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Background: Parkinson's disease is a progressive neurodegenerative disorder with multifactorial causes, among which genetic risk factors play a part. The RAB GTPases are regulators and substrates of LRRK2, and variants in the LRRK2 gene are important risk factors for Parkinson's disease. We aimed to explore genetic variability in RAB GTPases within cases of familial Parkinson's disease., Methods: We did whole-exome sequencing in probands from families in Canada and Tunisia with Parkinson's disease without a genetic cause, who were recruited from the Centre for Applied Neurogenetics (Vancouver, BC, Canada), an international consortium that includes people with Parkinson's disease from 36 sites in 24 countries. 61 RAB GTPases were genetically screened, and candidate variants were genotyped in relatives of the probands to assess disease segregation by linkage analysis. Genotyping was also done to assess variant frequencies in individuals with idiopathic Parkinson's disease and controls, matched for age and sex, who were also from the Centre for Applied Neurogenetics but unrelated to the probands or each other. All participants were aged 18 years or older. The sequencing and genotyping findings were validated by case-control association analyses using bioinformatic data obtained from publicly available clinicogenomic databases (AMP-PD, GP2, and 100 000 Genomes Project) and a private German clinical diagnostic database (University of Tübingen). Clinical and pathological findings were summarised and haplotypes were determined. In-vitro studies were done to investigate protein interactions and enzyme activities., Findings: Between June 1, 2010, and May 31, 2017, 130 probands from Canada and Tunisia (47 [36%] female and 83 [64%] male; mean age 72·7 years [SD 11·7; range 38-96]; 109 White European ancestry, 18 north African, two east Asian, and one Hispanic] underwent whole-exome sequencing. 15 variants in RAB GTPase genes were identified, of which the RAB32 variant c.213C>G (Ser71Arg) cosegregated with autosomal dominant Parkinson's disease in three families (nine affected individuals; non-parametric linkage Z score=1·95; p=0·03). 2604 unrelated individuals with Parkinson's disease and 344 matched controls were additionally genotyped, and five more people originating from five countries (Canada, Italy, Poland, Turkey, and Tunisia) were identified with the RAB32 variant. From the database searches, in which 6043 individuals with Parkinson's disease and 62 549 controls were included, another eight individuals were identified with the RAB32 variant from four countries (Canada, Germany, UK, and USA). Overall, the association of RAB32 c.213C>G (Ser71Arg) with Parkinson's disease was significant (odds ratio [OR] 13·17, 95% CI 2·15-87·23; p=0·0055; I 2 =99·96%). In the people who had the variant, Parkinson's disease presented at age 54·6 years (SD 12·75, range 31-81, n=16), and two-thirds had a family history of parkinsonism. RAB32 Ser71Arg heterozygotes shared a common haplotype, although penetrance was incomplete. Findings in one individual at autopsy showed sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In functional studies, RAB32 Arg71 activated LRRK2 kinase to a level greater than RAB32 Ser71., Interpretation: RAB32 Ser71Arg is a novel genetic risk factor for Parkinson's disease, with reduced penetrance. The variant was found in individuals with Parkinson's disease from multiple ethnic groups, with the same haplotype. In-vitro assays show that RAB32 Arg71 activates LRRK2 kinase, which indicates that genetically distinct causes of familial parkinsonism share the same mechanism. The discovery of RAB32 Ser71Arg also suggests several genetically inherited causes of Parkinson's disease originated to control intracellular immunity. This shared aetiology should be considered in future translational research, while the global epidemiology of RAB32 Ser71Arg needs to be assessed to inform genetic counselling., Funding: National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J Fox Foundation for Parkinson's Research, and the UK Medical Research Council., Competing Interests: Declaration of interests AR receives unrestricted research support from the Dr Ali Rajput Endowment for Parkinson's Disease and Movement Disorders; in the past 2 years AR has received honoraria from Quebec Consortium for Drug Discovery–Brain Canada and Ipsen Biopharmaceuticals Canada. MSG reports grants from