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Margaret A Pericakvance - One of the best experts on this subject based on the ideXlab platform.

  • mutation screening of spastin atlastin and reep1 in Hereditary Spastic Paraplegia
    Clinical Genetics, 2011
    Co-Authors: Donald S Mccorquodale, Margaret A Pericakvance, Uzoezi Ozomaro, Jia Huang, Gladys Montenegro, Arielle Kushman, Luigi Citrigno, Justin Price, Fiorella Speziani, Stephan Zuchner
    Abstract:

    Hereditary Spastic Paraplegia (HSP) comprises a group of clinically and genetically heterogeneous diseases that affect the upper motor neurons and their axonal projections. Over 40 chromosomal loci have been identified for autosomal dominant, recessive, and X-linked HSP. Mutations in the genes atlastin, spastin and REEP1 are estimated to account for up to 50% of autosomal dominant HSP and currently guide the molecular diagnosis of HSP. Here we report the mutation screening results of 120 HSP patients from North America for spastin, atlastin, and REEP1, with the latter one partially reported previously. We identified mutations in 36.7% of all tested HSP patients and describe 20 novel changes in spastin and atlastin. Our results add to a growing number of HSP disease associated variants and confirm the high prevalence of atlastin, spastin, and REEP1 mutations in the HSP patient population.

  • mutations in the novel mitochondrial protein reep1 cause Hereditary Spastic Paraplegia type 31
    American Journal of Human Genetics, 2006
    Co-Authors: Stephan Zuchner, Allison E Ashleykoch, Perry C Gaskell, Gaofeng Wang, Khanh Nhat Tranviet, Martha Nance, Jeffery M Vance, Margaret A Pericakvance
    Abstract:

    Hereditary Spastic Paraplegia (HSP) comprises a group of clinically and genetically heterogeneous diseases that affect the upper motor neurons and their axonal projections. For the novel SPG31 locus on chromosome 2p12, we identified six different mutations in the receptor expression–enhancing protein 1 gene (REEP1). REEP1 mutations occurred in 6.5% of the patients with HSP in our sample, making it the third-most common HSP gene. We show that REEP1 is widely expressed and localizes to mitochondria, which underlines the importance of mitochondrial function in neurodegenerative disease.

  • a kinesin heavy chain kif5a mutation in Hereditary Spastic Paraplegia spg10
    American Journal of Human Genetics, 2002
    Co-Authors: Evan Reid, Andrew M Dearlove, Mark T Kloos, Lori Hughes, Simon Bevan, Ingrid K Svenson, Allison E Ashleykoch, Perry C Gaskell, Felicia L. Graham, Margaret A Pericakvance
    Abstract:

    We have identified a missense mutation in the motor domain of the neuronal kinesin heavy chain gene KIF5A, in a family with Hereditary Spastic Paraplegia. The mutation occurs in the family in which the SPG10 locus was originally identified, at an invariant asparagine residue that, when mutated in orthologous kinesin heavy chain motor proteins, prevents stimulation of the motor ATPase by microtubule-binding. Mutation of kinesin orthologues in various species leads to phenotypes resembling Hereditary Spastic Paraplegia. The conventional kinesin motor powers intracellular movement of membranous organelles and other macromolecular cargo from the neuronal cell body to the distal tip of the axon. This finding suggests that the underlying pathology of SPG10 and possibly of other forms of Hereditary Spastic Paraplegia may involve perturbation of neuronal anterograde (or retrograde) axoplasmic flow, leading to axonal degeneration, especially in the longest axons of the central nervous system.

  • Hereditary Spastic Paraplegia advances in genetic research
    Neurology, 1996
    Co-Authors: John K. Fink, Margaret A Pericakvance, Terry Heimanpatterson, Thomas D Bird, Franca Cambi, Mariepierre Dube, Denise A Figlewicz, J L Haines, Afif Hentati, Wendy H Raskind
    Abstract:

