AAN Meeting Report

Here is a summary of news reported at the American Academy of Neurology Annual Meeting, April 28-May 4 in Boston.

Among the hundreds of presentations were dozens related to neuromuscular disorders in MDA’s program. Many of the findings resulted from MDA research funding and/or the contributions of MDA clinic physicians.

MINOCYCLINE INEFFECTIVE FOR ALS

Disappointing results of a nine-month trial of the drug minocycline for amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) were announced.

Minocycline demonstrated no beneficial effect, and for some patients, worsened measurable outcomes.

People with ALS who are currently taking the drug, an antibiotic in the tetracycline family, are urged to contact their physician to discuss discontinuing its use, said MDA Medical Director Valerie Cwik, who attended the meeting.

The drug did not affect survival or quality of life measures for people with ALS in the trial.

The trial tested minocycline versus a placebo (inert, look-alike substance) in 412 people at 31 U.S. centers. The drug was thought to reduce inflammation and counteract cell death.

Other highlights from the meeting, by disease or topic:

AMYOTROPHIC LATERAL SCLEROSIS (ALS)

• Variations in a gene for a protein called progranulin can modify the course of ALS according to a study of 230 people with ALS and 436 without the disease in Belgium. This finding could have implications for understanding and treatment of ALS.
  
  
• Administering a compound called SOD1 antisense directly into the brains of rats destined to develop a genetic form of ALS slowed the progression of the disease early in its course and extended survival. If the drug was given prior to the onset of the disease, the increase in survival was 30 days; but if treatment was started close to disease onset, survival increased by 10 days. SOD1 antisense blocks genetic instructions for the SOD1 protein. In this form of ALS, these instructions are abnormal and lead to production of a highly toxic, disease-causing protein. Plans to test this treatment in people with SOD1-caused ALS are under way.
  
  
• An analysis of muscle tissue in 33 people with ALS, ALS with dementia or dementia alone, seven people with various other neuromuscular disorders, and 12 people without a neuromuscular disorder showed that a protein in muscle called Nogo-A was found in 20 out of 23 (87 percent) of the ALS patients. It was also found in five out of five people with ALS and dementia (100 percent) and three out of five with dementia alone (60 percent). None of the other 19 study participants, who had another neuromuscular disease or no neuromuscular disease, had this protein in their muscle tissue. The significance of these results isn’t yet clear.
  
  
• In a second study about Nogo_A, researchers reported that detection of this protein in muscle tissue may be a way to identify ALS very early in the course of the disease, when the diagnosis is still uncertain. Further studies are necessary to determine whether Nogo-A may be a potential biomarker for ALS.
  
  
• A comparison of the DNA in all genes of 276 Americans and 277 Italians with ALS and 2,130 Americans and Italians without the disease has been completed. Two genetic variants that may increase the risk for developing sporadic ALS were identified in the Italian cohort but not in the US cohort of individuals with ALS. These results may yield new clues for understanding the causes of and biochemical pathways involved in sporadic ALS.
  
  
• Variations in the genes for two enzymes, known as PON1 and PON3, appear to be risk factors for ALS, according to a study of 221 Irish ALS patients and 202 healthy subject of similar age, gender and ethnic background. These PON genes, which have previously been implicated in other ALS studies, are involved in detoxification of pesticides and other chemical compounds.
  
  
• A study of 65 people with ALS and their primary caregivers (who were separately interviewed) found that the diagnostic phase of ALS is a time of moderate to high anxiety levels for patients, but that these tend to decrease as the disease progresses. Anxiety in caregivers, however, did not decrease with disease progression.
  
  
• Mutations in a gene for the SOD1 protein, known to cause a type of familial ALS, don’t do so by damaging muscle tissue, a new study shows. Increasing muscle mass and strength did not slow the onset or progression of ALS in mice with the SOD1 form of the disease, although enhanced muscle mass led to temporary strength gains.
  
  
• Phrenic nerve conduction studies are a useful tool in evaluating whether the respiratory status of paralyzed patients will benefit from implantation of electrodes that stimulate the diaphragm. The phrenic nerve normally controls diaphragm movement. This type of “diaphragm pacemaker implantation” strategy is being tested in people with spinal cord injuries and ALS.
  
