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Hereditary spastic paraplegia

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https://www.readbyqxmd.com/read/28626794/febrile-ataxia-and-myokymia-broaden-the-spg26-hereditary-spastic-paraplegia-phenotype
#1
Rubina Dad, Susan Walker, Stephen W Scherer, Muhammad Jawad Hassan, Mohammad Domaia Alghamdi, Berge A Minassian, Reem A Alkhater
No abstract text is available yet for this article.
June 2017: Neurology. Genetics
https://www.readbyqxmd.com/read/28600743/-ataxias-and-hereditary-spastic-paraplegias
#2
REVIEW
R Schüle, L Schöls
Hereditary ataxias and spastic paraplegias are genetic disorders with age-dependent nearly complete penetrance. The mostly monogenetic etiology allows one to establish the diagnosis, study pathogenesis and to develop new causative therapeutic approaches for these diseases. Both the causative genes as well as the clinical presentation overlap considerably between hereditary ataxias and spastic paraplegias. This strongly argues towards a united classification for these two groups of diseases. Next generation sequencing technologies have greatly expanded the number of genes known to be causative for hereditary ataxias and spastic paraplegias and allow simultaneous time- and cost-effective diagnostic testing of > 200 genes...
June 9, 2017: Der Nervenarzt
https://www.readbyqxmd.com/read/28572275/truncating-mutations-in-spast-patients-are-associated-with-a-high-rate-of-psychiatric-comorbidities-in-hereditary-spastic-paraplegia
#3
Viorica Chelban, Arianna Tucci, David S Lynch, James M Polke, Liana Santos, Hallgeir Jonvik, Stanislav Groppa, Nicholas W Wood, Henry Houlden
BACKGROUND: The hereditary spastic paraplegias (HSPs) are a rare and heterogeneous group of neurodegenerative disorders that are clinically characterised by progressive lower limb spasticity. They are classified as either 'pure' or 'complex' where spastic paraplegia is complicated with additional neurological features. Mutations in the spastin gene (SPAST) are the most common cause of HSP and typically present with a pure form. METHODS: We assessed in detail the phenotypic and genetic spectrum of SPAST-related HSP focused on 118 patients carrying SPAST mutations...
June 1, 2017: Journal of Neurology, Neurosurgery, and Psychiatry
https://www.readbyqxmd.com/read/28554554/expanding-the-phenotypic-spectrum-associated-with-mutations-of-dync1h1
#4
Sarah J Beecroft, Catriona A McLean, Martin B Delatycki, Kurian Koshy, Eppie Yiu, Goknur Haliloglu, Diclehan Orhan, Phillipa J Lamont, Mark R Davis, Nigel G Laing, Gianina Ravenscroft
Autosomal dominant mutations of DYNC1H1 cause a range of neurogenetic diseases, including mental retardation with cortical malformations, hereditary spastic paraplegia and spinal muscular atrophy. Using SNP array, linkage analysis and next generation sequencing, we identified two families and one isolated proband sharing a known spinal muscular atrophy, lower extremity predominant (SMALED) causing mutation DYNC1H1 c.1792C>T, p.Arg598Cys, and another family harbouring a c.2327C>T, p.Pro776Leu mutation...
July 2017: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/28546998/uniparental-disomy-determined-by-whole-exome-sequencing-in-a-spectrum-of-rare-motoneuron-diseases-and-ataxias
#5
Dana M Bis, Rebecca Schüle, Jennifer Reichbauer, Matthis Synofzik, Tim W Rattay, Anne Soehn, Peter de Jonghe, Ludger Schöls, Stephan Züchner
BACKGROUND: The genetic causes of many rare inherited motoneuron diseases and ataxias (MND and ATX) remain largely unresolved, especially for sporadic patients, despite tremendous advances in gene discovery. Whole exome data is often available for patients, but it is rarely evaluated for unusual inheritance patterns, such as uniparental disomy (UPD). UPD is the inheritance of two copies of a chromosomal region from one parent, which may generate homozygosity for a deleterious recessive variant from only one carrier-parent...
May 2017: Molecular Genetics & Genomic Medicine
https://www.readbyqxmd.com/read/28545922/diseases-of-connexins-expressed-in-myelinating-glia
#6
REVIEW
Charles K Abrams
Connexins are a family of integral membrane proteins most of which form gap junctions and many of which form hemichannels as well. Mutations in at least 9 of the 21 genes encoding human connexin proteins cause human diseases. Mutations in GJB1 (Cx32), expressed in both Schwann cells and oligodendrocytes, cause both a form of inherited peripheral neuropathy and a variety of CNS symptoms. Mutations in GJC2 (Cx47), expressed only in oligodendrocytes within the nervous system, cause a severe early onset dysmyelinating disorder, Pelizaeus-Merzbacher-Like disease (PMLD1 or HLD2), hereditary spastic paraplegia (SPG44), which has a milder phenotype and later onset, and a subclinical leukodystrophy...
