Primary lateral sclerosis, hereditary spastic paraplegia, and mutations in the<i>alsin</i>gene: Historical background for the first International Conference

Rowland, Lewis P.

doi:10.1080/14660820510039032

Cited by 27 publications

(17 citation statements)

References 71 publications

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“…Recent data suggest a continuum in motoneuron disorders; several genes can underlie different phenotypes, resembling ALS, HSP and HM(SA)N respectively (reviewed in [19]), e.g. Alsin (ALS2) [20-22], Senataxin (ALS4) [23,24], NIPA1 (SPG6, NIPA1 repeat expansions associated with ALS) [25,26], BSCL2 (SPG17, HMSN V) [27-29], Atlastin-1 (SPG3, HSN-I) [30-32], KIF1A (SPG 30, HSAN-II) [33,34], and REEP1 (SPG31, dHMN-V) [35,36]. …”

Section: Discussionmentioning

confidence: 99%

Electrophysiological characterisation of motor and sensory tracts in patients with hereditary spastic paraplegia (HSP)

Karle

Schüle

Klebe

et al. 2013

Orphanet J Rare Dis

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BackgroundHereditary spastic paraplegias (HSPs) are characterised by lower limb spasticity due to degeneration of the corticospinal tract. We set out for an electrophysiological characterisation of motor and sensory tracts in patients with HSP.MethodsWe clinically and electrophysiologically examined a cohort of 128 patients with genetically confirmed or clinically probable HSP. Motor evoked potentials (MEPs) to arms and legs, somato-sensory evoked potentials of median and tibial nerves, and nerve conduction studies of tibial, ulnar, sural, and radial nerves were assessed.ResultsWhereas all patients showed clinical signs of spastic paraparesis, MEPs were normal in 27% of patients and revealed a broad spectrum with axonal or demyelinating features in the others. This heterogeneity can at least in part be explained by different underlying genotypes, hinting for distinct pathomechanisms in HSP subtypes. In the largest subgroup, SPG4, an axonal type of damage was evident. Comprehensive electrophysiological testing disclosed a more widespread affection of long fibre tracts involving peripheral nerves and the sensory system in 40%, respectively. Electrophysiological abnormalities correlated with the severity of clinical symptoms.ConclusionsWhereas HSP is primarily considered as an upper motoneuron disorder, our data suggest a more widespread affection of motor and sensory tracts in the central and peripheral nervous system as a common finding in HSP. The distribution patterns of electrophysiological abnormalities were associated with distinct HSP genotypes and could reflect different underlying pathomechanisms. Electrophysiological measures are independent of symptomatic treatment and may therefore serve as a reliable biomarker in upcoming HSP trials.

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Section: Discussionmentioning

confidence: 99%

Electrophysiological characterisation of motor and sensory tracts in patients with hereditary spastic paraplegia (HSP)

Karle

Schüle

Klebe

et al. 2013

Orphanet J Rare Dis

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“…Intriguingly, igf-I and alsin are among the putative retrograde response genes (Figure 6E). IGF-I promotes neuronal survival by binding to IGF-IR and activating PI3 kinase and Akt (Dudek et al, 1997; Bondy and Cheng, 2004), while the alsin gene is mutated in ALS2, an early onset motor neuron degenerative disease (Yang et al, 2001; Eymard-Pierre et al, 2002; Rowland, 2005). Alsin protein is a vesicle-associated molecule that has been implicated in the endocytosis and trafficking of neurotrophin receptors (Devon et al, 2006) and so is potentially important for long-range survival pathways.…”

Section: Discussionmentioning

confidence: 99%

A Retrograde Neuronal Survival Response: Target-Derived Neurotrophins Regulate MEF2D and bcl-w

Pazyra-Murphy¹,

Hans

Courchesne

et al. 2009

J. Neurosci.

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Survival and maturation of dorsal root ganglia sensory neurons during development depend on target-derived neurotrophins. These target-derived signals must be transmitted across long distances to alter gene expression. Here, we address the possibility that long-range retrograde signals initiated by target-derived neurotrophins activate a specialized transcriptional program. The transcription factor MEF2D is expressed in sensory neurons; we show that expression of this factor is induced in response to target-derived neurotrophins that stimulate the distal axons. We demonstrate that MEF2D regulates expression of an anti-apoptotic bcl-2 family member, bcl-w. Expression of mef2d and bcl-w is stimulated in response to activation of a Trk-dependent ERK5/MEF2 pathway, and our data indicate that this pathway promotes sensory neuron survival. We find that mef2d and bcl-w are members of a larger set of retrograde response genes, which are preferentially induced by neurotrophin stimulation of distal axons. Thus, activation of an ERK5/MEF2D transcriptional program establishes and maintains the cellular constituents of functional sensory circuits.

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“…There is also potentially overlap between juvenile ALS, early onset HSP, and what is termed juvenile PLS (all due to mutations in alsin gene, ALS2). 43 …”

Section: Pathophysiologymentioning

confidence: 99%

Primary Lateral Sclerosis

et al. 2015

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Synopsis Primary lateral sclerosis (PLS) is characterized by insidious onset of progressive upper motor neuron dysfunction in the absence of clinical signs of lower motor neuron involvement. Patients experience stiffness, decreased balance and coordination, and mild weakness, and if the bulbar region is affected, difficulty speaking and swallowing, and emotional lability. The diagnosis is made based on clinical history, typical exam findings, and diagnostic testing negative for other causes of upper motor neuron dysfunction. EMG is normal, or only shows mild neurogenic findings in a few muscles, not meeting El Escorial criteria. Although no test is specific for PLS, some neurodiagnostic tests are supportive: including absent or delayed central motor conduction times; and changes in the precentral gyrus or corticospinal tracts on MRI, DTI or MR Spectroscopy. Treatment is largely supportive, and includes medications for spasticity, baclofen pump, and treatment for pseudobulbar affect. The prognosis in PLS is more benign than ALS, making this a useful diagnostic category.

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Primary lateral sclerosis, hereditary spastic paraplegia, and mutations in thealsingene: Historical background for the first International Conference

Cited by 27 publications

References 71 publications

Electrophysiological characterisation of motor and sensory tracts in patients with hereditary spastic paraplegia (HSP)

Electrophysiological characterisation of motor and sensory tracts in patients with hereditary spastic paraplegia (HSP)

A Retrograde Neuronal Survival Response: Target-Derived Neurotrophins Regulate MEF2D and bcl-w

Primary Lateral Sclerosis

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