Search

Background: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder involving degeneration of anterior horn cells of spinal cord, resulting in progressive muscle weakness and atrophy. Aims: The purpose of our study was to determine the frequency of SMN and NAIP deletions in Tunisian SMA patients. Materials and Methods: Polymerase chain reaction (PCR) combined with restriction fragment length polymorphism (RFLP) was used to detect the deletion of exon 7 and exon 8 of SMN1 gene, as well as multiplex PCR for exon 5 and 13 of NAIP gene. Results: Fifteen (45.4%) out of 33 SMA patients were homozygously deleted for exons 7 and/or 8 of SMN1. Homozygous deletion of NAIP gene was observed in 20% (3 / 15) of patients. Conclusions: The molecular diagnosis system based on PCR-RFLP analysis can conveniently be applied in the clinical testing, genetic counseling, prenatal diagnosis, and pre-implantation genetic diagnosis of SMA.

ObjectifEvaluer la frequence de la depression et sa correlation avec le coping et la qualite de vie (QdV) chez une population de patients tunisiens atteints de la maladie de Parkinson (MP).Patients et methodeNous avons realise une etude transversale portant sur 50 patients atteints de la MP. L’evaluation de la QdV, de la depression et des strategies de coping a ete realisee respectivement a l’aide d’une version arabisee de l’echelle SF-36, l’echelle MDRS et le Brief-COPE test.Resultats et conclusionsLa depression a ete retrouvee chez 58 % des parkinsoniens. Les strategies de coping les plus utilisees etaient centrees sur l’emotion, en particulier la religion (54 %). L’alteration de la QdV interessait particulierement la limitation emotionnelle (98,6 %) et l’activite physique (60,7 %). La presence d’une depression et l’utilisation d’un coping emotionnel sont associees a une mauvaise QdV et doivent etre considerees dans la prise en charge somato-psychique des patients Tunisiens atteints de la MP.

Thirty-four different loci for hereditary spastic paraplegias have been mapped, and 16 responsible genes have been identified. Autosomal recessive forms of spastic paraplegias usually have clinically complex phenotypes but the SPG5, SPG24 and SPG28 loci are considered to be associated with 'pure' forms of the disease. Very recently, five mutations in the CYP7B1 gene, encoding a cytochrome P450 oxysterol 7-alpha hydroxylase and expressed in brain and liver, have been found in SPG5 families. We analysed the coding region and exon-intron boundaries of the CYP7B1 gene by direct sequencing in a series of 82 unrelated autosomal recessive hereditary spastic paraplegia index patients, manifesting either a pure (n = 52) or a complex form (n = 30) of the disease, and in 90 unrelated index patients with sporadic pure hereditary spastic paraplegia. We identified eight, including six novel, mutations in CYP7B1 segregating in nine families. Three of these mutations were nonsense (p.R63X, p.R112X, p.Y275X) and five were missense mutations (p.T297A, p.R417H, p.R417C, p.F470I, p.R486C), the last four clustering in exon 6 at the C-terminal end of the protein. Residue R417 appeared as a mutational hot-spot. The mean age at onset in 16 patients was 16.4 +/- 12.1 years (range 4-47 years). After a mean disease duration of 28.3 +/- 13.4 years (10-58), spasticity and functional handicap were moderate to severe in all cases. Interestingly, hereditary spastic paraplegia was pure in seven SPG5 families but complex in two. In addition, white matter hyperintensities were observed on brain magnetic resonance imaging in three patients issued from two of the seven pure families. Lastly, the index case of one family had a chronic autoimmune hepatitis while his eldest brother died from cirrhosis and liver failure. Whether this association is fortuitous remains unsolved, however. The frequency of CYP7B1 mutations were 7.3% (n = 6/82) in our series of autosomal recessive hereditary spastic paraplegia families and 3.3% (n = 3/90) in our series of sporadic pure spastic paraplegia. The recent identification of CYP7B1 as the gene responsible for SPG5 highlights a novel molecular mechanism involved in hereditary spastic paraplegia determinism.

