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Arachnoiditis is a rare clinical entity that usually presents with severe debilitating radiating pain that can pose a challenge in diagnosis especially in areas without appropriate imaging modalities. We present a 26-year-old male with progressive lower back pain with radiation to the lower extremities, aggravated by movement and touch. We diagnosed idiopathic arachnoiditis based on cerebrospinal fluid analysis and magnetic resonance imaging. He was managed with a 5-day course of methylprednisolone and analgesics with a good outcome. Severe back pain without a specific cause in a young patient should be investigated with proper imaging modalities and lumbar puncture if warranted to evaluate the cause.

Carpenter syndrome (acrocephalopolysyndactyly type II) is a rare autosomal recessive disorder. It was clinically diagnosed in a female baby with polysyndactyly and craniosynostosis in a referral clinic in Northern Tanzania. In the RAB23 gene, a previously described homozygous variant c.82C>T p.(Arg28*) was detected that results in a premature stop codon. Both parents were demonstrated to be heterozygous carriers of this variant. Herewith, its pathogenicity is proved. A literature search suggests this is the first molecularly confirmed case of Carpenter syndrome in continental Africa.

Introduction A significant number of climbers on Mount Kilimanjaro are affected by altitude-related disorders. The aim of this study was to determine the main causes of morbidity and mortality in a representative cohort of climbers based on local hospital records. Methods We conducted a 2-y retrospective chart review of all patients presenting to the main referral hospital in the region after a climb on Mount Kilimanjaro, including all relevant records and referrals for postmortem studies. Results We identified 62 climbers who presented to the hospital: 47 inpatients and 15 outpatients. Fifty-six presented with high altitude illness, which included acute mountain sickness (n=8; 14%), high altitude pulmonary edema (HAPE) (n=30; 54%), high altitude cerebral edema (HACE) (n=7; 12%), and combined HAPE/HACE (n=11; 20%). The mean altitude of symptom onset ranged from 4600±750 m for HAPE to 5000±430 m for HAPE/HACE. The vast majority of inpatients (n=41; 87%) were improved on discharge. Twenty-one deceased climbers, most having died while climbing (n=17; 81%), underwent postmortem evaluation. Causes of death were HAPE (n=16; 76%), HAPE/HACE (n=3; 14%), trauma (1), and cardiopulmonary (1). Conclusions HAPE was the main cause of death during climbing as well as for hospital admissions. The vast majority of climbers who presented to hospital made a full recovery.

Study design Prospective Study. Objectives To describe a unique site-specific injury mechanism for spinal cord injury: incidents involving ox-carts. Setting Main referral hospital for North-eastern Tanzania. Methods A prospective cohort study on Spinal Cord Injury (SCI) in a tertiary referral center in North-eastern Tanzania was examined for accidents related to the use of ox-carts, a major means of transport in a rugged rural area where the economy is largely based on agricultural practices. Results Five out of a total of 163 individuals admitted with SCI were injured in incidents directly related to the use of ox-carts. On admission each of the five individuals had different neurological level and corresponding injury severity as follows; C4 (American Spinal Injury Association Impairment Scale) AIS A), C5 (AIS D), C7 (AIS C), T1 (AIS C) and L1 (AIS D). Two out of the five patients developed secondary complications during their hospital stay. Conclusion The nature of these injuries highlights the influence of one's environment and social circumstances on the risk of sustaining a SCI. Such cases also serve to illustrate the need for tailored prevention, rehabilitation, and reintegration into society.

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder linked to mutations in the ATM gene, and is characterized by neurodegeneration with an early onset cerebellar syndrome, hyperkinetic movement disorders, neuropathy, and oculocutaneous telangiectasia. Immunodeficiency, pulmonary disease, growth failure, diabetes mellitus, increased malignancy risk and hypersensitivity to ionizing radiation complicate the clinical picture. Serum alpha-fetoprotein levels are increased in patients with A-T and can therefore serve as a diagnostic marker for the disease. In resource-limited settings, diagnosis and management of patients with a rare and complex disorder such as A-T may be extremely challenging. This expert opinion-based guideline aims to give an overview of diagnosis and management of A-T in resource-limited settings, by prioritizing different options based on medical necessity, availability, and costs.

