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Frans Brugman - One of the best experts on this subject based on the ideXlab platform.
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Upper and extra-motoneuron involvement in early motoneuron disease: a diffusion tensor imaging study.
Brain, 2011Co-Authors: Maaike M. Van Der Graaff, Charles B. L. M. Majoie, Caroline A. Sage, Matthan W.a. Caan, Erik M. Akkerman, Cristina Lavini, Aart J. Nederveen, Aeilko H. Zwinderman, Frans M. Vos, Frans BrugmanAbstract:Motoneuron disease is a term encompassing three phenotypes defined largely by the balance of upper versus lower motoneuron involvement, namely amyotrophic Lateral Sclerosis, Primary Lateral Sclerosis and progressive muscular atrophy. However, neuroradiological and pathological findings in these phenotypes suggest that degeneration may exceed the neuronal system upon which clinical diagnosis is based. To further delineate the phenotypes within the motoneuron disease spectrum, this controlled study assessed the upper- and extra-motoneuron white matter involvement in cohorts of patients with motoneuron disease phenotypes shortly after diagnosis by comparing diffusion tensor imaging data of the different cohorts to those of healthy controls and directly between the motoneuron disease phenotypes ( n = 12 for each cohort). Furthermore, we acquired follow-up data 6 months later to evaluate fractional anisotropy changes over time. Combined use of diffusion tensor tractography of the corticospinal tract and whole-brain voxel-based analysis allowed for comparison of the sensitivity of these techniques to detect white matter involvement in motoneuron disease. The voxel-based analysis demonstrated varying extents of white matter involvement in different phenotypes of motoneuron disease, albeit in quite similar anatomical locations. In general, fractional anisotropy reductions were modest in progressive muscular atrophy and most extensive in Primary Lateral Sclerosis. The most extensive patterns of fractional anisotropy reduction were observed over time in the voxel-based analysis, indicating progressive extra-motor white matter degeneration in limb- and bulbar onset amyotrophic Lateral Sclerosis and in progressive muscular atrophy. The observation of both upper motor and extra-motoneuron involvement in all phenotypes of motoneuron disease shortly after diagnosis suggests that these are all part of a single spectrum of multisystem neurodegenerative disease. Voxel-based analysis was more sensitive to detect longitudinal changes than diffusion tensor tractography of the corticospinal tract. Voxel-based analyses may be particularly valuable in the evaluation of motor and extra-motor white matter involvement in the early symptomatic stages of motoneuron disease, and for monitoring the spread of pathology over time. * Abbreviations : ALS : amyotrophic Lateral Sclerosis ALSFRS-R : revised amyotrophic Lateral Sclerosis functional rating scale PLS : Primary Lateral Sclerosis PMA : progressive muscular atrophy
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differentiation of hereditary spastic paraparesis from Primary Lateral Sclerosis in sporadic adult onset upper motor neuron syndromes
JAMA Neurology, 2009Co-Authors: Frans Brugman, Jan H Veldink, H Franssen, Marianne De Visser, J Vianney M B De Jong, C G Faber, Berry H P Kremer, Jurgen H Schelhaas, Pieter A Van Doorn, Jan J G M VerschuurenAbstract:Objective To study whether clinical characteristics can differentiate sporadic presentations of hereditary spastic paraparesis (HSP) from Primary Lateral Sclerosis (PLS). Differentiation between these diseases is important for genetic counseling and prognostication. Design Case series. Setting Tertiary referral center. Patients One hundred four Dutch patients with an adult-onset, sporadic upper motor neuron syndrome of at least 3 years' duration. Hereditary spastic paraparesis was genetically confirmed in 14 patients (7 with SPG4 and 7 with SPG7 mutations). Results All 14 patients with the SPG4 or SPG7 mutation had symptom onset in the legs, and 1 of the patients with the SPG7 mutation also developed symptoms in the arms. Of the other 90 patients, 78 (87%) had symptom onset in the legs. Thirty-six patients developed a PLS phenotype (bulbar region involvement), 15 had a phenotype that was difficult to classify as similar to HSP or PLS (involvement of legs and arms only), and 39 continued to have a phenotype similar to typical HSP (involvement of the legs only). Median age at onset was lower in patients with the SPG4 or SPG7 mutation (39 [range, 29-69] years), but there was considerable overlap with patients with the PLS phenotype (52 [range, 32-76] years). No differences were found in the features used by previous studies to distinguish HSP from PLS, including evidence of mild dorsal column impairment (decreased vibratory sense or abnormal leg somatosensory evoked potentials), symptoms of urinary urgency, or mild electromyographic abnormalities. Conclusions In most patients with a sporadic adult-onset upper motor neuron syndrome, differentiation of sporadic presentations of HSP from PLS based on clinical characteristics is unreliable and therefore depends on results of genetic testing.
