Upper Motor Neuron Disorders: Primary Lateral Sclerosis, Upper Motor Neuron Dominant Amyotrophic Lateral Sclerosis, and Hereditary Spastic Paraplegia

Fullam, Timothy; Statland, Jeffrey

doi:10.3390/brainsci11050611

Cited by 13 publications

(4 citation statements)

References 85 publications

(187 reference statements)

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“…Diagnostic criteria for HSPs typically include slowly progressing spastic weakness of the legs that results in ambulatory dysfunction ( 43 ). To determine whether animals expressing the TFG p.R106C mutation exhibit progressive difficulty walking, we conducted a series of quantitative kinematic gait analyses by recording animals from three different vantage points as they traversed a clear platform ( Fig.…”

Section: Resultsmentioning

confidence: 99%

TFG regulates secretory and endosomal sorting pathways in neurons to promote their activity and maintenance

Peotter

Pustova

Lettman

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Molecular pathways that intrinsically regulate neuronal maintenance are poorly understood, but rare pathogenic mutations that underlie neurodegenerative disease can offer important insights into the mechanisms that facilitate lifelong neuronal function. Here, we leverage a rat model to demonstrate directly that the TFG p.R106C variant implicated previously in complicated forms of hereditary spastic paraplegia (HSP) underlies progressive spastic paraparesis with accompanying ventriculomegaly and thinning of the corpus callosum, consistent with disease phenotypes identified in adolescent patients. Analyses of primary cortical neurons obtained from CRISPR-Cas9–edited animals reveal a kinetic delay in biosynthetic secretory protein transport from the endoplasmic reticulum (ER), in agreement with prior induced pluripotent stem cell–based studies. Moreover, we identify an unexpected role for TFG in the trafficking of Rab4A-positive recycling endosomes specifically within axons and dendrites. Impaired TFG function compromises the transport of at least a subset of endosomal cargoes, which we show results in down-regulated inhibitory receptor signaling that may contribute to excitation-inhibition imbalances. In contrast, the morphology and trafficking of other organelles, including mitochondria and lysosomes, are unaffected by the TFG p.R106C mutation. Our findings demonstrate a multifaceted role for TFG in secretory and endosomal protein sorting that is unique to cells of the central nervous system and highlight the importance of these pathways to maintenance of corticospinal tract motor neurons.

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Section: Resultsmentioning

confidence: 99%

TFG regulates secretory and endosomal sorting pathways in neurons to promote their activity and maintenance

Peotter

Pustova

Lettman

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…The current definition of UMND ALS is still empirical and debated ( 24 ). In this study, we also explored the possible heterogenicity of this ALS subtype.…”

Section: Discussionmentioning

confidence: 99%

Postural instability and lower extremity dysfunction in upper motor neuron-dominant amyotrophic lateral sclerosis

Liu,

Chen,

et al. 2024

Front. Neurol.

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BackgroundUpper motor neuron-dominant ALS (UMND ALS) is recognized to have early onset and good prognosis, but may have a rapid decline in motor function due to gait instability in the early stage. We investigated changes in lower extremity function in UMND ALS, particularly UMND ALS patients accompanied with postural instability or repeated falls (UMND ALS plus).ResultsAmong the 2,353 ALS patients reviewed, 211 (9.0%) had UMND ALS. UMND ALS had a longer diagnosis delay and restricted symptoms. Although UMND ALS patients had better lower extremity function and strength than matched classic ALS patients on first evaluation, there was no difference in the time of needing assistance or not being able to walk after disease onset. In contrast, UMND ALS plus has severe UMN symptoms and a more rapid decline in motor function. The lower extremity function was no better than that in the matched classic ALS. The prognosis of UMND ALS and UMND ALS plus were significantly better than those of overall ALS.ConclusionUMND ALS has restricted symptoms but has a rapid decline in lower extremity function in the early stage of the disease. The motor function decline of UMND ALS plus is as fast as classic ALS. Whether these patients represent a distinct subgroup of ALS deserves further investigation.

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“…In the most common form of autosomal-dominant disease, the SPG4 (caused by genetic variants in the gene encoding for spastin) is associated with a "pure" phenotype, while, among the autosomal-recessive forms, SPG11 is the most frequent, and associated with a "complicated" phenotype. Some clinical elements may help in distinguishing HSP from PLS, such as the presence of a family history (PLS is mainly considered a sporadic disease), the earlier and symmetric onset of the disease, the presence of a diminished vibratory sensation on clinical examination, the absence of bulbar involvement, and the slower disease progression in patients with HSP compared to PLS [121]. Nonetheless, the clinical distinction between these two entities could be practically impossible in some circumstances, and genetic testing remains essential for ruling out HSP as the etiology for an apparently sporadic adult-onset UMN syndrome with leg onset.…”

Section: Differential Diagnosesmentioning

confidence: 99%

Primary Lateral Sclerosis: An Overview

Vacchiano,

Bonan,

Liguori

et al. 2024

JCM

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Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder which causes the selective deterioration of the upper motor neurons (UMNs), sparing the lower motor neuron (LMN) system. The clinical course is defined by a progressive motor disability due to muscle spasticity which typically involves lower extremities and bulbar muscles. Although classically considered a sporadic disease, some familiar cases and possible causative genes have been reported. Despite it having been recognized as a rare but distinct entity, whether it actually represents an extreme end of the motor neuron diseases continuum is still an open issue. The main knowledge gap is the lack of specific biomarkers to improve the clinical diagnostic accuracy. Indeed, the diagnostic imprecision, together with some uncertainty about overlap with UMN-predominant ALS and Hereditary Spastic Paraplegia (HSP), has become an obstacle to the development of specific therapeutic trials. In this study, we provided a comprehensive analysis of the existing literature, including neuropathological, clinical, neuroimaging, and neurophysiological features of the disease, and highlighting the controversies still unsolved in the differential diagnoses and the current diagnostic criteria. We also discussed the current knowledge gaps still present in both diagnostic and therapeutic fields when approaching this rare condition.

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Upper Motor Neuron Disorders: Primary Lateral Sclerosis, Upper Motor Neuron Dominant Amyotrophic Lateral Sclerosis, and Hereditary Spastic Paraplegia

Cited by 13 publications

References 85 publications

TFG regulates secretory and endosomal sorting pathways in neurons to promote their activity and maintenance

TFG regulates secretory and endosomal sorting pathways in neurons to promote their activity and maintenance

Postural instability and lower extremity dysfunction in upper motor neuron-dominant amyotrophic lateral sclerosis

Primary Lateral Sclerosis: An Overview

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