A revision of the El Escorial criteria - 2015

Ludolph, Albert C.; Drory, Vivian E.; Hardiman, Orla; Nakano, Imaharu; Ravits, John; Robberecht, Wim; Shefner, Jeremy M.; Mnd,

doi:10.3109/21678421.2015.1049183

Cited by 395 publications

(315 citation statements)

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“…PLS involves UMNs only, represents 1-4% of cases with motor neuron disease, 28 and is now considered a restricted phenotype of ALS in the most recent revision of the El Escorial diagnostic criteria. 29 As PLS is associated with a better prognosis than other ALS forms, 2,30 we compared disease duration in FIG4 variant versus non-variant carriers. In our ALS cohort, mean disease duration was longer in patients carrying deleterious FIG4 variants compared with non-FIG4 variant carriers (4.9 versus 3.2 years).…”

Section: Fig4 Variants In a Centralmentioning

confidence: 99%

FIG4 variants in central European patients with amyotrophic lateral sclerosis: a whole-exome and targeted sequencing study

et al. 2017

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We aimed to identify the genetic cause of the devastating neurodegenerative disease amyotrophic lateral sclerosis (ALS) in a German family with two affected individuals, and to assess the prevalence of variants in the identified risk gene, FIG4, in a central European ALS cohort. Whole-exome sequencing (WES) and an overlapping data analysis strategy were performed in an ALS family with autosomal dominant inheritance and incomplete penetrance. Additionally, 200 central European ALS patients were analyzed using whole-exome or targeted sequencing. All patients were subjected to clinical, electrophysiological, and neuroradiological characterization to explore genotype-phenotype relationships. WES analysis of the ALS family identified the rare heterozygous frameshift variant FIG4:c.759delG, p.(F254Sfs*8) predicted to delete the catalytic domain and active center from the encoded phosphoinositide 5-phosphatase with a key role in endosomal vesicle trafficking. Additionally, novel or rare heterozygous FIG4 missense variants predicted to be deleterious were detected in five sporadic ALS patients revealing an overall FIG4 variant frequency of 3% in our cohort. Four of six variants identified were previously associated with ALS or the motor and sensory neuropathy Charcot-Marie-Tooth disease type 4J (CMT4J), whereas two variants were novel. In FIG4 variant carriers, disease duration was longer and upper motor neuron predominance was significantly more frequent compared with ALS patients without FIG4 variants. Our study provides evidence for FIG4 as an ALS risk gene in a central European cohort, adds new variants to the mutational spectrum, links ALS to CMT4J on a genetic level, and describes a distinctive ALS phenotype for FIG4 variant carriers.

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Section: Fig4 Variants In a Centralmentioning

confidence: 99%

FIG4 variants in central European patients with amyotrophic lateral sclerosis: a whole-exome and targeted sequencing study

et al. 2017

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Does Sporadic Amyotrophic Lateral Sclerosis Spread via Axonal Connectivities?

