ABSTRACT
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, cross‐over study of ...VPA in ambulatory SMA adults. Methods: There were 33 subjects, aged 20–55 years, included in this investigation. After baseline assessment, subjects were randomized to receive VPA (10–20 mg/kg/day) 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, electrophysiological, 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. Muscle Nerve 49: 187–192, 2014
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Reliable outcome measures that reflect the underlying disease process and correlate with motor function in children with SMA are needed for clinical trials. Maximum ulnar compound muscle action ...potential (CMAP) data were collected at two visits over a 4–6‐week period in children with SMA types II and III, 2–17 years of age, at four academic centers. Primary functional outcome measures included the Modified Hammersmith Functional Motor Scale (MHFMS) and MHFMS‐Extend. CMAP negative peak amplitude and area showed excellent discrimination between the ambulatory and non‐ambulatory SMA cohorts (ROC = 0.88). CMAP had excellent test–retest reliability (ICC = 0.96–0.97, n = 64) and moderate to strong correlation with the MHFMS and MHFMS‐Extend (r = 0.61–0.73, n = 68, P < 0.001). Maximum ulnar CMAP amplitude and area is a feasible, valid, and reliable outcome measure for use in pediatric multicenter clinical trials in SMA. CMAP correlates well with motor function and has potential value as a relevant surrogate for disease status. Muscle Nerve, 2010
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
This is a retrospective radiographic review to assess post-operative sagittal plane deformities in patients with Spinal Muscular Atrophy type 2 that had been treated with posterior spinal ...instrumentation. Thirty-two patients with a history of either spinal fusion (N = 20) or growing rods (N = 12) were identified with an average of 7.6 (2.1–16.6) years post-operative follow-up. Forty percent (13/32) of the patients were identified as having obvious “tucked chin” (N = 4), “tipped trunk” (N = 9), or both (N = 3). Sacral incidence was the only parameter that was statistically significant change between pre-operative or immediate post-operative measurements (66.9° vs. 55.2° p = 0.03). However, at final follow-up, the post-operative thoracic kyphosis had decreased over time in those that developed a subsequent sagittal deformity (24.2°) whereas it increased in those that did not (44.7°, p = 0.008). This decrease in thoracic kyphosis throughout the instrumented levels, resulted in a greater lordotic imbalance (30.4° vs. 5.6°, p = 0.001) throughout the instrumented levels in the group that developed the subsequent cervical or pelvic sagittal deformities. In conclusion, sagittal plane deformities commonly develop outside the instrumented levels in children with SMA type 2 following posterior spinal instrumentation and may be the result of lordotic imbalance that occurs through continued anterior growth following posterior instrumentation.
ABSTRACT
Introduction: The aim of this study was to determine the safety and therapeutic potential of L‐carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA). Methods: Our ...investigation was an open‐label phase 2 multicenter trial of L‐carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were: safety and adverse events; secondary outcomes were survival, time to death/>16 hours/day of ventilator support; motor outcomes; and maximum ulnar compound motor action potential amplitude. Results: A total of 245 AEs were observed in 35 of the 37 treated subjects (95%). Respiratory events accounted for 49% of all adverse events, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts. Discussion: This trial provides evidence that, in infants with SMA type I, L‐carnitine/VPA is ineffective at altering survival. The substantial proportion of infants reaching end‐points within 6 months of enrollment underscores the urgent need for pre‐symptomatic treatment in SMA type I. Muscle Nerve 57: 193–199, 2018
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The mechanisms by which rhinovirus (RV) infections produce lower airway symptoms in asthmatic individuals are not fully established. To determine effects of RV infection on lung epithelial cells, ...primary human bronchial epithelial (BE) cells were infected with either RV16 or RV49, and viral replication, cell viability, and cell activation were measured. Both viral serotypes replicated in BE cells at 33 degrees C (DeltaTCID50 / ml = 2 to 2.5 log units) and at 37 degrees C (DeltaTCID50 /ml = 1.6 log units), but only high doses of RV49 (10(6) TCID50 /ml) caused cytopathic effects and reduced cell viability. In addition, regulated on activation, normal T cells expressed and secreted (RANTES) secretion was increased in epithelial cells infected with RV16 or RV49 (243 and 398 pg/ml versus 13 pg/ml uninfected control cells), and a similar pattern was seen for RANTES messenger RNA. RV infection also caused increased secretion of interleukin-8 and granulocyte macrophage colony-stimulating factor, but did not alter expression of either intercellular adhesion molecule-1 or human leukocyte-associated antigen-DR. These observations suggest that RVs can replicate in lower airway cells in vivo, and support epidemiologic studies that link RV with lower respiratory illnesses. Further, RV-induced secretion of RANTES and other cytokines could trigger antiviral immune responses in vivo, but these effects could also contribute to the pathogenesis of respiratory symptoms in subjects with asthma.
