Clinical, genetic, and pathologic characterization of FKRP Mexican founder mutation c.1387A>G.

OBJECTIVE: To characterize the clinical phenotype, genetic origin, and muscle pathology of patients with the FKRP c.1387A>G mutation. METHODS: Standardized clinical data were collected for all patients known to the authors with c.1387A>G mutations in FKRP. Muscle biopsies were reviewed and used for histopathology, immunostaining, Western blotting, and DNA extraction. Genetic analysis was performed on extracted DNA. RESULTS: We report the clinical phenotypes of 6 patients homozygous for the c.1387A>G mutation in FKRP. Onset of symptoms was <2 years, and 5 of the 6 patients never learned to walk. Brain MRIs were normal. Cognition was normal to mildly impaired. Microarray analysis of 5 homozygous FKRP c.1387A>G patients revealed a 500-kb region of shared homozygosity at 19q13.32, including FKRP. All 4 muscle biopsies available for review showed end-stage dystrophic pathology, near absence of glycosylated α-dystroglycan (α-DG) by immunofluorescence, and reduced molecular weight of α-DG compared with controls and patients with homozygous FKRP c.826C>A limb-girdle muscular dystrophy. CONCLUSIONS: The clinical features and muscle pathology in these newly reported patients homozygous for FKRP c.1387A>G confirm that this mutation causes congenital muscular dystrophy. The clinical severity might be explained by the greater reduction in α-DG glycosylation compared with that seen with the c.826C>A mutation. The shared region of homozygosity at 19q13.32 indicates that FKRP c.1387A>G is a founder mutation with an estimated age of 60 generations (∼1,200-1,500 years).

Feasibility and Reproducibility of Echocardiographic Measures in Children with Muscular Dystrophies.

BACKGROUND: Cardiac disease is a major cause of death in patients with muscular dystrophies. The use of feasible and reproducible echocardiographic measures of cardiac function is critical to advance the field of therapeutics for dystrophic cardiomyopathy. METHODS: Participants aged 8 to 18 years with genetically confirmed Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, or limb-girdle muscular dystrophy were enrolled at five centers, and standardized echocardiographic examinations were performed. Measures of systolic and diastolic function and speckle-tracking echocardiography-derived cardiac strain were reviewed independently by two central readers. Furthermore, echocardiographic measures from participants with DMD were compared with those from retrospective age-matched control subjects from a single site to assess measures of myocardial function. RESULTS: Forty-eight participants (mean age, 13.3 ± 2.7 years) were enrolled. Shortening fraction had a greater interobserver correlation (intraclass correlation coefficient [ICC] = 0.63) compared with ejection fraction (ICC = 0.49). One reader could measure ejection fraction in only 53% of participants. Myocardial performance index measured by pulse-wave Doppler and Doppler tissue imaging showed similar ICCs (0.55 and 0.54). Speckle-tracking echocardiography showed a high ICC (0.96). Focusing on participants with DMD (n = 33), significantly increased mitral A-wave velocities, lower E/A ratios, and lower Doppler tissue imaging mitral lateral E' velocities were observed compared with age-matched control subjects. Speckle-tracking echocardiography demonstrated subclinical myocardial dysfunction with decreased average circumferential and longitudinal strain in three distinct subgroups: participants with DMD with normal shortening fractions, participants with DMD aged < 13 years, and participants with DMD with myocardial performance index scores < 0.40 compared with control subjects. CONCLUSIONS: In a muscular dystrophy cohort, assessment of cardiac function is feasible and reproducible using shortening fraction, diastolic measures, and myocardial performance index. Cardiac strain measures identified early myocardial disease in patients with DMD.

The quick motor function test: a new tool to rate clinical severity and motor function in Pompe patients.

Pompe disease is a lysosomal storage disorder characterized by progressive muscle weakness. With the emergence of new treatment options, psychometrically robust outcome measures are needed to monitor patients' clinical status. We constructed a motor function test that is easy and quick to use. The Quick Motor Function Test (QMFT) was constructed on the basis of the clinical expertise of several physicians involved in the care of Pompe patients; the Gross Motor Function Measure and the IPA/Erasmus MC Pompe survey. The test comprises 16 items. Validity and test reliability were determined in a cohort of 91 Pompe patients (5 to 76 years of age). In addition, responsiveness of the scale to changes in clinical condition over time was examined in a subgroup of 18 patients receiving treatment and 23 untreated patients. Interrater and intrarater reliabilities were good (intraclass correlation coefficients: 0.78 to 0.98 and 0.76 to 0.98). The test correlated strongly with proximal muscle strength assessed by hand held dynamometry and manual muscle testing (rs= 0.81, rs=0.89), and showed significant differences between patient groups with different disease severities. A clinical-empirical exploration to assess responsiveness showed promising results, albeit it should be repeated in a larger group of patients. In conclusion, the Quick Motor Function Test can reliably rate clinical severity and motor function in children and adults with Pompe disease.