  
• Mice with a genetic form of ALS because of a mutation in the gene for the SOD1 protein responded well to a compound called anti-SOD1 siRNA, designed to block erroneous SOD1 genetic instructions. Mice bred to produce this anti-SOD1 compound and also bred to have an SOD1 mutation didn’t develop ALS symptoms until they were 280 days old, whereas all the animals with an SOD1 mutation without it died by 160 days.
  
  
• A 20-week trial of sodium phenylbutyrate in 40 people with ALS at eight centers showed the drug was safe and tolerable for the majority of participants at dosages between 12 and 21 grams per day.
  
  
• Cells called microglia taken from the nervous systems of mice with ALS caused by mutated SOD1 genes are more toxic when active than are microglia taken from healthy mice. Microglia are the cells that carry out an immune response in the nervous system. The study supports the hypothesis that activated microglia play a role in ALS.

DUCHENNE AND BECKER MD

• An experimental drug called PTC124 was well tolerated with few potentially drug-related adverse events in boys with Duchenne muscular dystrophy (DMD). Twenty-six participants, ages 5 to 13, received this drug, which is designed to coax cells to ignore a type of genetic mutation known as a premature stop codon in the gene for the muscle protein dystrophin. Further testing is under way.
  
  
• An analysis of a large database of patients with DMD or Becker muscular dystrophy (BMD) reveals that severity of the disease cannot always be predicted from analysis of the genetic mutation. About 10 percent of the time, mutations that predict the more severe DMD actually turn out to be the less severe BMD.
  
  
• Delivering therapeutic genes for the muscle protein dystrophin to a whole limb at a time, via the bloodstream, to treat DMD or BMD, is feasible, suggest tests in a dystrophin-deficient mouse and a larger animal. The best delivery systems were viral shells called AAV6 and AAV8.
  
  
• A drug called idebenone, which may increase cellular energy production, improved heart function and exercise performance in dystrophin-deficient mice with a disease resembling DMD.
  
  
• Treatment with a drug called idebenone significantly improved cardiac function and long-term voluntary wheel running performance in a mouse model of DMD. Idebenone is thought to increase cellular energy production and reduce damage from a biochemical phenomenon known as oxidative stress. The drug is being tested in patients with DMD in Europe.

MYOTONIC DYSTROPHY

• Using antisense technology to change the way muscle cells interpret genetic information for the so-called chloride channel protein was effective in a mouse model of type 1 myotonic muscular dystrophy (MMD). The treatment restored normal chloride channel production and relieved myotonia (prolonged muscle contractions) in the mice.
  
  
• Treatment with statin drugs, used to lower cholesterol levels, can damage muscle and can also reveal a previously undiagnosed underlying muscle disease, including type 2 myotonic dystrophy (MMD2).
  
  
• Myotonia (inability to relax muscles at will) in a mouse model of MMD1 was corrected with a strategy known as antisense-mediated exon skipping. Researchers used a compound called antisense to induce cells to skip over part of the genetic instructions for a protein called ClC-1. Abnormalities in ClC-1 are a secondary effect of the underlying DNA abnormality in MMD1.

SPINAL MUSCULAR ATROPHY

• Two drugs, valproic acid and hydroxyurea, showed significant benefit when tested in mice with spinal muscular atrophy (SMA). Valproic-acid-treated mice had higher body weights, longer life span, better back leg strength and better motor function than untreated animals. Those treated with hydroxyurea also showed improvements in body weight, back leg strength and some aspects of motor performance, as well as longer survival. Both drugs have shown promise in tests of cells in laboratory containers, and both are now being evaluated in clinical trials.

SPINAL BULBAR MUSCULAR ATROPHY

• A drug called goserelin (Zoladex LA) was effective in improving strength in four men with spinal-bulbar muscular atrophy (SBMA) who took it by injection every three months for three years. The drug decreases levels of the male hormone testosterone (an androgen). The underlying cause of SBMA is a mutation in the gene for the so-called androgen receptor protein.

LIMB-GIRDLE MD

• Doctors were able to identify the precise molecular defect in 148 of 328 people (44percent) with severe limb-girdle muscular dystrophy (LGMD) and in 40 of 292 (14 percent) with less severe LGMD. However, in many with LGMD, a precise diagnosis remains elusive. To date, 19 different genetic mutations have been found to cause LGMD.
  