National Institutes of Health (NIH)–National Institute of Neurological Disorders and Stroke (NINDS) and the Michael J Fox Foundation for Parkinson's Research. AJS has received fees from Neurocrine (Chair, Data and Safety Monitoring Board [DSMB]), AskBio (Member, DSMB) and Capsida (advisor), receives a stipend from the International Parkinson's and Movement Disorders Society (Editor-in-Chief, Movement Disorders) and grant funding from Michael J Fox Foundation, Weston Brain Institute, and Brain Canada. ZG-O received consultancy fees from Bial Biotec, Bial, Capsida, Handl Therapeutics, Idorsia, Neuron23, Ono Therapeutics, Prevail Therapeutics, UCB, and Vanqua. He reports grants from the Michael J Fox Foundation for Parkinson's Research, The Weston Family Foundation, The Silverstein Foundation, NIH, and the Canadian Consortium on Neurodegeneration in Aging. HRM is employed by University College Londn. In the last 12 months he reports paid consultancy from Roche, Aprinoia, AI Therapeutics, and Amylyx; lecture fees or honoraria from BMJ, Kyowa Kirin, Movement Disorders Society; and research grants from Parkinson's UK, Cure Parkinson's Trust, PSP Association, Medical Research Council, and Michael J Fox Foundation. HRM is a co-applicant on a patent application related to C9ORF72: method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). MJF reports US patents associated with LRRK2 mutations and mouse models (8409809 and 8455243), and methods of treating neurodegenerative disease (20110092565). SA-C has received honoraria from Merz, and grant funding from the Pacific Parkinson's Research Institute, the Weston Family Foundation, Parkinson Canada, Canadian Institutes of Health Research (CIHR), the VGH and UBC Hospital Foundation, Rick's Heart Foundation, and the Jack and Darlene Poole Foundation. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Biallelic mutations in PINK1/PRKN cause recessive Parkinson's disease. Given the established role of PINK1/Parkin in regulating mitochondrial dynamics, we explored mitochondrial DNA integrity and inflammation as disease modifiers in carriers of mutations in these genes. Mitochondrial DNA integrity was investigated in a large collection of biallelic (n = 84) and monoallelic (n = 170) carriers of PINK1/PRKN mutations, idiopathic Parkinson's disease patients (n = 67) and controls (n = 90). In addition, we studied global gene expression and serum cytokine levels in a subset. Affected and unaffected PINK1/PRKN monoallelic mutation carriers can be distinguished by heteroplasmic mitochondrial DNA variant load (area under the curve = 0.83, CI 0.74-0.93). Biallelic PINK1/PRKN mutation carriers harbour more heteroplasmic mitochondrial DNA variants in blood (P = 0.0006, Z = 3.63) compared to monoallelic mutation carriers. This enrichment was confirmed in induced pluripotent stem cell-derived (controls, n = 3; biallelic PRKN mutation carriers, n = 4) and post-mortem (control, n = 1; biallelic PRKN mutation carrier, n = 1) midbrain neurons. Last, the heteroplasmic mitochondrial DNA variant load correlated with IL6 levels in PINK1/PRKN mutation carriers (r = 0.57, P = 0.0074). PINK1/PRKN mutations predispose individuals to mitochondrial DNA variant accumulation in a dose- and disease-dependent manner., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: During the COVID-19 pandemic, decreased volumes of stroke admissions and mechanical thrombectomy were reported. The study's objective was to examine whether subarachnoid haemorrhage (SAH) hospitalisations and ruptured aneurysm coiling interventions demonstrated similar declines., Methods: We conducted a cross-sectional, retrospective, observational study across 6 continents, 37 countries and 140 comprehensive stroke centres. Patients with the diagnosis of SAH, aneurysmal SAH, ruptured aneurysm coiling interventions and COVID-19 were identified by prospective aneurysm databases or by International Classification of Diseases, 10th Revision, codes. The 3-month cumulative volume, monthly volumes for SAH hospitalisations and ruptured aneurysm coiling procedures were compared for the period before (1 year and immediately before) and during the pandemic, defined as 1 March-31 May 2020. The prior 1-year control period (1 March-31 May 2019) was obtained to account for seasonal variation., Findings: There was a significant decline in SAH hospitalisations, with 2044 admissions in the 3 months immediately before and 1585 admissions during the pandemic, representing