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Alexandra Durr - One of the best experts on this subject based on the ideXlab platform.
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alteration of ornithine metabolism leads to dominant and recessive hereditary Spastic Paraplegia
Brain, 2015Co-Authors: Marie Coutelier, Alexandre Dionnelaporte, Cyril Goizet, Juliette Konop, Perrine Charles, Sara Morais, Florence Habarou, Marion Stoll, Alexandra Durr, Maxime JacoupyAbstract: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
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Alteration of ornithine metabolism leads to dominant and recessive hereditary Spastic Paraplegia.
Brain : a journal of neurology, 2015Co-Authors: Marie Coutelier, Alexandre Dionne-laporte, Cyril Goizet, Juliette Konop, Sara Morais, Florence Habarou, Marion Stoll, Alexandra Durr, Perrine CharlesAbstract: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.
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cyp7b1 mutations in pure and complex forms of hereditary Spastic Paraplegia type 5
Brain, 2009Co-Authors: Amir Boukhris, Jeremy Truchetto, Cyril Goizet, Christian Beetz, Christelle Tesson, Alexandra DurrAbstract: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.
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mental deficiency in three families with spg4 Spastic Paraplegia
European Journal of Human Genetics, 2008Co-Authors: Pascale Ribai, Christel Depienne, Alexis Brice, Estelle Fedirko, Annecatherine Jothy, Caterine Viveweger, Valerie Hahnbarma, Alexandra DurrAbstract:Mutations and deletions in the SPG4 gene are responsible for up to 40% of autosomal dominant hereditary Spastic Paraplegia (HSP). Patients have pyramidal signs in the lower limbs and some present additional features including cognitive impairment such as executive dysfunction or subcortical dementia. We report 13 patients from three SPG4 families, who had Spastic Paraplegia associated with mental retardation (n=1), extensive social dependence (n=10), or isolated psychomotor delay (n=2). In family FSP-698, 10 affected individuals had both HSP and mental deficiency leading to social dependence in 9 and institutionalization in 5. The mean age at onset of Spastic Paraplegia was 11+/-20 years, ranging from 1 to 51 years. This phenotype segregated either with a novel p.Glu442Lys mutation or the two previously described p.Arg459Thr and p.Arg499Cys substitutions in the SPG4 gene. Since two of these mutations were previously reported in families with a pure form of the disease, another genetic factor linked to SPG4 could be responsible for this complex phenotype.
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spg3a is the most frequent cause of hereditary Spastic Paraplegia with onset before age 10 years
Neurology, 2006Co-Authors: Michito Namekawa, Christel Depienne, Pascale Ribai, F Fellmann, Cyril Goizet, Sylvie Forlani, I. Nelson, Merle Ruberg, Giovanni Stevanin, Alexandra DurrAbstract: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.
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hereditary Spastic Paraplegia clinical principles and genetic advances
Seminars in Neurology, 2014Co-Authors: John K. FinkAbstract: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.
