Clinical and genetic heterogeneity of amyotrophic lateral sclerosis

Sabatelli, Mario; Conte, Amelia; Zollino, Marcella

doi:10.1111/cge.12117

Cited by 98 publications

(83 citation statements)

References 117 publications

(157 reference statements)

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“…64 Interestingly, bulbar onset is (almost) never seen in mutant-SOD1-associated ALS, and cognitive impairment is equally rare in patients with this mutation. 12,66,67 It should be noted that cognitive assessment in patients with bulbar failure can be challenging because of the speech problems and pseudobulbar affect that these patients experience, and instruments for bedside evaluation are still being developed.…”

Section: Lessons From C9orf72 Expansionsmentioning

confidence: 99%

The phenotypic variability of amyotrophic lateral sclerosis

2014

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| Classic textbook neurology teaches that amyotrophic lateral sclerosis (ALS) is a degenerative disease that selectively affects upper and lower motor neurons and is fatal 3-5 years after onset-a description which suggests that the clinical presentation of ALS is very homogenous. However, clinical and postmortem observations, as well as genetic studies, demonstrate that there is considerable variability in the phenotypic expression of ALS. Here, we review the phenotypic variability of ALS and how it is reflected in familial and sporadic ALS, in the degree of upper and lower motor neuron involvement, in motor and extramotor involvement, and in the spectrum of ALS and frontotemporal dementia. Furthermore, we discuss some unusual clinical characteristics regarding presentation, age at onset and disease progression. Finally, we address the importance of this variability for understanding the pathogenesis of ALS and for the development of therapeutic strategies.

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Section: Lessons From C9orf72 Expansionsmentioning

confidence: 99%

The phenotypic variability of amyotrophic lateral sclerosis

2014

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“…An escalating library of data in this regard is available through an online registry (http://alsod.iop.kcl.ac.uk) [87]. The hope is that a potential etiology, at least for a specific phenotype, will emerge and highlight a primary disease mechanism [3,5,88,89].…”

Section: The Role Of Molecular Biology In Understanding Als/mndmentioning

confidence: 99%

“…Since the earliest description in the mid 1800s, our understanding, diagnosis, and management of patients with amyotrophic lateral sclerosis (ALS) and the related motor neuron diseases (MNDs) has progressed dramatically [1][2][3][4][5]. The rate of discovery of novel pathogenic mechanisms, new phenotypes, mutations, and therapeutic interventions has escalated more in the last 15 years than ever before.…”

Section: Introductionmentioning

confidence: 99%

“…Our inability to find effective therapeutics that fundamentally alter the disease course of ALS/MND is often attributed to this heterogeneity of the patient population; thus, there is a need for better diagnostic definitions that will allow for the prognostically relevant categorizations of the disease [3][4][5][7][8][9][10][11]. Our difficulty in identifying reliable biomarkers of disease progression and therapeutic benefit further confound this challenge [4,[12][13][14].…”

Section: Introductionmentioning

confidence: 99%

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Challenges in the Understanding and Treatment of Amyotrophic Lateral Sclerosis/Motor Neuron Disease

Rosenfeld¹,

Strong

2015

Neurotherapeutics

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With the acceleration in our understanding of ALS and the related motor neuron disease has come even greater challenges in reconciling all of the proposed pathogenic mechanisms and how this will translate into impactful treatments. Fundamental issues such as diagnostic definition(s) of the disease spectrum, relevant biomarkers, the impact of multiple novel genetic mutations and the significant effect of symptomatic treatments on disease progression are all areas of active investigation. In this review, we will focus on these key issues and highlight the challenges that confront both clinicians and basic science researchers.

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“…ALS is a complex disease associated with numerous pathologic mechanisms, including oxidative stress, mitochondrial dysfunction, axonal damage, microglial activation, inflammation, excitotoxicity, and protein aggregation [7][8][9][10][11]. Current diagnostic measures rely upon clinical examination and electrophysiological measurements [6,12], which, in most cases, have not enabled early diagnosis where potential therapies would likely be most effective.…”

Section: Introductionmentioning

confidence: 99%

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

Bowser

2017

Neurotherapeutics

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Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease with no effective treatment. Drug development has been hampered by the lack of biomarkers that aid in early diagnosis, demonstrate target engagement, monitor disease progression, and can serve as surrogate endpoints to assess the efficacy of treatments. Fluid-based biomarkers may potentially address these issues. An ideal biomarker should exhibit high specificity and sensitivity for distinguishing ALS from control (appropriate disease mimics and other neurologic diseases) populations and monitor disease progression within individual patients. Significant progress has been made using cerebrospinal fluid, serum, and plasma in the search for ALS biomarkers, with urine and saliva biomarkers still in earlier stages of development. A few of these biomarker candidates have demonstrated use in patient stratification, predicting disease course (fast vs slow progression) and severity, or have been used in preclinical and clinical applications. However, while ALS biomarker discovery has seen tremendous advancements in the last decade, validating biomarkers and moving them towards the clinic remains more elusive. In this review, we highlight biomarkers that are moving towards clinical utility and the challenges that remain in order to implement biomarkers at all stages of the ALS drug development process.

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Clinical and genetic heterogeneity of amyotrophic lateral sclerosis

Cited by 98 publications

References 117 publications

The phenotypic variability of amyotrophic lateral sclerosis

The phenotypic variability of amyotrophic lateral sclerosis

Challenges in the Understanding and Treatment of Amyotrophic Lateral Sclerosis/Motor Neuron Disease

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

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