May 22, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28536081/structural-annotation-of-beta-1-4-n-acetyl-galactosaminyltransferase-1-b4galnt1-causing-hereditary-spastic-paraplegia-26
#7
Rubina Dad, Uzma Malik, Aneela Javed, Berge A Minassian, Muhammad Jawad Hassan
Beta-1,4-N-acetyl galactosaminyltransferase 1, B4GALNT1, is a GM2/GD2 synthase, involved in the expression of glycosphingolipids (GSLs) containing sialic acid. Mutations in the gene B4GALNT1 cause Hereditary Spastic Paraplegia 26 (HSP26). In present study we have made attempt to predict the potential structural of the human B4GALNT1 protein. The results illustrated that the amino acid sequences of B4GALNT1 are not 100% conserved among selected twenty species. One signal peptide and one transmembrane domain predicted in human wild type B4GALNT1 protein with aliphatic index of 92...
May 20, 2017: Gene
https://www.readbyqxmd.com/read/28534044/hsp-and-deafness-neurocristopathy-caused-by-a-novel-mosaic-sox10-mutation
#8
Sandra Donkervoort, Diana Bharucha-Goebel, Pomi Yun, Ying Hu, Payam Mohassel, Ahmet Hoke, Wadih M Zein, Daniel Ezzo, Andrea M Atherton, Ann C Modrcin, Majed Dasouki, A Reghan Foley, Carsten G Bönnemann
OBJECTIVE: To identify the underlying genetic cause in 2 sisters affected with progressive lower extremity spasticity, neuropathy, and early-onset deafness. METHODS: Whole-exome sequencing was performed, and segregation testing of variants was investigated using targeted Sanger sequencing. An inherited paternal mosaic mutation was further evaluated through quantitative analysis of the ratio of mutant vs wild-type allele in genomic DNA from various tissues, including blood, dermal fibroblasts, and saliva...
June 2017: Neurology. Genetics
https://www.readbyqxmd.com/read/28495799/studies-on-truncating-mutations-of-spast-associated-with-hereditary-spastic-paraplegia-indicate-greater-accumulation-and-toxicity-of-the-m1-isoform-of-spastin
#9
Joanna M Solowska, Anand N Rao, Peter W Baas
The SPAST gene, which produces two isoforms (M1 and M87) of the microtubule-severing protein called spastin, is the chief gene mutated in hereditary spastic paraplegia. Haploinsufficiency is a popular explanation for the disease, in part because most of the over 200 pathogenic mutations of the gene are truncating, and expected to produce only vanishingly small amounts of shortened proteins. Here we studied two such mutations, N184X and S245X, and our results suggest another possibility. We found that the truncated M1 proteins can accumulate to notably higher levels than their truncated M87 or wild-type counterparts...
May 11, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28491902/de-novo-reep2-missense-mutation-in-pure-hereditary-spastic-paraplegia
#10
Ricardo H Roda, Alice B Schindler, Craig Blackstone
Alterations in proteins that regulate endoplasmic reticulum morphology are common causes of hereditary spastic paraplegia (SPG1-78, plus others). Mutations in the REEP1 gene that encodes an endoplasmic reticulum-shaping protein are well-known causes of SPG31, a common autosomal dominant spastic paraplegia. A closely-related gene, REEP2, is mutated in SPG72, with both autosomal and recessive inheritances. Here, we report a patient with a pure hereditary spastic paraplegia due to a de novo missense mutation (c...
May 2017: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/28488683/progressive-hereditary-spastic-paraplegia-caused-by-a-homozygous-ky-mutation
#11
Yuval Yogev, Yonatan Perez, Iris Noyman, Anwar Abu Madegem, Hagit Flusser, Zamir Shorer, Eugene Cohen, Leonid Kachko, Analia Michaelovsky, Ruth Birk, Arie Koifman, Max Drabkin, Ohad Wormser, Daniel Halperin, Rotem Kadir, Ohad S Birk
Twelve individuals of consanguineous Bedouin kindred presented with autosomal recessive progressive spastic paraplegia evident as of age 0-24 months, with spasticity of lower limbs, hyperreflexia, toe walking and equinus deformity. Kyphoscolisois was evident in older patients. Most had atrophy of the lateral aspects of the tongue and few had intellectual disability. Nerve conduction velocity, electromyography and head and spinal cord magnetic resonance imaging were normal in tested subjects. Muscle biopsy showed occasional central nuclei and fiber size variability with small angular fibers...