Summary Objective Functional neurological disorders (FNDs) and psychogenic nonepileptic seizures (PNES) are likely as common in Sub‐Saharan Africa (SSA) as in the rest of the world, but there is a dearth of literature on the epidemiology and clinical presentation of these disorders in Africa. The purpose of this paper is to describe a case series of FNDs presenting to a referral hospital in SSA. In addition, we review the existing literature on FNDs in Africa. Methods A hospital‐based retrospective cross‐sectional study was conducted to determine the prevalence, epidemiology, and clinical phenotype of FNDs and PNES in a referral hospital in Northern Tanzania over a 6‐year period (2007–2013). Results Of 2,040 patients presenting with neurological complaints, 44 (2.2%) were diagnosed with FNDs. Half (n = 22) had the clinical presentation of PNES. Age of presentation for FNDs and PNES peaked in the teen years 12–19 (n = 21 48%; and n = 14, 63%, respectively), and the majority were female (n = 30, 68%; and n = 14, 63%, respectively). The majority presented acutely with short‐lived and self‐limiting symptoms (only 2 recurrent cases). Literature review revealed multiple reports of “mass hysteria” in SSA often meeting the clinical criteria of epidemic FNDs. Significance FNDs and PNES occur in Africa with age and gender distribution comparable to that found elsewhere. Although the percentage of FND cases overall was relatively low (2.2%), it is likely to be an underestimate because not all cases were recorded, and cases may be appropriately managed locally before patients are referred to a hospital. PNES was the most common phenotype of FNDs reported, and the African phenotype may be short‐lived and self‐limiting rather than chronic and recurrent, as reported elsewhere in the world. PNES presentations may also occur in clusters, which may have cultural significance in Africa. FNDs in Africa appear to be underreported, particularly over the last 30 years.

This letter comes from Kilimanjaro in Tanzania, a land where grateful patients may express their appreciation by giving a neurologist a cow or even by naming children after the doctor. The United Republic of Tanzania is in East Africa. It comprises the mainland Tanzania and Zanzibar with a total population of 53 million, over 70% of whom are aged

Study design Cross-sectional pilot study on spinal cord injury (SCI) among in- and outpatients. Objectives To evaluate the challenges faced by individuals with SCI during Clean Intermittent Catheterisation (CIC). Setting Kilimanjaro Christian Medical Center (KCMC), a tertiary referral hospital in Moshi, Tanzania. Methods A questionnaire was sent to individuals with SCI who were either admitted to the Orthopedic Rehabilitation Unit or attended the Outpatient clinic between January and April 2018. Inpatients were less than 1 year post-injury and outpatients were one to 3 years post-injury. Results In total, 48 individuals responded: 28 outpatients and 20 inpatients. Among the inpatient group, 80% were performing CIC as compared with 25% of outpatient group. Of the entire cohort, 35.4% reported doing well without catheter-based management. Failure to perform CIC was present in 16.7% of all individuals. CIC-equipment was unavailable in local villages for 58.3% of all patients. The most frequent complications of CIC were urinary tract infections (20.8%) and mild bleeding (14.6%). The majority of individuals (79.2%) reported satisfaction with their situation, regardless of the severity. Conclusions Some individuals performed CIC upon discharge, but the majority discontinued use, for which unavailability of CIC-equipment was a major determinant. While all individuals reported concerns prior to CIC, only a small minority actually experienced anxiety, pain or shame. Through targeted counselling and enhanced regular follow-up we will likely improve compliance to CIC. Sponsorship We are grateful to the International Network of SCI Nurses in collaboration with Wellspect Health Care for funding this study.

Background Chronic subdural hematomas (CSDH) initially present as focal neurological deficits with or without signs of increased intracranial pressure, for which admission to the general medical ward may occur if they present with poorly understood neurological deficits and no evident history of trauma. The symptoms may be long standing and mimic stroke upon presentation. Their distribution and specific clinical features in sub-Saharan Africa are largely unknown. Methods We describe a series of subdural hematoma (SDH) inpatients from the medical ward of a tertiary referral center in Northern Tanzania, describing clinical and radiological characteristics and providing clinical outcome where possible. Results Our study population numbered 30, with a male majority (n = 19, 63.3%) and a mean age of 66.8 ± 14.5 years. Mean duration from symptom onset to admission in the medical ward was 20.0 ± 30.8 days. History of head injury was reported in only 43.3% of patients. Improvement in the neurological examination was noted in 68.1% of the 22 patients who underwent surgery. The mortality rate was 20.0%. Conclusion A majority of the patients were elderly males and presented late to the hospital. Delayed presentation and diagnosis due to, amongst other reasons, postponed imaging resulted in a prolonged time to definitive treatment and a high mortality rate compared to other regions of the world.

BackgroundThere is a newly emergent ageing population of people living with HIV (PLWH) in Africa. However, there is little research into HIV-associated neurocognitive disorder (HAND) in this population. Existing research suggests HAND is prevalent however the aetiology remains unclear. This study aims to determine whether HAND is truly prevalent and explore potential causes in PLWH on c-ART using objective structural measures.AimsExplore whether substantial atrophy and/or white matter hyperintensities (WMH) is present on the clinical magnetic resonance imaging (MRI) reports and quantitative analysis of people with optimally managed HIV in Northern Tanzania.Explore the aetiology of HAND by assessing whether cerebral atrophy and/or WMH is associated with demographic risk factors, HIV–related factors and/or comorbidities.Investigate whether structural damage is related to objectively measured cognitive impairment, and whether this is a subcortical or cortical impairment.Explore which neurocognitive test is the best predictor of structural damage and therefore most valid diagnostic test for HAND.MethodsA systematic sample of PLWH aged ≥ 50 were recruited from a HIV clinic in Kilimanjaro, Tanzania. Demographic data and comorbidities were self-reported. HIV-disease management data were obtained. Viral load and CD4 count were measured. A neurocognitive battery and informant history of functional impairment identified HAND. Cerebral atrophy (brain and ventricle volume) and WMH were measured using quantitative analysis of 1.5T MRI.Preliminary resultsThis cohort (n=91) had well-managed HIV (75.9% suppressed viral load, median CD4 507 cells/ul). The significant independent predictor (IP) of decreased brain volume was older age at HIV diagnosis (p=.001), and of increased ventricle volume was increased age (pConclusionsThis is the first MRI study of older c-ART treated PLWH in Africa. Despite c-ART and good disease management, HAND was objectively prevalent and unrelated to measures of HIV. Cerebral atrophy and WMH were associated with factors of neurodegeneration. Cerebral atrophy was associated with male gender and age at diagnosis (legacy effect).

