Introduction: An open label trial suggested that valproic acid (VPA) improved strength in adults with spinal muscular atrophy (SMA). We report a 12 month, double blind, crossover study of VPA in ambulatory SMA adults.

Methods:

There were 33 subjects aged 20-55 years. After baseline assessments subjects were randomized to receive VPA (10-20 mg/kg/daily) or placebo. At 6 months, patients were switched to the other group. Assessments were performed at 3, 6, and 12 months. The primary outcome was the 6-month change in maximum voluntary isometric contraction testing with pulmonary, electrophysiologic, and functional secondary outcomes.

Results:

Thirty subjects completed the study. VPA was well tolerated, and compliance was good. There was no change in primary or secondary outcomes at 6 or 12 months.

Conclusions:

VPA did not improve strength or function in SMA adults. The outcomes used are feasible and reliable and can be employed in future trials in SMA adults. © 2013 Wiley Periodicals, Inc.

Introduction: Duchenne muscular dystrophy (DMD) subjects ≥5 years with nonsense mutations were followed for 48 weeks in a multicenter, randomized, double-blind, placebo-controlled trial of ataluren. Placebo arm data (N=57) provide insight into the natural history of the 6-minute walk test (6MWT) and other endpoints.

Methods:

Evaluations performed every 6 weeks included the 6 minute walk distance (6MWD), timed function tests (TFTs), and quantitative strength using hand-held myometry.

Results:

Baseline age (≥7 years), 6MWD, and selected TFT performance, are strong predictors of decline in ambulation (Δ 6MWD) and time to 10% worsening in 6MWD. A baseline 6MWD of <350 meters was associated with greater functional decline, and loss of ambulation was only seen in those with baseline 6MWD <325 meters. Only 1/42 (2.3%) subjects able to stand from supine lost ambulation. Discussion: Findings confirm the clinical meaningfulness of the 6MWD as the most accepted primary clinical endpoint in ambulatory DMD trials. © 2013 Wiley Periodicals, Inc.

Introduction: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is characterized by early selective involvement of small nerve fibers. Initial clinical diagnosis is complicated by psychosocial factors.

Objective:

To evaluate diagnostic accuracy of sural sensory nerve action potentials, plantar sympathetic skin response (SSR), and cortical laser-evoked potentials (LEP) to dorsal foot stimulation in early diagnosis of TTR-FAP.

Methods:

Sixty-three subjects with TTR-FAP (Val30Met) mutation were split into 2 groups (asymptomatic carriers and early-symptomatic patients) and compared with 33 healthy controls.

Results:

The diagnostic accuracy of plantar SSR amplitude and LEP N2 latency was similar; all had very high specificity (94 to 97%) but low sensitivity (22 to 32%) in distinguishing controls from carriers and early-symptomatic patients. No control had abnormal results on both tests.

Conclusions:

Plantar SSR and LEPs have similar diagnostic performance in detecting small-fiber dysfunction in early TTR-FAP; we propose that both tests should be used to investigate this population. © 2013 Wiley Periodicals, Inc.

Neuromuscular ultrasound involves the use of high-resolution ultrasound to image the peripheral nervous system of patients with suspected neuromuscular diseases. It complements electrodiagnostic studies well by providing anatomic information regarding nerves, muscles, vessels, tendons, ligaments, bones, and other structures that cannot be obtained with nerve conduction studies and electromyography. Neuromuscular ultrasound has been studied closely over the past 10 years and has been used most often in the assessment of entrapment neuropathies. This review focuses on the use of neuromuscular ultrasound in 4 of the most common entrapment neuropathies: carpal tunnel syndrome, ulnar neuropathy at the elbow and wrist, and fibular neuropathy at the knee. © 2013 Wiley Periodicals, Inc.

INTRODUCTION:

Focal peripheral neuropathy of the median nerve is mainly caused by a traumatic event or pressure, but it may also be produced by systemic illnesses. Among the latter, leprosy is a rare cause.

METHODS:

Six cases of isolated median neuropathy as the first sign of leprosy were selected from patients with an exclusively neurological complaint as the initial symptom. The patients, evaluated at the National Leprosy Reference Center in Rio de Janeiro, Brazil, followed routine and specialized procedures.

RESULTS:

Three of the patients had pure neural leprosy, and 3 had skin lesions. Clinical median nerve function impairment was confirmed by neurophysiological testing and histopathology. Both mononeuritis and mononeuritis multiplex were observed.

CONCLUSIONS:

This case series demonstrates an additional form of presentation of leprosy, which, if not diagnosed and treated in time, may lead to permanent disability. Muscle Nerve, 2013.

Contemporary natural history data in Duchenne muscular dystrophy (DMD) is needed to assess care recommendations and aid in planning future trials.