May 10, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28471471/pathophysiology-diagnostic-work-up-and-management-of-balance-impairments-and-falls-in-patients-with-hereditary-spastic-paraplegia
#12
Jorik Nonnekes, Bas van Lith, Bart P van de Warrenburg, Vivian Weerdesteyn, Alexander C H Geurts
INTRODUCTION: Balance impairments are common in patients with hereditary spastic paraplegia and are among the most debilitating symptoms, as they frequently result in falls and fall-related injuries. Several features of hereditary spastic paraplegia contribute to balance impairments and multiple treatment options exist. However, an overview of these underlying mechanisms and their treatment is currently lacking. METHODS: This paper reviews the pathophysiology, diagnostic workup, and management of balance impairments in hereditary spastic paraplegia...
April 27, 2017: Journal of Rehabilitation Medicine
https://www.readbyqxmd.com/read/28471035/arl6ip1-mutation-causes-congenital-insensivity-to-pain-self-mutilation-and-spastic-paraplegia
#13
Mathilde Nizon, Sébastien Küry, Yann Péréon, Thomas Besnard, Delphine Quinquis, Pierre Boisseau, Thierry Marsaud, Armelle Magot, Jean-Marie Mussini, Emmanuelle Mayrargue, Sébastien Barbarot, Stéphane Bézieau, Bertrand Isidor
Hereditary sensory neuropathies (HSAN) type II are characterized by autosomal recessive inheritance, onset at birth and self-mutilating behavior. Here, we described a new patient with congenital insensitivity to pain, sensory neuropathy, self-mutilation, and spastic paraplegia. Whole exome sequencing showed a homozygous frameshift variant c.[577_580del], p.(Lys193Phefs*37) in ARL6IP1. The protein harbours reticulon-like short hairpin transmembrane domains and has a role in endoplasmic reticulum shaping. The variant causes an additional C-terminus hydrophobic domain which could disrupt its function...
May 4, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28466468/loss-of-dynamin-2-gtpase-function-results-in-microcytic-anaemia
#14
Fiona C Brown, Michael Collett, Cedric S Tremblay, Gerhard Rank, Pietro De Camilli, Carmen J Booth, Marc Bitoun, Phillip J Robinson, Benjamin T Kile, Stephen M Jane, David J Curtis
In a dominant mouse ethylnitrosurea mutagenesis screen for genes regulating erythropoiesis, we identified a pedigree with a novel microcytic hypochromia caused by a V235G missense mutation in Dynamin 2 (Dnm2). Mutations in Dnm2, a GTPase, are highly disease-specific and have been implicated in four forms of human diseases: centronuclear myopathy, Charcot-Marie Tooth neuropathy and, more recently, T-cell leukaemia and Hereditary Spastic Paraplegia, but red cell abnormalities have not been reported to date. The V235G mutation lies within a crucial GTP nucleotide-binding pocket of Dnm2, and resulted in defective GTPase activity and incompatibility with life in the homozygous state...
May 3, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28459997/hypomorphic-mutations-in-polr3a-are-a-frequent-cause-of-sporadic-and-recessive-spastic-ataxia
#15
Martina Minnerop, Delia Kurzwelly, Holger Wagner, Anne S Soehn, Jennifer Reichbauer, Feifei Tao, Tim W Rattay, Michael Peitz, Kristina Rehbach, Alejandro Giorgetti, Angela Pyle, Holger Thiele, Janine Altmüller, Dagmar Timmann, Ilker Karaca, Martina Lennarz, Jonathan Baets, Holger Hengel, Matthis Synofzik, Burcu Atasu, Shawna Feely, Marina Kennerson, Claudia Stendel, Tobias Lindig, Michael A Gonzalez, Rüdiger Stirnberg, Marc Sturm, Sandra Roeske, Johanna Jung, Peter Bauer, Ebba Lohmann, Stefan Herms, Stefanie Heilmann-Heimbach, Garth Nicholson, Muhammad Mahanjah, Rajech Sharkia, Paolo Carloni, Oliver Brüstle, Thomas Klopstock, Katherine D Mathews, Michael E Shy, Peter de Jonghe, Patrick F Chinnery, Rita Horvath, Jürgen Kohlhase, Ina Schmitt, Michael Wolf, Susanne Greschus, Katrin Amunts, Wolfgang Maier, Ludger Schöls, Peter Nürnberg, Stephan Zuchner, Thomas Klockgether, Alfredo Ramirez, Rebecca Schüle
Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7...