We report an African infant with Ellis-van Creveld (EVC) syndrome. EVC syndrome is a chondral and ectodermal dysplasia with autosomal recessive transmission. The baby presented with polydactyly, short limbs and atrioventricular septal defect, but was withdrawn from clinical follow up for the first year of life. Initial hematological abnormalities could not be explained and normalized later. EVC syndrome was confirmed by genetic analysis that showed two pathogenic mutations in the EVC2 gene, c.653_654del, p.Val218Glyfs*12 in exon 5, and c.2710C>T, p.Gln904* in exon 16. The variant c.653_654del; p.Val218Glyfs*12 in exon 5 has not been described before. Our review of medical literature suggested this is the first molecularly confirmed case of EVC syndrome in sub-Saharan Africa.

Background Epilepsy is one of the commonest neurological conditions affecting women of reproductive age. Epilepsy management during pregnancy is a clinical conundrum, requiring a balance between seizure control and risk minimization for the women with epilepsy (WWE) as well as for their fetuses. The objective of this comprehensive review is to explore the reproductive health challenges of WWE in sub-Saharan Africa (SSA) and ways to address them. Method Relevant documentation published until June 2019 were retrieved via literature searches performed in PubMed and Google Scholar, as well as a manual search to identify grey literature. Results WWE in SSA are generally more stigmatized and sexually exploited than women without epilepsy. Contraception use among WWE was reported only in Senegal (51%) and Kenya (14.7%). Only two prospective studies (one in Senegal and one in Nigeria) investigated pregnancy outcomes for a total of 97 WWE. The prevalence of convulsive epilepsy in pregnancy was estimated at 3.33 per 1000. Among pregnant WWE treated with first line anti-epileptic drugs, 16.2% had miscarriages, 41.9% premature births, and 4.1% had babies with malformations. Carbamazepine, which is frequently prescribed to pregnant WWE in SSA, still entails a 2.1-fold increased risk of congenital malformation. No reports were found concerning pre-conceptual counseling and post-natal outcomes in WWE in SSA. Conclusion Our review underscores the need for contextualized evidence-based clinical guidelines and a collaborative approach to treat WWE in SSA. High risks of congenital malformations and drug interactions with first line AED warrant the provision of safer second line alternatives.

Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder with classical features, which can be also recognised in a low resource setting. It had been described in various populations across the globe, but very few cases have been reported from Africa. In a boy with features of a progressive central nervous system condition and adrenal failure, ABCD1 gene screening was performed based on a clinical history and basic radiological features which were compatible with ALD. A common ABCD1 mutation was identified in this patient, which is the first report of genetically confirmed ALD in Sub-Saharan Africa. ALD is likely under recognised in those areas where there is no neurologist. This genetic confirmation widens geographical distribution of ABCD1-associated disease, and illustrates recognisability of this disorder, even when encountered in a low-resource environment.

In African neurological practice, muscle disorders are either underdiagnosed or underrepresented. This may in part be due to the large burden of other more common neurological disorders. In this report we describe the first Tanzanian patient with genetically confirmed Becker muscular dystrophy. His phenotype and genotype were compatible with elsewhere in the world. Remarkably, this patient reported his progressive weakness of the legs with difficulty in walking only after a fall. We demonstrate that muscular dystrophies occur in sub-Saharan Africa. Neurologists must however be aware that patients are likely to delay seeking medical care for muscle disorders. (C) 2019 Elsevier B.V. All rights reserved.

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INTRODUCTION: Down Syndrome (DS)—also referred to as Trisomy 21—is associated with multiple deformities affecting various systems of the body. Joint laxity resulting in unstable atlanto-occipital and atlanto-axial joints—with an increased susceptibility to fatal cord injuries—is a recognized phenomenon in patients with DS. CASE PRESENTATION: We report on a 30-year-old man with DS from Tanzania with no previous neck complaints, who presented with a 5-week progressive history of paraparesis that evolved into a quadriparesis. During his initial presentation, the patient reported that 5 months ago he had been involved in a headlock during a playground encounter. DISCUSSION: Primary prevention of the traumatic spinal cord injuries is an important public health measure and a heightened emphasis should be placed to prevent such injuries in high risk populations—including DS patients.

