Criteria For Amyotrophic Lateral Sclerosis Research Articles

Diagnostic utility of Gold Coast criteria for amyotrophic lateral sclerosis in Asia

Objective: This study aimed to reveal the diagnostic utility of Gold Coast (GC) criteria in Japanese patients with amyotrophic lateral sclerosis (ALS) by comparing the sensitivity/specificity with revised El Escorial (R-EE) and Awaji criteria, because its utility has not been studied in Asian ALS. Methods: Consecutive 639 patients (529 with ALS and 110 with ALS mimics), who were suspected of ALS and referred to three Japanese ALS centers, were enrolled. Diagnostic accuracy and characteristics of false positive and negative in GC criteria were compared with those of the Awaji and R-EE criteria. Patients were categorized as definite, probable or possible ALS according to each criterion. Results: The sensitivity of GC criteria (96.8%, 95% confidence interval [CI]: 95.3–98.3%) was higher than that of Awaji (89.6%, 95% CI: 87.0–92.2%) and R-EEC (89.2, 95% CI: 86.6–91.8%) criteria (both, p < 0.001). The specificity was also higher with GC criteria (77.3%, 95% CI: 69.5–85.1%) than Awaji (65.5%, 95% CI: 56.6–74.4%) and R-EEC (66.4, 95% CI: 57.6–75.2%) criteria (both, p < 0.01). Using GC criteria, patients with cervical spondylosis and Parkinson’s syndrome tended to be diagnosed with ALS (i.e. “false positive”). Additionally, ALS patients diagnosed only by GC criteria less frequently had upper motor neuron (UMN) signs, compared with the other two criteria. Conclusion: Gold Coast criteria improve diagnostic accuracy for ALS in an Asian population, especially in patients with subtle UMN signs.

Evolving Diagnostic Criteria in Amyotrophic Lateral Sclerosis and Its Differential Diagnosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of upper motor neurons in the brainstem and spinal cord and lower motor neurons. ALS was first described by Jean-Martin Charcot in 1874 based on clinical features and postmortem examinations. In 1990, the first diagnostic criteria for ALS were developed based on clinical features. Subsequently, three additional diagnostic criteria were published. In this article, we introduce the clinical features, diagnostic criteria, and diseases that need to be differentiated in ALS.

Gold Coast diagnostic criteria increase sensitivity in amyotrophic lateral sclerosis

ObjectiveThis study evaluates diagnostic accuracy of the proposed ‘Gold Coast’ (GC) diagnostic criteria for amyotrophic lateral sclerosis (ALS). MethodsFive European centres retrospectively sampled consecutive patients referred for electromyography on suspicion of ALS. Patients were classified according to the GC criteria, the revised El Escorial (rEE) criteria and the Awaji (AW) criteria without and with the ‘Possible’ category (+ Poss). Reference standard was ALS confirmed by disease progression at follow-up. ResultsOf 404 eligible patients 272 were diagnosed as ALS, 94 had mimicking disorders, 35 were lost for follow-up, and three had insufficient data. Sensitivity for the GC criteria was 88.2% (95% CI: 83.8-91.8%), which was higher than for previous criteria, of which the AW + Poss criteria reached the highest sensitivity of 77.6% (95% CI: 72.2–82.4%) (p < 0.001). Specificity was high for all criteria. The increase in sensitivity for the GC criteria was mainly due to the inclusion of 28 patients with progressive muscular atrophy (PMA). ConclusionsThe simpler GC criteria increase the sensitivity, primarily due to considering PMA as a form of ALS with high specificity preserved. SignificanceThis validation study supports that GC criteria should be used in clinical practice and may be used for inclusion in trials.

Gold Coast diagnostic criteria: Implications for ALS diagnosis and clinical trial enrollment.

Diagnostic criteria for amyotrophic lateral sclerosis (ALS) are complex, incorporating multiple levels of certainty from possible through to definite, and are thereby prone to error. Specifically, interrater variability was previously established to be poor, thereby limiting utility as diagnostic enrollment criteria for clinical trials. In addition, the different levels of diagnostic certainty do not necessarily reflect disease progression, adding confusion to the diagnostic algorithm. Realizing these inherent limitations, the World Federation of Neurology, the International Federation of Clinical Neurophysiology, the International Alliance of ALS/MND Associations, the ALS Association (United States), and the Motor Neuron Disease Association convened a consensus meeting (Gold Coast, Australia, 2019) to consider the development of simpler criteria that better reflect clinical practice, and that could merge diagnostic categories into a single entity. The diagnostic accuracy of the novel Gold Coast criteria was subsequently interrogated through a large cross-sectional study, which established an increased sensitivity for ALS diagnosis when compared with previous criteria. Diagnostic accuracy was maintained irrespective of disease duration, functional status, or site of disease onset. Importantly, the Gold Coast criteria differentiated atypical phenotypes, such as primary lateral sclerosis, from the more typical ALS phenotype. It is proposed that the Gold Coast criteria should be incorporated into routine practice and clinical trial settings.

