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.
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.
Objective: To explore the predictive factors of student mental health within the college environment. Participants: Students enrolled at 7 unique universities during years 2008 (n = 1,161) and 2009 ...(n = 1,459). Methods: Participants completed survey measures of mental health, consequences of alcohol use, and engagement in the college environment. Results: In addition to replicating previous findings related to Keyes' Mental Health Continuum, multiple regression analysis revealed several predictors of college student mental health, including supportive college environments, students' sense of belonging, professional confidence, and civic engagement. However, multiple measures of engaged learning were not found to predict mental health. Conclusions: Results suggest that supportive college environments foster student flourishing. Implications for promoting mental health across campus are discussed. Future research should build on exploratory findings and test confirmatory models to better understand relationships between the college environment and student flourishing.
Primary lateral sclerosis (PLS) is a neurodegenerative disorder of the adult motor system. Characterised by a slowly progressive upper motor neuron syndrome, the diagnosis is clinical, after ...exclusion of structural, neurodegenerative and metabolic mimics. Differentiation of PLS from upper motor neuron-predominant forms of amyotrophic lateral sclerosis remains a significant challenge in the early symptomatic phase of both disorders, with ongoing debate as to whether they form a clinical and histopathological continuum. Current diagnostic criteria for PLS may be a barrier to therapeutic development, requiring long delays between symptom onset and formal diagnosis. While new technologies sensitive to both upper and lower motor neuron involvement may ultimately resolve controversies in the diagnosis of PLS, we present updated consensus diagnostic criteria with the aim of reducing diagnostic delay, optimising therapeutic trial design and catalysing the development of disease-modifying therapy.
In ischemic stroke, intravenous tenecteplase is noninferior to alteplase in selected patients and has some practical advantages. Several stroke centers in New Zealand changed to routine off-label ...intravenous tenecteplase due to improved early recanalization in large vessel occlusion, inconsistent access to thrombectomy within stroke networks, and for consistency in treatment protocols between patients with and without large vessel occlusion. We report the feasibility and safety outcomes in tenecteplase-treated patients.
We performed a retrospective analysis of consecutive patients thrombolyzed with intravenous tenecteplase at 1 comprehensive and 2 regional stroke centers from July 14, 2018, to February 29, 2020. We report the baseline clinical characteristics, rates of symptomatic intracranial hemorrhage, and angioedema. These were then compared with patient outcomes with those treated with intravenous alteplase at 2 other comprehensive stroke centers. Multivariable mixed-effects logistic regression models were performed assessing the association of tenecteplase with symptomatic intracranial hemorrhage and independent outcome (modified Rankin Scale score, 0-2) at day 90.
There were 165 patients treated with tenecteplase and 254 with alteplase. Age (75 versus 74 years), sex (56% versus 60% male), National Institutes of Health Stroke Scale scores (8 versus 10), median door-to-needle times (47 versus 48 minutes), or onset-to-needle time (129 versus 130 minutes) were similar between the groups. Symptomatic intracranial hemorrhage occurred in 3 (1.8% 95% CI, 0.4-5.3) tenecteplase patients compared with 7 (2.7% 95% CI, 1.1-5.7) alteplase patients (
=0.75). There were no differences between tenecteplase and alteplase in the rates of angioedema (4 2.4%; 95% CI, 0.7-6.2 versus 1 0.4%; 95% CI, 0.01-2.2,
=0.08) or 90-day functional independence (100 61% versus 140 57%,
=0.47), respectively. In mixed-effects logistic regression models, there was no significant association between thrombolytic choice and symptomatic intracranial hemorrhage (odds ratio tenecteplase, 0.62 95% CI, 0.14-2.80,
=0.53) or functional independence (odds ratio tenecteplase, 1.20 95% CI, 0.74-1.95,
=0.46).
Routine use of tenecteplase for stroke thrombolysis was feasible and had comparable safety profile and outcome to alteplase.
Hereditary spastic paraplegia Fink, John K
Current neurology and neuroscience reports,
01/2006, Letnik:
6, Številka:
1
Journal Article
Recenzirano
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.
Using detailed administrative data from Virginia, this paper examines whether community college “vertical transfer” students who resemble “native four-year” students in their accumulated ...college-level credits and performance at their point of entry into the four-year sector perform equally well in terms of both academic and labor market outcomes. We compare matching strategies typically used in existing literature to one where we match vertical transfer and native four-year students based on prior credits earned, accumulative GPA, and the destination four-year institution, and find substantial differences in estimates based on different matching strategies. We also examine potential mechanisms underlying vertical transfer students’ relative performance at the four-year institution and in the labor market. The results show that vertical transfer students’ probability of baccalaureate attainment is comparable to that of similar native students attending the same four-year institution. However, when considering their earnings eight years after initial college enrollment, vertical transfer students experience a significant and nontrivial earnings penalty. Subsequent analyses examining possible mechanisms suggest the earning decrement is partly due to a delayed entry into the labor market as a result of credit loss at the point of transfer.
Whole-genome sequencing of patient DNA can facilitate diagnosis of a disease, but its potential for guiding treatment has been under-realized. We interrogated the complete genome sequences of a ...14-year-old fraternal twin pair diagnosed with dopa (3,4-dihydroxyphenylalanine)-responsive dystonia (DRD; Mendelian Inheritance in Man #128230). DRD is a genetically heterogeneous and clinically complex movement disorder that is usually treated with l-dopa, a precursor of the neurotransmitter dopamine. Whole-genome sequencing identified compound heterozygous mutations in the SPR gene encoding sepiapterin reductase. Disruption of SPR causes a decrease in tetrahydrobiopterin, a cofactor required for the hydroxylase enzymes that synthesize the neurotransmitters dopamine and serotonin. Supplementation of l-dopa therapy with 5-hydroxytryptophan, a serotonin precursor, resulted in clinical improvements in both twins.
Acknowledges the need for, and challenges of, delivering quality acute stroke care across NZ, but recognises progress that has been made. Suggests ways by which improvement can be further ...accelerated. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.
Human PNPLA6 gene encodes Neuropathy Target Esterase protein (NTE). PNPLA6 gene mutations cause hereditary spastic paraplegia (SPG39 HSP), Gordon-Holmes syndrome, Boucher-Neuhäuser syndromes, ...Laurence-Moon syndrome, and Oliver-McFarlane syndrome. Mutations in the Drosophila NTE homolog swiss cheese (sws) cause early-onset, progressive behavioral defects and neurodegeneration characterized by vacuole formation. We investigated sws5 flies and show for the first time that this allele causes progressive vacuolar formation in the brain and progressive deterioration of negative geotaxis speed and endurance. We demonstrate that inducible, neuron-specific expression of full-length human wildtype NTE reduces vacuole formation and substantially rescues mobility. Indeed, neuron-specific expression of wildtype human NTE is capable of rescuing mobility defects after 10 days of adult life at 29°C, when significant degeneration has already occurred, and significantly extends longevity of mutants at 25°C. These results raise the exciting possibility that late induction of NTE function may reduce or ameliorate neurodegeneration in humans even after symptoms begin. In addition, these results highlight the utility of negative geotaxis endurance as a new assay for longitudinal tracking of degenerative phenotypes in Drosophila.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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