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Hereditary Spastic Paraplegia: clinico-pathologic features and emerging molecular mechanisms
Acta Neuropathologica, 2013Co-Authors: John K. FinkAbstract:Hereditary Spastic Paraplegia (HSP) is a syndrome designation describing inherited disorders in which lower extremity weakness and Spasticity are the predominant symptoms. There are more than 50 genetic types of HSP. HSP affects individuals of diverse ethnic groups with prevalence estimates ranging from 1.2 to 9.6 per 100,000. Symptoms may begin at any age. Gait impairment that begins after childhood usually worsens very slowly over many years. Gait impairment that begins in infancy and early childhood may not worsen significantly. Postmortem studies consistently identify degeneration of corticospinal tract axons (maximal in the thoracic spinal cord) and degeneration of fasciculus gracilis fibers (maximal in the cervico-medullary region). HSP syndromes thus appear to involve motor-sensory axon degeneration affecting predominantly (but not exclusively) the distal ends of long central nervous system (CNS) axons. In general, proteins encoded by HSP genes have diverse functions including (1) axon transport (e.g. SPG30/KIF1A, SPG10/KIF5A and possibly SPG4/Spastin); (2) endoplasmic reticulum morphology (e.g. SPG3A/Atlastin, SPG4/Spastin, SPG12/reticulon 2, and SPG31/REEP1, all of which interact); (3) mitochondrial function (e.g. SPG13/chaperonin 60/heat-shock protein 60, SPG7/paraplegin; and mitochondrial ATP6); (4) myelin formation (e.g. SPG2/Proteolipid protein and SPG42/Connexin 47); (5) protein folding and ER-stress response (SPG6/NIPA1, SPG8/K1AA0196 (Strumpellin), SGP17/BSCL2 (Seipin), “mutilating sensory neuropathy with Spastic Paraplegia” owing to CcT5 mutation and presumably SPG18/ERLIN2); (6) corticospinal tract and other neurodevelopment (e.g. SPG1/L1 cell adhesion molecule and SPG22/thyroid transporter MCT8); (7) fatty acid and phospholipid metabolism (e.g. SPG28/DDHD1, SPG35/FA2H, SPG39/NTE, SPG54/DDHD2, and SPG56/CYP2U1); and (8) endosome membrane trafficking and vesicle formation (e.g. SPG47/AP4B1, SPG48/KIAA0415, SPG50/AP4M1, SPG51/AP4E, SPG52/AP4S1, and VSPG53/VPS37A). The availability of animal models (including bovine, murine, zebrafish, Drosophila, and C. elegans ) for many types of HSP permits exploration of disease mechanisms and potential treatments. This review highlights emerging concepts of this large group of clinically similar disorders.
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Hereditary Spastic Paraplegia
Current Neurology and Neuroscience Reports, 2006Co-Authors: John K. FinkAbstract: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.
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hereditary Spastic Paraplegia
Encyclopedia of Neuroscience, 2004Co-Authors: John K. FinkAbstract: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.
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hereditary Spastic Paraplegia
Neurologic Clinics, 2002Co-Authors: John K. FinkAbstract:The hereditary Spastic Paraplegias (HSPs) are a clinically and genetically diverse group of disorders in which the predominant symptom is lower extremity weakness and Spasticity that usually, though not always, progresses insidiously. HSP is also referred to as familial Spastic Paraplegia (FSP), hereditary (or familial) Spastic paraparesis, and Strumpell-Lorrain syndrome.
Cyril Goizet - One of the best experts on this subject based on the ideXlab platform.
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alteration of ornithine metabolism leads to dominant and recessive hereditary Spastic Paraplegia
Brain, 2015Co-Authors: Marie Coutelier, Alexandre Dionnelaporte, Cyril Goizet, Juliette Konop, Perrine Charles, Sara Morais, Florence Habarou, Marion Stoll, Alexandra Durr, Maxime JacoupyAbstract: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
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Alteration of ornithine metabolism leads to dominant and recessive hereditary Spastic Paraplegia.
Brain : a journal of neurology, 2015Co-Authors: Marie Coutelier, Alexandre Dionne-laporte, Cyril Goizet, Juliette Konop, Sara Morais, Florence Habarou, Marion Stoll, Alexandra Durr, Perrine CharlesAbstract: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.
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cyp7b1 mutations in pure and complex forms of hereditary Spastic Paraplegia type 5
Brain, 2009Co-Authors: Amir Boukhris, Jeremy Truchetto, Cyril Goizet, Christian Beetz, Christelle Tesson, Alexandra DurrAbstract: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.
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spg3a is the most frequent cause of hereditary Spastic Paraplegia with onset before age 10 years
Neurology, 2006Co-Authors: Michito Namekawa, Christel Depienne, Pascale Ribai, F Fellmann, Cyril Goizet, Sylvie Forlani, I. Nelson, Merle Ruberg, Giovanni Stevanin, Alexandra DurrAbstract: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.
