Diana M. Escolar

A Randomized Study of Alglucosidase Alfa in Late-Onset Pompe's Disease

BACKGROUND Pompes disease is a metabolic myopathy caused by a deficiency of acid alpha glucosidase (GAA), an enzyme that degrades lysosomal glycogen. Late-onset Pompes disease is characterized by progressive muscle weakness and loss of respiratory function, leading to early death. We conducted a randomized, placebo-controlled trial of alglucosidase alfa, a recombinant human GAA, for the treatment of late-onset Pompes disease. METHODS Ninety patients who were 8 years of age or older, ambulatory, and free of invasive ventilation were randomly assigned to receive biweekly intravenous alglucosidase alfa (20 mg per kilogram of body weight) or placebo for 78 weeks at eight centers in the United States and Europe. The two primary end points were distance walked during a 6-minute walk test and percentage of predicted forced vital capacity (FVC). RESULTS At 78 weeks, the estimated mean changes from baseline in the primary end points favored alglucosidase alfa (an increase of 28.1+/-13.1 m on the 6-minute walk test and an absolute increase of 3.4+/-1.2 percentage points in FVC; P=0.03 and P=0.006, respectively). Similar proportions of patients in the two groups had adverse events, serious adverse events, and infusion-associated reactions; events that occurred only in patients who received the active study drug included anaphylactic reactions and infusion-associated reactions of urticaria, flushing, hyperhidrosis, chest discomfort, vomiting, and increased blood pressure (each of which occurred in 5 to 8% of the patients). CONCLUSIONS In this study population, treatment with alglucosidase alfa was associated with improved walking distance and stabilization of pulmonary function over an 18-month period. (ClinicalTrials.gov number, NCT00158600.)

A Phase I/II trial of MYO-029 in Adult Subjects with Muscular Dystrophy

Myostatin is an endogenous negative regulator of muscle growth and a novel target for muscle diseases. We conducted a safety trial of a neutralizing antibody to myostatin, MYO‐029, in adult muscular dystrophies (Becker muscular dystrophy, facioscapulohumeral dystrophy, and limb‐girdle muscular dystrophy).

Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations.

Aminoglycosides have previously been shown to suppress nonsense mutations, allowing translation of full‐length proteins in vitro and in animal models. In the mdx mouse, where muscular dystrophy is due to a nonsense mutation in the dystrophin gene, gentamicin suppressed truncation of the protein and ameliorated the phenotype. A subset of patients with Duchenne and Becker muscular dystrophy similarly possess a nonsense mutation, causing premature termination of dystrophin translation. Four such patients, with various stop codon sequences, were treated once daily with intravenous gentamicin at 7.5 mg/kg/day for 2 weeks. No ototoxicity or nephrotoxicity was detected. Full‐length dystrophin was not detected in pre‐ and post‐treatment muscle biopsies.

CLINICAL EVALUATOR RELIABILITY FOR QUANTITATIVE AND MANUAL MUSCLE TESTING MEASURES OF STRENGTH IN CHILDREN

Measurements of muscle strength in clinical trials of Duchenne muscular dystrophy have relied heavily on manual muscle testing (MMT). The high level of intra‐ and interrater variability of MMT compromises clinical study results. We compared the reliability of 12 clinical evaluators in performing MMT and quantitative muscle testing (QMT) on 12 children with muscular dystrophy. QMT was reliable, with an interclass correlation coefficient (ICC) of >0.9 for biceps and grip strength, and >0.8 for quadriceps strength. Training of both subjects and evaluators was easily accomplished. MMT was not as reliable, and required repeated training of evaluators to bring all groups to an ICC >0.75 for shoulder abduction, elbow and hip flexion, knee extension, and ankle dorsiflexion. We conclude that QMT shows greater reliability and is easier to implement than MMT. Consequently, QMT will be a superior measure of strength for use in pediatric, neuromuscular, multicenter clinical trials.

ALLOGENEIC STEM CELL TRANSPLANTATION CORRECTS BIOCHEMICAL DERANGEMENTS IN MNGIE

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a multisystemic autosomal recessive disease due to primary thymidine phosphorylase (TP) deficiency. To restore TP activity, we performed reduced intensity allogeneic stem cell transplantations (alloSCTs) in two patients. In the first, alloSCT failed to engraft, but the second achieved mixed donor chimerism, which partially restored buffy coat TP activity and lowered plasma nucleosides. Thus, alloSCT can correct biochemical abnormalities in the blood of patients with MNGIE, but clinical efficacy remains unproven.

Clinical features of late-onset Pompe disease: a prospective cohort study.

