Central nervous system vasculitis in a patient with HIV infection: a diagnostic challenge

Univ Fed Sao Paulo, Dept Neurol, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Div Doencas Infecciosas, Rua Napoleao Barros,715, BR-04023900 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Radiol, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Neurol, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Div Doencas Infecciosas, Rua Napoleao Barros,715, BR-04023900 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Radiol, Sao Paulo, SP, BrazilWeb of Scienc

ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for similar to 40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6). Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot-Marie-Tooth disease type 2H on chromosome 8q13-21.1 was excluded by linkage analysis. Pedigrees originated in Italy, Brazil, Canada, England, Iran, and Japan. Interestingly, we identified 15 ALS5/SPG11/KIAA1840 mutations in 12 families (two sequence variants were never reported before, p.Gln198* and p.Pro2212fs*5). No large deletions/duplications were detected in these patients. The novel mutations seemed to be pathogenic since they co-segregated with the disease in all pedigrees and were absent in 300 unrelated controls. Furthermore, in silico analysis predicted their pathogenic effect. Our results indicate that ALS5/SPG11/KIAA1840 is the causative gene of a wide spectrum of clinical features, including autosomal recessive axonal Charcot-Marie-Tooth disease

Dopaminergic Neuronal Imaging in Genetic Parkinson's Disease: Insights into Pathogenesis

Objectives:To compare the dopaminergic neuronal imaging features of different subtypes of genetic Parkinson's Disease.Methods:A retrospective study of genetic Parkinson's diseases cases in which DaTSCAN (123I-FP-CIT) had been performed. Specific non-displaceable binding was calculated for bilateral caudate and putamen for each case. The right:left asymmetry index and striatal asymmetry index was calculated.Results:Scans were available from 37 cases of monogenetic Parkinson's disease (7 glucocerebrosidase (GBA) mutations, 8 alpha-synuclein, 3 LRRK2, 7 PINK1, 12 Parkin). The asymmetry of radioligand uptake for Parkinson's disease with GBA or LRRK2 mutations was greater than that for Parkinson's disease with alpha synuclein, PINK1 or Parkin mutations.Conclusions:The asymmetry of radioligand uptake in Parkinsons disease associated with GBA or LRRK2 mutations suggests that interactions with additional genetic or environmental factors may be associated with dopaminergic neuronal loss

Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness

Blindness due to retinal degeneration affects millions of people worldwide, but many disease-causing mutations remain unknown. PNPLA6 encodes the patatin-like phospholipase domain containing protein 6, also known as neuropathy target esterase (NTE), which is the target of toxic organophosphates that induce human paralysis due to severe axonopathy of large neurons. Mutations in PNPLA6 also cause human spastic paraplegia characterized by motor neuron degeneration. Here we identify PNPLA6 mutations in childhood blindness in seven families with retinal degeneration, including Leber congenital amaurosis and Oliver McFarlane syndrome. PNPLA6 localizes mostly at the inner segment plasma membrane in photo-receptors and mutations in Drosophila PNPLA6 lead to photoreceptor cell death. We also report that lysophosphatidylcholine and lysophosphatidic acid levels are elevated in mutant Drosophila. These findings show a role for PNPLA6 in photoreceptor survival and identify phospholipid metabolism as a potential therapeutic target for some forms of blindness.Foundation Fighting Blindness CanadaCanadian Institutes of Health ResearchNIHCharles University institutional programmesBIOCEV-Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University, from the European Regional Development FundMinistry of Health of the Czech RepublicGraduate School of Life Sciences (University of Wuerzburg)Government of Canada through Genome CanadaOntario Genomics InstituteGenome QuebecGenome British ColumbiaMcLaughlin CentreCharles Univ Prague, Inst Inherited Metab Disorders, Fac Med 1, Prague 12000 2, Czech RepublicMcGill Univ, Dept Human Genet, Fac Med, Montreal, PQ H3A 0G1, CanadaGenome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, CanadaClin Res Inst Montreal, Cellular Neurobiol Res Unit, Montreal, PQ H2W 1R7, CanadaMcGill Univ, Montreal, PQ H3A 0G4, CanadaMcGill Univ, Ctr Hlth, Montreal Childrens Hosp, McGill Ocular Genet Lab, Montreal, PQ H3H 1P3, CanadaMcGill Univ, Ctr Hlth, Montreal Childrens Hosp, Dept Paediat Surg, Montreal, PQ H3H 1P3, CanadaMcGill Univ, Ctr Hlth, Montreal Childrens Hosp, Dept Human Genet, Montreal, PQ H3H 1P3, CanadaMcGill Univ, Ctr Hlth, Montreal Childrens Hosp, Dept Ophthalmol, Montreal, PQ H3H 1P3, CanadaUniv Alberta, Royal Alexandra Hosp, Dept Ophthalmol & Visual Sci, Edmonton, AB T5H 3V9, CanadaCharles Univ Prague, Inst Biol & Med Genet, Fac Med 1, Prague 12000 2, Czech RepublicBaylor Coll Med, Dept Mol & Human Genet, Human Genome Sequencing Ctr, Houston, TX 77030 USAUniversidade Federal de São Paulo, Dept Neurol, Div Gen Neurol, BR-04021001 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Neurol, Ataxia Unit, BR-04021001 São Paulo, BrazilNewcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, EnglandUniversidade Federal de São Paulo, Dept Ophthalmol, BR-04021001 São Paulo, BrazilSo Gen Hosp, Dept Clin Genet, Glasgow G51 4TF, Lanark, ScotlandCardiff Univ, Sch Med, Inst Med Genet, Cardiff CF14 4XN, S Glam, WalesHadassah Hebrew Univ Med Ctr, Dept Ophthalmol, IL-91120 Jerusalem, IsraelOregon Hlth & Sci Univ, Oregon Inst Occupat Hlth Sci, Portland, OR 97239 USAUniv Wurzburg, Lehrstuhl Neurobiol & Genet, D-97074 Wurzburg, GermanyUniv Montreal, Dept Med, Montreal, PQ H3T 1P1, CanadaMcGill Univ, Dept Anat & Cell Biol, Div Expt Med, Montreal, PQ H3A 2B2, CanadaUniversidade Federal de São Paulo, Dept Neurol, Div Gen Neurol, BR-04021001 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Neurol, Ataxia Unit, BR-04021001 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Ophthalmol, BR-04021001 São Paulo, BrazilNIH: EY022356-01NIH: EY018571-05NIH: NS047663-09Charles University institutional programmes: PRVOUK-P24/LF1/3Charles University institutional programmes: UNCE 204011Charles University institutional programmes: SVV2013/266504BIOCEV-Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University, from the European Regional Development Fund: CZ.1.05/1.1.00/02.0109Ministry of Health of the Czech Republic: NT13116-4/2012Ministry of Health of the Czech Republic: NT14015-3/2013Ontario Genomics Institute: OGI-049Web of Scienc

Anti-N-methyl-D-aspartate receptor encephalitis and Epstein-Barr virus: another tale on autoimmunity?

Jubilaumsfonds der Osterreichischen NationalbankUniv Fed São Paulo, Dept Neurol & Neurosurg, São Paulo, BrazilMed Univ Vienna, Inst Neurol, Vienna, AustriaUniv Fed São Paulo, Dept Neurol & Neurosurg, São Paulo, BrazilJubilaumsfonds der Osterreichischen Nationalbank: 16919Web of Scienc

Clinical correlates of olfactory dysfunction in spinocerebellar ataxia type 3

Olfactory dysfunction is a very common and early sign in neurodegenerative disorders, but few data are already available in hereditary ataxias. Our aim was to evaluate the sense of smell in patients with molecular-proven spinocerebellar ataxia type 3 (SCA3). Forty-one patients with SCA3 and 46 control subjects were studied. the sense of smell was tested using the Sniffin's Sticks (SS-16). We also evaluated Mini-Mental State Examination (MMSE) and non-cerebellar symptoms, such as parkinsonism, dystonia, and restless legs syndrome (RLS). the SCA3 group had significantly lower SS-16 scores than controls (11.5 +/- 2.4 vs 12.8 +/- 1.5, p = 0.003). Multiple linear regression analyses, controlling for age, sex, education, cigarette smoking, and MMSE scores, showed that SCA3 (p = 0.021), sex (p = 0.003) and MMSE scores (p = 0.002) had significant regression coefficients. All the variables taken together were significantly associated with the SS-16 scores (p <= 0.001). Although MMSE scores and female sex were stronger predictors of the SS-16 scores than SCA3. subjects with SCA3 had lower scores on the SS-16, regardless of sex or MMSE scores. Additionally, MMSE scores, sex and presence of RLS were the best predictors of SS-16 scores. Overall, our results strengthen that the sense of smell is significantly reduced in patients with SCA3 and that sex, MMSE scores and RLS also influence the SS-16 scores. Crown Copyright (C) 2011 Published by Elsevier B.V. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Neurol & Neurosurg, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Neurol & Neurosurg, São Paulo, BrazilWeb of Scienc