Gaëlle Bruneteau et al. Brain (2013) 136 (8): 2359-2368.doi: 10.1093/brain/awt164
Submitted by Zaeem Siddiqi, MD, PhD, NSE Board
The typical course of amyotrophic lateral sclerosis (ALS) is rapidly progressive usually leading to death in 3 to 5 years due to muscle paralysis and respiratory failure. In some patients though the course is protracted with prolonged survival, sometimes for decades. The etiology and factors associated with this variable disease course are unclear.
In the transgenic mouse model of ALS the muscle histone deacetylase 4 (HDA) and its regulator microRNA-2m06 play an important role in compensatory collateral reinnervation and that can modify disease progression. Bruneteau et al. assessed the role of HDA expression in a cohort comprising of 11 patients with ALS, which included five long-term survivors. Using high-resolution confocal imaging the investigators studied muscle reinnervation of neuromuscular junctions (NMJ) and showed that the proportion of reinnervated NMJ was significantly higher in the long-term survivors than those having a rapid disease course. The HDA gene expression was significantly more in patients with rapidly progressive disease and was negatively correlated with the extent of muscle reinnervation and functional outcome. The regulator of HDA i.e. microRNA-206, was upregulated in both groups, but did not correlate with disease progression or reinnervation. The study concluded that expression of HDA in the affected muscles in ALS patients appears to have a key deleterious affect in muscle reinnervation and is associated with rapid disease progression.
ALS has a relentlessly progressive course and little is known about the factors that determine disease characteristics. Predominance of upper motor neuron signs, presence of superoxide dismutase (SOD 1) gene mutation, and disease onset at younger age have been shown to be associated with a relatively slower progression. This study shows another gene expression to have a major impact on disease course in ALS by affecting compensatory reinnervation of denervated muscles. If the results are replicated in a larger population, the HDA gene may be a potential target for therapeutic approaches to slow the disease progression in ALS.
More from the News Science Editorial Board
The evolving natural history of neurophysiologic function in patients with well-controlled diabetes
Gibbons CH, et al., J Periph Nerv Syst (2013)18:153-161.
Submitted by Carlos A. Luciano, MD, NSE Board
In a study focusing on patients with well-controlled diabetes and optimal medical management of co-morbid risk factors, Gibbons et al. analyzed changes in neurophysiologic measures over a 3-year period, as a measure of progression of peripheral nerve involvement. The investigators studied a cohort of 62 patients and collected clinical and neurophysiologic measures serially at 18-month intervals. Following measures were studied: changes in the neurologic examination, symptom scores, autonomic tests, nerve conduction studies (NCS), quantitative sensory tests, and laser-doppler flowmetry (LDF), which is a non-invasive method of measuring perfusion in the cutaneous microvasculature. While they did not find changes in the frequency or severity of neuropathy in these patients, they did find significant increases in monofilament detection thresholds (p<0.001) and distal hypersensitivity on clinical testing (p<0.005). On NCS there was a borderline-significant decrease in sural sensory response amplitude (1µV; p=0.05) and a more robust decrease in axon-reflex vasodilation in the foot (p<0.005) and forearm (P<0.05), as measured with LDF.
There is consensus that the severity and progression of diabetic neuropathy is related to the control and duration of diabetes and related co-morbid factors. However, there is limited knowledge about progression in the well-controlled diabetic patients. This study provides additional evidence in favor of diabetes control as an important measure to limit severity and progression of neuropathy, although it may need a control group to support that. It is interesting that despite the optimal glucose control, changes do occur over time. Among the measured changes in these patients, those related to small-fiber function showed the greatest differences over the period of three years in the study. These parameters could be used as biomarkers in clinical trials for diabetic polyneuropathy. This study also suggests that in individual patients, sural sensory amplitudes and monofilament thresholds can be used in clinical practice to detect neuropathy over time, if LDF is not readily available.
Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomized, double-blind, phase 3 trial
Lancet Neurol. (2013)12(11):1059-67.