a relative decline of 22.5% (95% CI -24.3% to -20.7%, p<0.0001). Embolisation of ruptured aneurysms declined with 1170-1035 procedures, respectively, representing an 11.5% (95%CI -13.5% to -9.8%, p=0.002) relative drop. Subgroup analysis was noted for aneurysmal SAH hospitalisation decline from 834 to 626 hospitalisations, a 24.9% relative decline (95% CI -28.0% to -22.1%, p<0.0001). A relative increase in ruptured aneurysm coiling was noted in low coiling volume hospitals of 41.1% (95% CI 32.3% to 50.6%, p=0.008) despite a decrease in SAH admissions in this tertile., Interpretation: There was a relative decrease in the volume of SAH hospitalisations, aneurysmal SAH hospitalisations and ruptured aneurysm embolisations during the COVID-19 pandemic. These findings in SAH are consistent with a decrease in other emergencies, such as stroke and myocardial infarction., Competing Interests: Competing interests: TNN: PI CLEAR study (Medtronic). DCH: Stryker, Vesalio, Cerenovus consultant. AEH: consultant and speaker for Medtronic, Stryker, Microvention, Penumbra, Balt, Scientia, Genentech and GE Healthcare. PJ: Medtronic, Microvention, Balt, Cerenovus consultant. SO-G: Medtronic, Stryker consultant. DSL: Cerenovus, Genentech, Stryker, Medtronic consultant. TGJ: advisor/investor for Anaconda, Route92, FreeOx, and Blockade Medical; Medtronic grants, DAWN, AURORA PI (Stryker). WJM: consultant: Rebound Therapeutics, Viseon Imperative Care, Q’Apel, Stryker, Stream Biomedical, Spartan Micro; Investor: Cerebrotech, Endostream, Q’Apel, Viseon, Rebound, and Spartan Micro. RGN: Stryker; Cerenovus/Neuravi; Anaconda, Cerebrotech, Ceretrieve, Vesalio (Advisory Board); Imperative Care., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The effect of environmental and lifestyle factors on patients with LRRK2 (leucine-rich repeat kinase 2) p.Gly2019Ser (LRRK2 + /PD + ) compared to idiopathic PD (iPD) has yet to be thoroughly investigated., Methods: In a homogeneous Tunisian Arab Berber population, we recruited 200 idiopathic PD and 199 LRRK2 p.Gly2019Ser mutation carriers, of whom 142 had PD (LRRK2 + /PD + ) and 57 were unaffected (LRRK2 + /PD - ). Case report form (CRF) questionnaires (motor and non-motor symptoms) including the Geoparkinson Questionnaire were used to assess environmental and lifestyle factors., Results: In LRRK2 + /PD + , tobacco use was significantly associated with a later median age at onset (AAO). The median AAO was 60 years (interquartile range = 52-67.25) for tobacco users, compared to 52 years (interquartile range = 45.25-61) for non-users (P = 0.0042 at adjusted α = 0.025). Additionally, we observed an independent but additive effect of black tea consumption and tobacco use., Conclusions: Our data suggest that tobacco and black tea have a protective effect on age at onset in LRRK2 + /PD + . © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background and Purpose: Multinodular and vacuolating neuronal tumor (MVNT) of the cerebrum is a rare brain lesion with suggestive imaging features. The aim of our study was to report the largest series of MVNTs so far and to evaluate the utility of advanced multiparametric magnetic resonance (MR) techniques., Methods: This multicenter retrospective study was approved by our institutional research ethics board. From July 2014 to May 2019, two radiologists read in consensus the MR examinations of patients presenting with a lesion suggestive of an MVNT. They analyzed the lesions' MR characteristics on structural images and advanced multiparametric MR imaging., Results: A total of 64 patients (29 women and 35 men, mean age 44.2 ± 15.1 years) from 25 centers were included. Lesions were all hyperintense on fluid-attenuated inversion recovery and T2-weighted imaging without post-contrast enhancement. The median relative apparent diffusion coefficient on diffusion-weighted imaging was 1.13 [interquartile range (IQR), 0.2]. Perfusion-weighted imaging showed no increase in perfusion, with a relative cerebral blood volume of 1.02 (IQR, 0.05) and a relative cerebral blood flow of 1.01 (IQR, 0.08). MR spectroscopy showed no abnormal peaks. Median follow-up was 2 (IQR, 1.2) years, without any changes in size., Conclusions: A comprehensive characterization protocol including advanced multiparametric magnetic resonance imaging sequences showed no imaging patterns suggestive of malignancy in MVNTs. It might be useful to better characterize MVNTs., (© 2020 European Academy of Neurology.)