The\xa0Gold Coast criteria increases the diagnostic sensitivity for amyotrophic lateral sclerosis in a Chinese population

ObjectivesThe aim of this study was to assess and compare the diagnostic utility of a new diagnostic criteria for amyotrophic lateral sclerosis (ALS), abbreviated as the ‘Gold Coast Criteria’, with the revised El Escorial (rEEC) and Awaji criteria.MethodsClinical and electrophysiological data of 1185 patients from January 2014 to December 2019 in the Peking Union Medical College Hospital ALS database were reviewed. The sensitivity of the Gold Coast criteria was compared to that of the possible rEEC and Awaji criteria (defined by the proportion of patients categorized as definite, probable, or possible ALS).ResultsA final diagnosis of ALS was recorded in 1162 patients. The sensitivity of the Gold Coast criteria (96.6%, 95% confidence interval [CI] = 95.3%–97.5%) was greater than that of the rEEC (85.1%, 95%CI = 82.9%–87.1%) and Awaji (85.3%, 95%CI = 83.2%–87.3%). In addition, the sensitivity of the novel criteria maintained robust across subgroups, and the advantage was more prominent in limb-onset ALS patients and those who completed electromyographic tests. In those who did not achieve any of the rEEC diagnostic categories, the sensitivity of Gold Coast criteria was 84.4%.ConclusionsThe current study demonstrated that the Gold Coast criteria exhibited greater diagnostic sensitivity than the rEEC and Awaji criteria in a Chinese ALS population. The application of the Gold Coast criteria should be considered in clinical practice and future therapeutic trials.

Diagnostic Utility of Gold Coast Criteria in Amyotrophic Lateral Sclerosis.

The diagnosis of amyotrophic lateral sclerosis (ALS) remains problematic, with current diagnostic criteria (revised El Escorial [rEEC] and Awaji) being complex and prone to error. Consequently, the diagnostic utility of the recently proposed Gold Coast criteria was determined in ALS. We retrospectively reviewed 506 patients (302 males, 204 females) to compare the diagnostic accuracy of the Gold Coast criteria to that of the Awaji and rEEC criteria (defined by the proportion of patients categorized as definite, probable, or possible ALS) in accordance with standards of reporting of diagnostic accuracy criteria. The sensitivity of Gold Coast criteria (92%, 95% confidence interval [CI] = 88.7-94.6%) was comparable to that of Awaji (90.3%, 95% CI = 86.69-93.2%) and rEEC (88.6, 95% CI = 84.8-91.7%) criteria. Additionally, the Gold Coast criteria sensitivity was maintained across different subgroups, defined by site of onset, disease duration, and functional disability. In atypical ALS phenotypes, the Gold Coast criteria exhibited greater sensitivity and specificity. The present study established the diagnostic utility of the Gold Coast criteria in ALS, with benefits evident in bulbar and limb onset disease patients, as well as atypical phenotypes. The Gold Coast criteria should be considered in clinical practice and therapeutic trials. ANN NEUROL 2021;89:979-986.

Anti-IgLON5 Disease: A New Bulbar-Onset Motor Neuron Mimic Syndrome.

ObjectiveTo expand the spectrum of anti-IgLON5 disease by adding 5 novel anti-IgLON5–seropositive cases with bulbar motor neuron disease-like phenotype.MethodsWe characterized the clinical course, brain MRI and laboratory findings, and therapy response in these 5 patients.ResultsPatients were severely affected by bulbar impairment and its respiratory consequences. Sleep-related breathing disorders and parasomnias were common. All patients showed clinical or electrophysiologic signs of motor neuron disease without fulfilling the diagnostic criteria for amyotrophic lateral sclerosis. One patient regained autonomy in swallowing and eating, possibly related to immunotherapy.ConclusionIgLON5 disease is an important differential diagnosis to evaluate in patients with bulbar motor neuron disease-like phenotype and sleep disorders. There is need for a deeper understanding of the underlying pathobiology to determine whether IgLON5 disease is an immunotherapy-responsive condition.