Akinori Nakamura - One of the best experts on this subject based on the ideXlab platform.
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linkage of autosomal recessive hereditary Spastic Paraplegia with mental impairment and thin corpus callosum to chromosome 15q13 15
Annals of Neurology, 2000Co-Authors: Yoko Shibasaki, Hajime Tanaka, Kiyoshi Iwabuchi, Sari Kawasaki, Hiroshi Kondo, Kazutoshi Uekawa, Masayuki Ueda, Tatsushi Kamiya, Yasuo Katayama, Akinori NakamuraAbstract:To date, three loci for autosomal recessive hereditary Spastic Paraplegia (ARHSP) linked to chromosomes 8p12-q13, 16qter, and 15q13-15 have been characterized. We have clinically characterized 13 Japanese ARHSP families and performed genetic linkage analyses. All 13 families were classified as having the "complicated" form, which manifests with mental impairment and thin corpus callosum. Linkage to the 8p12-q13 and 16qter loci was excluded, although 10 of the 13 families showed marker data consistent with linkage to the 15q13-15 locus. The multipoint LOD score of the 10 families linked to chromosome 15 was above 9.00 in the 3-centimorgan segment flanked by D15S994 and D15S659, with a maximum multipoint LOD score of 9.68 at a position 1.2 centimorgans telomeric from D15S994 to D15S659. We have shown that ARHSP with thin corpus callosum, a subtype of recessive Spastic Paraplegia, maps to chromosome 15q13-15.
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linkage of autosomal recessive hereditary Spastic Paraplegia with mental impairment and thin corpus callosum to chromosome 15q13 15
Annals of Neurology, 2000Co-Authors: Yoko Shibasaki, K. Iwabuchi, Hajime Tanaka, Sari Kawasaki, Hiroshi Kondo, Kazutoshi Uekawa, Masayuki Ueda, Tatsushi Kamiya, Yasuo Katayama, Akinori NakamuraAbstract:To date, three loci for autosomal recessive hereditary Spastic Paraplegia (ARHSP) linked to chromosomes 8p12-q13, 16qter, and 15q13–15 have been characterized. We have clinically characterized 13 Japanese ARHSP families and performed genetic linkage analyses. All 13 families were classified as having the “complicated” form, which manifests with mental impairment and thin corpus callosum. Linkage to the 8p12-q13 and 16qter loci was excluded, although 10 of the 13 families showed marker data consistent with linkage to the 15q13–15 locus. The multipoint LOD score of the 10 families linked to chromosome 15 was above 9.00 in the 3-centimorgan segment flanked by D15S994 and D15S659, with a maximum multipoint LOD score of 9.68 at a position 1.2 centimorgans telomeric from D15S994 to D15S659. We have shown that ARHSP with thin corpus callosum, a subtype of recessive Spastic Paraplegia, maps to chromosome 15q13–15. Ann Neurol 2000;48:108–112
Filippo M Santorelli - One of the best experts on this subject based on the ideXlab platform.
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biallelic variants in hpdl cause pure and complicated hereditary Spastic Paraplegia
Brain, 2021Co-Authors: Manuela Wiessner, Christian Beetz, Filippo M Santorelli, Reza Maroofian, Andrea Pedroni, Juliane S Muller, Rolf Stucka, Stephanie Efthymiou, Ahmed Alfares, Changlian ZhuAbstract:Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary Spastic Paraplegia to infantile-onset Spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary Spastic Paraplegia to infantile-onset Spastic tetraplegia associated with global developmental delays.
