mitochondrial cytopathies, 4 had definite or probable muscular dystrophy (MD), 1 progressive supranuclear palsy and 1 with a multiple sclerosis brainstem relapse. Median age at symptom onset was 10 years for CMS, 18 for mitochondrial cytopathies, 53 for FNS, 58 for the muscular dystrophy cases and 63 years for those with MND. The median time delay between the false “MG” diagnoses to the reviewed diagnosis, which also corresponds to the time on immunotherapies, was 45 months in CMS, 48 months in mitochondrial cytopathy, 4 in MND, and less than 3 months in FNS, MD, PSP and MS. The most important factor for reviewing the diagnosis was treatment unresponsiveness to immune therapy. Some of the CMS and mitochondrial cytopathy cases were treated with immune therapies for many years, without responsiveness, before referral to our centre. Additional features for CMS were childhood onset, family history of similar symptoms and, although no response to immune therapies, they responded to pyridostigmine +/- salbutamol. Mitochondrial cytopathies had long duration of symptoms and the diagnosis was confirmed by mitochondrial DNA deletion detection. MND patients showed disease progression within a few weeks despite some transient improvement with anticholinesterases. The FNS diagnoses were based on signs which were inconsistent and symptoms resolved after psychotherapy. Two MD cases (myotonic muscular dystrophy and probable oculopharyngeal muscular dystrophy, respectively) presented with respiratory failure, and could not be weaned off invasive ventilation. Conclusion: The main points are that, not all patients with ptosis and fatigable symptoms have myasthenia gravis. Non-responsiveness to immune therapies should raise suspicion of an alternative diagnosis and prompt referral to a specialist clinic. Transient modest improvement in bulbar and limb muscle symptoms have been observed in patients with early manifestations of motor neuron disease.
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The efficacy of an online learning tool in improving EEG analysis and interpretation skills of Technologists, Neurology Registrars and NeurologistsAsukile, Melody Tunsubilege 15 July 2021 (has links)
Background Scalp electroencephalography (EEG) remains an invaluable neurophysiological tool in supporting the diagnosis and management of epilepsy and encephalopathy, however, most sub-Saharan countries have very few neurologists per population for EEG analysis and training. Web-based, distance learning programs may provide effective electroencephalogram (EEG) training in resource-poor settings. EEGonline is an interactive, web-based, 6-month multi-modality, learning program designed to teach basic principles and clinical application of EEG. This study aimed to determine the effectiveness of EEGonline in improving EEG analysis and interpretation skills for neurologists, neurology residents and technologists, particularly in resource-limited settings. Methods Between June 2017 and November 2018, 179 learners were registered on the EEGonline course. Of these, 128 learners originating from 20 African countries, Europe, the UK and USA participated in the study. Pre- and post-course multiplechoice question (MCQ) test results and EEGonline user logs were analyzed. Differences in pre- and post-test performance were correlated with quantified exposure to various EEGonline learning modalities. Participants' impressions of EEGonline efficacy and usefulness were assessed through pre- and post-course perception surveys. Results Ninety-one participants attempted both pre- and post-course tests. Mean scores improved from 46.7% ± 17.6% to 64.1% ± 18% respectively (p< 0.001, Cohen's d 0.974). Almost all participants improved regardless of the amount of course material used, however those who used more, tended to have higher scores. The largest percentage-improvement was in the correct identification of normal features (43.2% to 59.1%, p< 0.001, Cohen's d 0.664) and artefacts (43.3% to 61.6%, p< 0.001, Cohen's d 0.836). Improvement in competence was associated with improvement in subjective confidence in EEG analysis. Overall confidence among 72 survey respondents improved significantly from 25.3% to 64.8% (p< 0.001). Lecture notes, end-of-module self-assessment quizzes and discussion forums were the most utilised learning modalities. The majority of survey respondents (97.2%) concluded that EEGonline was a useful learning tool and 93% recommended that similar courses should be included in EEG training curricula. Discussion Almost all participants showed significant improvement in EEG analysis competence (MCQ test scores) and confidence (survey responses) following the educational intervention, regardless of the amount of course material used. Improved identification of normal features and artefacts is particularly useful as it reduces the risk of misdiagnosis which can cause harm. The EEGonline course employed several learning techniques, through its multi-modality format, that may have contributed to the improvement observed, including, self-directed learning, cognitivism, collaborative learning, contextual learning and reflective learning. Subjective confidence likely correlates with competence and may be useful to gauge learners' needs and levels of understanding about a subject. Learning preferences vary among adult learners, it is unclear if one learning modality (that is, video, audio, lecture notes, epoch activities, discussion forums) is superior to others, but it seems as though a multi-modal approach may be the most sensible. Conclusions This study demonstrated that a multi-modal, online EEG teaching tool was effective in improving EEG analysis and interpretation skills and may be a useful supplement for EEG teaching especially in resource-poor settings. Given the optimistic findings of this study, we encourage the development and evaluation of further online neurology teaching tools.
