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Hereditary spastic paraplegia

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https://www.readbyqxmd.com/read/28916646/serac1-deficiency-causes-complicated-hsp-evidence-from-a-novel-splice-mutation-in-a-large-family
#1
Benjamin Roeben, Rebecca Schüle, Susanne Ruf, Benjamin Bender, Bader Alhaddad, Tanja Benkert, Thomas Meitinger, Selina Reich, Judith Böhringer, Claus-Dieter Langhans, Frédéric M Vaz, Saskia B Wortmann-Hagemann, Thorsten Marquardt, Tobias B Haack, Ingeborg Krägeloh-Mann, Ludger Schöls, Matthis Synofzik
OBJECTIVE: To demonstrate that mutations in the phosphatidylglycerol remodelling enzyme SERAC1 can cause juvenile-onset complicated hereditary spastic paraplegia (cHSP) clusters, thus adding SERAC1 to the increasing number of complex lipid cHSP genes. METHODS: Combined genomic and functional validation studies (whole-exome sequencing, mRNA, cDNA and protein), biomarker investigations (3-methyl-glutaconic acid, filipin staining and phosphatidylglycerols PG34:1/PG36:1), and clinical and imaging phenotyping were performed in six affected subjects from two different branches of a large consanguineous family...
September 15, 2017: Journal of Medical Genetics
https://www.readbyqxmd.com/read/28884889/novel-homozygous-missense-mutation-in-nt5c2-underlying-hereditary-spastic-paraplegia-spg45
#2
Rachel Straussberg, Alexandros Onoufriadis, Osnat Konen, Yasmin Zouabi, Lior Cohen, John Y W Lee, Chao-Kai Hsu, Michael A Simpson, John A McGrath
SPG45 is a rare form of autosomal recessive spastic paraplegia associated with mental retardation. Detailed phenotyping and mutation analysis was undertaken in three individuals with SPG45 from a consanguineous family of Arab Muslim origin. Using whole-exome sequencing, we identified a novel homozygous missense mutation in NT5C2 (c.1379T>C; p.Leu460Pro). Our data expand the molecular basis of SPG45, adding the first missense mutation to the current database of nonsense, frameshift, and splice site mutations...
September 8, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28878906/first-patient-with-hereditary-spastic-paraplegia-type-8-in-poland
#3
Piotr Bogucki, Agnieszka Sobczyńska-Tomaszewska
SPG 8 is an autosomal dominant HSP, which phenotype results from KIAA0196 gene mutations. There have been twelve types of KIAA0196 mutations described in HGMD, which are located in conservative region of gene encoding strumpellin. We describe first patient in Poland, simultaneously second in the world with KIAA0196 mutation - p.V620A.
September 2017: Clinical Case Reports
https://www.readbyqxmd.com/read/28870597/spastic-paraplegia-type-4-a-novel-spast-splice-site-donor-mutation-and-expansion-of-the-phenotype-variability
#4
Toshitaka Kawarai, Celeste Montecchiani, Ryosuke Miyamoto, Fabrizio Gaudiello, Carlo Caltagirone, Yuishin Izumi, Ryuji Kaji, Antonio Orlacchio
Mutations in SPG4/SPAST are the most frequent molecular aetiology in the autosomal dominant form of hereditary spastic paraplegia (HSP). Loss-of-function and haploinsufficiency in SPAST have been demonstrated and the pure form of spastic paraplegia is a main clinical manifestation. This study is to explore the novel SPAST splice site donor variant, c.1004+3A>C, in seven patients from two families, one from Italy and the other from Japan. Exon 6 is skipped out by the variant, leading to a premature termination of translation, p...
September 15, 2017: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/28860117/drosophila-atlastin-in-motor-neurons-is-required-for-locomotion-and-presynaptic-function
#5
Cristian De Gregorio, Ricardo Delgado, Andrés Ibacache, Jimena Sierralta, Andrés Couve
Hereditary spastic paraplegias (HSP) are characterized by spasticity and weakness of the lower limbs that result from length-dependent axonopathy of the corticospinal tracts. atlastin, the second most common HSP gene, catalyzes homotypic membrane fusion of endoplasmic reticulum (ER) tubules. How defects in neuronal Atlastin contribute to axonal degeneration has not been explained satisfactorily. Using Drosophila we demonstrate that downregulation or overexpression of Atlastin in motor neurons result in decreased crawling speed and contraction frequency in larvae, while adult flies show progressive decline in climbing ability...
August 31, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28834584/a-de-novo-dominant-mutation-in-kif1a-associated-with-axonal-neuropathy-spasticity-and-autism-spectrum-disorder
#6
Pedro J Tomaselli, Alexander M Rossor, Alejandro Horga, Matilde Laura, Julian C Blake, Henry Houlden, Mary M Reilly
Mutations in the kinesin family member 1A (KIF1A) gene have been associated with a wide range of phenotypes including recessive mutations causing hereditary sensory neuropathy and hereditary spastic paraplegia and de novo dominant mutations causing a more complex neurological disorder affecting both the central and peripheral nervous system. We identified by exome sequencing a de novo dominant missense variant, (c.38G>A, p.R13H), within an ATP binding site of the kinesin motor domain in a patient manifesting a complex phenotype characterized by autism spectrum disorder, spastic paraplegia and axonal neuropathy...