Diagnostic criteria for amyotrophic lateral sclerosis: A multicentre study of inter-rater variation and sensitivity

ObjectiveThis study assesses inter-rater agreement and sensitivity of diagnostic criteria for amyotrophic lateral sclerosis (ALS). MethodsClinical and electrophysiological data of 399 patients with suspected ALS were collected by eleven experienced physicians from ten different countries. Eight physicians classified patients independently and blinded according to the revised El Escorial Criteria (rEEC) and to the Awaji Criteria (AC). Inter-rater agreement was assessed by Kappa coefficients, sensitivity by majority diagnosis on 350 patients with follow-up data. ResultsInter-rater agreement was generally low both for rEEC and AC. Agreement was best on the categories “Not-ALS”, “Definite”, and “Probable”, and poorest for “Possible” and “Probable Laboratory-supported”.Sensitivity was equal for rEEC (64%) and AC (63%), probably due to downgrading of “Probable Laboratory-supported” patients by AC. However, AC was significantly more effective in classifying patients as “ALS” versus “Not-ALS” (p < 0.0001). ConclusionsInter-rater variation is high both for rEEC and for AC probably due to a high complexity of the rEEC inherent in the AC.The gain of AC on diagnostic sensitivity is reduced by the omission of the “Probable Laboratory-supported” category. SignificanceThe results highlight a need for initiatives to develop simpler and more reproducible diagnostic criteria for ALS in clinical practice and research.

Platform Session – Electromyography: Large inter-rater variation on revised El Escorial and Awaji diagnostic criteria for amyotrophic lateral sclerosis

Introduction The revised El Escorial Criteria (rEEC) from 2000 and their amendment, the Awaji Criteria (AC) from 2008, are widely used diagnostic criteria for amyotrophic lateral sclerosis (ALS) and their sensitivity and specificity have been evaluated in several studies, however, reproducibility among different raters has not been studied. This study was undertaken to assess inter-rater agreement on rEEC and AC. Methods Eight experienced physicians from seven different countries independently classified 399 patients referred for ALS according to the rEEC and the AC. Clinical and electrophysiological data were presented in standardised forms. Agreement was evaluated by Kappa coefficients. Diagnostic sensitivity and specificity were calculated from the majority diagnosis of the eight physicians for 349 cases with follow-up data. Results Kappa coefficients differed among the diagnostic categories for rEEC (“Definite”: 0.50, CI:0.39–0.60, “Probable”: 0.36, CI:0.31–0.41, “Probable Laboratory Supported”: 0.25,CI:0.18–0.34, “Possible”: 0.14, CI:0.09–0.20, and “Not-ALS”: 0.59, CI:0.51–0.65) as well as for AC (“Definite”: 0.44, CI:0.37–0.51, “Probable”: 0.34, CI:0.29–0.39, “Possible”: 0.33, CI:0.26–0.40, and “Not-ALS”: 0.65, CI:0.58–0.72). The only significant difference in agreement between rEEC and AC was for the category “Possible”. A large fraction of cases classified as “Probable” using the rEEC were upgraded to “Definite” using the AC, however, many cases classified as “Probable Laboratory Supported” by rEEC were downgraded to “Possible” by the AC. Sensitivity for “Definite/Probable” versus “Possible/Not-ALS” did not differ between rEEC (0.64, CI:0.58–0.69) and AC (0.63, CI:0.58–0.69). Similarly, there was no difference in specificity between rEEC (0.91, CI:0.74–0.98) and AC (0.85, CI:0.67–0.94). Conclusion There is a large inter-rater variation on rEEC and AC most pronounced for the “Probable Laboratory Supported” and “Possible” categories. The sensitivity was rather low compared to other studies and was not significantly increased using AC, probably due to omission of the “Probable Laboratory Supported” category. However, in trials including patients with possible disease AC may be advantageous. Inter-rater variation may be due to (1) a high complexity of the rEEC, which is also inherited in the AC, including definition of four body regions, interpretation of clinical findings (upper/lower motor neuron signs), significance of rostral/caudal signs, and significance of EMG findings (acute/chronic signs), and (2) the need to apply rEEC together with AC. However, pre-study training and quality control at individual laboratories may reduce variation and improve sensitivity and specificity. The results indicate that there is a need for initiatives to develop more simple and reproducible criteria.