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adult onset Primary Lateral Sclerosis is not associated with mutations in the als2 gene
Neurology, 2007Co-Authors: Frans Brugman, Eleonore Eymardpierre, L H Van Den Berg, J H J Wokke, F Gauthierbarichard, Odile BoespflugtanguyAbstract:Primary Lateral Sclerosis (PLS) is a diagnosis of exclusion in patients with an adult-onset gradually progressive pure upper motor neuron (UMN) syndrome. It has been debated whether PLS is a separate disease or part of the spectrum of ALS. Adult-onset PLS is almost always sporadic; it can, however, be a rare manifestation of familial ALS (FALS).1 Homozygous mutations in the ALS2 gene are causative for autosomal recessive, early-onset forms of UMN diseases described as infantile–ascending hereditary spastic paralysis (IAHSP)2 and juvenile PLS (JPLS).3,4 They are also rarely associated with lower motor neuron (LMN) involvement (juvenile ALS, ALS2).3,4 Whether ALS2 mutations may also cause adult-onset PLS is not known. We, therefore, analyzed the ALS2 gene in 51 Dutch patients with adult-onset PLS. ### Methods. We included 51 Dutch patients (31 men and 20 women) with a progressive UMN syndrome of adult onset (median 51 years, range 18 to 76 years) and a median disease duration of 8 years (range 2 to 25 years). Onset was in the legs in 39, in the …
Huned S Patwa - One of the best experts on this subject based on the ideXlab platform.
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utility of intrathecal baclofen pump in Primary Lateral Sclerosis
Journal of the Neurological Sciences, 2021Co-Authors: Adeel S Zubair, Matthew Raymond, Huned S PatwaAbstract:Abstract Primary Lateral Sclerosis is a disorder categorized by insidious onset of progressive upper motor neuron dysfunction without lower motor neuron involvement. PLS often presents with gradual-onset, progressive lower extremity stiffness and pain due to muscle spasticity. Intrathecal Baclofen pumps (ITB) have been used to effectively treat spasticity in several neurologic conditions including MS and spinal cord injury. This study aimed at reviewing a cohort of PLS patients with spasticity requiring ITB to assess the clinical course, benefits, and complications in these patients. A series of 5 patients were identified who were diagnosed with PLS and received ITB as treatment for spasticity. The average age of the patients at the time of ITB insertion was 56.4 years. The average length of treatment was 10.4 years with a range of 4–15 years. All patients reported improvement in spasticity as measured by clinical examinations and Ashworth scores; 1/5 had complications with the pump related to migration of catheter. No patients required permanent removal of the ITB. ITB is a safe and effective treatment for spasticity in PLS and should be considered in other patients.