June 1, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28449883/hereditary-spastic-paraplegia-more-than-an-upper-motor-neuron-disease
#16
REVIEW
L Parodi, S Fenu, G Stevanin, A Durr
Hereditary spastic paraplegias (HSPs) are a group of rare inherited neurological diseases characterized by extreme heterogeneity in both their clinical manifestations and genetic backgrounds. Based on symptoms, HSPs can be divided into pure forms, presenting with pyramidal signs leading to lower-limb spasticity, and complex forms, when additional neurological or extraneurological symptoms are detected. The clinical diversity of HSPs partially reflects their underlying genetic backgrounds. To date, 76 loci and 58 corresponding genes [spastic paraplegia genes (SPGs)] have been linked to HSPs...
April 24, 2017: Revue Neurologique
https://www.readbyqxmd.com/read/28422159/spastic-paraplegia-linked-phospholipase-papla1-is-necessary-for-development-reproduction-and-energy-metabolism-in-drosophila
#17
Martina Gáliková, Peter Klepsatel, Judith Münch, Ronald P Kühnlein
The human PAPLA1 phospholipase family is associated with hereditary spastic paraplegia (HSP), a neurodegenerative syndrome characterized by progressive spasticity and weakness of the lower limbs. Taking advantage of a new Drosophila PAPLA1 mutant, we describe here novel functions of this phospholipase family in fly development, reproduction, and energy metabolism. Loss of Drosophila PAPLA1 reduces egg hatchability, pre-adult viability, developmental speed, and impairs reproductive functions of both males and females...
April 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28398512/mutant-spastin-proteins-promote-deficits-in-axonal-transport-through-an-isoform-specific-mechanism-involving-casein-kinase-2-activation
#18
Lanfranco Leo, Carina Weissmann, Matthew Burns, Minsu Kang, Yuyu Song, Liang Qiang, Scott T Brady, Peter W Baas, Gerardo Morfini
Mutations of various genes cause hereditary spastic paraplegia (HSP), a neurological disease involving dying-back degeneration of upper motor neurons. From these, mutations in the SPAST gene encoding the microtubule-severing protein spastin account for most HSP cases. Cumulative genetic and experimental evidence suggests that alterations in various intracellular trafficking events, including fast axonal transport (FAT), may contribute to HSP pathogenesis. However, the mechanisms linking SPAST mutations to such deficits remain largely unknown...
June 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28396731/clinical-features-and-genotype-phenotype-correlation-analysis-in-patients-with-atl1-mutations-a-literature-reanalysis
#19
Guo-Hua Zhao, Xiao-Min Liu
BACKGROUND: The hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders. Approximately 10% of the autosomal dominant (AD) HSPs (ADHSPs) have the spastic paraplegia 3A (SPG3A) genotype which is caused by ATL1 gene mutations. Currently there are more than 60 reported ATL1 gene mutations and the genotype-phenotype correlation remains unclear. The study aims to investigate the genotype-phenotype correlation in SPG3A patients. METHODS: We performed a reanalysis of the clinical features and genotype-phenotype correlations in 51 reported studies exhibiting an ATL1 gene mutation...
2017: Translational Neurodegeneration
https://www.readbyqxmd.com/read/28389476/defects-in-er-endosome-contacts-impact-lysosome-function-in-hereditary-spastic-paraplegia
#20
Rachel Allison, James R Edgar, Guy Pearson, Tania Rizo, Timothy Newton, Sven Günther, Fiamma Berner, Jennifer Hague, James W Connell, Jürgen Winkler, Jennifer Lippincott-Schwartz, Christian Beetz, Beate Winner, Evan Reid
Contacts between endosomes and the endoplasmic reticulum (ER) promote endosomal tubule fission, but the mechanisms involved and consequences of tubule fission failure are incompletely understood. We found that interaction between the microtubule-severing enzyme spastin and the ESCRT protein IST1 at ER-endosome contacts drives endosomal tubule fission. Failure of fission caused defective sorting of mannose 6-phosphate receptor, with consequently disrupted lysosomal enzyme trafficking and abnormal lysosomal morphology, including in mouse primary neurons and human stem cell-derived neurons...
May 1, 2017: Journal of Cell Biology
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