O96 Large inter- and intra-rater variation on diagnostic criteria for amyotrophic lateral sclerosis

Objectives To study inter- and intra-rater agreement on diagnostic criteria for amyotrophic lateral sclerosis (ALS). Methods Four-hundred-and-two patients referred for ALS were classified according to the revised El Escorial criteria (EEC) and the Awaji criteria (AwC) independently by eight experienced physicians from seven different countries. Intra-rater agreement was further assessed from 352 of the cases, which were interpreted twice by the same physician. Clinical and electrophysiological data were presented in standardised forms. Results Two-by-two Kappa coefficients among the eight physicians varied from 0.15 to 0.75 (mean 0.40) for EEC and from 0.18 to 0.80 (mean 0.43) for AwC. Kappa coefficients for intra-rater agreement varied from 0.08 to 0.81 (mean 0.56) for EEC and from 0.18 to 0.85 (mean 0.67) for AwC. Disagreement was seen on all diagnostic categories, most pronounced for “probable lab-supported” and “possible”. There were no differences between EEC and AwC. Discussion The large variation on EEC and AwC may be due to the complexity of the criteria including the definition of four body regions, interpretation and significance of clinical findings of upper or lower motor neuron signs, significance of findings being rostral or caudal to each other, and interpretation of detailed electrophysiological findings as evidence of acute or chronic denervation. Conclusions The large variation in interpretation of both EEC and AwC may be considered unacceptable for criteria used to include patients in research studies. Significance Variability on interpretation of diagnostic criteria for ALS should be considered in the assessment of scientific studies. Initiatives to develop more reproducible diagnostic criteria for ALS are needed.

Diagnostic criteria in amyotrophic lateral sclerosis: A multicenter prospective study.

In the article “Diagnostic criteria in amyotrophic lateral sclerosis: A multicenter prospective study” by N. Geevasinga et al.,1 …

Author response: Diagnostic criteria in amyotrophic lateral sclerosis: A multicenter prospective study.

We thank Dr. Ali for the review of our article1 and for the identification of 2 typographical errors. In the Results, the correct number of patients with ALS is 233 (page 686, column 2, line 3), while the number of non-ALS mimic cases is 183 (page 686, column 2, line 5). The correct and detailed number of ALS/non-ALS mimic patients is outlined in table 1.1

Editors' Note

Editors' Note: Commenting on “Acute intermittent porphyria-related leukoencephalopathy,” Dr. Pinto et al. suggest that the family described could be classified as complicated hereditary spastic paraplegia. Authors van der Knaap et al. disagree and explain that the term complicated hereditary spastic paraplegia is reserved for neuronal degenerative disorders predominantly affecting the long fibers of the corticospinal tracts and that leukodystrophies are specifically excluded. In the article “Diagnostic criteria in amyotrophic lateral sclerosis: A multicenter prospective study” by Geevasinga et al., Dr. Ali identified 2 errors. A correction appears on page 719. —Chafic Karam, MD, and Robert C. Griggs, MD Editors' Note: Commenting on “Acute intermittent porphyria-related leukoencephalopathy,” Dr. Pinto et al. suggest that the family described could be classified as complicated hereditary spastic paraplegia. Authors van der Knaap et al. disagree and explain that the term complicated hereditary spastic paraplegia is reserved for neuronal degenerative disorders predominantly affecting the long fibers of the corticospinal tracts and that leukodystrophies are specifically excluded.

Letter re: Diagnostic criteria in amyotrophic lateral sclerosis: A multicenter prospective study.

I read the article by Geevasinga et al.1 with interest. The study had a large sample size, the authors did a good job with subgroup analyses, and the methods were simple and robust.

Involvement of distal sensory nerves in amyotrophic lateral sclerosis.

The diagnostic criteria for amyotrophic lateral sclerosis (ALS) require normal sensory nerve conduction studies (NCS) or abnormal NCS only in the presence of neuropathy of identified etiology. In this study, we investigated the presence and extent of involvement of Aß sensory fibers in ALS. Distal sensory NCS [antidromic dorsal sural (DS) and orthodromic medial plantar (MP)] and conventional sensory NCS (unilateral median sensory and bilateral sural nerves) were performed in 16 definite and 2 probable ALS patients (based on Awaji criteria) and 31 controls. Abnormal conventional sensory NCS were found in 8 (44.4%) ALS patients and 1 (3.2%) control subject (P = 0.002), whereas abnormal distal sensory NCS were found in 12 (66.7%) ALS patients and 3 (9.6%) controls (P < 0.0001). Distal sensory NCS were more often abnormal than conventional sensory NCS in ALS. Muscle Nerve 54: 1086-1092, 2016.