Motor neuron disease (MND) is an overarching term for progressive conditions affecting anterior horn cells and the primary motor neurons. In a multiethnic population study (estimated incidence rate 144 per 100 000 person-years), there was a relatively lower age-adjusted risk for patients of African descent.1 For the sub-Saharan African region, most epidemiological studies on MND come from Western Africa.2 From the United Republic of Tanzania, no reports are available. The original predominance of infectious disease, a lower life expectancy, scarce healthcare facilities and a threshold to neurological care with one neurologist per 8–10 million inhabitants of the country3 contribute to this gap. The study was conducted in Kilimanjaro Christian Medical Centre, a tertiary referral hospital in Northern Tanzania. During two periods in which neurologists were present (1984–1992 with 1628 subjects and 2007–2015 with 2040 subjects), epidemiological data on consecutive neurological patients (age, sex, primary neurological diagnosis and disease category) were collected.3 Apart from the neuromuscular disease category which comprised MND, disease categories included stroke, infection, paraplegia, confusion/coma, space-occupying lesion and neurodegenerative disease. Medical ethical clearance was obtained and all patients provided written informed consent. On neurological examination by a neurologist (WH and/or MD), patients with MND with ALS phenotype were further classified by the original El Escorial (EE) criteria4 into ‘possible’, ‘probable’ and ‘definite’ ALS with cross-validation by the other neurologist and an independent third neurologist (MA). Clinical …

Contains fulltext : 174745.pdf (Publisher’s version ) (Open Access) We report a case of a male baby who has characteristic signs of Freeman-Sheldon syndrome, a rare but recognizable, severe autosomal dominant form of distal arthrogryposis. Diagnosis was based on the distinctive clinical characteristics of the syndrome and confirmed by genetic analysis that showed a de novo missense mutation c.2015G>A (p.Arg672His) of the MYH3 gene. We highlight the different features present in our patient and describe the etiology of the Freeman-Sheldon phenotype and how its clinical complications can be dealt with. To the best of our knowledge, this is the first molecularly confirmed case of Freeman-Sheldon syndrome in sub-Saharan Africa.

Contains fulltext : 175954.pdf (Publisher’s version ) (Open Access) To our knowledge, this is the first case report of juvenile dermatomyositis (JDM) in Tanzania. It demonstrates that the characteristic cutaneous findings of JDM may easily be overlooked, especially on dark skin, and the difficulty of clinical management in resource-constrained settings.

Item does not contain fulltext STUDY DESIGN: Retrospective study. OBJECTIVES: To describe the epidemiology of traumatic spinal cord injury (TSCI) in Northern Tanzania. SETTING: Main referral hospital for Northern Tanzania. METHODS: A retrospective review of 125 TSCI cases admitted to Kilimanjaro Christian Medical Centre (KCMC) over a period of 5 years. RESULTS: We included 125 patients in the sample size, with a male majority of 107 (85.6%), giving a male-to-female ratio of 5.9:1. The mean age at injury was 39.9 (+/-16.0) years. Overall, 66 (52.8%) were farmers and an overwhelming majority (109 (87.2%)) were referrals from peripheral medical centres. Fall injuries accounted for 65 (52.0%) of the admissions and 49 (39.2%) were injured due to a Road Traffic Accident (RTA). Severity of injury was classified according to the American Spinal Injury Association Impairment Scale (AIS) and 57 (45.6%) injuries were categorised as AIS A and 68 (54.4%) as AIS BCD. Cervical level injuries (59 (47.2%)) were the most frequent among the cohort. The in-hospital mortality rate was 24.1%. CONCLUSION: The majority of patients affected by TSCIs were young males and the most common cause was fall injuries. Cervical level injuries were the most common and in-hospital mortality was high.

Carriers of the Huntington disease (HD) mutation develop a progressive neurodegenerative disorder after a pre-clinical phase. We examined the value of (11)C-raclopride PET (RAC) as a biomarker for pre-clinical HD pathophysiology.In a prospective cohort study with clinical and neuropsychological assessment we collected complete RAC data in 18 pre-clinical mutation carriers (HD-PMC) and 11 controls. Follow-up was 2 years. We calculated striatal RAC binding potential (BP) to measure dopamine D2 receptor availability.No HD-PMC had overt neuropsychological dysfunction. RAC-BP in putamen was abnormal in up to 44% of HD-PMC. The rate of RAC-BP decline (2.6% per year) was not significantly higher than in controls. Follow-up putaminal BP correlated weakly with predicted distance to onset of clinical HD (P = 0.034), but the rate of decline did not. Three HD-PMC developed motor abnormalities suspect for HD but did not show an increased rate of decline of putaminal BP.Many HD-PMC have striatal abnormalities but we found no clearly increased rate of D2 receptor changes around the onset of clinical HD. A longer follow-up of the present study cohort is needed to establish the value of RAC-BP in assessing the risk of clinical conversion from striatal D2 binding data.