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utility of intrathecal baclofen pump in Primary Lateral Sclerosis p3 429
Neurology, 2018Co-Authors: Adeel S Zubair, Matthew Raymond, Huned S PatwaAbstract:Objective: To describe the use of Intrathecal Baclofen pump (ITB) in a case series of Primary Lateral Sclerosis (PLS) Background: Primary Lateral Sclerosis is a condition characterized by insidious onset of progressive upper motor neuron dysfunction without lower motor neuron involvement. PLS is a diagnosis of exclusion; it exists on a spectrum of sporadic motor neuron disorders and is quite rare, representing about 1–4% of patients with motor neuron disorder. Intrathecal Baclofen pumps have been used effectively to treat spasticity in numerous neurologic conditions including CVA, TBI, CP, MS and spinal cord injury. Design/Methods: We retrospectively reviewed the charts of PLS patients with spasticity treated with ITB to assess the clinical course, benefits, and complications in these patients. Patients were included only if they had a diagnosis of PLS diagnosed by a neurologist; patients were excluded if they had any other cause of spasticity. Results: A series of 5 patients were identified who were diagnosed with PLS and received ITB as treatment for spasticity. The average age of the patients at the time of ITB insertion was 56.5 years. The average duration of pump placement was 7.25 years with a range of 8 months to 20 years. All patients had a Medtronic baclofen pump. All patients reported improvement in spasticity as well as objective improvement in tone as compared to baseline Ashworth score; 2/5 had complications with the pump related to catheter, both successfully repaired with return of treatment response. No patients required permanent removal of the ITB. Pump replacement was required in 4/5 patients secondary to end of battery life. Conclusions: ITB is a safe and effective treatment for spasticity in PLS. Disclosure: Dr. Zubair has nothing to disclose. Dr. Raymond has nothing to disclose. Dr. Patwa has nothing to disclose.
Johe Ikeda - One of the best experts on this subject based on the ideXlab platform.
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molecular and cellular function of als2 alsin implication of membrane dynamics in neuronal development and degeneration
Neurochemistry International, 2007Co-Authors: Shinji Hadano, Asako Otomo, Ryota Kunita, Johe Ikeda, Kyoko SuzukiutsunomiyaAbstract:ALS2 is a causative gene for a juvenile autosomal recessive form of motor neuron diseases (MNDs), including amyotrophic Lateral Sclerosis 2 (ALS2), juvenile Primary Lateral Sclerosis, and infantile-onset ascending hereditary spastic paralysis. These disorders are characterized by ascending degeneration of the upper motor neurons with or without lower motor neuron involvement. Thus far, a total of 12 independent ALS2 mutations, which include a small deletion, non-sense mutation, or missense mutation spreading widely across the entire coding sequence, are reported. They are predicted to result in either premature termination of translation or substitution of an evolutionarily conserved amino acid. Thus, a loss of functions in the ALS2-coded protein accounts for motor dysfunction and/or degeneration in the ALS2-linked MNDs. The ALS2 gene encodes a novel 184kDa protein of 1657 amino acids, ALS2 or alsin, comprising three predicted guanine nucleotide exchange factor (GEF) domains: the N-terminal RCC1-like domain, the central Dbl homology and pleckstrin homology (DH/PH) domains, and the C-terminal vacuolar protein sorting 9 (VPS9) domain. In addition, eight consecutive membrane occupation and recognition nexus (MORN) motifs are noted in the region between DH/PH and VPS9 domains. ALS2 activates Rab5 small GTPase and involves in endosome/membrane trafficking and fusions in the cells, and also promotes neurite outgrowth in neuronal cultures. Further, a neuroprotective role for ALS2 against cytotoxicity; i.e., the mutant Cu/Zn-superoxide dismutase 1 (SOD1)-mediated toxicity, oxidative stress, and excitotoxicity, has recently been implied. This review outlines current understandings of the molecular and cellular functions of ALS2 and its related proteins on safeguarding the integrity of motor neurons, and sheds light on the molecular pathogenesis of MNDs as well as other conditions of neurodegenerative diseases.
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recessive motor neuron diseases mutations in the als2 gene and molecular pathogenesis for the upper motor neurodegeneration
Rinshō shinkeigaku Clinical neurology, 2004Co-Authors: Johe IkedaAbstract:We have initially identified a mutation in ALS2 as a causative for a juvenile autosomal recessive form of amyotrophic Lateral Sclerosis (ALS), termed ALS2 (OMIM 205100). ALS2 mutations also are causative for an autosomal recessive juvenile Primary Lateral Sclerosis, and infantile-ascending hereditary spastic paralysis. To date, nine homozygous ALS2 mutaions from nine independent families have been identified. All of these mutations result in predicted premature translation termination caused by the recessive frameshift or nonsense mutation. ALS2 is a 184-kD protein comprising several putative guanine nucleotide exchange factor (GEF) domains [RLD; RCC1 like domain, DH. PH domain, VPS9; Vacuolar protein sorting 9 domain]. In vitro, ALS2 specifically binds to the small GTPase Rab5 and functions as a GEF for Rab5. Ectopic expression of full-length ALS2 has further implied an association with endosomal membranes mediated by the VPS9 domain, consistent with ALS2 involvement in endosomal trafficking and fusion in conjunction with the activation of Rab5. These results combined with our findings suggest that an obstruction of endosomal dynamics might underlie neuronal dysfunction and degeneration in ALS2, PLSJ, and HSP, as well as in a number of other motor neuron diseases.
