Clinical heterogeneity in Italian patients with amyotrophic lateral sclerosis

Piaceri, Irene; Mastio, Monica Del; Tedde, Andrea; Bagnoli, Silvia; Latorraca, Stefania; Massaro, Francesca; Paganini, Marco; Corrado, Antonio; Sorbi, Sandro; Nacmias, Benedetta

doi:10.1111/j.1399-0004.2011.01726.x

Cited by 14 publications

(8 citation statements)

References 16 publications

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“…In this study, none of the 4 families with the p.M337 V mutation developed cognitive impairment; this result is similar to the results from a Taiwanese cohort. The substantial clinical heterogeneity between p.M337 V mutation pedigrees indicated the potential presence of other underlying phenotype-modifying factors [ 14 , 15 ]. Kühnlein P et al described the first ALS patient with the p.G348C mutation who presented with early spinal onset (31 years) without cognitive impairment [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

High frequency of the TARDBP p.M337 V mutation among south-eastern Chinese patients with familial amyotrophic lateral sclerosis

Zhan

et al. 2018

BMC Neurol

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BackgroundAmyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease characterized by substantial clinical and genetic heterogeneity. Thus far, only a few TARDBP-ALS families have been reported in China, and no mutation analysis has been reported in south-eastern China.MethodsSeven index cases from ALS families negative for SOD1 and FUS mutations were screened by Sanger sequencing for TARDBP gene exons 2-6. TARDBP exon 6 was analysed in 215 sporadic ALS patients.ResultsTwo TARDBP mutations in exon 6 (p.M337 V and p.G348C) were identified in 5 unrelated families. Four of these 5 families carried the same p.M337 V mutation (family 1II3, family 2II6, family 3II4, and family 4II4), and the p.G348C mutation was identified in family 5 (II5). Among the 215 sporadic patients, only a single nucleotide polymorphism (p.A366A) was detected in 5 patients, and no responsible mutation was identified. Among the TARDBP-linked familial ALS patients, the average age of onset was 57.0 ± 4.7 years, and a trend towards higher rates of bulbar (50.0%, 6/12) onset and upper limb (41.7%, 5/12) onset than lower rates of limb onset (8.3%, 1/12) was observed. Furthermore, ALS patients with TARDBP mutations showed a benign disease course, and the average survival was 106.5 ± 41.8 months (n = 8).ConclusionsWe found a high frequency of the TARDBP p.M337 V mutation in familial ALS in south-eastern China. The TARDBP-linked ALS patients showed a benign disease course and prolonged survival.Electronic supplementary materialThe online version of this article (10.1186/s12883-018-1028-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

High frequency of the TARDBP p.M337 V mutation among south-eastern Chinese patients with familial amyotrophic lateral sclerosis

Zhan

et al. 2018

BMC Neurol

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“…Two more missense variants (p.G294A and p.Q331K) were reported by this group in SALS cases (Table ) [Sreedharan et al, ]. Following these studies, a number of reports of TARDBP screening in ALS patients have described a total of 47 missense variants in 110 FALS and 100 SALS cases and one deletion/insertion in one FALS (Table ) [Bäumer et al, ; Benajiba et al, ; Borghero et al, ; Brown et al, ; Chiang et al, ; Chiò et al, ; Conforti et al, ; Corrado et al, ; Daoud et al, ; Del Bo et al, ; De Marco et al, ; Fujita et al, ; Gitcho et al, ; Huang et al, ; Iida et al, ; Kabashi et al, ; Kirby et al, ; Kühnlein et al, ; Lattante et al, ; Lemmens et al, ; Millecamps et al, ; Mosca et al, ; Nozaki et al, ; Origone et al, ; Piaceri et al, ; Rutherford et al, ; Solski et al, ; Sreedharan et al, ; Tamaoka et al, ; Ticozzi et al, ; Tsai et al, ; Van Blitterswijk et al, ; Van Deerlin et al, ; Williams et al, ; Xiong et al, ; Yokoseki et al, ; Zou et al, ]. The only nonsense TARDBP mutation, p.Y374X, was identified in a screen of French SALS patients [Daoud et al, ] (Table ).…”