Multinodular and vacuolating neuronal tumor of the cerebrum is a rare supratentorial brain tumor described for the first time in 2013. Here, we report 11 cases of infratentorial lesions showing similar striking imaging features consisting of a cluster of low T1-weighted imaging and high T2-FLAIR signal intensity nodules, which we referred to as multinodular and vacuolating posterior fossa lesions of unknown significance. No relationship was found between the location of the lesion and clinical symptoms. A T2-FLAIR hypointense central dot sign was present in images of 9/11 (82%) patients. Cortical involvement was present in 2/11 (18%) of patients. Only 1 nodule of 1 multinodular and vacuolating posterior fossa lesion of unknown significance showed enhancement on postcontrast T1WI. DWI, SWI, MRS, and PWI showed no malignant pattern. Lesions did not change in size or signal during a median follow-up of 3 years, suggesting that multinodular and vacuolating posterior fossa lesions of unknown significance are benign malformative lesions that do not require surgical intervention or removal., (© 2019 by American Journal of Neuroradiology.)

Context: Hodgkin Lymphoma is rarely diagnosed as spinal cord compression syndrome. Caused by an epidural mass, this complication is often encountered in a late stage of the disease. We report the case of a 40-year-old man presenting with symptoms of low thoracic spinal cord compression due to an epidural tumor on the MRI., Findings: Emergent surgery was undertaken on this patient, consisting in laminectomy and tumor resection. After surgery, pain relief and mild neurological improvement were noticed. The histological study revealed a Hodgkin Lymphoma and the patient was referred to chemotherapy and radiotherapy., Conclusion: Though chemotherapy is the gold standard treatment for Hodgkin Lymphoma, surgical spinal decompression may be required in epidural involvement of the disease. Diagnosis may be suspected in the presence of lymphadenopathy and general health decay.

