No abstract

With a 3-fold increase in the number of cancer survivors noted since the 1970s, there are now over 28 million cancer survivors worldwide. Accordingly, there is a heightened awareness of long-term toxicities and the impact on quality of life following treatment in cancer survivors. This review will address the increasing importance and challenge of chemotherapy-induced neurotoxicity, with a focus on neuropathy associated with the treatment of breast cancer, colorectal cancer, testicular cancer, and hematological cancers. An overview of the diagnosis, symptomatology, and pathophysiology of chemotherapy-induced peripheral neuropathy will be provided, with a critical analysis of assessment strategies, neuroprotective approaches, and potential treatments. The review will concentrate on neuropathy associated with taxanes, platinum compounds, vinca alkaloids, thalidomide, and bortezomib, providing clinical information specific to these chemotherapies.

Axonal excitability studies allow deductions about membrane and ion channel properties in vivo. Excitability studies have investigated nerve function and pathophysiology in neurological disease. Guidelines summarise physiological basis, methodology and interpretation of excitability studies.

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1–10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results in progressive loss of bulbar and limb function. Patients typically die from respiratory failure within 3 years of symptom onset. The incidence of ALS in Europe is 2-3 cases per 100,000 individuals in the general population, and the overall lifetime risk of developing the disease is 1:400. ALS is familial in 5% of cases, and shows a Mendelian pattern of inheritance. ALS is recognized to overlap with frontotemporal dementia. Diagnosis is made on clinical grounds, using internationally recognized consensus criteria, after exclusion of conditions that can mimic ALS. The Revised ALS Functional Rating Scale is currently the most widely used assessment tool; scores are used to predict survival, and have been employed extensively in clinical trials. Riluzole remains the only effective drug, and extends the average survival of patients by 3-6 months. Optimal treatment is based on symptom management and preservation of quality of life, provided in a multidisciplinary setting. The discovery of further effective disease-modifying therapies remains a critical need for patients with this devastating condition.

Summary Two decades after the discovery that 20% of familial amyotrophic lateral sclerosis (ALS) cases were linked to mutations in the superoxide dismutase-1 (SOD1) gene, a substantial proportion of the remainder of cases of familial ALS have now been traced to an expansion of the intronic hexanucleotide repeat sequence in C9orf72. This breakthrough provides an opportunity to re-evaluate longstanding concepts regarding the cause and natural history of ALS, coming soon after the pathological unification of ALS with frontotemporal dementia through a shared pathological signature of cytoplasmic inclusions of the ubiquitinated protein TDP-43. However, with profound clinical, prognostic, neuropathological, and now genetic heterogeneity, the concept of ALS as one disease appears increasingly untenable. This background calls for the development of a more sophisticated taxonomy, and an appreciation of ALS as the breakdown of a wider network rather than a discrete vulnerable population of specialised motor neurons. Identification of C9orf72 repeat expansions in patients without a family history of ALS challenges the traditional division between familial and sporadic disease. By contrast, the 90% of apparently sporadic cases and incomplete penetrance of several genes linked to familial cases suggest that at least some forms of ALS arise from the interplay of multiple genes, poorly understood developmental, environmental, and age-related factors, as well as stochastic events.

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Familial amyotrophic lateral sclerosis (FALS) is an inherited neurodegenerative disorder of the motor neurons. While 10-15% of cases are caused by mutations in the copper/zinc superoxide-dismutase-1 (SOD-1) gene, the dying-forward hypothesis, in which corticomotoneurons induce anterograde excitotoxic motoneuron degeneration, has been proposed as a potential mechanism. The present study applied novel threshold tracking transcranial magnetic stimulation techniques to investigate the mechanisms underlying neurodegeneration in FALS. Studies were undertaken in 14 asymptomatic and 3 pre-symptomatic SOD-1 mutation carriers, followed longitudinally for up to 3-years. The pre-symptomatic subjects were asymptomatic at the time of their initial study but developed symptoms during the follow-up period. Results were compared to 7 SOD-1 FALS patients, 50 sporadic ALS patients and 55 normal controls. Short-interval intracortical inhibition (SICI) was significantly reduced in SOD-1 FALS (-1.2 +/- 0.6%) and sporadic ALS patients (-0.7 +/- 0.3%) compared to asymptomatic SOD-1 mutation carriers (9.8 +/- 1.5%, P<0.00001) and normal controls (8.5 +/- 1.0%, P<0.00001). SICI reduction was accompanied by increases in intracortical facilitation, motor evoked potential amplitudes and the slope of the magnetic stimulus-response curve. In two pre-symptomatic SOD-1 mutation carriers SICI was completely absent (SICI patient 1, -3.2%; patients 2, -1.3%), while in one subject there was a 32% reduction in SICI prior to symptom onset. These three individuals subsequently developed clinical features of ALS. Simultaneous investigation of central and peripheral excitability has established that cortical hyperexcitability develops in clinically affected SOD-1 FALS patients, similar to that seen in sporadic ALS patients, thereby suggesting that a similar pathophysiological process in evident in both familial and sporadic ALS patients. In addition, the present study has established that cortical hyperexcitability precedes the development of clinical symptoms in pre-symptomatic carriers of the SOD1 mutation, thereby suggesting that cortical hyperexcitability underlies neurodegeneration in FALS.