  
• The microscopic appearance of muscle fibers in mice with dysferlin-deficient limb-girdle muscular dystrophy (LGMD2B) was improved by blocking a group of immune-system proteins called complement.

INCLUSION BODY MYOSYTIS (IBM)

• A study of 13 patients with nonfamilial inclusion-body myositis (sporadic IBM) showed that the immunosuppressant drug alemtuzumab can improve strength or halt disease progression up to six months after therapy. Some study participants noted improved walking and ability to lift objects, along with an improvement in activities of daily living and quality of life.
  
  
• Patients with inclusion-body myositis (IBM) make immune-system proteins called antibodies that attack muscle proteins. Understanding this process should help determine targets for drug development.

CHARCOT-MARIE-TOOTH

• Abnormal movement of mitochondria, the energy production centers inside cells, is the likely mechanism by which mutations in a gene called MFN2 cause a form of Charcot-Marie-Tooth disease (CMT).
  
  
• A protein called krox20 is required for maintenance of a sheath made of myelin (proteins and fats) that surrounds nerve fibers. Understanding krox20’s actions may shed light on some types of CMT or Dejerine-Sottas disease (DSD).
  
  
• Fluctuations in levels of the hormone progesterone in women who have or have not been pregnant don’t worsen physical measurements in women with type 1A Charcot-Marie-Tooth Disease (CMT1A), although about half the women in this study reported that their disease had temporarily worsened during pregnancy, when progesterone levels are elevated. Blocking progesterone was helpful in rats with this type of CMT.
  
  
• A five-year study of 45 adults with CMT1A found that approximately two-thirds reported deterioration in this time period and were found to have an increase in disability. Disease progression was detectable with different impairment and disability scales, and electrical tests showed an increase in dysfunction of the nerve fibers themselves, even though CMT1A is considered primarily a disease of the sheath around the fibers.
  
  
• Mice with a type of CMT resulting from a mutation in the myelin protein zero gene benefited from gene therapy with insulin-like growth factor (IGF). When researchers injected IGF genes encased in adeno-associated virus shells into leg muscles of eight mice, they found their ability to stay on a rotating rod was better than that of untreated animals nine months later. Performance, however, declined in both groups over the nine months.
  
  
• High-dose ascorbic acid (vitamin C) was neither well tolerated nor effective in a small study of adults with type CMT1A. Out of 12 CMT patients who took 5 grams per day of ascorbic acid, six tolerated the treatment for the one-year study period, while five needed to reduce the dose because of gastrointestinal side effects; two of those five later discontinued treatment because side effects continued. One additional participant stopped the medication because of general malaise. No significant differences in clinical or electrophysiological measurements between baseline and final evaluations were detected in any of the participants.

OCULOPHARYNGEAL MD

• An 18-year study of six people with a genetic mutation in each of their two PABPN1 genes found that such patients develop very severe oculopharyngeal muscular dystrophy (OPMD), which normally results from only one PABPN1 mutation. All six developed drooping eyelids and difficulty swallowing before age 30. They later developed weak eye movement muscles, trouble speaking, limb weakness and cognitive deficits. Five required feeding tubes.

FACIOSCAPULOHUMERAL MD

• An analysis of 50 children with the rare early childhood form of facioscapulohumeral muscular dystrophy (FSHD) confirmed earlier reports that this form of FSHD is more severe than adult FSHD. The majority had facial and other muscle weakness and muscle pain. Other problems reported more frequently in the infantile form of FSH were hearing loss, respiratory effects and requiring a wheelchair by age 18.

FRIEDREICH’S ATAXIA

• A phase 2 study of the drug Idebenone, a derivative of coQ10, in 48 individuals with Friedreich’s ataxia (FA) demonstrated encouraging results. For those taking intermediate and high doses of the drug there was an improvement in performance of activities of daily living and in clinical signs. The improvement was most significant in those individuals who were not wheelchair dependent. Phase 3 studies of Idebenone for FA are already underway in Europe and are planned for the United States.
  
  
• A comparison of heart, skeletal muscle and liver tissues from a mouse model of FA and those from mice without the disease revealed, in about 200 genes, changes that are secondary effects of the primary FA defect. The primary problem is a genetic mutation in the gene for the frataxin protein. The findings should contribute to understanding the disease and identifying markers with which to follow disease progression and the effects of treatments.