Objective: "Entrapped temporal horn" is an unusual form of obstructive hydrocephalus which is due to an obstacle at the trigone of the lateral ventricle that seals off the temporal horn that may act as a space occupying process. In this study, our aim was to assess the clinical presentation, imaging, pathophysiology and the management of this entity., Methods: The medical records of patients with entrapped temporal horn diagnosed between January 2003 and December 2012 were reviewed retrospectively., Results: Five patients were identified. In four cases, the condition developed after cranial surgery; an infant having two revisions of a ventriculoperitoneal shunt; an adult operated for a glioblastoma, an infant operated on for cerebral hydatidosis and an infant operated for an occipital encephalocele. In the last patient, the entrapped temporal horn revealed sarcoidosis., Conclusions: Trapped temporal horn syndrome can act as a space occupying process and requires surgical management. Internal shunting provides good results. However, the long term outcome depends on the etiology., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Introduction: Herpes simplex encephalitis is a severe neurological condition, whose outcome is improved if treated early with acyclovir. Post-herpes simplex encephalitis with acute chorea has rarely been reported., Case Report: We report on two observations of children presenting with post-herpes simplex encephalitis with acute chorea, related to two different pathophysiological mechanisms. The first one is an 11-month-old girl developing relapsing herpes simplex encephalitis with chorea due to resumption of viral replication. The second one is a 2-year-old boy with relapsing post-herpes simplex encephalitis acute chorea caused by an immunoinflammatory mechanism. We discuss the different neurological presentations of herpetic relapses, notably those presenting with movement disorders, as well as their clinical, paraclinical, physiopathological, and therapeutic aspects., Conclusion: Post-herpes simplex encephalitis with acute chorea may involve two mechanisms: resumption of viral replication or an immunoinflammatory mechanism. Treatment of post-herpes simplex encephalitis with acute chorea depends on the underlying mechanism, while prevention is based on antiviral treatment of herpes simplex encephalitis with acyclovir at the dose of 20mg/kg/8h for 21 days., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Non-tumoral stenosis of interventricular foramen is a rare clinical condition. It can be either unilateral, causing monoventricular hydrocephalus, or bilateral leading to biventricular hydrocephalus. The pathophysiology of this misdiagnosed entity remains controversial. The non-tumoral stenosis of interventricular foramen can be either acquired or congenital. The latter usually manifesting with a neonatal hydrocephalus. We report a case of congenital bilateral stenosis of interventricular foramen, in an 8-year-old girl, revealed by recurrent intracranial hypertension. Diagnosis was relied on 3D-CISS sequences MRI. The child showed full recovery after neuroendoscopic septal fenestration and ventriculo-peritoneal shunt., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Introduction: Studies of dystonia are heterogeneous and there are no studies on this disease in Tunisia. The aim of our study was to determine the frequency of dystonia in the hospital population, to identify different forms of dystonia according to age of onset, distribution, to determine etiologies and to describe treatment., Methods: We conducted a prospective study over a 5-year period (from January 2005 to November 2009) including all patients diagnosed with dystonia and followed at the Child and Adolescent Neurology Department and "Movement Disorders and Botulinum Toxin" consultation of the National Institute of Neurology of Tunis., Results: Two hundred patients were included (2.2% of our patients). Mean age was 26.4±21.4 years and sex ratio H:F 1.3. Consanguinity rate was 29%. Main features of dystonia were action dystonia (78.5%), generalized forms (47%) and secondary forms (58%). A pyramidal syndrome and other movement disorders were the most common signs associated with dystonia (36.5% and 33.5% respectively). In the group of secondary dystonia, mains etiologies were dystonia due to exogenic agent (56%), neuro-metabolic diseases (26%), hereditary degenerative disease (13%) and psychogenic dystonia (5%). Dystonia was primary in 44% (84 patients). Different treatments were used and a dramatic improvement in some patients was noted with levodopa and botulinum toxin injections. A multidisciplinary approach associated with medical treatment led to recovery or improved prognosis., Discussion and Conclusion: Very few studies have been devoted to reporting a large series of dystonic patients. Our study is the first to describe both primary and secondary dystonia in 200 Tunisian patients. The presence of familial dystonia in our country suggests a genetic origin. Further work including genetic analysis with a screening of known mutations responsible for dystonia and the informative families with unknown mutations would be useful. Specific studies designed to identify new genes causal in dystonia are needed., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Subdural effusions are uncommon but known complications of arachnoid cysts of the middle cranial fossa. They mainly occur after minor head traumas in young patients. Here, we report eight cases of arachnoid cyst of the middle cranial fossa associated with subdural hematoma in five cases and hygroma in three cases. Major symptoms are signs of raised intracranial pressure. CT scan and MRI showed the cyst and the subdural effusion. An excellent therapeutic result was achieved with evacuation of the subdural fluid via burr holes in the five cases of subdural hematoma while in the two cases of hygroma a subduro-peritoneal shunt was necessary. In the last case, a temporal craniotomy was performed with evacuation of the hygroma and fenestration of the cyst. We suggest treating only the complicating event in the case of a subdural hematoma via burr holes evacuation. Whereas, in the case of hygroma we think that craniotomy with fenestration of the cyst or the use of a subdural shunt are more often needed., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Nonketotic hyperglycemia-induced hemichorea or hemiballism is a well-recognized entity that is rarely encountered. Particular computed tomography and magnetic resonance imaging findings have been described. The pathophysiological mechanism of this disease remains uncertain. We report here on two female patients that presented with hemiballism secondary to nonketotic hyperglycemia and underwent brain computed tomography and magnetic resonance imaging., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Central nervous system medulloepithelioma is a rare, highly malignant childhood tumor. It might be confused with medulloblastoma or other primitive neuroectodermal tumors, but it is quite particular by its clinical, radiological, and pathological features. The mean survival varies depending on whether or not a gross-total resection is possible. Adjuvant radiochemotherapy is often indicated. Only two reported cases in the literature survived beyond 4 years after treatment by gross total resection and radiotherapy without chemotherapy. We report three cases of supratentorial medulloepithelioma occurring in three children aged 11-17 years. Two patients underwent a gross-total resection followed by radiotherapy and survived more than 4 years after treatment. The third case had, however, recurred twice within the 1st postoperative month despite a complete resection each time and metastasis to the lung developed. Chemotherapy was then carried out after the third procedure and the patient died 7 months later., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Central neurocytoma is a rare benign neoplasm of the central nervous system. The intraventricular location close to the Monro foramina and the attachment to the septum pellucidum are characteristic for the diagnosis. However, atypical appearances may be encountered and confused with other neoplasms. The authors report the radiological findings of 32 surgically treated and pathologically confirmed neurocytomas., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Congenital myasthenic syndromes (CMSs) are a heterogeneous group of diseases caused by genetic defects affecting neuromuscular transmission. Mutations of DOK7 have recently been described in recessive forms of CMS. Dok-7 is a cytoplasmic post-synaptic protein co-activator of the muscle-specific receptor-tyrosine kinase (MuSK) involved in neuromuscular synaptogenesis and maintenance. We report clinical, morphological and molecular data on 15 patients with mutations in DOK7. Eleven different mutations (5 novel) were identified and all patients but one were found to carry at least the common c.1124&#95;1127dupTGCC mutation. Patients with DOK7 mutations have a particular limb-girdle pattern, without tubular aggregates but a frequent lipidosis on the muscle biopsy. Changes in pre- and post-synaptic compartments of the neuromuscular junction were also observed in muscle biopsies: terminal axons showed defective branching which resulted in a unique terminal axon contacting en passant postsynaptic cups. Clinical features, muscle biopsy findings or response to therapy were confusing in several patients. Characterization of this distinct phenotype is essential to provide clues for targeted genetic screening and to predict the therapeutic response to anticholinesterase treatments or ephedrine as has been suggested.