    Hereditary Spastic Paraplegia (HSP) is a diverse group of inherited disorders characterized by progressive lower-extremity Spasticity and weakness. Insight into the genetic basis of these disorders is expanding rapidly. Uncomplicated autosomal dominant, autosomal recessive, and X-linked HSP are genetically heterogeneous: different genes cause clinically indistinguishable disorders. A locus for autosomal recessive HSP is on chromosome 8q. Loci for autosomal dominant HSP have been identified on chromosomes 2p, 14q, and 15q. One locus (Xq22) has been identified for X-linked, uncomplicated HSP and shown to be due to a proteolipoprotein gene mutation in one family. The existence of HSP families for whom these loci are excluded indicates the existence of additional, as yet unidentified HSP loci. There is marked clinical similarity among HSP families linked to each of these loci, suggesting that gene products from HSP loci may participate in a common biochemical cascade, which, if disturbed, results in axonal degeneration that is maximal at the ends of the longest CNS axons. Identifying the single gene defects that cause HSPs distal axonopathy may provide insight into factors responsible for development and maintenance of axonal integrity. We review clinical, genetic, and pathologic features of HSP and present differential diagnosis and diagnostic criteria of this important group of disorders. We discuss polymorphic microsatellite markers useful for genetic linkage analysis and genetic counseling in HSP. NEUROLOGY 1996;46: 1507-1514

Alexandra Durr - One of the best experts on this subject based on the ideXlab platform.

  • alteration of ornithine metabolism leads to dominant and recessive Hereditary Spastic Paraplegia
    Brain, 2015
    Co-Authors: Marie Coutelier, Cyril Goizet, Alexandra Durr, Florence Habarou, Sara Morais, Alexandre Dionnelaporte, Juliette Konop, Marion Stoll, Perrine Charles, Maxime Jacoupy
    Abstract:

    Hereditary Spastic Paraplegias are heterogeneous neurological disorders characterized by a pyramidal syndrome with symptoms predominantly affecting the lower limbs. Some limited pyramidal involvement also occurs in patients with an autosomal recessive neurocutaneous syndrome due to ALDH18A1 mutations. ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthase (P5CS), an enzyme that catalyses the first and common step of proline and ornithine biosynthesis from glutamate. Through exome sequencing and candidate gene screening, we report two families with autosomal recessive transmission of ALDH18A1 mutations, and predominant complex Hereditary Spastic Paraplegia with marked cognitive impairment, without any cutaneous abnormality. More interestingly, we also identified monoallelic ALDH18A1 mutations segregating in three independent families with autosomal dominant pure or complex Hereditary Spastic Paraplegia, as well as in two sporadic patients. Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from two families suggested P5CS deficiency. Glutamine loading tests in two fibroblast cultures from two related affected subjects confirmed a metabolic block at the level of P5CS in vivo. Besides expanding the clinical spectrum of ALDH18A1 -related pathology, we describe mutations segregating in an autosomal dominant pattern. The latter are associated with a potential trait biomarker; we therefore suggest including amino acid chromatography in the clinico-genetic work-up of Hereditary Spastic Paraplegia, particularly in dominant cases, as the associated phenotype is not distinct from other causative genes. * Abbreviations : HSP : Hereditary Spastic Paraplegia P5CS : delta-1-pyrroline-5-carboxylate synthase

  • Alteration of ornithine metabolism leads to dominant and recessive Hereditary Spastic Paraplegia.
    Brain : a journal of neurology, 2015
    Co-Authors: Marie Coutelier, Cyril Goizet, Alexandra Durr, Florence Habarou, Sara Morais, Juliette Konop, Marion Stoll, Alexandre Dionne-laporte, Perrine Charles
    Abstract:

    Hereditary Spastic Paraplegias are heterogeneous neurological disorders characterized by a pyramidal syndrome with symptoms predominantly affecting the lower limbs. Some limited pyramidal involvement also occurs in patients with an autosomal recessive neurocutaneous syndrome due to ALDH18A1 mutations. ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthase (P5CS), an enzyme that catalyses the first and common step of proline and ornithine biosynthesis from glutamate. Through exome sequencing and candidate gene screening, we report two families with autosomal recessive transmission of ALDH18A1 mutations, and predominant complex Hereditary Spastic Paraplegia with marked cognitive impairment, without any cutaneous abnormality. More interestingly, we also identified monoallelic ALDH18A1 mutations segregating in three independent families with autosomal dominant pure or complex Hereditary Spastic Paraplegia, as well as in two sporadic patients. Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from two families suggested P5CS deficiency. Glutamine loading tests in two fibroblast cultures from two related affected subjects confirmed a metabolic block at the level of P5CS in vivo. Besides expanding the clinical spectrum of ALDH18A1-related pathology, we describe mutations segregating in an autosomal dominant pattern. The latter are associated with a potential trait biomarker; we therefore suggest including amino acid chromatography in the clinico-genetic work-up of Hereditary Spastic Paraplegia, particularly in dominant cases, as the associated phenotype is not distinct from other causative genes.

