Infantile ascending hereditary spastic paralysis (IAHSP)

Lesca, Gaëtan; Eymard-Pierre, Éléonore; Santorelli, Filippo M.; Cusmai, Raffaella; Capua, M. Di; Valente, Enza Maria; Attia‐Sobol, Jocelyne; Plauchu, H; Leuzzi, Vincenzo; Ponzone, A; Boespflug‐Tanguy, Odile; Bertini, Enrico

doi:10.1212/01.wnl.0000048207.28790.25

Cited by 69 publications

(53 citation statements)

References 37 publications

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“…5,15,17 This sign was seen in 5 of our patients (55%) (Fig 2A, -B). In family III, it was present in the older patient but absent in the younger one.…”

Section: Discussionmentioning

confidence: 65%

“…Whereas findings of brain and spinal MR imaging may appear normal in some patients as in our patient 9, there is a spectrum of MR imaging findings seen in patients with HSP, including mild brain and spinal atrophy, high T2 signal intensity in the posterior limb of the internal capsule, unspecific white matter lesions, thinning of the corpus callosum, 3-10 and brain and cerebellar atrophy predominantly in the motor areas and pericentral gyri. 5 A quantitative 3D MR imaging study of the brain volume demonstrated marked brain atrophy associated with HSP compared with agematched controls, and it was more severe and involved both gray and white matter 16 in the complicated forms of HSP. In our study, 4 patients had mild cerebral atrophy and just 1 had mild cerebellar atrophy (patient 7).…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Recent genetic studies have identified multiple loci on different chromosomes responsible for autosomal recessive, autosomal dominant, or X-linked forms of HSP and some of the proteins encoded by those genes. [3][4][5] The radiologic findings of HSP are nonspecific, including mild-to-moderate brain atrophy, thinning of the corpus callosum, nonspecific white matter lesions in the cerebral hemispheres, abnormal T2 high signal intensity in the posterior limb of the internal capsules, and atrophy of the spinal cord. [3][4][5][6][7][8][9][10] Pathologic studies have shown that the corticospinal tracts, which route through the posterior limb of the internal capsules on their way to the brain stem and spinal cord, are the main tracts involved in HSP.…”

mentioning

confidence: 99%

“…[3][4][5] The radiologic findings of HSP are nonspecific, including mild-to-moderate brain atrophy, thinning of the corpus callosum, nonspecific white matter lesions in the cerebral hemispheres, abnormal T2 high signal intensity in the posterior limb of the internal capsules, and atrophy of the spinal cord. [3][4][5][6][7][8][9][10] Pathologic studies have shown that the corticospinal tracts, which route through the posterior limb of the internal capsules on their way to the brain stem and spinal cord, are the main tracts involved in HSP. Recently, in brain MR imaging of 2 unrelated patients with autosomal recessive HSP, we found high signal intensities in the posterior limb of the internal capsules bilaterally in the anatomic location of the corticospinal tracts.…”

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confidence: 99%

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MR Imaging Findings in Autosomal Recessive Hereditary Spastic Paraplegia

Hourani

El-Hajj²,

Barada³

et al. 2009

AJNR Am J Neuroradiol

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BACKGROUND AND PURPOSE:Hereditary spastic paraplegia (HSP) is a disorder characterized by degeneration of the corticospinal tracts and posterior column of the spinal cord. Previously described radiologic findings included nonspecific brain abnormalities such as brain atrophy and white matter lesions, as well as atrophy of the spinal cord. In our study, we aimed to better characterize brain and spine MR imaging findings in a series of patients with HSP.

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“…5,15,17 This sign was seen in 5 of our patients (55%) (Fig 2A, -B). In family III, it was present in the older patient but absent in the younger one.…”

Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

MR Imaging Findings in Autosomal Recessive Hereditary Spastic Paraplegia

Hourani

El-Hajj²,

Barada³

et al. 2009

AJNR Am J Neuroradiol

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“…AlsinLF contains three guanine nucleotide exchange factor (GEF) homologous domains consisting of a regulator of chromosome condensation 1 (RCC1), Rho guanine nucleotide exchanging factor (RhoGEF), and vacuolar protein sorting 9 (VPS9) (5). All known ALS2 mutations are nucleotide deletions causing a C-terminal truncation of alsinLF (5)(6)(7)(8)(9)(10). Patients with a C-terminally truncated alsinLF show a variety of infantile-onset motoneuronal disorders, including ALS, which involves both upper and lower motor neurons, and hereditary spastic paraplegia, which involves only upper motor neurons.…”

