Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy.

Myotonic dystrophy (DM1), the most common muscular dystrophy in adults, is caused by an expanded (CTG)n tract in the 3' UTR of the gene encoding myotonic dystrophy protein kinase (DMPK), which results in nuclear entrapment of the 'toxic' mutant RNA and interacting RNA-binding proteins (such as MBNL1) in ribonuclear inclusions. It is unclear if therapy aimed at eliminating the toxin would be beneficial. To address this, we generated transgenic mice expressing the DMPK 3' UTR as part of an inducible RNA transcript encoding green fluorescent protein (GFP). We were surprised to find that mice overexpressing a normal DMPK 3' UTR mRNA reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, histopathology and RNA splicing defects in the absence of detectable nuclear inclusions. However, we observed increased levels of CUG-binding protein (CUG-BP1) in skeletal muscle, as seen in individuals with DM1. Notably, these effects were reversible in both mature skeletal and cardiac muscles by silencing transgene expression. These results represent the first in vivo proof of principle for a therapeutic strategy for treatment of myotonic dystrophy by ablating or silencing expression of the toxic RNA molecules.

Electrophysiologically guided untethering of secondary tethered spinal cord syndrome.

OBJECT: Many patients develop neurological symptoms related to spinal cord tethering after perinatal repair of myelomeningocele. This is referred to as secondary tethered cord syndrome (STCS). The authors describe their methodology and evaluate the intraoperative utility and postoperative outcomes of electrophysiologically guided untethering for STCS. In addition, the authors describe the use of electrophysiological guidance to identify an "autonomous placode" in the untethering of the cord in STCS. METHODS: The authors retrospectively identified 46 untethering procedures in 38 patients who had undergone perinatal myelomeningocele repair and in whom the index surgery was for tethered cord release at the site of the repair. In all cases, both passive (electromyography) and active (detection of compound muscle action potentials) electrophysiological monitoring was used. The proximity to neural elements was determined based on the current used; eliciting compound muscle action potentials with a

Creatine monohydrate in ALS: effects on strength, fatigue, respiratory status and ALSFRS.

Our objective was to determine the effect of creatine monohydrate on disease progression in patients with amyotrophic lateral sclerosis (ALS). One hundred and seven patients with the diagnosis of probable or definite ALS, of less than five years duration from symptom onset, were randomized to either treatment with daily creatine monohydrate (5 g/d) or placebo. In this multicenter, double-blinded study we followed changes in disease progression: using quantitative measures of strength via maximal isometric voluntary contraction, forced vital capacity, ALSFRS, quality of life, fatigue and survival. Patients were followed for nine months. The results showed that creatine monohydrate did not significantly improve motor, respiratory or functional capacity in this patient population. The drug was well tolerated and the study groups well balanced, especially considering the absence of forced vital capacity criteria for entrance into the study. There was a trend toward improved survival in patients taking daily creatine monohydrate and this was identical to the trend seen in another recently published report of creatine in ALS patients 1. In conclusion, creatine monohydrate (5 g/d) did not have an obvious benefit on the multiple markers of disease progression measured over nine months. We measured fatigue during isometric contraction and found no significant improvement despite anecdotal patient reports prior to and during the study. The trend toward improved survival was also found in another recently completed blinded trial using creatine monohydrate. Further investigation on the possible survival benefit of creatine in this patient population is ongoing.

R+ pramipexole as a mitochondrially focused neuroprotectant: initial early phase studies in ALS.

R+ pramipexole (PPX) is a lipophilic cation that concentrates into brain and mitochondria and efficiently scavenges reactive oxygen and nitrogen species (RONS). Under the auspices of a Physician-Sponsor IND, R+PPX was dosed to small numbers of ALS patients for tolerability and safety while efficacy measures were also collected. The purpose of this paper is to describe the outcomes of these initial clinical studies. In a futility design study, 30 patients with early SALS were evaluated monthly for ALSFRS-R scores and FVC measurements for three months during lead-in, followed by open-label dosing at 30 mg/day of R+PPX for the next six months. In the dose escalation study, 10 subjects with early ALS received daily doses of R+PPX from 10 mg t.i.d. to 100 mg t.i.d. over seven weeks. In the open-label extension analysis, subjects from the initial studies were treated with 30 mg/day for at least six months, then switched to 60 mg/day. R+PPX was tolerated well in all studies. In the futility study, slopes of decline in ALSFRS-R scores and neurophysiological index (NI) values yielded non-significant reductions during treatment. In the dose-escalation study, all subjects increased daily R+PPX intake safely to 100 mg t.i.d. Markers of ALS did not change (ALSFRS-R) or improved (FVC). Trough and peak plasma (PPX) increased linearly with dosing, and several subjects achieved plasma (PPX) >1 microM. In the open-label extension protocol, changing from 30 to 60 mg/day caused a non-significant 17% reduction in slope of decline of ALSFRS-R. It was concluded that R+PPX was tolerated well in long-term dosing at 30 and 60 mg/day. Encouraging but non-significant effects of R+PPX on ALS decline were observed. High doses of R+PPX were tolerated well and yielded neuroprotective plasma levels. These findings support longer-term testing of higher R+PPX doses as a potential disease-altering therapy for SALS.