  • cyp7b1 mutations in pure and complex forms of Hereditary Spastic Paraplegia type 5
    Brain, 2009
    Co-Authors: Alexandra Durr, C Goizet, Amir Boukhris, Christian Beetz, Jeremy Truchetto, Christelle Tesson
    Abstract:

    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-α 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.

  • spg3a is the most frequent cause of Hereditary Spastic Paraplegia with onset before age 10 years
    Neurology, 2006
    Co-Authors: Michito Namekawa, C Goizet, Christel Depienne, Giovanni Stevanin, Pascale Ribai, I Nelson, Sylvie Forlani, F Fellmann, Merle Ruberg, Alexandra Durr
    Abstract:

    Seven families with six different SPG3A mutations were identified among 106 with autosomal dominant Hereditary Spastic Paraplegia (HSP). Two mutations were novel (T162P, C375R). SPG3A was twice as frequent as SPG4 in patients with onset before age 10 years (31.8%). Later onset was not observed. The phenotype was pure HSP, but disease duration was longer than in non-SPG3A/SPG4 patients, leading ultimately to greater handicap.

John K. Fink - One of the best experts on this subject based on the ideXlab platform.

  • Hereditary Spastic Paraplegia clinical principles and genetic advances
    Seminars in Neurology, 2014
    Co-Authors: John K. Fink
    Abstract:

    Hereditary Spastic Paraplegia (HSP) refers to inherited disorders in which Spastic gait is either the only feature or is a major syndrome feature. There are more than 70 genetic types of HSP. Neuropathological studies, albeit limited to only a few genetic types of HSP, have identified axon degeneration involving the distal ends of the corticospinal tracts and fasciculus gracilis fibers. In this review, the author highlights the clinical and genetic features of HSP.

  • Hereditary Spastic Paraplegia
    Current Neurology and Neuroscience Reports, 2006
    Co-Authors: John K. Fink
    Abstract:

    The Hereditary Spastic Paraplegias (HSPs) comprise a large group of inherited neurologic disorders. HSP is classified according to the mode of inheritance, the HSP locus when known, and whether the Spastic Paraplegia syndrome occurs alone or is accompanied by additional neurologic or systemic abnormalities. Analysis of 11 recently discovered HSP genes provides insight into HSP pathogenesis. Hereditary Spastic Paraplegia is a clinical diagnosis for which laboratory confirmation is sometimes possible, and careful exclusion of alternate and co-existing disorders is an important element in HSP diagnosis. Treatment for HSP is presently limited to symptomatic reduction of muscle Spasticity, reduction in urinary urgency, and strength and gait improvement through physical therapy. Prenatal genetic testing in HSP is possible for some individuals with the increasing availability of HSP gene analysis.

  • Spinal cord magnetic resonance imaging in autosomal dominant Hereditary Spastic Paraplegia
    Neuroradiology, 2005
    Co-Authors: P. Hedera, Shirley Rainier, O. P. Eldevik, P. Maly, John K. Fink
    Abstract:

    Hereditary Spastic Paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative disorders characterized by progressive lower extremity weakness and Spasticity. HSP pathology involves axonal degeneration that is most pronounced in the terminal segments of the longest descending (pyramidal) and ascending (dorsal columns) tracts. In this study, we compared spinal cord magnetic resonance imaging (MRI) in 13 HSP patients with four different types of autosomal dominant Hereditary Spastic Paraplegia (SPG3A, SPG4, SPG6, and SPG8) with age-matched control subjects. The cross-section area of HSP subjects at cervical level C2 was 59.42±12.57 mm^2 and at thoracic level T9 was 28.58±5.25 mm^2. Both of these values were less than in the healthy controls ( p

  • Hereditary Spastic Paraplegia
    Encyclopedia of Neuroscience, 2004
    Co-Authors: John K. Fink
    Abstract:

    Hereditary Spastic Paraplegia (HSP) (also known as familial Spastic paraparesis and Strumpell–Lorrain syndrome) refers to clinically and genetically diverse disorders that share the primary feature of progressive, generally severe, lower extremity weakness, and Spasticity. HSP is classified according to the mode of inheritance and whether progressive Spasticity occurs in isolation (uncomplicated HSP) or with other neurologic abnormalities (complicated HSP), including optic neuropathy, retinopathy, extrapyramidal disturbance, dementia, ataxia, ichthyosis, mental retardation, and deafness.