Spotlight on the August 16 Issue

#### Notable in Neurology This issue features an article that determines whether large but nonstenotic carotid artery atherosclerotic plaque predominantly occurs ipsilateral rather than contralateral to cryptogenic stroke and another one that assesses the sensitivity and specificity of the Awaji and revised El Escorial diagnostic criteria in amyotrophic lateral sclerosis. A featured article explores longitudinal changes in brain activity in patients with Parkinson disease, multiple system atrophy, and progressive supranuclear palsy using task-based functional MRI. ### The effect of anesthetic management during intra-arterial therapy for acute stroke in MR CLEAN![Graphic][1]</img> Currently, centers treat stroke patients intra-arterially with or without general anesthesia. Both strategies have clear benefits, but until now, it remains unclear what … [1]: /embed/inline-graphic-1.gif

The role of cranial and thoracic electromyography within diagnostic criteria for amyotrophic lateral sclerosis

The contribution of cranial and thoracic region electromyography (EMG) to diagnostic criteria for amyotrophic lateral sclerosis (ALS) has not been evaluated. Clinical and EMG data from each craniospinal region were retrospectively assessed in 470 patients; 214 had ALS. Changes to diagnostic classification in Awaji-Shima and revised El Escorial criteria after withdrawal of cranial/thoracic EMG data were ascertained. Sensitivity for lower motor neuron involvement in ALS was highest in the cervical/lumbar regions; specificity was highest in cranial/thoracic regions. Cranial EMG contributed to definite/probable Awaji-Shima categorization in 1.4% of patients. Thoracic EMG made no contribution. For revised El Escorial criteria, cranial and thoracic data reclassified 1% and 5% of patients, respectively. Cranial EMG data make small contributions to both criteria, whereas thoracic data contribute only to the revised El Escorial criteria. However, cranial and thoracic region abnormalities are specific in ALS. Consideration should be given to allowing greater diagnostic contribution from thoracic EMG. Muscle Nerve 54: 378-385, 2016.

Primary Lateral Sclerosis and Early Upper Motor Neuron Disease: Characteristics of a Cross-Sectional Population.

The goals of this study were to characterize clinical and electrophysiologic findings of subjects with upper motor neuron disease and to explore feasibility of clinical trials in this population. Twenty northeast amyotrophic lateral sclerosis consortium (northeast amyotrophic lateral sclerosis) sites performed chart reviews to identify active clinical pure upper motor neuron disease patients. Patients with hereditary spastic paraplegia or meeting revised El Escorial electrodiagnostic criteria for amyotrophic lateral sclerosis were excluded. Patients were classified into 2 groups according to the presence or absence of minor electromyography (EMG) abnormalities. Two hundred thirty-three subjects with upper motor neuron disease were identified; 217 had available EMG data. Normal EMGs were seen in 140 subjects, and 77 had minor denervation. Mean disease duration was 84 (±80) months for the entire cohort with no difference seen between the 2 groups. No difference was seen in clinical symptoms, disability, or outcome measures between the 2 groups after correcting for multiple comparisons. Minor EMG abnormalities were not associated with phenotypic differences in a clinical upper motor neuron disease population. These findings suggest that subtle EMG abnormalities can not necessarily be used as a prognostic tool in patients with clinical upper motor neuron disease. This study also demonstrates the availability of a large number of patients with upper motor neuron diseases within the northeast amyotrophic lateral sclerosis network and suggests feasibility for conducting clinical trials in this population.