Contains fulltext : 165771.pdf (Publisher’s version ) (Open Access) Neural tube defects result from failure of neural tube fusion during early embryogenesis, the fourth week after conception. The spectrum of severity is not uniform across the various forms of this congenital anomaly as certain presentations are not compatible with extrauterine life (anencephaly) while, on the other hand, other defects may remain undiagnosed as they are entirely asymptomatic (occult spina bifida). We report a child with previously normal neurological development, a devastating clinical course following superinfection of a subtle spina bifida defect which resulted in a flaccid paralysis below the level of the lesion and permanent neurological deficits following resolution of the acute infection and a back closure surgery.

We address the use of two informants in genetic studies and whether familial aggregation is similar for the three phenotypic subtypes of ADHD. Lifetime ADHD was diagnosed in a Dutch isolated population using parents and teachers as informants, creating two subgroups (one or two informants), then further divided into three phenotypic categories (inattentive, hyperactive/impulsive, combined). Genealogy was collected for all patients. Mean kinship coefficients for the subgroups were calculated. Fifteen of 26 children were linked to a common ancestor within 10 generations. The mean kinship coefficient of patients confirmed by two informants was significantly higher than in patients only scored positive by one informant (p = 0.03). All patients of the inattentive subtype were connected to a common ancestor, which was significantly higher (p = 0.03) than expected. Eighty-one percent of these patients derive of consanguineous marriages, also higher than expected. This means that recessive mutations may be involved in the inattentive subtype. These patients were more closely related than those with the other phenotypes (p

The DJ-1 gene is associated with autosomal recessive early-onset Parkinsonism, most likely through its role in defense against oxidative stress. Oxidative stress is not only involved in Parkinson's disease, but also in other neurodegenerative disorders, such as dementia. We assessed the presence of a 14 kb DJ-1 deletion in 191 patients with dementia, ascertained from the genetically isolated population where the first kindred with DJ-1 related Parkinsonism was originally identified. The control group consisted of 129 non-demented subjects. We found the deletion in two patients and one control. There was no evidence for an increased risk of dementia in carriers. All subjects were heterozygous for the deletion and related to a common ancestor within eight generations. Our results suggest it is unlikely that haploinsufficiency in the DJ-1 gene imparts an increased risk for dementia. (C) 2004 Elsevier Ireland Ltd. All rights reserved

The role of genetics in the pathogenesis of Parkinson's disease has been subject to debate for decades. In recent years, the discovery of five genes and several more loci has provided important insight into its molecular aetiology. Some Parkinson's disease genes possibly cause Parkinson's disease by protein aggregation. The presence of Lewy bodies in carriers of mutations in one gene and their absence in carriers of another, however, still point towards a complex pathogenic network, with Parkinson's disease as a common clinical end point. The recent identification of the fourth and fifth Parkinson's disease genes suggests multiple pathways-an impaired oxidative stress defence for mutations in DJ-1, and a defect in another signalling pathway for mutations in NR4A2. Despite knowledge of genetics in familial Parkinson's disease, our knowledge of the common, late-onset form of Parkinson's disease remains limited. In non-familial Parkinson's disease, genes and environment probably interact to give rise to the disease. We review advances in the genetics of Parkinson's disease, focusing on the monogenic forms and their clinical and population-genetic consequences.

The role of genetic factors in idiopathic, late-onset Parkinson's disease (PD) remains unclear, in spite of the recent advances in the genetics of early-onset forms of familial parkinsonism. There is increasing interest in using genetically isolated populations to unravel the genetics of complex diseases such as late-onset PD. We have studied genetic and clinical features of 109 patients with parkinsonism from an area comprising a genetically isolated population in the South-West of the Netherlands. Of the 109 patients with ascertained parkinsonism, 41 patients were diagnosed with PD and could be linked to a common founder 14 generations ago. The distribution of ages at onset of PD in the genetically isolated population was significantly bimodal, showing two peaks (one with a mean at age 67 years and another with a mean at 44 years, the former peak being significantly larger than that in a population-based study, the Rotterdam Study). In other clinical features, the only statistically significant difference between early-onset and late-onset PD was a decreased motor and cognitive function in patients with late-onset PD. Involvement of other PD genes including DJ-1, a gene implicated in a kindred with early-onset parkinsonism from the same genetic isolate, was excluded in other PD patients in the population. The finding of a common ancestor in 41 idiopathic-PD patients along with the exclusion of known PD genes and loci suggests the presence of at least one other, yet unknown, susceptibility gene involved in PD in this population.

Genetic epidemiology is a young but rapidly developing discipline. Although its early years were largely dedicated to family-based research in monogenic disorders, now genetic-epidemiologic research increasingly focuses on complex, multifactorial disorders. Along with the development of the human-genome map and advances in molecular technology grows the importance of genetic-epidemiologic applications. Large-scale population-based studies, requiring close integration of genetic and epidemiologic research, determine future research in the field. In this paper, we review the basic principles underlying genetic-epidemiologic research, such as molecular genetics and familial aggregation of disease, as well as the typical study approaches of genome screening and candidate-gene studies.