Section: Tardbp Mutations In Alsmentioning

confidence: 99%

TARDBPandFUSMutations Associated with Amyotrophic Lateral Sclerosis: Summary and Update

2013

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Mutations in the TAR DNA Binding Protein gene (TARDBP), encoding the protein TDP-43, were identified in amyotrophic lateral sclerosis (ALS) patients. Interestingly, TDP-43 positive inclusion bodies were first discovered in ubiquitin-positive, tau-negative ALS and frontotemporal dementia (FTD) inclusion bodies, and subsequently observed in the majority of neurodegenerative disorders. To date, 47 missense and one truncating mutations have been described in a large number of familial (FALS) and sporadic (SALS) patients. Fused in sarcoma (FUS) was found to be responsible for a previously identified ALS6 locus, being mutated in both FALS and SALS patients. TARDBP and FUS have a structural and functional similarity and most of mutations in both genes are also clustered in the C-terminus of the proteins. The molecular mechanisms through which mutant TDP-43 and FUS may cause motor neuron degeneration are not well understood. Both proteins play an important role in mRNA transport, axonal maintenance, and motor neuron development. Functional characterization of these mutations in in vitro and in vivo systems is helping to better understand how motor neuron degeneration occurs. This report summarizes the biological and clinical relevance of TARDBP and FUS mutations in ALS. All the data reviewed here have been submitted to a database based on the Leiden Open (source) Variation Database (LOVD) and is accessible online at www.lovd.nl/TARDBP, www.lovd.nl/FUS.

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“…The course of the appearance of these symptoms differs from patient to patient, as does the rate of disease progression. Some studies [25,26] show that the disease progression rate is heterogeneous, and that there may be sub-groups of patients that exhibit similar progression rates and patterns. To exemplify this, Figure 1 shows two groups of three representative patients that demonstrate different behaviors of disease progression.…”

Section: Background To Alsmentioning

confidence: 99%

Insights into Amyotrophic Lateral Sclerosis from a Machine Learning Perspective

Gordon

Lerner

2019

JCM

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Objective: Amyotrophic lateral sclerosis (ALS) disease state prediction usually assumes linear progression and uses a classifier evaluated by its accuracy. Since disease progression is not linear, and the accuracy measurement cannot tell large from small prediction errors, we dispense with the linearity assumption and apply ordinal classification that accounts for error severity. In addition, we identify the most influential variables in predicting and explaining the disease. Furthermore, in contrast to conventional modeling of the patient’s total functionality, we also model separate patient functionalities (e.g., in walking or speaking). Methods: Using data from 3772 patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, we introduce and train ordinal classifiers to predict patients’ disease state in their last clinic visit, while accounting differently for different error severities. We use feature-selection methods and the classifiers themselves to determine the most influential variables in predicting the disease from demographic, clinical, and laboratory data collected in either the first, last, or both clinic visits, and the Bayesian network classifier to identify interrelations among these variables and their relations with the disease state. We apply these methods to model each of the patient functionalities. Results: We show the error distribution in ALS state prediction and demonstrate that ordinal classifiers outperform classifiers that do not account for error severity. We identify clinical and lab test variables influential to prediction of different ALS functionalities and their interrelations, and specific value combinations of these variables that occur more frequently in patients with severe deterioration than in patients with mild deterioration and vice versa. Conclusions: Ordinal classification of ALS state is superior to conventional classification. Identification of influential ALS variables and their interrelations help explain disease mechanism. Modeling of patient functionalities separately allows relation of variables and their connections to different aspects of the disease as may be expressed in different body segments.

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Clinical heterogeneity in Italian patients with amyotrophic lateral sclerosis

Cited by 14 publications

References 16 publications

High frequency of the TARDBP p.M337 V mutation among south-eastern Chinese patients with familial amyotrophic lateral sclerosis

High frequency of the TARDBP p.M337 V mutation among south-eastern Chinese patients with familial amyotrophic lateral sclerosis

TARDBPandFUSMutations Associated with Amyotrophic Lateral Sclerosis: Summary and Update

Insights into Amyotrophic Lateral Sclerosis from a Machine Learning Perspective

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