METHODS:

The Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study (DMD-NHS) enrolled 340 individuals, aged 2-28 years, with DMD in a longitudinal, observational study at 20 centers. Assessments obtained every 3 months for 1 year, at 18 months, and annually thereafter included: clinical history; anthropometrics; goniometry; manual muscle testing; quantitative muscle strength; timed function tests; pulmonary function; and patient-reported outcomes/health-related quality-of-life instruments.

RESULTS:

Glucocorticoid (GC) use at baseline was 62% present, 14% past, and 24% GC-naive. In those ≥6 years of age, 16% lost ambulation over the first 12 months (mean age 10.8 years).

CONCLUSIONS:

Detailed information on the study methodology of the CINRG DMD-NHS lays the groundwork for future analyses of prospective longitudinal natural history data. These data will assist investigators in designing clinical trials of novel therapeutics. Muscle Nerve, 2013.

Introduction: An international clinical trial enrolled 174 ambulatory males ≥5 years old with nonsense mutation Duchenne muscular dystrophy (nmDMD). Pre-treatment data provide insight into reliability, concurrent validity, and minimal clinically important differences (MCID) of the 6-minute walk test (6MWT) and other endpoints.

Methods:

Screening and baseline evaluations included the 6-minute walk distance (6MWD), timed function tests (TFTs), quantitative strength by myometry, the PedsQL(TM) , heart rate determined energy expenditure index, and other exploratory endpoints.

Results:

The 6MWT proved feasible and reliable in a multicenter context. Concurrent validity with other endpoints was excellent. The MCID for 6MWD was 28.5 and 31.7 meters based on 2 statistical distribution methods. Discussion: The ratio of MCID to baseline mean is lower for 6MWD than for other endpoints. The 6MWD is an optimal primary endpoint for Duchenne muscular dystrophy (DMD) clinical trials that are focused therapeutically on preservation of ambulation and slowing of disease progression. © 2013 Wiley Periodicals, Inc.

INTRODUCTION.

While deficits in muscle function, particularly power production, develop in old age and are risk factors for mobility impairment, a complete understanding of muscle fatigue during dynamic contractions is lacking. We tested hypotheses related to torque-producing capacity, fatigue resistance, and variability of torque production during repeated maximal contractions in healthy older, mobility-impaired older, and young women.

METHODS.

Knee extensor fatigue (decline in torque) was measured during 4 min of dynamic contractions. Torque variability was characterized using a novel 4-component logistic regression model.

RESULTS.

Young women produced more torque at baseline and during the protocol than older women (P<0.001). While fatigue did not differ between groups (P=0.53), torque variability differed by group (P=0.022) and was greater in older impaired compared with young women (P=0.010).

CONCLUSIONS.

These results suggest that increased torque variability may combine with baseline muscle weakness to limit function, particularly in older adults with mobility impairments. © 2013 Wiley Periodicals, Inc.

Introduction: Nerve cross-sectional area reference values have been reported for many nerves, but there have been few studies in pediatric and geriatric populations. This study was conducted to determine the influence of age on nerve cross-sectional area.

Methods:

Thirty-two children (3 months to 16 years) and 20 geriatric adults (67-92 years) without known neurologic conditions underwent bilateral ultrasound to measure the area of the following nerves: median at the wrist and forearm; ulnar at the wrist and elbow; radial in the spiral groove; sciatic in the distal thigh; fibular at the knee; tibial at the knee and ankle; and sural at the ankle.

Results:

In general, nerve cross-sectional area increased with age. Nerve size correlated most closely with age, but a correlation was also seen with body mass index.

Conclusions:

Nerve cross-sectional area increases with age, which is important to note when using ultrasound to evaluate children and geriatric patients. Muscle Nerve, 2013.

INTRODUCTION:

Clinical heterogeneity of limb-girdle muscular dystrophies (LGMDs, 24 known subtypes), which includes overlapping phenotypes and varying ages of onset and morbidity, adds complexity to clinical and molecular diagnoses.

METHODS:

To diagnose LGMD subtype, protein analysis, using immunohistochemistry (IHC) and immunoblotting, was followed by gene sequencing through a panel approach (simultaneous sequencing of known LGMD genes) in 9 patients from unrelated families of the Indian Agarwal community. Haplotype studies were performed by targeted SNP genotyping to establish mutation segregation.

RESULTS:

We identified 2 founder mutations in CAPN3, a missense (c.2338G>C; p.D780H) and a splice-site (c.2099-1G>T) mutation, on 2 different haplotype backgrounds. The patients were either heterozygous for both or homozygous for either of these mutations.

CONCLUSIONS:

Founder mutations have immediate clinical application, at least in selected population groups. Clinically available gene panels may provide a definitive molecular diagnosis for heterogeneous disorders such as LGMD. Muscle Nerve, 2013.