Objective HIV infection is a major cause of disease burden and disability across sub-Saharan Africa (SSA). HIV-associated neurocognitive impairment (HAND) is estimated to affect 8 million people with HIV infection across the continent and is associated with increased mortality and morbidity. As a result of demographic transition and increased coverage of combination antiretroviral therapy (cART) the proportion of people aged 50 and over living with HIV infection in SSA is predicted to triple (to over 9 million people by 2040). Despite this, few published data exist on the prevalence of, or risk factors for, HAND in older individuals in SSA. We aimed to estimate prevalence and risk factors for HAND in a stable population of HIV positive individuals under long term follow up at a government clinic in Northern Tanzania, one of the pioneer sites for cART in SSA. Method A systematic sample of individuals aged 50 and over attending a HIV care and treatment centre for routine follow up were assessed for HAND using a locally normed neuropsychological battery adapted to a low literacy setting. All participants subsequently underwent a clinical interview, neurological examination, informant history for functional impairment and standardised psychiatric screening questionnaire. HAND was defined according the American Academy of Neurology (AAN) 2007 criteria for Asymptomatic Neurocognitive Impairment, Minor Neurocognitive Disorder (MND) and HIV-associated Dementia (HAD). General and HIV-specific risk factors for symptomatic HAND were examined using univariable and multivariable logistic regression. Results Complete data were available for 227 participants (162 (71%) female, median age 57.9 years) of whom 35% had 4 years formal education or fewer. Median Cd4 count was 500/µl and 95.5% of participants were on cART. Preliminary data indicate that the overall prevalence of HAND was 61.2% (ANI 35.2%, MND 23.8%, HAD 2.2%) and of symptomatic HAND (MND and HAD) 25%. Presence of symptomatic HAND was not related to current or nadir Cd4 count, or time since HIV diagnosis, but was independently associated with older age, illiteracy, living alone and greater number of depression symptoms. Conclusion HAND was very prevalent in this stable outpatient cohort of older adults most of whom were on cART. Initial results suggest that in this cohort of older adults in SSA, risk factors for symptomatic neurocognitive impairment appeared to be less related to HIV infection and more similar to factors commonly associated with neurodegenerative dementias in both high income and low income country settings.

Cancer predisposition in hereditary non-polyposis colon cancer (HNPCC) is caused by defects in DNA mismatch repair (MMR). Mismatch recognition is attributed to two heterodimeric protein complexes: MutSalpha (refs 2, 3, 4, 5), a dimer of MutS homologues MSH2 and MSH6; and MutSbeta (refs 2,7), a dimer of MSH2 and MSH3. These complexes have specific and redundant mismatch recognition capacity. Whereas MSH2 deficiency ablates the activity of both dimers, causing strong cancer predisposition in mice and men, loss of MSH3 or MSH6 (also known as GTBP) function causes a partial MMR defect. This may explain the rarity of MSH6 and absence of MSH3 germline mutations in HNPCC families. To test this, we have inactivated the mouse genes Msh3 (formerly Rep3 ) and Msh6 (formerly Gtmbp). Msh6-deficient mice were prone to cancer; most animals developed lymphomas or epithelial tumours originating from the skin and uterus but only rarely from the intestine. Msh3 deficiency did not cause cancer predisposition, but in an Msh6 -deficient background, loss of Msh3 accelerated intestinal tumorigenesis. Lymphomagenesis was not affected. Furthermore, mismatch-directed anti-recombination and sensitivity to methylating agents required Msh2 and Msh6, but not Msh3. Thus, loss of MMR functions specific to Msh2/Msh6 is sufficient for lymphoma development in mice, whereas predisposition to intestinal cancer requires loss of function of both Msh2/Msh6 and Msh2/Msh3.

The hypothalamus is a major target for glucocorticoids and a key structure for hypothalamic-pituitary-adrenal (HPA) axis setpoint regulation. The enzyme 11β hydroxysteroid dehydrogenase type 1 (11βHSD1) modulates glucocorticoid signalling in various tissues at the prereceptor level by converting biologically inactive cortisone to its active form cortisol. The present study aimed to assess 11βHSD1 expression in the human hypothalamus. We studied 11βHSD1 expression in five frozen and four formalin-fixed, paraffin-embedded human hypothalami (obtained from the Netherlands Brain Bank) by the polymerase chain reaction and immunocytochemistry, respectively. 11βHSD1 mRNA was expressed in the area of the suprachiasmatic nucleus, which is the biological clock of the brain, in the supraoptic nucleus and paraventricular nucleus (PVN), and in the infundibular nucleus, which is the human homologue of the rodent arcuate nucleus. 11βHSD1 was detected by immunocytochemistry in the same nuclei. In the PVN, neuronal 11βHSD1 immunoreactivity colocalised with corticotrophin-releasing hormone (CRH), arginine vasopressin and oxytocin, as shown by dual fluorescence staining. Our data demonstrate that 11βHSD1 is widely expressed in the human hypothalamus. Its colocalisation with CRH in the PVN suggests a role in modulation of glucocorticoid feedback of the HPA axis, whereas the expression of 11βHSD1 in additional and functionally diverse hypothalamic nuclei points to a role for the enzyme in the regulation of metabolism, appetite and circadian rhythms.

Mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, an autosomal recessive neurodegenerative disease presenting with severe levodopa-responsive parkinsonism and pyramidal disturbances. Understanding the PARK15 pathogenesis might thus provide clues on the mechanisms of maintenance of brain dopaminergic neurons, the same which are lost in Parkinson's disease. The protein(s) encoded by FBXO7 remain very poorly characterized. Here, we show that two protein isoforms are expressed from the FBXO7 gene in normal human cells. The isoform 1 is more abundant, particularly in primary skin fibroblasts. Both isoforms are undetectable in cell lines from the PARK15 patient of an Italian family; the isoform 1 is undetectable and the isoform 2 is severely decreased in the patients from a Dutch PARK15 family. In human cell lines and mouse primary neurons, the endogenous or over-expressed, wild type FBXO7 isoform 1 displays mostly a diffuse nuclear localization. An intact N-terminus is needed for the nuclear FBXO7 localization, as N-terminal modification by PARK15-linked missense mutation, or N-terminus tag leads to cytoplasmic mislocalization. Furthermore, the N-terminus of wild type FBXO7 (but not of mutant FBXO7) is able to confer nuclear localization to profilin (a cytoplasmic protein). Our data also suggest that overexpressed mutant FBXO7 proteins (T22M, R378G and R498X) have decreased stability compared to their wild type counterpart. In human brain, FBXO7 immunoreactivity was highest in the nuclei of neurons throughout the cerebral cortex, intermediate in the globus pallidum and the substantia nigra, and lowest in the hippocampus and cerebellum. In conclusion, the common cellular abnormality found in the PARK15 patients from the Dutch and Italian families is the depletion of the FBXO7 isoform 1, which normally localizes in the cell nucleus. The activity of FBXO7 in the nucleus appears therefore crucial for the maintenance of brain neurons and the pathogenesis of PARK15.

Contains fulltext : 89839.pdf (Publisher’s version ) (Closed access) The combination of recessive early-onset parkinsonism and pyramidal tract signs caused by pallidopyramidal degeneration is known as pallidopyramidal disease or syndrome (PPD/S). We investigated whether patients diagnosed as Davison's PPD/S showed any definite proof of pyramidal and pallidal involvement, without findings suggestive of other nosological entities. Since Davison's original description, 15 other PPD/S cases have been reported, yet all lack proof of pyramidal or pallidal degeneration. Because of the dopa-responsiveness in all patients subsequent to Davison's report, we argue that these patients probably suffered from early-onset nigral parkinsonism or dopa-responsive dsystonia, rather than pallidal parkinsonism; in such cases, the presumed pyramidal Babinski could be a pseudobabinski ("striatal toe"). Secondary pallidopyramidal syndromes do occur, for example, in multiple system atrophy or Wilson's disease, but in these patients additional findings indicate diseases other than Davison's PPD/S. We conclude that the existence of PPD/S as a distinct clinico-pathological nosological entity, as proposed by Davison, is doubtful. In cases reported as Davison's PPD/S, the description "pallidopyramidal" seems to be a misnomer.

Attention deficit/hyperactivity disorder (ADHD) is a common, highly heritable, neuropsychiatric disorder among children. Linkage studies in isolated populations have proved powerful to detect variants for complex diseases, such as ADHD. We performed a genome-wide linkage scan for ADHD in nine patients from a genetically isolated population in the Netherlands, who were linked to each other within 10 generations through multiple lines of descent. The genome-wide scan was performed with a set of 400 microsatellite markers with an average spacing of +/- 10-12 cM. We performed multipoint parametric linkage analyses using both recessive and dominant models. Our genome scan pointed to several chromosomal regions that may harbour ADHD susceptibility genes. None exceeded the empirical genome-wide significance threshold, but the Log of odds (LOD) scores were >1.5 for regions 6p22 (Heterogenetic log of odds (HLOD) = 1.67) and 18q21-22 (HLOD = 2.13) under a recessive model. We followed up these two regions in a larger sample of ADHD patients (n = 21, 9 initial and 12 extra patients). The LOD scores did not increase after increasing the sample size (6p22 (HLOD = 1.51), 18q21-22 (HLOD = 1.83)). However, the LOD score on 6p22 increased to 2 when a separate analysis was performed for the inattentive type ADHD children. The linkage region on chromosome 18q overlaps with the findings of association of rs2311120 (P = 10(-5)) and rs4149601 (P = 10(-4)) in the genome-wide association analysis for ADHD performed by the Genetic Association Information Network consortium. Furthermore, there was an excess of regions harbouring serotonin receptors (HTR1B, HTR1E, HTR4, HTR1D, and HTR6) that showed a LOD score >1 in our genome-wide scan. European Journal of Human Genetics (2009) 17, 958-966; doi:10.1038/ejhg.2008.260; published online 21 January 2009