Novel myelin protein zero mutation (Arg36Trp) in a patient with acute onset painful neuropathy.

We present a patient with acute onset painful polyneuropathy found to have a novel MPZ mutation (Arg36Trp). The Arg36Trp mutation described in this report occurs at a putative adhesion interface. An alternative explanation for his polyneuropathy was not found and his mother was identified to have polyneuropathy and carry the same mutation. Two hundred normal controls were without this base alteration. The temporal profile of the index case may provide further indirect evidence suggesting an immune mechanism contributing to the pathogenesis of some cases of MPZ mutations. We predict that other rapid symptom onset polyneuropathies will be found to have direct genetic susceptibility.

Hypnotic analgesia reduces R-III nociceptive reflex: further evidence concerning the multifactorial nature of hypnotic analgesia.

Mechanisms of hypnotic analgesia were investigated by examining changes in the R-III, a nociceptive spinal reflex, during hypnotic reduction of pain sensation and unpleasantness. The R-III was measured in 15 healthy volunteers who gave VAS-sensory and VAS-affective ratings of an electrical stimulus during conditions of resting wakefulness, suggestions for hypnotic analgesia, and attempted suppression of the reflex during non-hypnotic conditions. The H-reflex was also measured to monitor and control for general changes in alpha-motoneuron excitability. Hypnotic sensory analgesia was related to reduction in the R-III after controlling for changes in the H-reflex (R2 = 0.51, P < 0.003), suggesting that hypnotic sensory analgesia is at least in part mediated by descending antinociceptive mechanisms that exert control at spinal levels in response to hypnotic suggestion. The relationship between hypnotic affective analgesia and reduction in R-III approached significance (R2 = 0.26; P = 0.053). Reduction in R-III was 67% as great and accounted for 51% of the variance in reduction of pain sensation. In turn, reduction in pain sensation was 75% as great and accounted for 77% of the variance in reduction of unpleasantness. The results suggest that 3 general mechanisms may be involved in hypnotic analgesia. The first, implicated by reductions in R-III, is related to spinal cord antinociceptive mechanisms. The second, implicated by reductions in pain sensation over and beyond reductions in R-III, may be related to brain mechanisms that serve to prevent awareness of pain once nociception has reached higher centers, as suggested by Hilgard.(ABSTRACT TRUNCATED AT 250 WORDS)

The epidemiology of myasthenia gravis.

Population-based studies of the epidemiology of myasthenia gravis (MG) have been conducted for over 50 years. Over that time, there has been a clear trend towards an increase in the reported prevalence of the disease. In recent years, there has also been an interest in determining a reasonably accurate estimate of the number of MG patients in the United States. Current estimates place the prevalence at a high value of about 20 per 100,000. The year 2000 U.S. population estimate is slightly less than 280 million. A crude estimate of the number of MG patients derived from the population estimate and the reported prevalence from selected populations indicates that there are between 53,000 and 59,900 patients in the United States at this time. The age and ethnic distributions in the United States are evolving from those that were present when the majority of the population-based studies were done, and the distribution of severity of the disease may also have changed. Future studies of the epidemiology of MG should take these factors into account, and further research into the economic and quality-of-life impact of the disease in the population is needed.

Neurologic manifestations of sarcoidosis.

Sarcoidosis is multisystem granulomatous disease of unknown etiology. Although the nervous system is involved in only 5% to 16% of patients, neurosarcoidosis is one of the more serious manifestations of the disease. Cranial neuropathies are common, but involvement of the mininges or the brain or spinal cord parenchyma causes more severe morbidity. MR imaging of affected portions of the neuraxis is a very sensitive diagnostic technique. Treatment with corticosteroids is the mainstay of therapy.