Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis

Goutman, Stephen A.; Hardiman, Orla; Al‐Chalabi, Ammar; Chiò, Adriano; Savelieff, Masha G.; Kiernan, Matthew C.; Feldman, Eva L.

doi:10.1016/s1474-4422(21)00414-2

Cited by 214 publications

(147 citation statements)

References 100 publications

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“…The multivariate Cox regression model used in the present study showed that the predictors of favorable survival were younger age of onset, longer diagnostic delay, and carrying C9orf72 repeats of 2. However, the sex effect was not identified here, which has been regarded as a prognostic predictor in previous studies ( 1 ). C9orf72 HRE is not fully penetrant until the age of 80 years ( 21 ).…”

Section: Discussioncontrasting

confidence: 56%

“…Amyotrophic lateral sclerosis (ALS) is a fatal and rare neurodegenerative disorder characterized by involvement of the motor system and a final lethal course within 2–4 years after symptom onset ( 1 ). Since Superoxide Dismutase 1 ( SOD1 ) mutations were identified to cause ALS in 1993 ( 2 ), a number of causative genes of ALS have been found.…”

Section: Introductionmentioning

confidence: 99%

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The repeat length of C9orf72 is associated with the survival of amyotrophic lateral sclerosis patients without C9orf72 pathological expansions

et al. 2022

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ObjectiveTo explore whether the repeat lengths of the chromosome 9 open reading frame 72 (C9orf72) gene and the ataxin-2 (ATXN2) gene in amyotrophic lateral sclerosis (ALS) patients without C9orf72 repeat expansions confer a risk of ALS or survival disadvantages in ALS.MethodsWe screened a hospital-based cohort of Chinese patients with sporadic ALS without C9orf72 repeat expansions and neurologically healthy controls for C9orf72 GGGGCC and AXTN2 CAG repeat length to compare the frequency of possible detrimental length alleles using several thresholds. Furthermore, the clinical features of ALS were compared between patients with ALS subgroups using different length thresholds of maximum C9orf72 and ATXN2 repeat alleles, such as sex, age of onset, diagnostic delay, and survival.ResultsOverall, 879 sporadic patients with ALS and 535 controls were included and the repeat lengths of the C9orf72 and ATXN2 were both detected. We found significant survival differences in patients using a series of C9orf72 repeat length thresholds from 2 to 5, among which the most significant difference was at the cutoff value of 2 (repeats 2 vs. >2: median survival 67 vs. 55 months, log-rank p = 0.032). Furthermore, Cox regression analysis revealed the role of age of onset [hazard ratio (HR) 1.04, 95% CI 1.03–1.05, p < 0.001], diagnostic delay (0.95, 0.94–0.96, p < 0.001), and carrying C9orf72 repeat length of 2 (0.72, 0.59–0.89, p = 0.002) in the survival of patients without C9orf72 repeat expansions. In addition, bulbar onset was associated with poorer survival when the patients carried the maximum C9orf72 repeat allele over 2 (1.81, 1.32–2.48, p < 0.001). However, no survival difference was found when applying a series of continuous cutoff values of ATXN2 or stratified by C9orf72 repeats of 2.ConclusionThe length of 2 in the maximum C9orf72 repeat allele was identified to be associated with favorable survival in ALS patients without C9orf72 repeat expansions. Our findings from the clinical setting implicated the possible cutoff definition of detrimental C9orf72 repeats, which should be helpful in the understanding of genetics in ALS and in clinical genetic counseling.

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Section: Discussioncontrasting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

The repeat length of C9orf72 is associated with the survival of amyotrophic lateral sclerosis patients without C9orf72 pathological expansions

et al. 2022

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“…While this may at first suggest that the genetic components of sALS play only a minor role in ALS pathology, twin studies have estimated a genetic contribution to the disease of up to 65% [ 15 , 16 ]. It is therefore likely that a substantial component of the heritability of sALS still remains unidentified and may lie within under-characterised regions of the human genome [ 17 ]. Variable sequences within the non-coding regions of the genome, known as structural variants (i.e., short tandem repeats), have been reported to influence the binding of regulatory elements that can alter gene expression and disease pathology [ 18 ].…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

Synucleinopathy in Amyotrophic Lateral Sclerosis: A Potential Avenue for Antisense Therapeutics?

Roberts

Theunissen

Mastaglia

et al. 2022

IJMS

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Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease classified as both a neurodegenerative and neuromuscular disorder. With a complex aetiology and no current cure for ALS, broadening the understanding of disease pathology and therapeutic avenues is required to progress with patient care. Alpha-synuclein (αSyn) is a hallmark for disease in neurodegenerative disorders, such as Parkinson’s disease, Lewy body dementia, and multiple system atrophy. A growing body of evidence now suggests that αSyn may also play a pathological role in ALS, with αSyn-positive Lewy bodies co-aggregating alongside known ALS pathogenic proteins, such as SOD1 and TDP-43. This review endeavours to capture the scope of literature regarding the aetiology and development of ALS and its commonalities with “synucleinopathy disorders”. We will discuss the involvement of αSyn in ALS and motor neuron disease pathology, and the current theories and strategies for therapeutics in ALS treatment, as well as those targeting αSyn for synucleinopathies, with a core focus on small molecule RNA technologies.

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“…Despite a large variety of ALS animal models [ 39 ], studies evaluating BBB alterations focused almost exclusively on SOD1 mutated rodents which validity is questionable. However, SOD1 mutations represent only 1–2 % of sporadic ALS cases, and the number of genes associated with ALS has risen dramatically [ 40 ]. Even if QAlb is not a perfect marker of BBB integrity, the inconsistency of its elevation illustrates, once again, the complex heterogeneity of ALS, and suggests the implication of different pathophysiological mechanisms in different subsets of patients.…”

Section: Bbb Alterations In Als and Their Consequencesmentioning

confidence: 99%

Taking Advantages of Blood–Brain or Spinal Cord Barrier Alterations or Restoring Them to Optimize Therapy in ALS?

Alarcan

Ojaimi

Lanznaster

et al. 2022

JPM

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that still lacks an efficient therapy. The barriers between the central nervous system (CNS) and the blood represent a major limiting factor to the development of drugs for CNS diseases, including ALS. Alterations of the blood–brain barrier (BBB) or blood–spinal cord barrier (BSCB) have been reported in this disease but still require further investigations. Interestingly, these alterations might be involved in the complex etiology and pathogenesis of ALS. Moreover, they can have potential consequences on the diffusion of candidate drugs across the brain. The development of techniques to bypass these barriers is continuously evolving and might open the door for personalized medical approaches. Therefore, identifying robust and non-invasive markers of BBB and BSCB alterations can help distinguish different subgroups of patients, such as those in whom barrier disruption can negatively affect the delivery of drugs to their CNS targets. The restoration of CNS barriers using innovative therapies could consequently present the advantage of both alleviating the disease progression and optimizing the safety and efficiency of ALS-specific therapies.

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Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis

Cited by 214 publications

References 100 publications

The repeat length of C9orf72 is associated with the survival of amyotrophic lateral sclerosis patients without C9orf72 pathological expansions

The repeat length of C9orf72 is associated with the survival of amyotrophic lateral sclerosis patients without C9orf72 pathological expansions

Synucleinopathy in Amyotrophic Lateral Sclerosis: A Potential Avenue for Antisense Therapeutics?

Taking Advantages of Blood–Brain or Spinal Cord Barrier Alterations or Restoring Them to Optimize Therapy in ALS?

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