Introduction: Tuberculosis continues to be a public health problem in emerging countries with a recent evidence of increased incidence of extrapulmonary localization in developed countries probably linked to HIV. To our knowledge the occurrence of cerebro-mediastinal tuberculosis in an immuno-competent child has not been previously described; moreover the child we describe has a probable Say-Barber-Miller syndrome. We discuss a putative causative link between this syndrome and the occurrence of tuberculosis., Case Report: A seven-year-old girl presented to our department with a history of infantile encephalopathy since birth characterized by a facial dysmorphy (evocative of a bird face), microcephaly, and mental retardation, and with recurrent infections. The child had complained of back pain for several months; the parents reported anorexia, loss of weight. Spinal and cerebral MRI showed a mediastinal mass involving the spine and cerebral lesions evocative of tuberculomas. The tuberculin interdermal reaction was positive. Culture of a vertebral biopsy was positive for Koch bacillus. Anti-tuberculosis treatment improved general and local status. An extensive immunological work-up was normal., Conclusion: [corrected] This observation is exceptional in many aspects: very early age of onset of extrapulmonary tuberculosis, no immune deficit, association with a rare congenital neurological syndrome. We discuss the possible link between this entity and the occurrence of tuberculosis.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a distinct form of hereditary early-onset spastic ataxia. In 2000, the causative gene, SACS, encoding the protein sacsin, was identified in Quebec patients. The open reading frame (ORF) of SACS was initially reported to contain 11,487 bp and to be encoded by a single gigantic exon. Recently, eight additional exons upstream of the original ORF were found (ENST00000382298). We report four Tunisian ARSACS patients homozygous for a novel mutation in SACS exon 9 gene, c.12846&#95;12850delAGAG. This mutation is localized upstream from the DnaJ domain leading to the loss of this domain, suggesting that the disease is associated with loss of critical chaperone function of sacsin.