Objective: Hereditary spastic paraplegias (HSPs) are very heterogeneous inherited neurodegenerative disorders. Our group recently identified ZFYVE26 as the gene responsible for one of the clinical and genetic entities, SPG15. Our aim was to describe its clinical and mutational spectra. Methods: We analyzed all exons of SPG15 / ZFYVE26 gene by direct sequencing in a series of 60 non-SPG11 HSP subjects with associated mental or MRI abnormalities, including 30 isolated cases. The clinical data were collected through the SPATAX network. Results: We identified 13 novel truncating mutations in ZFYVE26 , 12 of which segregated at the homozygous or compound heterozygous states in 8 new SPG15 families while 1 was found at the heterozygous state in a single family. Two of 3 splice site mutations were validated on mRNA of 2 patients. The SPG15 phenotype in 11 affected individuals was characterized by early onset HSP, severe progression of the disease, and mental impairment dominated by cognitive decline. Thin corpus callosum and white matter hyperintensities were MRI hallmarks of the disease in this series. Conclusions: The mutations are truncating, private, and distributed along the entire coding sequence of ZFYVE26 , which complicates the analysis of this gene in clinical practice. In our series of patients with hereditary spastic paraplegia–thin corpus callosum, the largest analyzed so far, SPG15 was the second most frequent form (11.5%) after SPG11. Both forms share similar clinical and imaging presentations with very few distinctions, which are, however, insufficient to infer the molecular diagnosis when faced with a single patient.

International audience; OBJECTIVE: To perform a clinical and genetic study of Tunisian families with autosomal recessive (AR) hereditary spastic paraplegia with thin corpus callosum (HSP-TCC). DESIGN: Linkage studies and mutation screening. SETTING: Reference Center for Neurogenetics in South and Center Tunisia. PARTICIPANTS: Seventy-three subjects from 33 "apparently" unrelated Tunisian families with AR HSP. MAIN OUTCOME MEASURES: Families with AR HSP-TCC were subsequently tested for linkage to the corresponding loci using microsatellite markers from the candidate intervals, followed by direct sequencing of the KIAA1840 gene in families linked to SPG11. RESULTS: We identified 8 Tunisian families (8 of 33 [24%]), including 19 affected patients, fulfilling the clinical criteria for HSP-TCC. In 7 families, linkage to either SPG11 (62.5%) or SPG15 (25%) was suggested by haplotype reconstruction and positive logarithm of odds score values for microsatellite markers. The identification of 2 recurrent mutations (R2034X and M245VfsX) in the SPG11 gene in 5 families validated the linkage results. The neurological and radiological findings in SPG11 and SPG15 patients were relatively similar. The remaining family, characterized by an earlier age at onset and the presence of cataracts, was excluded for linkage to the 6 known loci, suggesting further genetic heterogeneity. CONCLUSIONS: Autosomal recessive HSP-TCC is a frequent subtype of complicated HSP in Tunisia and is clinically and genetically heterogeneous. SPG11 and SPG15 are the major loci for this entity, but at least another genetic form with unique clinical features exists.

Hereditary spastic paraplegias (HSP) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by slowly progressive spasticity of the lower limbs. The locus designated spastic paraplegia 15 (SPG15), located in a 16-Mb interval on chromosome 14q, is associated with a rare autosomal recessive complicated form of HSP known as Kjellin's syndrome. In this study, we describe three additional families, of Tunisian origin, linked to the SPG15 locus, one of which had a significant multipoint LOD score of 3.46. In accordance with previous reports, the phenotype of our patients consisted of early onset spastic paraparesis associated with mental impairment and severe progression. Retinal degeneration was not observed, however, but we extended the phenotype of this form to include peripheral neuropathy and white matter abnormalities on MRI. Interestingly, like retinal degeneration, thin corpus callosum is not a constant feature in this entity.