Braak

Neumann

Ludolph

et al. 2017

Neurology International Open

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IntroductionAmyotrophic lateral sclerosis (ALS) is characterized by rapid progressive paralysis of the striated skeletal musculature [1,2]. The present review focuses on sporadic disease (sALS), which constitutes the majority of cases without a known genetic mutation. Clinically similar but inherited (familial) forms that display very diverse pathologies [3][4][5][6][7] are not taken into account here.The pathological process underlying sALS entails abnormal changes of an endogenous and predominantly intranuclear protein, TDP-43 (transactive response DNA-binding protein 43). Following nuclear clearance, the protein remains delocalized in the cytoplasm of susceptible nerve cells, where it undergoes defective phosphorylation and conformational change followed by ubiquitination, which ultimately prevent its re-entry into the nuclear compartment [7][8][9][10][11].The pathomechanisms that lead to the dysfunction and death of involved cells are still unknown. Along with a "loss of function" attributable to the loss of intranuclear TDP-43 expression accompanied by disrupted RNA metabolism, a "gain of function" mechanism owing to a noxious effect on cells by toxic TDP-43 forms has been discussed [7,12] Which Nerve Cell Types Develop TDP-43-immunoreactive Inclusions in sALS?The abnormal nuclear clearance and development of cytoplasmic TDP-43-immunopositive inclusions are confined to a few types ABsTr AC TThe pathological process underlying sporadic amyotrophic lateral sclerosis (sALS) that is associated with the formation of cytoplasmic inclusions of a nuclear protein (TDP-43) is confined to only a few types of long-axoned projection neurons. The giant Betz pyramidal cells of the primary motor neocortex as well as large α-motor neurons of the lower brainstem and spinal cord become involved early. In the human brain, these 2 neuronal types are to a large extent interconnected by monosynaptic axonal projections. The cell nuclei of affected neurons gradually forfeit their normal expression of the protein TDP-43. In α-motor neurons, this nuclear loss is followed by the formation of insoluble TDP-43-immunopositive inclusions in the cytoplasm, whereas in Betz cells the loss of nuclear expression remains for an unknown period of time unaccompanied by somatodendritic and/or axoplasmic aggregations. It is possible that in cortical pyramidal cells (Betz cells) the nuclear clearing initially leads to the formation of an abnormal but still soluble cytoplasmic TDP-43 which may enter the axoplasm and, following transmission via direct synaptic contacts, induces anew TDP-43 dysregulation and aggregation in recipient neurons. The trajectory of the spreading pattern that consecutively develops during the course of sALS is consistent with the dissemination from chiefly cortical projection neurons via axonal transport through direct synaptic contacts leading to the secondary induction of TDP-43-containing inclusions within recipient nerve cells in involved subcortical regions. E136Braak H et al. Does Sporadic Amyotrophic Lateral … Neurolo...

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“…Patients develop a progressive muscle phenotype characterized by spasticity, hyperreflexia, fasciculations, muscle atrophy, and paralysis. Depending on the disease variant, upper or lower neurons are damaged, or both [1]. The paralysis progresses affecting more and more muscles and the patients finally die from asphyxia.…”

Section: Introductionmentioning

confidence: 99%

Healing of Amyotrophic Lateral Sclerosis: A Case Report

Mangelsdorf¹,

Walach

Mutter

2017

Complement Med Res

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Background: Amyotrophic lateral sclerosis (ALS) is a devastating disease leading to death within 3-5 years in most cases. New approaches to treating this disease are needed. Here, we report a successful therapy. Case Report: In a 49-year-old male patient suffering from muscle weakness and fasciculations, progressive muscular atrophy, a variant of ALS, was diagnosed after extensive examinations ruling out other diseases. Due to supposed mercury exposure from residual amalgam, the patient's teeth were restored. Then, the patient received sodium 2,3-dimercaptopropanesulfate (DMPS; overall 86 × 250 mg in 3 years) in combination with α-lipoic acid and followed by selenium. In addition, he took vitamins and micronutrients and kept a vegetarian diet. The excretion of metals was monitored in the urine. The success of the therapy was followed by scoring muscle weakness and fasciculations and finally by electromyography (EMG) of the affected muscles. First improvements occurred after the dental restorations. Two months after starting therapy with DMPS, the mercury level in the urine was increased (248.4 µg/g creatinine). After 1.5 years, EMG confirmed the absence of typical signs of ALS. In the course of 3 years, the patient recovered completely. Conclusions: The therapy described here is a promising approach to treating some kinds of motor neuron disease and merits further evaluation in rigorous trials.

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A revision of the El Escorial criteria - 2015

Cited by 395 publications

References 0 publications

FIG4 variants in central European patients with amyotrophic lateral sclerosis: a whole-exome and targeted sequencing study

FIG4 variants in central European patients with amyotrophic lateral sclerosis: a whole-exome and targeted sequencing study

Does Sporadic Amyotrophic Lateral Sclerosis Spread via Axonal Connectivities?

Healing of Amyotrophic Lateral Sclerosis: A Case Report

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