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare autosomal recessive disorder characterized by the congenital absence of horizontal gaze, progressive scoliosis, and failure of the corticospinal and somatosensory axon tracts to decussate in the medulla. HGPPS is caused by mutations of the ROBO3 gene, which encodes a protein that shares homology with the roundabout family of transmembrane receptors that are important in axon guidance and neuronal migration. To date, over 15 mutations have been found in consanguineous families of Greek, Italian, Turkish, Pakistani, Saudi Arabian, and Indian descent. To detail clinical, cerebral magnetic resonance imaging (MRI) and genetic findings of ten HGPPS patients from four unrelated Tunisian families. Four unrelated consanguineous Tunisian families with a total of ten patients suffering from horizontal gaze palsy with progressive scoliosis. Genetic linkage analysis and direct sequencing of the ROBO3 gene. All patients shared similar clinical gaze movement abnormalities and variable degrees of scoliosis. Four distinct homozygous mutations were identified. This study extends the molecular spectrum of the ROBO3 gene and the geographic origin of patients with ROBO3 gene mutations, and underlines the homogeneity of the motor ocular syndrome whatever type of mutation is encountered.

Introduction: Neurometabolic diseases are a large group of genetic diseases. In our country, the diagnostic and therapeutic approach to theses diseases is rather difficult. The aim of our study was to determine the frequency of neurometabolic diseases in the hospital population, to describe the problems in diagnosing these conditions and difficulties encountered during patient care. Our goal was to propose guidelines for a practical diagnostic and therapeutic approach to neurometabolic disorders in our country., Methods: We have conducted a prospective study over a 3-year period including all patients diagnosed with "metabolic disease" and followed at the Child and Adolescent Neurology Department of the National Institute of Neurology of Tunis., Results: One hundred and thirty-six patients were included (2.4% of our patients). Mean age was 7.3 +/- 5.1 years. Mean age at onset was 4.3 years. There was a high consanguinity rate. Respiratory chain defects were the most frequently suspected diseases (16.9%), followed by lysosomal diseases (8.8%). Chromatography, initially systematically prescribed, became targeted with a higher diagnostic efficacy. Metabolic diseases diagnosed as certain, represented 22% of the studied cases. This can be explained by the insufficiency of available laboratory tests of confirmation. The prescription of specific treatment was insufficient, even for confirmed pathologies (14.7%) because of the high cost of these therapies., Conclusion: The diagnostic approach has to be rational, targeted, multidisciplinar and conducted within a care network. Diagnostic priority should focus on treatable neurometabolic diseases. The establishment of a systematized registry and neonatal screening for the main treatable neurometabolic diseases constitute the final objective of our work to prepare for biochemical and genetic studies.

Background: This is a report of the endovascular treatment of three intracranial dural arteriovenous malformations (DAVM) using Onyx., Patients and Methods: We analyzed the clinical and angiographic results in three patients with intracranial DAVM, revealed by a hemorrhagic event and treated by endovascular way by the use Onyx. Angiographic investigation showed the DAVM to be located in the lateral sinus in two cases and in the tentorium region in the third., Results: In all three cases, embolization was performed by selective catheterization of the meningeal arterial feeder of the DAVM. The injection of Onyx resulted in complete anatomical exclusion of the DAVM, as demonstrated by posttreatment angiography. Clinically, the patients recovered partially or completely their neurological deficit., Conclusion: Onyx is a liquid embolization agent recently introduced for the treatment of DAVM. When used under optimal conditions, it offers a feasible alternative option in the treatment of such vascular malformations.

Severe sub-cortical white matter abnormalities are unusual features in Wilson's disease and are reported to be poorly or not responsive to copper chelating therapy or to be worsened by it. We report on a 12-year-old boy with Wilson's disease and extensive sub-cortical white matter involvement. After five years of copper chelating therapy, an appreciable improvement of these lesions was obtained. The physiopathology of these unusual cerebral white matter abnormalities is discussed.

Non tumoral stenosis of the foramen of Monro is rare; pathogenic mechanisms remain a subject of debate. The narrowing can be unilateral causing monoventicular hydrocephalus, and exceptionally bilateral causing biventricular hydrocephalus. We present two cases of monoventricular hydrocephalus and two other cases of biventricular hydrocephalus. Clinically, all patients had the same signs as in common hydrocephalus. The CT scan and mainly the MRI allowed us to confirm the diagnosis and to avoid tumor obstruction of the foramen of Monro. With neuroendoscopy we were able to describe the foramen of Monro and perform a fenestration of the septum pellucidum. The prognosis is usually good.

Autosomal recessive cerebellar ataxias are a group of clinically and genetically heterogeneous neurodegenerative disorders. Growing data have shown that there is difficulty with genetic counseling in a deeply consanguineous population because of the presence of genetic heterogeneity in patients sharing similar phenotypes. The objective of this study was to report on 11 Tunisian patients belonging to the same large consanguineous family and sharing autosomal recessive ataxia phenotypes caused by three distinct gene defects. A large consanguineous Tunisian family with 11 affected patients was selected. All patients had a complete neurological examination. Blood samples were collected for molecular study. Mutation analysis revealed the presence of three distinct gene defects in the FXN (FRDA), TTPA (AVED), and SACS (ARSACS) genes within the same large family. The genetic heterogeneity observed in this family drew attention to the difficulty of genetic counseling in an inbred population and to the need for genotyping all affected members before giving genetic counseling.