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homo oligomerization of als2 through its unique carboxyl terminal regions is essential for the als2 associated rab5 guanine nucleotide exchange activity and its regulatory function on endosome trafficking
Journal of Biological Chemistry, 2004Co-Authors: Ryota Kunita, Asako Otomo, Shinji Hadano, Hikaru Mizumura, Junko Showguchimiyata, Yoshiko Yanagisawa, Johe Ikeda, Kyoko SuzukiAbstract:Mutations in the ALS2 gene have been known to account for a juvenile recessive form of amyotrophic Lateral Sclerosis (ALS2), a rare juvenile recessive form of Primary Lateral Sclerosis, and a form of hereditary spastic paraplegia (HSP), indicating that the ALS2 protein is essential for the maintenance of motor neurons. Recently, we have demonstrated that the ALS2 protein specifically binds to the small GTPase Rab5 and acts as a GEF (guanine nucleotide exchange factor) for Rab5. We have also shown that its Rab5GEF-requisite domain resides within the C-terminal 640-amino acid region spanning membrane occupation and recognition nexus motifs and the vacuolar protein sorting 9 domain. Transiently expressed ALS2 localized onto early endosomal compartments and stimulated endosome fusions in neuronal and non-neuronal cells in an Rab5GEF activity-dependent manner. These results indicate that the C-terminal region of ALS2 plays a crucial role in endosomal dynamics by its Rab5GEF activity. Here we delineate a molecular feature of the ALS2-associated function through the C-terminal region-mediated homo-oligomerization. A yeast two-hybrid screen for interacting proteins with the ALS2 C-terminal portion identified ALS2 itself. ALS2 forms a homophilic oligomer through its distinct C-terminal regions. This homo-oligomerization is crucial for the Rab5GEF activity in vitro and the ALS2-mediated endosome enlargement in the cells. Taken together, these results indicate that oligomerization of the ALS2 protein is one of the fundamental features for its physiological function involving endosome dynamics in vivo.
Odile Boespflugtanguy - One of the best experts on this subject based on the ideXlab platform.
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adult onset Primary Lateral Sclerosis is not associated with mutations in the als2 gene
Neurology, 2007Co-Authors: Frans Brugman, Eleonore Eymardpierre, L H Van Den Berg, J H J Wokke, F Gauthierbarichard, Odile BoespflugtanguyAbstract:Primary Lateral Sclerosis (PLS) is a diagnosis of exclusion in patients with an adult-onset gradually progressive pure upper motor neuron (UMN) syndrome. It has been debated whether PLS is a separate disease or part of the spectrum of ALS. Adult-onset PLS is almost always sporadic; it can, however, be a rare manifestation of familial ALS (FALS).1 Homozygous mutations in the ALS2 gene are causative for autosomal recessive, early-onset forms of UMN diseases described as infantile–ascending hereditary spastic paralysis (IAHSP)2 and juvenile PLS (JPLS).3,4 They are also rarely associated with lower motor neuron (LMN) involvement (juvenile ALS, ALS2).3,4 Whether ALS2 mutations may also cause adult-onset PLS is not known. We, therefore, analyzed the ALS2 gene in 51 Dutch patients with adult-onset PLS. ### Methods. We included 51 Dutch patients (31 men and 20 women) with a progressive UMN syndrome of adult onset (median 51 years, range 18 to 76 years) and a median disease duration of 8 years (range 2 to 25 years). Onset was in the legs in 39, in the …
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unstable mutants in the peripheral endosomal membrane component als2 cause early onset motor neuron disease
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Koji Yamanaka, Christine Vande Velde, Eleonore Eymardpierre, Enrico Bertini, Odile Boespflugtanguy, Don W ClevelandAbstract:Mutations in ALS2, carrying three putative guanine exchange factor (GEF) domains, are causative for a juvenile, autosomal recessive form of amyotrophic Lateral Sclerosis (ALS), Primary Lateral Sclerosis, and infantile-ascending hereditary spastic paralysis. Endogenous ALS2 is shown here to be enriched in nervous tissue and to be peripherally bound to the cytoplasmic face of endosomal membranes, an association that requires the amino-terminal “RCC1 (regulator of chromatin condensation)-like” GEF domain. Disease-causing mutants and a naturally truncated isoform of ALS2 are shown to be rapidly degraded when expressed in cultured human cells, including lymphocytes derived from patients with ALS2 mutations. Thus, mutations in the ALS2 gene linked to early-onset motor neuron disease uniformly produce loss of activity through decreased protein stability of this endosomal GEF.