August 23, 2017: Journal of the Peripheral Nervous System: JPNS
https://www.readbyqxmd.com/read/28832565/massive-sequencing-of-70-genes-reveals-a-myriad-of-missing-genes-or-mechanisms-to-be-uncovered-in-hereditary-spastic-paraplegias
#7
Sara Morais, Laure Raymond, Mathilde Mairey, Paula Coutinho, Eva Brandão, Paula Ribeiro, José Leal Loureiro, Jorge Sequeiros, Alexis Brice, Isabel Alonso, Giovanni Stevanin
Hereditary spastic paraplegias (HSP) are neurodegenerative disorders characterized by lower limb spasticity and weakness that can be complicated by other neurological or non-neurological signs. Despite a high genetic heterogeneity (>60 causative genes), 40-70% of the families remain without a molecular diagnosis. Analysis of one of the pioneer cohorts of 193 HSP families generated in the early 1990s in Portugal highlighted that SPAST and SPG11 are the most frequent diagnoses. We have now explored 98 unsolved families from this series using custom next generation sequencing panels analyzing up to 70 candidate HSP genes...
August 23, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28818478/mutations-in-ddhd1-encoding-a-phospholipase-a1-is-a-novel-cause-of-retinopathy-and-neurodegeneration-with-brain-iron-accumulation
#8
Rodolphe Dard, Claire Meyniel, Valérie Touitou, Giovanni Stevanin, Foudil Lamari, Alexandra Durr, Claire Ewenczyk, Fanny Mochel
Defects of phospholipids remodelling and synthesis are inborn errors of metabolism responsible for various clinical presentations including spastic paraplegia, retinopathy, optic atrophy, myo- and cardiomyopathies, and osteo-cutaneous manifestations. DDHD1 encodes a phospholipase A1, which is involved in the remodelling of phospholipids. We previously described a relatively pure hereditary spastic paraplegia (HSP) phenotype associated with mutations in DDHD1. Here we report a complex form of HSP associated with retinal dystrophy and a pattern of neurodegeneration with brain iron accumulation (NBIA) on brain MRI, due to a novel homozygous mutation in DDHD1...
August 14, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28742022/modeling-of-axonal-endoplasmic-reticulum-network-by-spastic-paraplegia-proteins
#9
Belgin Yalçın, Lu Zhao, Martin Stofanko, Niamh C O'Sullivan, Zi Han Kang, Annika Roost, Matthew R Thomas, Sophie Zaessinger, Olivier Blard, Alex L Patto, Anood Sohail, Valentina Baena, Mark Terasaki, Cahir J O'Kane
Axons contain a smooth tubular endoplasmic reticulum (ER) network that is thought to be continuous with ER throughout the neuron; the mechanisms that form this axonal network are unknown. Mutations affecting reticulon or REEP proteins, with intramembrane hairpin domains that model ER membranes, cause an axon degenerative disease, hereditary spastic paraplegia (HSP). We show that Drosophila axons have a dynamic axonal ER network, which these proteins help to model. Loss of HSP hairpin proteins causes ER sheet expansion, partial loss of ER from distal motor axons, and occasional discontinuities in axonal ER...
July 25, 2017: ELife
https://www.readbyqxmd.com/read/28736820/disease-causing-variants-in-the-atl1-gene-are-a-rare-cause-of-hereditary-spastic-paraplegia-among-czech-patients
#10
Anna Uhrová Mészárosová, Dagmar Grečmalová, Michaela Brázdilová, Nina Dvořáčková, Zdeněk Kalina, Marie Čermáková, Dagmar Vávrová, Irena Smetanová, David Staněk, Pavel Seeman
Variants in the ATL1 gene have been repeatedly described as the second most frequent cause of hereditary spastic paraplegia (HSP), a motor neuron disease manifested by progressive lower limb spasticity and weakness. Variants in ATL1 have been described mainly in patients with early onset HSP. We performed Sanger sequencing of all coding exons and adjacent intron regions of the ALT1 gene in 111 Czech patients with pure form of HSP and additional Multiplex-Ligation Probe Analysis (MLPA) testing targeting the ATL1 gene in 56 of them...