Submitted by Shan (Sarah) Chen, MD, NSE Board
Cudkowicz ME, van den Berg LH, Shefner JM, Mitsumoto H, Mora JS, Ludolph A, Hardiman O, Bozik ME, Ingersoll EW, Archibald D, Meyers AL, Dong Y, Farwell WR, Kerr DA; EMPOWER investigators.
Dexpramipexole is known to enhance mitochondrial function and offers neuroprotection in the in-vivo models of amyotrophic lateral sclerosis (ALS), leading to increased rates of survival and retention of motor function. In a preceding phase II study, the drug (25-150 mg twice daily) was well tolerated for up to nine months and appeared to show a significant benefit at the higher doses on a combined assessment of function and mortality in patients with ALS.
In this large phase III randomized, double-blind, placebo-controlled trial, 943 participants aged 18-80 years were enrolled at 81 centers in 11 countries. 474 of those were allocated to the dexpramipexole group and received 150mg twice-daily for 12-18 months. The drug was generally well tolerated but the outcomes did not differ from placebo on any prespecified efficacy endpoint measurement (Combined Assessment Function Survival (CAFS) score 441.76 vs. 438.84; p=0.86; in change of ALS Functional rating scale-revised ALSFRS (-13.34 vs. -13.42); or time to death 74 (16%) vs. 79 (17%) months. Rare events of neutrotropenia were more common in dexpramipexole-treated participants.
Riluzole is the only approved therapy for ALS and offers only a modest effect on survival and no proven effect on muscle strength. This was one of the largest phase III trial for ALS and showed negative efficacy results. The results showed again the challenges in the use of promising phase II studies to predict phase III studies in ALS. CAFS is a novel outcome measure that combines function and survival and has the potential to benefit the design of other upcoming ALS trials.
RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention
Neuron (2013) 16; 80(2): 415-28.
Submitted by Shan (Sarah) Chen, MD, NSE Board
Donnelly CJ, Zhang PW, Pham JT, Heusler AR, Mistry NA, Vidensky S, Daley EL, Poth EM, Hoover B, Fines DM, Maragakis N, Tienari PJ, Petrucelli L, Traynor BJ, Wang J, Rigo F, Bennett CF, Blackshaw S, Sattler R, Rothstein JD.
C9ORF72 gene mutation, a hexanucleotide GGGGCC repeat expansion in its noncoding region, is the most common genetic abnormality in familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To elucidate the pathogenic process of the repeat expansion and further the function of this protein, these investigators used induced pluripotent stem cell (iPSC)-differentiated neurons from C9ORF72 ALS patients and showed that this mutation dysregulates gene expression and sequestere of GGGGCCexp RNA binding protein ADARB2, and causes susceptibility to excitotoxicity, as in the proposed RNA gain-of-function mechanism.
In addition, the authors showed that these functions can be mitigated by antisense oligonucleotide (ASO) intervention. These pathological and pathogenic characteristics were confirmed in ALS brain and were mitigated with antisense oligonucleotide (ASO) therapeutics to the C9ORF72 transcript or repeat expansion despite the presence of repeat-associated non-ATG translation (RAN) products. These data indicate a toxic RNA gain-of-function mechanism as a potential cause of ALS in C9ORF7 mutated patients.
Since the recent breakthrough finding of hexanucleotide expansion in C9ORF72 as the most common mutation in familial and sporadic ALS, there have been many studies investigating the function of C9ORF72 protein and its role in pathogenesis of ALS. Since the repeats occur in the non-coding region, RNA toxicity has been proposed. Using C9ORF72 iPSC neurons, this study confirmed the RNA toxicity mechanism and also identified an antisense RNA that can mitigate the toxicity, providing potential pharmacological therapies for ALS.
About the News Science Editorial Board
The AANEM News Science Editorial (NSE) Board
compiles quarterly summaries of signficant research from journals and websites publishing neuromuscular and electrodiagnostic medicine research.