•We report an update on standards of care recommendations for spinal muscular atrophy.•The paper provides a review of the recent literature.•Expert opinion is provided where there was not enough ...published evidence.
Spinal muscular atrophy (SMA) is a severe neuromuscular disorder due to a defect in the survival motor neuron 1 (SMN1) gene. Its incidence is approximately 1 in 11,000 live births. In 2007, an International Conference on the Standard of Care for SMA published a consensus statement on SMA standard of care that has been widely used throughout the world. Here we report a two-part update of the topics covered in the previous recommendations. In part 1 we present the methods used to achieve these recommendations, and an update on diagnosis, rehabilitation, orthopedic and spinal management; and nutritional, swallowing and gastrointestinal management. Pulmonary management, acute care, other organ involvement, ethical issues, medications, and the impact of new treatments for SMA are discussed in part 2.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Background/Purpose Spinal muscular atrophy (SMA) in children leads to progressive muscle weakness, dysphagia, aspiration, and death. We hypothesized that early laparoscopic fundoplication ...and gastrostomy in infants with SMA type I could be performed safely perhaps leading to fewer aspiration events and improved nutritional status. Methods Children diagnosed with SMA type I from 2002 through 2005 were included (n = 12). All children underwent laparoscopic Nissen fundoplication with gastrostomy shortly after diagnosis. Postoperative respiratory management and discharge criteria were standardized. Results All patients were extubated immediately postoperatively. There were no significant complications. Average time to full feeding and inpatient length of stay were 42 ± 4.9 hours (range, 30-48 hours) and 78 ± 22.5 hours (range, 44-120 hours), respectively. Mean weight-for-length percentile was doubled at 1 year postoperatively ( P = .03). The number of respiratory-related hospitalizations in the cohort decreased by almost 50% in the ensuing 12 months after surgery, although this did not reach statistical significance in this small cohort ( P = .34). Conclusions Early laparoscopic fundoplication and gastrostomy is safe and is associated with improved nutritional status. A trend toward fewer significant long-term aspiration-related events was seen after fundoplication. To better assess the long-term benefits of performing an antireflux procedure in these high-risk patients, a larger prospective trial comparing current nutritional support practices is needed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Spinal muscular atrophy is one of the most heterogeneous of the single-gene neuromuscular disorders. The broad spectrum of severity, with onset from the prenatal period to adulthood, presents unique ...challenges in the design and implementation of clinical trials. The clinical classification of subjects into severe (type 1), intermediate (type 2), and mild (type 3) subtypes has proved useful both in enhancing communication among clinicians internationally and in forging the collaborative development of outcome measures for clinical trials. Ideally, clinical trial design in spinal muscular atrophy must take into account the spinal muscular atrophy type, patient age, severity-of-affection status, nature of the therapeutic approach, timing of the proposed intervention relative to disease progression, and relative homogeneity of the cohort to be studied. Following is an overview of the challenges and opportunities, current and future therapeutic strategies, and progress to date in clinical trials in spinal muscular atrophy.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Approach to the diagnosis of congenital myopathies North, Kathryn N; Wang, Ching H; Clarke, Nigel ...
Neuromuscular disorders : NMD,
02/2014, Volume:
24, Issue:
2
Journal Article, Conference Proceeding
Peer reviewed
Open access
Abstract Over the past decade there have been major advances in defining the genetic basis of the majority of congenital myopathy subtypes. However the relationship between each congenital myopathy, ...defined on histological grounds, and the genetic cause is complex. Many of the congenital myopathies are due to mutations in more than one gene, and mutations in the same gene can cause different muscle pathologies. The International Standard of Care Committee for Congenital Myopathies performed a literature review and consulted a group of experts in the field to develop a summary of (1) the key features common to all forms of congenital myopathy and (2) the specific features that help to discriminate between the different genetic subtypes. The consensus statement was refined by two rounds of on-line survey, and a three-day workshop. This consensus statement provides guidelines to the physician assessing the infant or child with hypotonia and weakness. We summarise the clinical features that are most suggestive of a congenital myopathy, the major differential diagnoses and the features on clinical examination, investigations, muscle pathology and muscle imaging that are suggestive of a specific genetic diagnosis to assist in prioritisation of genetic testing of known genes. As next generation sequencing becomes increasingly used as a diagnostic tool in clinical practise, these guidelines will assist in determining which sequence variations are likely to be pathogenic.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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