WCN 2013 No: 2196 Topic: 6 — MS & Demyelinating Diseases Atypical neurological presentation of GSS: Case report O.H. Daoud, O. Hdiji, I. Bouchhima, E. Turki, A. Boukhris, M. Damak, M.I. Miladi, I. Feki, C. Mhiri. Habib Bourguiba Hospital, Sfax's Medecine University, Sfax, Tunisia Introduction: Gougerot-Sjogren Syndrome (GSS) is an auto-immune exocrinopathy characterized by xerophthalmia and xerostomia. Neurological complications occur between 8.5 and 70%. Data concerning central nervous system (CNS) symptoms have been rarely described. We analyze the clinical, radiological and therapeutic aspects of a patient with CNS signs revealing primitive GSS and we discuss some particularities. Case report: A 52-year-old woman was hospitalized for recurrent clinical focal signs of CNS involvement. It consisted on sudden left hemiparesis on 2009 and two sudden regressed episodes of aphasia on 2011 and 2013. Brain MRI revealed micro nodular lesions appearing as hyper-signal in T2 on periventricular white matter and frontal cortex. Both lacrymal and salivary gland secretions were affected. A high level of antinuclear antibodies to SSA was associated with inflammatory lesions in minor salivary glands biopsy. The diagnosis of GSS was established. An oral corticosteroid therapy (1 mg/kg/day) was prescribed during 6 weeks followed by progressive degression, with good outcome. Discussion: CNS damages are less frequently associated with GSS's systemic damages, and are often inaugural. The pathophysiology remains unknown. Some authors suggest the pathologic role of the anti-SSA based on their higher frequency in patients with CNS manifestation. Neurological focal manifestations are the most observed, but deficit signs are polymorphic. Aphasia is rarely described. The onset may be sudden as stroke. The MRI can reveal T2 hyperintensities on periventricular white matter or juxtacortical, more rarely on the cerebral cortex. Treatment of GSS's neurological manifestations is usually based an oral corticosteroid with high dose. doi:10.1016/j.jns.2013.07.1398 Abstract — WCN 2013 No: 2001 Topic: 6 — MS & Demyelinating Diseases Onset of secondary progression and long-term prognosis in multiple sclerosis A. Scalfari, A. Neuhaus, M. Daumer, P. Muraro, G. Ebers. Centre of Neuroscience, Department of Medicine, Imperial College, London, UK; Sylvia Lawry Centre, Munich, Germany; Oxford University, Oxford, UK Background: Prognosis in multiple sclerosis (MS) remains largely unpredictable. Objectives and methods: Among 806 relapsing-remitting (RR) patients from the London Ontario database, we assessed: 1) the effect of baseline features on the risk of secondary progression (SP); 2) the risk of becoming disabled (DSS 6–8) according to latency to SP. Results: Longer latency to SP predicted lower risk of reaching DSS 6 (OR= 0.76 for 5 years and OR= 0.44 for 15 years of latency); same results were observed in patients matched for early (year-1 + year-2) relapses number. However, RR phase duration did not influence SP evolution. The latency to SP conversely related to the number of total relapses (1–2 = 8.8 years; 3–4 = 11.3 years; ≥5 = 12.2 years). Predictors of the risk of SP were male sex (HR= 1.41), older age at onset (age N 30years vs ≤20years, 21–30years HR= 0.52, 0.65, respectively) and high early relapse frequency (≥3 vs 1, 2 attacks HR= 0.63, 0.75, respectively). Disease duration affected the probability of becoming SP (OR= 1.07), increasing by 9% every 5 years. At baseline, OR for risk of SP yielded by 3 relapses were 3.6, 5.8, 9.5 in patients aged 20, 30 or 40 at onset respectively, and increased by 2-fold at 10 years (OR 7.5, 12.1, 19.8, respectively) and by 5-fold at 20 years (OR 15.6, 25.5, 41.4, respectively). Conclusions: Prevention/delay of SP represents a potential therapeutic target. Early relapse number and age at onset can be used for selecting groups at higher risk of developing severe disability and requiring more aggressive treatments. doi:10.1016/j.jns.2013.07.1399 Abstract — WCN 2013 No: 2105 Topic: 6 — MS & Demyelinating Diseases Pediatric and adult multiple sclerosis — Comparison of magnetic resonance imaging characteristics at disease onset WCN 2013 No: 2105 Topic: 6 — MS & Demyelinating Diseases Pediatric and adult multiple sclerosis — Comparison of magnetic resonance imaging characteristics at disease onset R.-I. Milos, M. Szimacsek, M. Pritsch, J. Penzien, M. Karenfort, A. Blaschek, R. Seidl, K. Rostasy, A. Bayas, K. Storm van's Gravesande, M. Weber, D. Prayer, B. Kornek. Department of Radiology, Medical University Vienna, Vienna, Austria; DRK-Children’s Hospital Siegen, Siegen, Germany; Children’s Hospital Klinikum Augsburg, Augsburg, Germany; Department of General Pediatrics, Pediatric Neurology, Heinrich Heine University, Dusseldorf, Germany; Department of Pediatric Neurology and Developmental Medicine, Dr. von Hauner's Children's Hospital, Ludwig-Maximilians University, Munich, Germany; Department of Pediatrics, Medical University of Vienna, Vienna, Austria; Department of Pediatrics IV, Division of Pediatric Neurology, InnsbruckMedical University, Innsbruck, Austria; Department of Neurology, Klinikum Augsburg, Augsburg, Germany; Gottfried von Preyer Children Hospital, Medical University of Vienna, Vienna, Austria; Department of Neurology, Medical University of Vienna, Vienna, Austria Background: Only few studies have compared MRI findings at disease onset between patients with pediatric(POMS) and adultonset multiple sclerosis (AOMS). Abstracts / Journal of the Neurological Sciences 333 (2013) e358–e421 e385