  • novel locus for autosomal dominant Hereditary Spastic Paraplegia on chromosome 8q
    American Journal of Human Genetics, 1999
    Co-Authors: Peter Hedera, Xinping Zhao, David Alvarado, Shirley Rainier, Jeffery Williamson, Brith Otterud, M Leppert, John K. Fink
    Abstract:

    Hereditary Spastic Paraplegia (HSP) is a clinically and genetically heterogeneous group of disorders characterized by insidiously progressive Spastic weakness in the legs. Genetic loci for autosomal dominant HSP exist on chromosomes 2p, 14q, and 15q. These loci are excluded in 45% of autosomal dominant HSP kindreds, indicating the presence of additional loci for autosomal dominant HSP. We analyzed a Caucasian kindred with autosomal dominant HSP and identified tight linkage between the disorder and microsatellite markers on chromosome 8q (maximum two-point LOD score 5.51 at recombination fraction 0). Our results clearly establish the existence of a locus for autosomal dominant HSP on chromosome 8q23-24. Currently this locus spans 6.2 cM between D8S1804 and D8S1774 and includes several potential candidate genes. Identifying this novel HSP locus on chromosome 8q23-24 will facilitate discovery of this HSP gene, improve genetic counseling for families with linkage to this locus, and extend our ability to correlate clinical features with different HSP loci.

John Q. Trojanowski - One of the best experts on this subject based on the ideXlab platform.

  • TDP-43 pathology in a case of Hereditary Spastic Paraplegia with a NIPA1/SPG6 mutation
    Acta Neuropathologica, 2012
    Co-Authors: Maria Martinez-lage, Laura Molina-porcel, Dana Falcone, Leo Mccluskey, Vivianna M. Deerlin, John Q. Trojanowski
    Abstract:

    Mutations in NIPA1 (non-imprinted in Prader–Willi/Angelman syndrome) have been described as a cause of autosomal dominant Hereditary Spastic Paraplegia (HSP) known as SPG6 (Spastic Paraplegia-6). We present the first neuropathological description of a patient with a NIPA1 mutation, and clinical phenotype of complicated HSP with motor neuron disease-like syndrome and cognitive decline. Postmortem examination revealed degeneration of lateral corticospinal tracts and dorsal columns with motor neuron loss. TDP-43 immunostaining showed widespread spinal cord and cerebral skein-like and round neuronal cytoplasmic inclusions. We ruled out NIPA1 mutations in 419 additional cases of motor neuron disease. These findings suggest that Hereditary Spastic Paraplegia due to NIPA1 mutations could represent a TDP-43 proteinopathy.

  • TDP-43 pathology in a case of Hereditary Spastic Paraplegia with a NIPA1 /SPG6 mutation
    Acta Neuropathologica, 2012
    Co-Authors: Maria Martinez-lage, Laura Molina-porcel, Dana Falcone, Leo Mccluskey, Vivianna M. Deerlin, John Q. Trojanowski
    Abstract:

    Mutations in NIPA1 (non-imprinted in Prader–Willi/Angelman syndrome) have been described as a cause of autosomal dominant Hereditary Spastic Paraplegia (HSP) known as SPG6 (Spastic Paraplegia-6). We present the first neuropathological description of a patient with a NIPA1 mutation, and clinical phenotype of complicated HSP with motor neuron disease-like syndrome and cognitive decline. Postmortem examination revealed degeneration of lateral corticospinal tracts and dorsal columns with motor neuron loss. TDP-43 immunostaining showed widespread spinal cord and cerebral skein-like and round neuronal cytoplasmic inclusions. We ruled out NIPA1 mutations in 419 additional cases of motor neuron disease. These findings suggest that Hereditary Spastic Paraplegia due to NIPA1 mutations could represent a TDP-43 proteinopathy.

Andrew H Crosby - One of the best experts on this subject based on the ideXlab platform.

  • Hereditary Spastic Paraplegia from diagnosis to emerging therapeutic approaches
    Lancet Neurology, 2019
    Co-Authors: Samuel Shribman, Henry Houlden, Evan Reid, Andrew H Crosby, Thomas T Warner
    Abstract:

    Summary Hereditary Spastic Paraplegia (HSP) describes a heterogeneous group of genetic neurodegenerative diseases characterised by progressive Spasticity of the lower limbs. The pathogenic mechanism, associated clinical features, and imaging abnormalities vary substantially according to the affected gene and differentiating HSP from other genetic diseases associated with Spasticity can be challenging. Next generation sequencing-based gene panels are now widely available but have limitations and a molecular diagnosis is not made in most suspected cases. Symptomatic management continues to evolve but with a greater understanding of the pathophysiological basis of individual HSP subtypes there are emerging opportunities to provide targeted molecular therapies and personalised medicine.