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confidence: 99%

A Rac1/Phosphatidylinositol 3-Kinase/Akt3 Anti-apoptotic Pathway, Triggered by AlsinLF, the Product of the ALS2 Gene, Antagonizes Cu/Zn-superoxide Dismutase (SOD1) Mutant-induced Motoneuronal Cell Death

Kanekura

Hashimoto

Kita

et al. 2005

Journal of Biological Chemistry

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AlsinLF, the product of the ALS2 gene, inhibits Cu/Znsuperoxide dismutase (SOD1) mutant-induced neurotoxicity via its Rho guanine nucleotide-exchanging factor domain. We here identified Rac1, a Rho family small GTPase, as a target for the Rho guanine nucleotide-exchanging factor activity of alsinLF. Rac1 associates with alsinLF. The amount of the GTP form of Rac1 is up-regulated by enforced overexpression of alsinLF. We further found not only that constitutively active Rac1 suppresses motoneuronal cell death induced by SOD1 mutants but also that the neuroprotective activity of alsinLF was completely inhibited by knocking down the endogenous Rac1 expression with small interfering RNA for Rac1, indicating that Rac1 is the major effector for alsinLF-mediated neuroprotection. Such alsinLF/Rac1-mediated neuroprotection occurs specifically against the SOD1 mutant-induced cell death but not against the cell death induced by any other neurotoxic insults in motoneuronal NSC34 cells. We further demonstrated that the alsinLF/Rac1-mediated neuroprotective signal is transmitted to the phosphatidylinositol 3-kinase/Akt anti-apoptotic axis. Among three Akt family proteins, Akt3 is the major downstream mediator for alsinLF/Rac1-mediated neuroprotection, which is specifically effective against SOD1 mutant-induced neurotoxicity.

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Molecular Genetics of Hereditary Spastic Paraplegias

Novelli

Contino

2009

Encyclopedia of Life Sciences

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Hereditary spastic paraplegias (HSPs) are a group of single‐gene disorders in which the axons of the corticospinal tract either fail to develop normally or undergo progressive degeneration. The main clinical feature of all HSPs is a bilateral, symmetrical, slowly progressive spastic paraparesis predominantly of the lower extremities, which occurs in relative isolation in pure or uncomplicated HSPs (PHSPs) or in combination with other features in complicated HSPs (CHSPs). So far, about 40 different chromosomal HSP loci have been identified by genetic linkage analysis and an increasing number of gene mutations are being identified, representing one of the most significant examples of genetic heterogeneity. Autosomal and X‐linked patterns of inheritance, both dominant and recessive, have been described. Defects in intracellular trafficking and transport in myelination and abnormalities of mitochondrial proteins have been involved in HSP pathogenesis. Key Concepts: Hereditary spastic paraplegias (HSP) are a group of single‐gene disorders characterized by bilateral, symmetrical, slowly progressive spastic paraparesis predominantly of the lower extremities (pure or uncomplicated HSPs). The phenotype can be complicated by additional features (complicated HSPs). HSPs affect 1/10 000 individuals. Pathogenesis depends on abnormalities in intracellular trafficking, trasnsport and endocytosis, neural cell recognition and signalling, myelination and mitochondrial proteins. About 40 different chromosomal loci and 20 genes have been identified indicating the extraordinarly strong genetic heterogeneity. Patterns of inheritance include autosomal and X‐linked, both recessive and dominant. Mutations in Spastin (SPG4) account for approximately 40% of autosomal dominant HSPs, and more then any other HSP defect. Autosomal recessive HSP account for approximately 15–20% of all types of HSPs. Genotype–phenotype correlation and penetrance can be extremely variable even among the same family and/or gene defect. Genetic counselling is particularly challenging because of genetic heterogeneity and should take in consideration pattern of inheritance, geographical epidemiology and clinical evaluation with a multidisciplinary approach. To date, treatment of HSPs is primarily directed symptomatically towards reducing muscle spasticity.

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Infantile ascending hereditary spastic paralysis (IAHSP)

Abstract: The syndrome of IAHSP is genetically heterogeneous, and no clinical sign can help to distinguish patients with and without Alsin mutations.

Cited by 69 publications

References 37 publications

MR Imaging Findings in Autosomal Recessive Hereditary Spastic Paraplegia

MR Imaging Findings in Autosomal Recessive Hereditary Spastic Paraplegia

A Rac1/Phosphatidylinositol 3-Kinase/Akt3 Anti-apoptotic Pathway, Triggered by AlsinLF, the Product of the ALS2 Gene, Antagonizes Cu/Zn-superoxide Dismutase (SOD1) Mutant-induced Motoneuronal Cell Death

Molecular Genetics of Hereditary Spastic Paraplegias

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