Objective: To decipher the pathophysiological mechanisms involved in SPG31 determinism. Background Hereditary spastic paraplegias (HSP) constitute a heterogeneous group of neurodegenerative disorders characterized at least by slowly progressive spasticity of the lower limbs. Mutations in REEP1 were recently associated with SPG31, a pure dominant HSP. We recently identified 12 different heterozygous mutations in REEP1 by screening 175 unrelated HSP index patients from kindreds with dominant inheritance (AD-HSP), associated with either a pure or a complex phenotype. The overall mutation rate in our clinically heterogeneous sample was 4.5% in French families with AD-HSP. The phenotype was restricted to pyramidal signs in the lower limbs in most patients but 9 had a complex phenotype. Design/Methods: We performed analyses on primary cultures of fibroblasts in 5 patients from 2 unrelated SPG31 families. In family 1 (one patient), the mutation c.103delG, p.Val36SerfsX4 was identified in exon 3 of REEP1. In family 2 (4 patients), the mutation c.124T>C, p.Trp42Arg was identified in exon 3 of REEP1. Results: We evidenced abnormal mitochondrial network organization in fibroblasts of all patients from two SPG31 families in addition to defective mitochondrial energy production in both fibroblasts and muscle. The localization of some mitochondrial proteins appeared dramatically impaired in all the fibroblasts studied. Conclusions: The alteration of mitochondrial morphogenesis seems correlated to the type of mutation. Studies of potential partners of REEP1 highlight the crucial role of mitochondrial fusion-fission balance in the pathogenesis of SPG31 and suggest a direct involvement of mitochondrial dysfunction in this neurodegenerative condition. Supported by: Association contre les maladies mitochondriales (AMMi), Association Strumpell-Lorrain (ASL). Disclosure: Dr. Goizet has received research support from Genzyme Corporation. Dr. Benard has nothing to disclose. Dr. Depienne has nothing to disclose. Dr. Boukhris has nothing to disclose. Dr. Sole has nothing to disclose. Dr. Coupry has nothing to disclose. Dr. Pilliod has nothing to disclose. Dr. Martin-Negrier has nothing to disclose. Dr. Forlani has nothing to disclose. Dr. Durr has nothing to disclose. Dr. Brice has nothing to disclose. Dr. Lacombe has received personal compensation for activities with Genzyme as a consultant. Dr. Rossignol has nothing to disclose. Dr. Stevanin has nothing to disclose.