July 23, 2017: Annals of Human Genetics
https://www.readbyqxmd.com/read/28725025/an-atypical-case-of-spg56-cyp2u1-related-spastic-paraplegia-presenting-with-delayed-myelination
#11
Gaku Minase, Satoko Miyatake, Shin Nabatame, Hiroshi Arai, Eriko Koshimizu, Takeshi Mizuguchi, Mitsuko Nakashima, Noriko Miyake, Hirotomo Saitsu, Toshinobu Miyamoto, Kazuo Sengoku, Naomichi Matsumoto
Hereditary spastic paraplegia (HSP) is a neurological disorder characterized by a progressive spasticity and muscle weakness of the lower limbs. It is divided into two subtypes, uncomplicated and complicated forms. Biallelic mutations in the cytochrome P450 2U1 gene (CYP2U1) are associated with spastic paraplegia type 56 (SPG56), manifesting both uncomplicated and complicated HSP. Accompanying clinical features include intellectual disability, dystonia, cerebellar ataxia, subclinical peripheral neuropathy, visual impairment, as well as abnormalities in brain magnetic resonance imaging...
July 20, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/28716533/novel-ubqln2-mutations-linked-to-amyotrophic-lateral-sclerosis-and-atypical-hereditary-spastic-paraplegia-phenotype-through-defective-hsp70-mediated-proteolysis
#12
Elisa Teyssou, Laura Chartier, Maria-Del-Mar Amador, Roselina Lam, Géraldine Lautrette, Marie Nicol, Selma Machat, Sandra Da Barroca, Carine Moigneu, Mathilde Mairey, Thierry Larmonier, Safaa Saker, Christelle Dussert, Sylvie Forlani, Bertrand Fontaine, Danielle Seilhean, Delphine Bohl, Séverine Boillée, Vincent Meininger, Philippe Couratier, François Salachas, Giovanni Stevanin, Stéphanie Millecamps
Mutations in UBQLN2 have been associated with rare cases of X-linked juvenile and adult forms of amyotrophic lateral sclerosis (ALS) and ALS linked to frontotemporal dementia (FTD). Here, we report 1 known (c.1489C>T, p.Pro497Ser, P497S) and 3 novel (c.1481C>T, p.Pro494Leu, P494L; c.1498C>T, p.Pro500Ser, P500S; and c.1516C>G, p.Pro506Ala, P506A) missense mutations in the PXX domain of UBQLN2 in familial motor neuron diseases including ALS and spastic paraplegia (SP). A novel missense mutation (c...
June 24, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28716262/new-genetic-causes-for-complex-hereditary-spastic-paraplegia
#13
Paulo Victor Sgobbi de Souza, Thiago Bortholin, Renan Braido Dias, Marco Antônio Troccoli Chieia, Stênio Burlin, Fernando George Monteiro Naylor, Wladimir Bocca Vieira de Rezende Pinto, Acary Souza Bulle Oliveira
INTRODUCTION: Hereditary Spastic Paraplegia (HSP) represents a complex and heterogeneous group of rare neurodegenerative disorders that share a common clinical feature of weakness and lower limb spasticity that can occur alone or in combination with a constellation of other neurological or systemic signs and symptoms. Although the core clinical feature of weakness and lower limb spasticity is virtually universal, the genetic heterogeneity is almost uncountable with more than 70 genetic forms described so far...
August 15, 2017: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/28679690/spg20-mutation-in-three-siblings-with-familial-hereditary-spastic-paraplegia
#14
Leila Dardour, Filip Roelens, Valerie Race, Erika Souche, Maureen Holvoet, Koen Devriendt
Troyer syndrome (MIM#275900) is an autosomal recessive form of complicated hereditary spastic paraplegia. It is characterized by progressive lower extremity spasticity and weakness, dysarthria, distal amyotrophy, developmental delay, short stature, and subtle skeletal abnormalities. It is caused by deleterious mutations in the SPG20 gene, encoding spartin, on Chromosome 13q13. Until now, six unrelated families with a genetically confirmed diagnosis have been reported. Here we report the clinical findings in three brothers of a consanguineous Moroccan family, aged 24, 17, and 7 yr old, with spastic paraplegia, short stature, motor and cognitive delay, and severe intellectual disability...
July 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28678816/characterization-of-kinesin-switch-i-mutations-that-cause-hereditary-spastic-paraplegia
#15
Scott Jennings, Madeline Chenevert, Liqiong Liu, Madhusoodanan Mottamal, Edward J Wojcik, Thomas M Huckaba
Kif5A is a neuronally-enriched isoform of the Kinesin-1 family of cellular transport motors. 23 separate mutations in the motor domain of Kif5A have been identified in patients with the complicated form of hereditary spastic paraplegia (HSP). We performed in vitro assays on dimeric recombinant Kif5A with HSP-causing mutations in the Switch I domain, which participates in the coordination and hydrolysis of ATP by kinesin. We observed a variety of significantly reduced catalytic and mechanical activities as a result of each mutation, with the shared phenotype from each that motility was significantly reduced...
2017: PloS One
https://www.readbyqxmd.com/read/28626794/febrile-ataxia-and-myokymia-broaden-the-spg26-hereditary-spastic-paraplegia-phenotype
#16
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
#17
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...
July 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
#18
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...
August 2017: Journal of Neurology, Neurosurgery, and Psychiatry
https://www.readbyqxmd.com/read/28554554/expanding-the-phenotypic-spectrum-associated-with-mutations-of-dync1h1
#19
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
#20
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
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