  • Hereditary Spastic Paraplegia clinical features and pathogenetic mechanisms
    Lancet Neurology, 2008
    Co-Authors: Sara Salinas, Christos Proukakis, Andrew H Crosby, Thomas T Warner
    Abstract:

    Summary Hereditary Spastic Paraplegia (HSP) describes a heterogeneous group of genetic neurodegenerative disorders in which the most severely affected neurons are those of the spinal cord. These disorders are characterised clinically by progressive Spasticity and weakness of the lower limbs, and pathologically by retrograde axonal degeneration of the corticospinal tracts and posterior columns. In recent years, genetic studies have identified key cellular functions that are vital for the maintenance of axonal homoeostasis in HSP. Here, we describe the clinical and diagnostic features of the various forms of HSP. We also discuss the genes that have been identified and the emerging pathogenic mechanisms.

  • Analysis of CYP7B1 in non-consanguineous cases of Hereditary Spastic Paraplegia
    neurogenetics, 2008
    Co-Authors: Rebecca Schüle, Andrew H Crosby, Elisabeth Brandt, Kathrin N. Karle, Maria Tsaousidou, Stephan Klebe, Sven Klimpe, Michaela Auer-grumbach, Christian A. Hübner, Ludger Schols
    Abstract:

    Hereditary Spastic Paraplegia (HSP) is a neurodegenerative condition defined clinically by lower limb Spasticity and weakness. Homozygous mutations in CYP7B1 have been identified in several consanguineous families that represented HSP type 5 (SPG5), one of the many genetic forms of the disease. We used direct sequencing and multiplex ligation-dependent probe amplification to screen for CYP7B1 alterations in apparently sporadic HSP patients ( n  = 12) as well as index patients from non-consanguineous families with recessive ( n  = 8) and dominant ( n  = 8) transmission of HSP. One sporadic patient showing HSP as well as optic atrophy carried a homozygous nonsense mutation. Compound heterozygosity was observed in a recessive family with a clinically pure phenotype. A heterozygous missense change segregated in a small dominant family. We also found a significant association of a known coding polymorphism with cerebellar signs complicating a primary HSP phenotype. Our findings suggest CYP7B1 alterations to represent a rather frequent cause of HSP that should be considered in patients with various clinical presentations.

  • is the transportation highway the right road for Hereditary Spastic Paraplegia
    American Journal of Human Genetics, 2002
    Co-Authors: Andrew H Crosby, Christos Proukakis
    Abstract:

    The term "Hereditary Spastic Paraplegia" (HSP) refers to a genetically and clinically diverse group of disorders whose primary feature is progressive Spasticity of the lower extremities. The condition arises because of degeneration of the longest motor and sensory axons on the spinal cord, which appear to be most sensitive to the underlying mutations. The marked genetic heterogeneity in HSP, with 20 loci chromosomally mapped and eight genes now identified, suggests that a number of defective cellular processes may be shown to result in the disease. Although previous studies have suggested a mitochondrial basis for at least one form of the disease, a mechanism common to a number of the other genes mutated in HSP has remained elusive until now. The identification of the most recent genes for the condition suggests that aberrant cellular-trafficking dynamics may be a common process responsible for the specific pattern of neurodegeneration seen in HSP.

  • spg20 is mutated in troyer syndrome an Hereditary Spastic Paraplegia
    Nature Genetics, 2002
    Co-Authors: Heema Patel, H Cross, Christos Proukakis, Ruth Hershberger, Peer Bork, Francesca D Ciccarelli, Michael A Patton, Victor A Mckusick, Andrew H Crosby
    Abstract:

    Troyer syndrome (TRS) is an autosomal recessive complicated Hereditary Spastic Paraplegia (HSP) that occurs with high frequency in the Old Order Amish. We report mapping of the TRS locus to chromosome 13q12.3 and identify a frameshift mutation in SPG20, encoding spartin. Comparative sequence analysis indicates that spartin shares similarity with molecules involved in endosomal trafficking and with spastin, a molecule implicated in microtubule interaction that is commonly mutated in HSP.