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A review of cases of motor neurone disease seen at Groote Schuur Hospital from 2005 to 2010Daude, Amina January 2014 (has links)
Includes bibliographical references. / Motor neurone disease (MND) is a rare progressive neurodegenerative disorder in which selective degeneration of the motor neurones of the brain and spinal cord occurs. Progressive weakness of limb, bulbar and respiratory muscles eventually results in death. Most descriptive and epidemiological studies of MND have been performed in the industrialized countries of Europe and North America. We know very little about the incidence or prevalence of MND in Africa in general and South Africa in particular. However, anecdotal evidence based on observations by clinicians in the neurology and geriatric medical clinics at Groote Schuur Hospital suggest that the condition is not uncommonly seen, even in younger patients. Furthermore, many cases appear to originate from the West Coast area of the Western Cape. The proposed study aimed at describing the demographic and clinical characteristics of MND seen at Groote Schuur Hospital between 2005 and 2010. I hypothesized that disease duration, measured from age of onset of first symptoms to death, would be shorter in patients with bulbar-onset disease, in younger-onset disease, and in patients with higher CSF protein and blood creatine kinase levels at baseline. Furthermore, age of onset of the disease would be younger in familial compared with sporadic MND. I also hypothesized that smoking and certain occupational exposures might be risk factors for MND, that there would be a male preponderance of the disease, and that a disproportionate number of cases would come from the West Coast region. This was a retrospective study. I reviewed the clinical notes of cases of motor neurone disease and collected data relevant to the aims and hypotheses described above. I applied the El Escorial diagnostic criteria for MND to check the validity of the diagnoses. Mortality data were obtained through the Burden of Diseases Research Unit at the South African Medical Research Council. Forty eight patients were identified who met El Escorial criteria for the diagnosis of probable or definite MND. The median age of onset of the disease was 54 (IQR 47-63) and the mean duration of the disease from earliest symptoms to death was 2 years (IQR 1-3). These did not differ significantly between bulbar and limb-onset disease sub-types. There was a male preponderance of the disease (60%) and the majority of patients (60%) were smokers. African patients tended to have a younger age of onset. Occupations involving potential exposure to chemicals were disproportionately represented in the MND patients compared with the general population of the Western Cape. People from the West Coast region were not disproportionately represented in the patient population. Baseline CSF protein and serum creatine kinase levels were not associated with disease duration. The characteristics of MND cases seen at Groote Schuur Hospital between 2005 and 2010 are similar to those described in the world literature. Smoking and chemical exposure may be risk factors for the disease. There was no evidence of clustering of cases. This study will serve as the basis for future larger prospective studies on MND prevalence and aetiology in South Africa.