Adeel S Zubair - One of the best experts on this subject based on the ideXlab platform.
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utility of intrathecal baclofen pump in Primary Lateral Sclerosis
Journal of the Neurological Sciences, 2021Co-Authors: Adeel S Zubair, Matthew Raymond, Huned S PatwaAbstract:Abstract Primary Lateral Sclerosis is a disorder categorized by insidious onset of progressive upper motor neuron dysfunction without lower motor neuron involvement. PLS often presents with gradual-onset, progressive lower extremity stiffness and pain due to muscle spasticity. Intrathecal Baclofen pumps (ITB) have been used to effectively treat spasticity in several neurologic conditions including MS and spinal cord injury. This study aimed at reviewing a cohort of PLS patients with spasticity requiring ITB to assess the clinical course, benefits, and complications in these patients. A series of 5 patients were identified who were diagnosed with PLS and received ITB as treatment for spasticity. The average age of the patients at the time of ITB insertion was 56.4 years. The average length of treatment was 10.4 years with a range of 4–15 years. All patients reported improvement in spasticity as measured by clinical examinations and Ashworth scores; 1/5 had complications with the pump related to migration of catheter. No patients required permanent removal of the ITB. ITB is a safe and effective treatment for spasticity in PLS and should be considered in other patients.
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utility of intrathecal baclofen pump in Primary Lateral Sclerosis p3 429
Neurology, 2018Co-Authors: Adeel S Zubair, Matthew Raymond, Huned S PatwaAbstract:Objective: To describe the use of Intrathecal Baclofen pump (ITB) in a case series of Primary Lateral Sclerosis (PLS) Background: Primary Lateral Sclerosis is a condition characterized by insidious onset of progressive upper motor neuron dysfunction without lower motor neuron involvement. PLS is a diagnosis of exclusion; it exists on a spectrum of sporadic motor neuron disorders and is quite rare, representing about 1–4% of patients with motor neuron disorder. Intrathecal Baclofen pumps have been used effectively to treat spasticity in numerous neurologic conditions including CVA, TBI, CP, MS and spinal cord injury. Design/Methods: We retrospectively reviewed the charts of PLS patients with spasticity treated with ITB to assess the clinical course, benefits, and complications in these patients. Patients were included only if they had a diagnosis of PLS diagnosed by a neurologist; patients were excluded if they had any other cause of spasticity. Results: A series of 5 patients were identified who were diagnosed with PLS and received ITB as treatment for spasticity. The average age of the patients at the time of ITB insertion was 56.5 years. The average duration of pump placement was 7.25 years with a range of 8 months to 20 years. All patients had a Medtronic baclofen pump. All patients reported improvement in spasticity as well as objective improvement in tone as compared to baseline Ashworth score; 2/5 had complications with the pump related to catheter, both successfully repaired with return of treatment response. No patients required permanent removal of the ITB. Pump replacement was required in 4/5 patients secondary to end of battery life. Conclusions: ITB is a safe and effective treatment for spasticity in PLS. Disclosure: Dr. Zubair has nothing to disclose. Dr. Raymond has nothing to disclose. Dr. Patwa has nothing to disclose.