L-2-Hydroxyglutaric aciduria (L-2-OHGA) is a rare autosomal recessive neurometabolic disease linked to chromosome 14q21.1 and is caused by mutations in the gene that most likely encodes L: -2-hydroxyglutarate dehydrogenase, which normally catalyses L: -2-hydroxyglutarate to alpha-ketoglutarate. It is characterized by progressive mental deterioration, pyramidal and cerebellar syndromes, macrocephaly and marked polycystic white-matter degeneration mainly involving frontal lobes. Brain tumours of variable nature have frequently been observed in L-2-OHGA. We report a patient affected by this disease who at the age of 20 years developed a bone tumour involving the right frontal region of the calvaria. He had first presented at the age of 10 years with psychomotor delay, clumsy gait and moderate mental impairment. Examination showed macrocephaly, cerebellar ataxia and quadripyramidal syndrome. Brain MRI showed low signal intensities on T1-weighted images and high signal intensities on T2-weighted images in cerebral subcortical white matter. Serum and urinary amino acid assay was normal. Urinary 2-hydroxyglutaric acid was 1418 mmol/mol creatinine (controls <25). Analysis of the L-2-hydroxyglutarate dehydrogenase gene revealed a homozygous mutation in exon 2 (A320G). At the age of 20 years, an osteoma of the right frontal bone was diagnosed. This finding reinforces the opinion concerning the association of L-2-OHGA and tumorigenesis and prompted us to verify the possible responsibility of some overproduced substances in this disease for the development of tumours and to look for any correlation between the type of mutation in the L-2-OHGA gene and the tumorigenic potential observed in some patients affected by this disease.

Hydatid cyst is rarely observed in the brain (0.5-4.5%). The frequency of calcified cyst is less than 1%. We present a case of a 15-year-old girl with a 5-year follow-up for grand mal seizures that became resistant to three-drug therapy. The CT scan revealed a calcified parieto-occipital lesion. MRI disclosed a suggestive detached membrane. At surgery, the cyst wall was calcified with typical hydatid sand contents. Since surgery, seizure control has been achieved with one drug. Calcification of a cerebral hydatid cyst is exceptional. MRI enabled the diagnosis in this patient.

Neurenteric cysts (NECs) are dysraphic lesions. They are usually extramedullary, the intramedullary forms are very rare. To our knowledge, only 10 cases of isolated intramedullary NECs have been reported. We report a case of intramedullary NEC without any associated dysraphic lesion. The clinical findings were: cervical pain and left hemicorporal weakness which predominated at the upper limb. Neuroradiological evaluation was performed by means of MRI which revealed a cystic lesion at C3-C4 level. A partial excision was performed and the diagnosis of NEC was established by histological study.

We report a case of an unusual epidermoid cyst (EC) of the cerebellopontine angle that appeared hyperdense on computed tomography (CT) scanning, hyperintense on T1-weighted MR images and hypointense on T2-weighted magnetic resonance (MR) images. Diffusion-weighted imaging showed a hypointense lesion. We discuss imaging characteristics of ECs, explain the atypical findings in our case and confirm that the signal seen on diffusion-weighted images in the EC is related to a T2 effect.

Background: Spinal epidermoid cysts are rare tumors and they are exceptionally intramedullary., Aim: Report of news cases, Case Report: The diagnosis is established by magnetic resonance imaging and the treatment is surgical. The prognosis is generally good, with possible recurrence after many years. The author report five new cases of intramedullary epidermoide cysts operated between 1996 and 2001.

The Gliomatosis Cerebri (GC) is an infiltrating and rare primitive tumour of the brain. It is characterized by diffuse neoplastic proliferation of glial cells involving of at least two lobes of the brain, without a distinct tumor mass and with the preservation of the anatomical and neuronal architecture. According to the WHO classification, GC is categorized as a high-grade neuroepithelial tumor of uncertain origin (GradelV). Now the diagnosis is facilitated via stereotactic biopsies of the representative lesion identified in magnetic resonance. Our objective is to present 4 new cases, and recall the clinical and radiological features and the prognosis.