Observational study of spinal muscular atrophy type 2 and 3: functional outcomes over 1 year.

OBJECTIVE: To characterize the short-term course of spinal muscular atrophy (SMA) in a genetically and clinically well-defined cohort of patients with SMA. DESIGN: A comprehensive multicenter, longitudinal, observational study. SETTING: The Pediatric Neuromuscular Clinical Research Network for SMA, a consortium of clinical investigators at 3 clinical sites. PARTICIPANTS: Sixty-five participants with SMA types 2 and 3, aged 20 months to 45 years, were prospectively evaluated. INTERVENTION: We collected demographic and medical history information and determined the SMN 2 copy number. MAIN OUTCOME MEASURES: Clinical outcomes included measures of motor function (Gross Motor Function Measure and expanded Hammersmith Functional Motor Scale), pulmonary function (forced vital capacity), and muscle strength (myometry). Participants were evaluated every 2 months for the initial 6 months and every 3 months for the subsequent 6 months. We evaluated change over 12 months for all clinical outcomes and examined potential correlates of change over time including age, sex, SMA type, ambulatory status, SMN2 copy number, medication use, and baseline function. RESULTS: There were no significant changes over 12 months in motor function, pulmonary function, and muscle strength measures. There was evidence of motor function gain in ambulatory patients, especially in those children younger than 5 years. Scoliosis surgery during the observation period led to a subsequent decline in motor function. CONCLUSIONS: Our results confirm previous clinical reports suggesting that SMA types 2 and 3 represent chronic phenotypes that have relatively stable clinical courses. We did not detect any measurable clinical disease progression in SMA types 2 and 3 over 12 months, suggesting that clinical trials will have to be designed to measure improvement rather than stabilization of disease progression.

Muscle volume estimation by magnetic resonance imaging in spinal muscular atrophy.

Thigh muscle volume was assessed using magnetic resonance imaging in 16 subjects with spinal muscular atrophy. Scans were successful for 14 of 16 subjects (1 type 1, 6 type 2, and 7 type 3) as young as 5.7 years. Muscle volume with normal and abnormal signal was measured using blinded, semiautomated analysis of reconstructed data. Results were compared with segmental lean mass estimated by dual-energy X-ray absorptiometry and correlated with clinical and electrophysiological measures of disease severity. Muscle volume was reduced with abnormal signal quality. Test-retest reliability (r = .99) and correlation with dual-energy X-ray absorptiometry (r = .91) were excellent. Type 2 subjects had lower volume (3.5 ± 1.6 vs 6.3 ± 2.8 mL/cm height; P = .06) and higher percentage of muscle with abnormal signal (68% ± 20% vs 47% ± 27%; P = .14) than type 3. Reproducibility, tolerability, and strong correlation with clinical measures make magnetic resonance imaging a candidate biomarker for clinical research.

Adiposity is increased among high-functioning, non-ambulatory patients with spinal muscular atrophy.

The relationship between body composition and function in spinal muscular atrophy (SMA) is poorly understood. 53 subjects with SMA were stratified by type and Hammersmith functional motor scale, expanded score into three cohorts: low-functioning non-ambulatory (type 2 with Hammersmith score < 12, n=19), high-functioning non-ambulatory (type 2 with Hammersmith score > or = 12 or non-ambulatory type 3, n=17), and Ambulatory (n=17). Lean and fat mass was estimated using dual-energy X-ray absorptiometry. Anthropometric data was incorporated to measure fat-free (lean mass in kg/stature in m(2)) and fat (fat mass in kg/stature in m(2)) mass indices, the latter compared to published age and sex norms. Feeding dysfunction among type 2 subjects was assessed by questionnaire. Fat mass index was increased in the high-functioning non-ambulatory cohort (10.4+/-4.5) compared with both the ambulatory (7.2+/-2.1, P=0.013) and low-functioning non-ambulatory (7.6+/-3.1, P=0.040) cohorts. 12 of 17 subjects (71%) in the high-functioning non-ambulatory cohort had fat mass index > 85th percentile for age and gender (connoting "at risk of overweight") versus 9 of 19 subjects (47%) in the low-functioning non-ambulatory cohort and 8 of 17 ambulatory subjects (47%). Despite differences in clinical function, a similar proportion of low functioning (7/18, 39%) and high functioning (2/7, 29%) type 2 subjects reported swallowing or feeding dysfunction. Non-ambulatory patients with relatively high clinical function may be at particular risk of excess adiposity, perhaps reflecting access to excess calories despite relative immobility, emphasizing the importance of individualized nutritional management in SMA.

Laboratory abnormalities in ambulatory patients with myotonic dystrophy type 1.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is the most prevalent form of adult muscular dystrophy worldwide. Although well known for the classic manifestations of myotonia, weakness, and early cataracts, it has broad effects on multiple organ systems. OBJECTIVE: To analyze and compile the laboratory abnormalities of 126 adult patients with DM1. DESIGN: Laboratory data obtained before treatment were compiled and include values for 45 different laboratory tests and 2860 total studies. SETTING: University hospital. PATIENTS: One hundred twenty-six medically healthy, mild to moderately affected, ambulatory patients with DM1 and good venous access enrolled in one of 12 major DM1 clinical trials at a university hospital from 1975 to 2005. RESULTS: Of the 2860 laboratory studies, results for 470 (16.4%) were outside their reference ranges. Of the 45 types of laboratory tests studied, 41 demonstrated abnormal findings. The relative frequency of an abnormally elevated laboratory value was greater than 50% in several tests, including levels of hemoglobin A(1c), follicle-stimulating hormone, luteinizing hormone in men, and gamma-glutamyltransferase and creatine kinase in women. In addition, levels of lactate dehydrogenase in men and hemoglobin in women were abnormally high or low in more than 50% of the test results evaluated. CONCLUSION: There is a high frequency of abnormal laboratory values in DM1 that may form a basis for early screening and monitoring and provide insight into the spectrum of tissues involved in this disease.