11. Revisiting early diagnosis in ALS

Objectives The currently utilized diagnostic Awaji criteria in Amyotrophic Lateral Sclerosis (ALS) can result in a diagnostic delay of up to ten months. Subsequently we utilized a three pronged approach, initially an individual patient data (IPD) meta-analysis was undertaken to evaluate the diagnostic utility of the Awaji criteria. We then performed the first prospective multicenter study looking at the current diagnostic criteria. Finally we looked at the addition of a novel Transcranial magnetic stimulation (TMS) technique as an objective biomarker of upper motor neuron dysfunction, to further improve the current criteria. Methods An IPD meta-analysis was performed after communicating with key researchers and authors who published diagnostic studies looking at the Awaji criteria. In total IPD was available for 1086 individuals across 8 published studies. Statistical modelling was undertaken using SAS (9.3). The first prospective multicenter study looking at the Awaji criteria was undertaken in Sydney, Australia, according to the STARD criteria in 369 patients. Finally, a prospective multicenter study was undertaken looking at the diagnostic utility of Threshold tracking TMS in 333 patients. Results An IPD meta analysis of 1086 individuals revealed that the current Awaji criteria were more sensitive than the revised El Escorial criteria (rEEC) in all, except one study (7/8 studies). The Awaji criteria were more robust than the rEEC criteria (Sensitivity Awaji 70%, rEEC 45%, P 0.0001). The Awaji criteria performed better than the rEEC in both bulbar and limb onset disease (P 0.0001). In the multicenter prospective study, the Awaji criteria were compared in a cohort of 369 patients. Specificity was 100% across both criteria. Sensitivity was 57% with the Awaji and 39% with the rEEC criteria. Finally in the TMS prospective study, by objectively measuring evidence of UMN dysfunction, an extra 34% of patients could be diagnosed at the first visit. If TMS changes of cortical dysfunction were added to the current Awaji criteria, the sensitivity of the Awaji criteria could be increased to 86%. Furthermore 88% of Awaji ‘Possible’ patients could be reclassified as ‘Probable/Definite’. Conclusion Whilst an individual patient data meta-analysis revealed a better sensitivity for the Awaji criteria when compared to the older rEEC criteria, there were still a number of patients that could not be classified early. Furthermore all the studies that have looked at the Awaji criteria have been single centre in design, and generally retrospective in nature. The first prospective multicenter study looking at the Awaji criteria, revealed that the sensitivity of the Awaji criteria was lower than expected, most likely related to the inclusion of patients with early onset disease. Finally by utilizing an objective neurophysiological marker of UMN dysfunction, the diagnosis of ALS could be made earlier, when will then hopefully translate into earlier recruitment into clinical trials, ideally within the critical time frame for therapeutic response.

Epigenetic Modifications of the C9Orf72 Gene: A Potential Biomarker of Disease?

123 ISSN 1479-6708 10.2217/FNL.14.5 © 2014 Future Medicine Ltd Future Neurol. (2014) 9(2), 123–126 Frontotemporal lobar degeneration (FTLD), the most common presenile onset neurodegenerative disease [1], results from progressive neuronal death in the frontal and anterior temporal lobes, and comprises three frontotemporal dementia (FTD) syndromes characterized by changes in personality and social conduct, impairments in naming and word comprehension, or deterioration of expressive language [2]. Approximately 40% of individuals affected with FTLD will eventually develop motor dysfunctions, 15% of which will reach the diagnostic criteria of amyotrophic lateral sclerosis (ALS) [3,4], the third most common neuro degenerative disease and the most common motor neuron disease [5]. Degeneration of upper and lower motor neurons in ALS progressively leads to muscle weakness, spasticity and atrophy [6]. In addition, approximately 40–50% of ALS patients develop cognitive dysfunctions that, in 15–18% of cases, will fill the diagnostic criteria of FTD [7,8]. These two devastating, lethal disorders are now seen as being part of the same disease spectrum, but the pathological mechanisms underlying neuronal degeneration still need to be better understood. Over the last two decades, genetic studies on ALS and FTLD, in particular linkage studies using families exhibiting Mendelian inheritance, shed light on more than two dozen genes implicated in the pathogenesis of both diseases [9]. The most intriguing locus, identified in 2006 on chromosome 9p21 [10–12], has been confirmed in 2010 by a genome-wide association study using the founder Finnish population and remains the most significant genome-wide association study signal observed to date for ALS [13]. A fruitful 5-year effort led to the 2011 discovery of the chromosome 9p21 genetic culprit: a major hexanucleotide repeat expansion carried by up to 50% of familial ALS and up to 25% of familial FTD patients [14,15], making the expanded C9ORF72 gene the most common genetic cause of ALS and FTLD identified to date, and bringing a wind of change to this field of research. This genetic finding provided a further link between these two disorders; patients carrying a pathogenic C9ORF72 repeat expansion are now being collectively referred to as c9FTD/ALS. Comparable repeat expansions have been shown to alter epigenetic mechanisms while simultaneously leading to toxic RNA gainof-function and protein loss-of-function; such dual involvement of toxicity and