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The role of the HIV-1 Tat protein in acute stroke: more than just a transactivator of transcription?McMullen, Kate Elizabeth 19 February 2019 (has links)
Background: Individuals infected with the human immunodeficiency virus (HIV) are at increased risk of developing ischaemic stroke. The reasons for this are multifactorial, but HIV-associated vasculopathy is a potentially important cause. HIVinduced chronic inflammation may initiate endothelial dysfunction or accelerate vascular injury from other disease processes. Viral proteins such as the transactivator of transcription (Tat) are emerging role-players in HIV disease pathogenesis and have a putative role in HIV-associated endothelial dysfunction. Tat has paracrine proinflammatory effects, but its role in HIV-related stroke has not yet been investigated. Aims: The primary aim of this study was to determine whether specific Tat amino acid variants are associated with ischaemic stroke and biomarkers of inflammation and endothelial dysfunction in a group of HIV-1 subtype-C-infected individuals. In order to do so, I first determined the aetiology of stroke in these participants using clinical, biochemical and neuro-imaging data. A secondary aim of the study was to identify any HIV-related and/or other traditional stroke-related risk factors that might independently or cumulatively increase stroke risk. For comparison, these putative risk factors were also determined in a group of age-matched HIV-infected non-stroke controls. Finally, I aimed to identify any HIV-related factors and/or Tat amino acid variants that might distinguish strokes due to HIV-associated vasculopathy from other mechanisms of stroke. Methods: A case-control study was performed on 58 Subtype-C HIV-infected individuals with acute ischaemic stroke and 71 HIV-1 Subtype-C-infected non-stroke controls. Clinical, demographic, laboratory and imaging data were used to determined baseline differences between groups and to distinguish different stroke aetiologies. Exon 1 of the HIV-1 Tat protein was sequenced from peripheral blood samples of stroke participants and controls and amino acid variants were identified using viral epidemiology signature pattern analysis. Regression analyses were used to examine the correlation between residues at signature positions with biomarkers of inflammation and endothelial activation. Results: Stroke and control groups were mostly young (mean age 33 years) females (62.1% & 71.8%), and of Black African ancestry. The strokes showed a higher prevalence of some traditional cardiovascular risk factors. Individuals with strokes had a higher prevalence of antiretroviral treatment interruption (25.9% vs 0.0%, p= 0.003), lower CD4 nadir (112 vs 177.5 cells/μl, p=0.008) and CD4 count (208.5 vs 322.5 cells/μl, p=0.012) than controls. Median viral loads were elevated in both strokes and controls (4.58 & 4.13 log10 copies/ml, p=0.28). The most common causes of stroke were HIV-associated vasculopathy (43.1%) and opportunistic infections (22.4%). Two amino acid variants (proline at position 21 and histidine at position 29) were associated with acute ischaemic stroke. These positions were also associated with modulation of plasma interleukin 6 and monocyte chemoattractant protein 1 levels. Threonine at position 58 distinguished strokes due to alternative mechanisms from strokes due to HIV-associated vasculopathy. Conclusions: Two Tat protein amino acid variants are associated with stroke in HIV. The precise mechanisms by which these associations occur are not known. However, they are likely to be part of a multiple-hit phenomenon in HIV stroke pathogenesis. Tatmediated inflammation with endothelial dysfunction, HIV disease severity, treatment interruption and conventional cardiovascular risk factors probably all contribute to stroke aetiology. Thus, a multi-modal approach is needed to reduce ischaemic stroke risk in HIV infection.
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Motor neuron disease in an African population: A review of current literature and a case series of the flail arm variant in the Western CapeCross, Helen January 2018 (has links)
Background: Motor neuron disease (MND) is a devastating neurodegenerative disorder, with recognised phenotypic subtypes. Although prevalent in all parts of the world, little is described in the literature with regards motor neuron disease as it occurs in African populations. Aims: This study had two main aims: to conduct a systematic review of the current available literature on motor neuron disease in persons of African genetic descent, and to describe the clinical phenotype in a subgroup of MND patients with the flail arm (FA) variant seen at Groote Schuur Hospital MND clinic. Methods: In order to identify the current published knowledge of motor neuron disease in African populations, a systematic literature review was conducted using Pubmed and Google Scholar. For the case series description, patients presenting to the Groote Schuur Hospital MND clinic with a phenotype of restricted proximal upper limb, lower motor neuron involvement for at least 12 months after symptom onset, during the time period of March 2014 to September 2016, were considered for inclusion. A full clinical description of each case, including history, examination and electrophysiological findings, was conducted. Results: Review of the available literature on MND as it occurs in persons with African ancestry revealed that little is well described. Although there are a few original studies, all are small and most are out-dated. Some trends emerged, including younger age at onset of disease, tendency to longer survival, and possibly more frequent presentation with bilateral upper limb involvement. Six cases of FA variant of MND, representing 13% of the MND clinic cohort seen over the 2.5 years given time period, all with African genetic ancestry by self-categorization, are reported illustrating the various previously described features of this phenotype. Even within these few cases, there is variation in presentation and disease course. Conclusions: More research is required on African populations to address the questions surrounding MND as it occurs in Africans, including phenotypic and genetic similarities or differences to other populations. Although controversy surrounding exact case definition of the FA variant of MND remains, it does represent a unique phenotype, and seems to occur in patients of African genetic ancestry in a similar manner to that described in Caucasian populations.
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