POMPE DISEASE

• Analysis of 58 people with late-onset Pompe disease (also known as acid maltase deficiency or AMD) revealed slow progression of limb and respiratory muscle weakness over a year’s time is probably typical. The average respiratory muscle test score dropped by 3.5 percent and the average leg muscle test score by 3.2 percent. The average age of symptom onset was 29.
  
  
• Preliminary results indicate significant improvement of adults with AMD (or Pompe disease) with enzyme replacement therapy. Six patients with AMD who had severe respiratory impairment and moderate to severe impairment of the muscles of the hip and shoulder areas received a laboratory-developed acid maltase enzyme between July 2005 and October 2006. The enzyme, developed by Genzyme, has the trade name Myozyme. It was approved in April 2006 for all patients with AMD based on its safety and effectiveness in the infantile-onset form of the disease. Genzyme is continuing studies in late-onset patients.
  
  
• Motor function improved in 13 out of 18 children and adults with severe Pompe disease who received enzyme replacement therapy with a lab-engineered form of acid maltase for eight months to six years. Almost all participants reported improvements in their quality of life, and the treatments were well tolerated, with the exception of one report of chills associated with enzyme infusion.

MYASTHENIA GRAVIS AND RELATED SYNDROMES

• A congenital myasthenic syndrome (disturbance of nerve-to-muscle signal transmission due to a genetic mutation) that results from a mutation in the gene for dok-7, a protein found at the junction of nerve and muscle, was described in 13 patients. The investigators said this type of myasthenia probably involves ongoing destruction and remodeling at the neuromuscular junction.
  
  
• Adding the immune-system suppressant mycophenolate mofetil (CellCept) to prednisone, a standard immune-system dampener, in patients with myasthenia gravis (MG), failed to improve strength, ability to perform daily activities or biochemical measurements of disease activity. MG is a disorder in which the immune system mistakenly attacks parts of the nerve-muscle junction. Participants took either prednisone at 20 milligrams per day plus 2.5 grams per day of CellCept, or prednisone plus a placebo (look-alike inactive substance) for three months.
  
  
• When the investigators examined the records of 21 patients who were treated for 24 episodes of myasthenic crisis (myasthenia-related respiratory failure) between 1987 and 2006, they found that 14 (58 percent) of the episodes were successfully treated with noninvasive methods alone. Noninvasive ventilation support is pressurized air supplied through a mask or oral or nasal interface; invasive ventilation support is pressurized air delivered through a surgically created hole in the trachea (tracheostomy).

LAMBERT-EATON SYNDROME

• Lambert-Eaton syndrome (LES), a type of myasthenia in which the immune system attacks the part of the nerve fiber from which signals are transmitted to muscle, is sometimes found in conjunction with small-cell lung cancer; and when it is, it appears to improve the cancer survival rate. At five years after diagnosis, 36 percent of patients with this type of cancer and LES were alive, which was significantly greater than the survival rate in the general small-cell lung cancer population. (LES may reflect the immune system’s efforts to attack the cancer, with off-target effects on the nerve-muscle junction.)

MYOPHOSPHORYLASE DEFICIENCY (MCARDLE’S DISEASE)

• The drug ramipril (Altace), approved to treat high blood pressure by interfering with an enzyme called ACE, failed to improve exercise performance or other objective measurements in people with myophosphorylase deficiency (McArdle’s disease), who took it for 12 weeks at 2.5 milligrams per day. However, those who took it perceived their disability level as improved, compared to those who took a placebo (look-alike inert substance). Lower ACE activity has been observed to be beneficial in people with McArdle’s disease.

MYOTUBULAR MYOPATHY

• Reducing levels or activity of a protein called myotubularin in immature mouse cells on their way to becoming muscle cells unexpectedly resulted in increased production of a protein called doublecortin. A disease known as X-linked myotubular myopathy (XLMTM) is caused by mutations in the myotubularin gene, so the observation may help shed light on this disease.

STEM CELL RESEARCH

Mouse embryonic stem cells injected into the skin or muscle tissue of other mice only survive if the recipients have the same genes as they do or have suppressed immune systems. They also form tumors and don’t necessarily become muscle after being injected into muscles. The studies suggest molecular modifications will have to be made to embryonic stem cells before they can be used in human muscles.

MYOSTATIN