Consensus treatment recommendations for late-onset Pompe disease.

INTRODUCTION: Pompe disease is a rare, autosomal recessive disorder caused by deficiency of the glycogen-degrading lysosomal enzyme acid alpha-glucosidase. Late-onset Pompe disease is a multisystem condition, with a heterogeneous clinical presentation that mimics other neuromuscular disorders. METHODS: Objective is to propose consensus-based treatment and management recommendations for late-onset Pompe disease. METHODS: A systematic review of the literature by a panel of specialists with expertise in Pompe disease was undertaken. CONCLUSIONS: A multidisciplinary team should be involved to properly treat the pulmonary, neuromuscular, orthopedic, and gastrointestinal elements of late-onset Pompe disease. Presymptomatic patients with subtle objective signs of Pompe disease (and patients symptomatic at diagnosis) should begin treatment with enzyme replacement therapy (ERT) immediately; presymptomatic patients without symptoms or signs should be observed without use of ERT. After 1 year of ERT, patients' condition should be reevaluated to determine whether ERT should be continued.

Antiretroviral therapy-associated acute motor and sensory axonal neuropathy.

Guillain-Barré syndrome (GBS) has been reported in HIV-infected patients in association with the immune reconstitution syndrome whose symptoms can be mimicked by highly active antiretroviral therapy (HAART)-mediated mitochondrial toxicity. We report a case of a 17-year-old, HIV-infected patient on HAART with a normal CD4 count and undetectable viral load, presenting with acute lower extremity weakness associated with lactatemia. Electromyography/nerve conduction studies revealed absent sensory potentials and decreased compound muscle action potentials, consistent with a diagnosis of acute motor and sensory axonal neuropathy. Lactatemia resolved following cessation of HAART; however, neurological deficits minimally improved over several months in spite of immune modulatory therapy. This case highlights the potential association between HAART, mitochondrial toxicity and acute axonal neuropathies in HIV-infected patients, distinct from the immune reconstitution syndrome.

A randomized study of alglucosidase alfa in late-onset Pompe's disease.

BACKGROUND: Pompe's disease is a metabolic myopathy caused by a deficiency of acid alpha glucosidase (GAA), an enzyme that degrades lysosomal glycogen. Late-onset Pompe's 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 Pompe's 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.)

Isolated cranial nerve enhancement in metachromatic leukodystrophy.

Metachromatic leukodystrophy is a lysosomal storage disorder with an estimated incidence of 1:40,000. Magnetic resonance imaging at time of diagnosis often shows symmetric white matter involvement, sparing the arcuate fibers. A 25-month-old female child presented with a cranial neuropathy, a spastic gait, decreased leukocyte arylsulfatase-A activity, and elevated urinary sulfatides. Magnetic resonance imaging revealed multiple cranial nerve enhancement, without intraparenchymal white matter involvement.

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.

Respiratory failure as a first presentation of myasthenia gravis.

BACKGROUND: Although respiratory failure commonly occurs during the course of myasthenia gravis (MG), it is rarely described at presentation in patients with previously unrecognized MG. MATERIAL/METHODS: We determined the prevalence and clinical characteristics of patients with respiratory failure associated with undiagnosed MG by review of the medical records of all patients who were diagnosed with MG related respiratory failure at four University hospitals. Respiratory failure was defined on the basis of a forced vital capacity < or =1 liter, negative inspiratory force < or =20 cm H2O, or requirement of mechanical ventilation. RESULTS: Out of 51 MG patients with respiratory failure, 7(14%) patients had no previous diagnosis of MG. Another patient was identified after the review. The mean age of these 8 patients was 56 years (range 23-76 years); six were women. Five had previous episodes of unexplained respiratory failure. On initial evaluation, ocular or bulbar signs were present in 7 patients. The diagnosis of MG was made by edrophonium test (n=3), edrophonium test with positive acetylcholine antibody levels or repetitive nerve stimulation (n=2), repetitive nerve stimulation with positive acetylcholine antibody levels (n=2), and positive acetylcholine antibody levels alone (n=1). Seven patients required mechanical ventilation. Plasma exchange (n=7) or intravenous immunoglobulins (n=1) resulted in successful extubation or resolution of symptoms in all patients. CONCLUSIONS: Respiratory failure can occur at presentation in MG. A high index of suspicion should be maintained in patients with previous history of unexplained respiratory failures.