Contains fulltext : 80713.pdf (Publisher’s version ) (Closed access) BACKGROUND: The combination of early-onset, progressive parkinsonism with pyramidal tract signs has been known as pallido-pyramidal or parkinsonian-pyramidal syndrome since the first description by Davison in 1954. Very recently, a locus was mapped in a single family with an overlapping phenotype, and an FBXO7 gene mutation was nominated as the likely disease cause. METHODS: We performed clinical and genetic studies in two families with early-onset, progressive parkinsonism and pyramidal tract signs. RESULTS: An FBXO7 homozygous truncating mutation (Arg498Stop) was found in an Italian family, while compound heterozygous mutations (a splice-site IVS7 + 1G/T mutation and a missense Thr22Met mutation) were present in a Dutch family. We also found evidence of expression of novel normal splice-variants of FBXO7. The phenotype associated with FBXO7 mutations consisted of early-onset, progressive parkinsonism and pyramidal tract signs, thereby matching clinically the pallido-pyramidal syndrome of Davison. The parkinsonism exhibits varying degrees of levodopa responsiveness in different patients. CONCLUSIONS: We conclusively show that recessive FBXO7 mutations cause progressive neurodegeneration with extrapyramidal and pyramidal system involvement, delineating a novel genetically defined entity that we propose to designate as PARK15. Understanding how FBXO7 mutations cause disease will shed further light on the molecular mechanisms of neurodegeneration, with potential implications also for more common forms of parkinsonism, such as Parkinson disease and multiple system atrophy.

We studied patients with idiopathic Parkinson's disease (PD) from an isolated population in the Netherlands aiming to map gene(s) involved in PD susceptibility. A total of 109 parkinsonism patients were independently ascertained, of whom 62 presented late-onset, idiopathic PD. Genealogical research showed that 45 index cases with idiopathic PD were linked to a common ancestor, indicating familiar clustering among the patients. This strong familial clustering was highly significant (P = 0.005) when compared to random controls from the same population. We performed a genome wide scan using 382 polymorphic markers in 44 distantly related PD patients plus 112 unaffected first-degree relatives and spouses. Our genome wide association analysis (DISLAMB) revealed evidence of association at a nominal P- value < 0.01 for markers D2S2333, D4S405, D9S158, D13S153. Other regions on chromosomes 3p, 4q, 14q, 17p and 17q were found at a significance level of P < 0.05. In a follow-up study, we investigated all the positive regions using a denser marker set and a larger sample (total of 630 individuals including all late-onset PD patients). The strongest evidence for association remained for the 9q and 14q region. A significant association was found for marker D9S1838 (OR = 2.0, 95% CI 1.1-3.5, P = 0.014) and D14S65 (OR = 3.2, 95% CI 1.7-6.1, P < 0.001). Moreover, a common haplotype with excess of sharing among late-onset PD cases was observed on both regions. Our results suggest the existence of two loci influencing PD susceptibility on chromosome 9q and 14q. © Springer-Verlag 2005.

Mutations in the DJ-1 gene lead to autosomal recessive early-onset parkinsonism. We performed F-DOPA and FDG PET neuroimaging in two parkinsonism patients homozygous for DJ-1 mutations, three relatives heterozygous for a DJ-1 mutation and one non-carrier, all from the originally described kindred from The Netherlands. Their characteristics were compared to those of typical Parkinson's disease patients and healthy controls. Both parkinsonism patients had reduced F-DOPA uptake concordant with typical Parkinson's disease. In the, clinically unaffected, heterozygous relatives, F-DOPA metabolism was unremarkable, thus not suggesting a dosage effect of the DJ-1 gene.

In a Dutch kindred we have identified a deletion of the DJ-1 gene, leading to autosomal-recessive parkinsonism. The parkinsonism patients also had short stature and brachydactyly. In the family and a control group from the same community, we used the DJ-1 deletion as a marker for the originally linked PARK7 region and found a significant association with body height (P = 0.005), which suggests a gene in linkage disequilibrium with DJ-1 to be implicated in short stature. Analysis of hand-bone length showed incomplete segregation of the PARK7 region with brachydactyly, such that a gene in PARK7 is unlikely to fully explain the brachydactyly. Since the bone length reduction was more pronounced in the homozygous parkinsonism patients than in their heterozygous relatives, however, the PARK7 region may contain a modifier gene for growth.

The aim of this study was to separate sources of observer and situational variance in reporting attentiondeficit/hyperactivity disorder (ADHD) symptomatology. In a sample of 30 children diagnosed with ADHD, ADHD symptomatology was assessed with the Diagnostic Interview Schedule for Children–Parent Version (DISC-P), with parents and teachers as informants. Both parents and teachers reported about the child’s ADHD symptomatology at home as well as at school. Parents and teachers showed high within-observer cross-situational presence of ADHD symptoms. However, the between-observer agreement on the presence of ADHD symptoms within the same situation (home or school) was low. This pattern held equally true for attention/concentration and hyperactivity/impulsivity symptom scores. In evaluating ADHD symptomatology, it is important to obtain independent reports about the child’s behaviour at school from the teacher and about the child’s behaviour at home from the parents.