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hereditary Spastic Paraplegia clinical genetic characteristics and evolving molecular mechanisms
Experimental Neurology, 2014Co-Authors: Temistocle Lo Giudice, Filippo M Santorelli, Toshitaka Kawarai, Federica Lombardi, Antonio OrlacchioAbstract:Hereditary Spastic Paraplegia (HSP) is a group of clinically and genetically heterogeneous neurological disorders characterized by pathophysiologic hallmark of length-dependent distal axonal degeneration of the corticospinal tracts. The prominent features of this pathological condition are progressive Spasticity and weakness of the lower limbs. To date, 72 Spastic gait disease-loci and 55 Spastic Paraplegia genes (SPGs) have been identified. All modes of inheritance (autosomal dominant, autosomal recessive, and X-linked) have been described. Recently, a late onset Spastic gait disorder with maternal trait of inheritance has been reported, as well as mutations in genes not yet classified as Spastic gait disease. Several cellular processes are involved in its pathogenesis, such as membrane and axonal transport, endoplasmic reticulum membrane modeling and shaping, mitochondrial function, DNA repair, autophagy, and abnormalities in lipid metabolism and myelination processes. Moreover, recent evidences have been found about the impairment of endosome membrane trafficking in vesicle formation and about the involvement of oxidative stress and mtDNA polymorphisms in the onset of the disease. Interactome networks have been postulated by bioinformatics and biological analyses of Spastic Paraplegia genes, which would contribute to the development of new therapeutic approaches.
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novel mutations in spg11 cause hereditary Spastic Paraplegia associated with early onset levodopa responsive parkinsonism
Movement Disorders, 2011Co-Authors: Arianna Guidubaldi, Carla Piano, Martina Petracca, Gabriella Silvestri, Alessandra Tessa, Filippo M Santorelli, Anna Rita BentivoglioAbstract:Background: Autosomal recessive hereditary Spastic Paraplegia with thin corpus callosum is a neurodegenerative disorder characterized by Spastic paraparesis, cognitive impairment, and peripheral neuropathy. The neuroradiologic hallmarks are thin corpus callosum and periventricular white matter changes. Mutations in the SPG11 gene have been identified to be a major cause of autosomal recessive hereditary Spastic Paraplegia with thin corpus callosum and recently also proven to be responsible for juvenile parkinsonism associated with Spastic Paraplegia. Methods: We describe one Italian autosomal recessive hereditary Spastic Paraplegia with thin corpus callosum patient who unusually presented at onset, 16 years, with parkinsonism-like features, responsive to dopaminergic therapy. Then the clinical picture evolved and became more complex. A brain magnetic resonance imaging scan showed thin corpus callosum and hyperintense T2-weighted lesions in periventricular regions, and the 123I-ioflupane single-photon emission coupled tomography was abnormal. Results: Genetic analysis detected two novel mutations, a c.3664insT variant in compound heterozygosity with a c.6331insG mutation, in SPG11. Discussion: This case confirms the high genetic and clinical heterogeneity associated with SPG11 mutations. It also offers further evidence that parkinsonism may initiate autosomal recessive hereditary Spastic Paraplegia with thin corpus callosum and that parkinsonian symptoms can have variable dopaminergic response in these patients. © 2011 Movement Disorder Society
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Mutations in SPG11, encoding spatacsin, are a major cause of Spastic Paraplegia with thin corpus callosum.
Nature Genetics, 2007Co-Authors: Giovanni Stevanin, Alessandra Tessa, Filippo M Santorelli, Paula Coutinho, Hamid Azzedine, Jacques Chomilier, Paola S Denora, Elodie Martin, Anne-marie Ouvrard-hernandez, Naima BouslamAbstract:Autosomal recessive hereditary Spastic Paraplegia (ARHSP) with thin corpus callosum (TCC) is a common and clinically distinct form of familial Spastic Paraplegia that is linked to the SPG11 locus on chromosome 15 in most affected families. We analyzed 12 ARHSP-TCC families, refined the SPG11 candidate interval and identified ten mutations in a previously unidentified gene expressed ubiquitously in the nervous system but most prominently in the cerebellum, cerebral cortex, hippocampus and pineal gland. The mutations were either nonsense or insertions and deletions leading to a frameshift, suggesting a loss-of-function mechanism. The identification of the function of the gene will provide insight into the mechanisms leading to the degeneration of the corticospinal tract and other brain structures in this frequent form of ARHSP.