The objective of this 12‐month study was to describe the clinical features of late‐onset Pompe disease and identify appropriate outcome measures for use in clinical trials. Assessments included quantitative muscle testing (QMT), functional activities (FAA), 6‐min walk test (6MWT), and pulmonary function testing (PFT). Percent predicted values indicated quantifiable upper and lower extremity weakness, impaired walking ability, and respiratory muscle weakness. Significant declines in arm and leg strength and pulmonary function were observed during the study period. The outcome measures were demonstrated to be safe and reliable. Symptom duration was identified as the best predictor of the extent of skeletal and respiratory muscle weakness. Muscle Nerve 38: 1236–1245, 2008

Reliable surrogate outcome measures in multicenter clinical trials of Duchenne muscular dystrophy

We studied the reliability of a series of endpoints in an evaluation of subjects with Duchenne muscular dystrophy (DMD). The endpoints included quantitative muscle tests (QMTs), timed function tests, forced vital capacity (FVC), and manual muscle tests (MMT). Thirty‐one ambulatory subjects with DMD (mean age 8.9 years; range 5–16 years) were evaluated at eight sites by 15 newly trained evaluators as a test of interrater reliability of outcome measures. Both total QMT score [intraclass correlation coefficient (ICC) 0.96] and individual QMT assessments (ICC 0.85–0.96) were highly reliable. Forced vital capacity and all timed function tests were also highly reliable (ICC 0.97–0.99). MMT was the least reliable assessment method (ICC 0.61). These data suggest that primary surrogate outcome measures in large multicenter clinical trials in DMD should use QMT, FVC, or time function tests to obtain maximum power and greatest sensitivity. Muscle Nerve, 2006

CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy

We tested the efficacy and safety of glutamine (0.6gm/kg/day) and creatine (5gm/day) in 50 ambulant boys with Duchenne muscular dystrophy in a 6‐month, double‐blind, placebo‐controlled clinical trial. Drug efficacy was tested by measuring muscle strength manually (34 muscle groups) and quantitatively (10 muscle groups). Timed functional tests, functional parameters, and pulmonary function tests were secondary outcome measures. Although there was no statistically significant effect of either therapy based on manual and quantitative measurements of muscle strength, a disease‐modifying effect of creatine in older Duchenne muscular dystrophy and creatine and glutamine in younger Duchenne muscular dystrophy cannot be excluded. Creatine and glutamine were well tolerated. Ann Neurol 2005;58:151–155

Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy

Objective: To perform a double-blind, randomized study comparing efficacy and safety of daily and weekend prednisone in boys with Duchenne muscular dystrophy (DMD). Methods: A total of 64 boys with DMD who were between 4 and 10 years of age were randomized at 1 of 12 centers of the Cooperative International Neuromuscular Research Group. Efficacy and safety of 2 prednisone schedules (daily 0.75 mg/kg/day and weekend 10 mg/kg/wk) were evaluated over 12 months. Results: Equivalence was met for weekend and daily dosing of prednisone for the primary outcomes of quantitative muscle testing (QMT) arm score and QMT leg score. Secondary strength scores for QMT elbow flexors also showed equivalence between the 2 treatment groups. Overall side effect profiles of height and weight, bone density, cataract formation, blood pressure, and behavior, analyzed at 12 months, did not differ between weekend and daily dosing of prednisone. Conclusions: Weekend dosing of prednisone is equally beneficial to the standard daily dosing of prednisone. Analysis of side effect profiles demonstrated overall tolerability of both dosing regimens. Classification of evidence: This study provides Class I evidence that weekend prednisone dosing is as safe and effective as daily prednisone in preserving muscle strength and preventing body mass index increases in boys with DMD over a 12-month period.

Novel LMNA Mutations in Patients With Emery-Dreifuss Muscular Dystrophy and Functional Characterization of Four LMNA Mutations

Mutations in LMNA cause a variety of diseases affecting striated muscle including autosomal Emery‐Dreifuss muscular dystrophy (EDMD), LMNA‐associated congenital muscular dystrophy (L‐CMD), and limb‐girdle muscular dystrophy type 1B (LGMD1B). Here, we describe novel and recurrent LMNA mutations identified in 50 patients from the United States and Canada, which is the first report of the distribution of LMNA mutations from a large cohort outside Europe. This augments the number of LMNA mutations known to cause EDMD by 16.5%, equating to an increase of 5.9% in the total known LMNA mutations. Eight patients presented with either p.R249W/Q or p.E358K mutations and an early onset EDMD phenotype: two mutations recently associated with L‐CMD. Importantly, 15 mutations are novel and include eight missense mutations (p.R189P, p.F206L, p.S268P, p.S295P, p.E361K, p.G449D, p.L454P, and p.W467R), three splice site mutations (c.IVS4 + 1G>A, c.IVS6 − 2A>G, and c.IVS8 + 1G>A), one duplication/in frame insertion (p.R190dup), one deletion (p.Q355del), and two silent mutations (p.R119R and p.K270K). Analysis of 4 of our lamin A mutations showed that some caused nuclear deformations and lamin B redistribution in a mutation specific manner. Together, this study significantly augments the number of EDMD patients on the database and describes 15 novel mutations that underlie EDMD, which will contribute to establishing genotype–phenotype correlations. Hum Mutat 31:–16, 2011.