Compare efficacies of deflazacort and prednisone/prednisolone in providing clinically meaningful delays in loss of physical milestones in patients with nonsense mutation Duchenne muscular dystrophy.
...Placebo data from Phase IIb (ClinicalTrials.gov Identifier: NCT00592553) and ACT DMD (ClinicalTrials.gov Identifier: NCT01826487) ataluren nonsense mutation Duchenne muscular dystrophy clinical trials were retrospectively combined in meta-analyses (intent-to-treat population; for change from baseline to week 48 in 6-min walk distance 6MWD and timed function tests).
Significant improvements in change in 6-min walk distance with deflazacort versus prednisone/prednisolone (least-squares mean difference 39.54 m 95% CI: 13.799, 65.286; p = 0.0026). Significant and clinically meaningful improvements in 4-stair climb and 4-stair descend for deflazacort versus prednisone/prednisolone.
Deflazacort provides clinically meaningful delays in loss of physical milestones over 48 weeks compared with prednisone/prednisolone for patients with nonsense mutation Duchenne muscular dystrophy.
Spinal muscular atrophy is an autosomal recessive neurodegenerative disease caused by homozygous mutation to the survival motor neuron 1 (SMN1) gene. Historically, spinal muscular atrophy has been ...considered to almost exclusively affect the function and survival of alpha motor neurons of the spinal cord and brainstem. With the development of animal models of spinal muscular atrophy, the presence of widespread systemic abnormalities affecting the brain, heart, and pancreas has been repeatedly noted among animals with diminished survival motor neuron protein expression. While these observations suggest similar possible effects in humans, reports of primary systemic disease manifestations among humans affected by spinal muscular atrophy are strikingly lacking. Here we report a case of a 29-year-old man with genetically confirmed spinal muscular atrophy type II who presented with new onset diabetes mellitus and diabetic ketoacidosis.
Since the initial description almost 25 years ago, the syndrome of mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS) has been a useful model to study the complex ...interplay of factors that define mitochondrial disease. This syndrome, most commonly caused by an A‐to‐G transition mutation at position 3243 of the mitochondrial genome, is typified by characteristic neurological manifestations including seizures, encephalopathy, and strokelike episodes, as well as other frequent secondary manifestations including short stature, cognitive impairment, migraines, depression, cardiomyopathy, cardiac conduction defects, and diabetes mellitus. In this review, we discuss the history, pathogenesis, clinical features, and diagnostic and management strategies of mitochondrial disease in general and of MELAS in particular. We explore features of mitochondrial genetics, including the concepts of heteroplasmy, mitotic segregation, and threshold effect, as a basis for understanding the variability and complicated inheritance patterns seen with this group of diseases. We also describe systemic manifestations of MELAS‐associated mutations, including cardiac, renal, endocrine, gastrointestinal, and endothelial abnormalities and pathology, as well as the hypothetical role of derangements to COX enzymatic function in driving the unique pathology and clinical manifestations of MELAS. Although therapeutic options for MELAS and other mitochondrial diseases remain limited, and recent trials have been disappointing, we also consider current and potential therapeutic modalities.
Growth failure is nearly universal in spinal muscular atrophy type 1 and common in type 2, although acuity is often underappreciated at initial diagnosis. We reviewed 44 consecutive spinal muscular ...atrophy patients (28 type 1, 16 type 2) under 3 years at initial presentation. Growth failure was conventionally defined: weight below the fifth percentile or dropping 2 major percentiles over 6 months. Growth failure differed among subjects stratified by age at disease onset using the Kaplan-Meier method (P = 0.011). Median time to growth failure among subjects with onset between 0 to 3 months of age was 5 months; Only 1 of 22 avoided failure by 22 months of age. Median time to failure with disease onset between 4 to 6 months was 15 months. Most late onset (> 6 months) subjects avoided growth failure. Early clinical symptoms predict feeding dysfunction and growth failure. Immediate, proactive nutritional intervention is indicated for patients with early symptom onset.
Abstract 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 ⩾ 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 m2 ) and fat (fat mass in kg/stature in m2 ) 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.
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.
Spinal Muscular Atrophy Type III Dunaway, Sally; Montes, Jacqueline; Ryan, Patricia A. ...
Journal of Child Neurology,
06/2012, Letnik:
27, Številka:
6
Book Review, Journal Article
Recenzirano
Spinal muscular atrophy is a relatively stable chronic disease. Patients may gradually experience declines in muscle strength and motor function over time. However, functional progression is ...difficult to document, and the mechanism remains poorly understood. An 11-year-old girl was diagnosed at 19 months and took a few steps without assistance at 25 months. She was evaluated for 54 months in a prospective multicenter natural history study. Outcome measures were performed serially. From 6 to 7.5 years, motor function improved. From 7.5 to 11 years, motor function declined with increasing growth. Manual muscle testing scores minimally decreased. Motor unit number estimation studies gradually increased over 4.5 years. Compared to the published natural history of spinal muscular atrophy type III, our patient lost motor function over time. However, she walked with assistance 2 years longer than expected. Our report highlights possible precipitating factors that could affect the natural history of spinal muscular atrophy type III.
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