Our patient had SMA type II, which had previously been confirmed by molecular studies during her pregnancy, dem- onstrating homozygous deletion of axons 7 and 8 on the SMN gene. She had been hoping for a ‘natural childbirth’ and finally agreed to undergo an elective induction of labor at 38 weeks gestation. She had been able to walk as a child but was now wheelchair bound. She had severe restrictive lung disease (which had slightly worsened during pregnancy: forced expiratory volume in one second [FEV 1 ] 1.23 L [34%], forced vital capacity [FVC] 1.35 L [32%]) due to kypho-scoliosis, which had required a mid-thoracic to sacral Harrington-rods instrumentation at age 10 (Figure 1). Her weight was 48 kg at term. The airway exam showed Malampati classification class III twice, neck extension was not possible, and flexion reduced. The neck musculature was hypertrophic, possibly to compensate for truncal muscle weakness.
Background: Spinal muscular atrophy (SMA) is an autosomal recessive disorder that affects the motoneurons of the spinal anterior horn, resulting in hypotonia and muscle weakness. The disease is caused by deletion or mutation in the telomeric copy of SMN gene (SMN1) and clinical severity is in part determined by the copy number of the centromeric copy of the SMN gene (SMN2). The SMN2 mRNA lacks exon 7, resulting in a production of lower amounts of the full-length SMN protein. Knowledge of the molecular mechanism of diseases has led to the discovery of drugs capable of increasing SMN protein level through activation of SMN2 gene. One of these drugs is the valproic acid (VPA), a histone deacetylase inhibitor.
Paraspinal muscles are commonly affected during spine surgery. The pur- pose of this study was to assess the potential factors that contribute to para- spinalmuscleatrophy (PMA) after lumbar spine surgery. A comprehensive review of the available English literature, including relevant abstracts and references of articles selected for review, was conducted to identify studies that reported PMA after spinal surgery. The amount of postoperative PMA was evaluated in (1) lumbar fusion vs nonfusion procedures; (2) posterior lumbar fusion vs anterior lumbar fusion; and (3) minimally invasive (MIS) posterior lumbar decompression and/or fusion vs non-MIS equivalent pro- cedures. In total, 12 studies that included 529 patients (262 men and 267 women) were reviewed. Of these, 365 patients had lumbar fusions and 164 had lumbar decompressions. There was a significantly higher mean post- operative volumetric PMA with fusion vs nonfusion procedures (P=.0001), with posterior fusion vs anterior fusion (P=.0001), and with conventional fusions vs MIS fusions (P=.001). There was no significant difference in mean volumetric lumbar PMA with MIS decompression vs non-MIS decompres- sion (P=.56). There was significantly higher postoperative PMA with lumbar spine fusions, posterior procedures, and non-MIS fusions. [Orthopedics.]
Skeletal MuscleAtrophy (SMA) is a phenomenon found in many diseases and disorders. SMA is characterized by protein degradation induced by various pathways. Ten years ago, little was known about the mechanisms that lead from these disorders to protein degradation. Current research focuses on the mechanisms thought to induce SMA. It is now known that many of these pathways involve ubiquitin conjugate accumulation and increased proteasome activity resulting in rapid protein degradation and decreased synthesis. HIV associated proteins, such as Vpr, cause overexpression of atrogin-1 which promotes atrophy. Cachexia operates mainly through the IKK/NF_B pathway and MuRF-1 Ub-ligase overexpression causes SMA. In contrast, the onset of oxidative stress increases intracellular calcium levels, activating endoproteases and stimulating myofilament degradation. Lastly, diabetes acts in a similar way. Low insulin levels trigger ub- conjugation and proteasome activity leading to SMA. In order to treat SMA in the aforementioned disorders, specified inhibitor drugs are being considered for hindering the pathway. This review proposes to use the HIV virus as a model to investigate how these diseases induce SMA with further investigations of the mechanisms from HIV to the aforementioned diseases. Possible treatments are associated with the reverse pathway, hypertrophy, which suppresses protein degradation and increases synthesis.
testosterone than women, with a normative range of ~ 82–257 ng/dL for young men and 0.8–10 ng/dL for young women . Testosterone is an androgenic hormone that works through the action of androgen receptors (AR) on various tissues to facilitate protein anabolism. Specifically, part of this anabolic response in- volves AR translocation to the nucleus to act as a tran- scription factor to increase myotube and muscle protein synthesis [107, 108]. Previous work has demonstrated that testosterone can work specifically through ARs to contribute to increased protein synthesis [107, 108]. In human primary myotubes from men, recent work has clarified the pathways for testosterone action . Specifically, it has been demonstrated that testosterone action can activate mTOR through androgen-mediated action of androgen receptor to activate PI3k/Akt signal- ing . AR receptor content varies based on the type of tissue, and in muscle by the fiber type . Interest- ingly, AR activation seems to favor a shift toward slow twitch fibers, with AR-knockout mice demonstrating a shift toward type II fibers . In animal models, remov- ing testosterone in male mice by castration induces a noted decrease in muscle size [99, 110, 111]. Whereas, when testosterone is given to those with low levels of testosterone, such as men with hypogonadism or older male mice, there appears to be increased muscle mass [110, 112]. In females, testosterone also appears to have anabolic effects, for example postmenopausal women given an acute treatment with testosterone exhibit increased fractional protein synthesis rates . However, that same study found greater FSR in older
SMA is a result of biallelic intragenic deletions or pathogenic variants in the SMN1 gene located on chromosome 5q13, which cause loss of function of the survival of motor neuron protein (SMN). SMN is ubiquitously expressed, and although SMA is characterized by loss of motor neurons in the ventral horn of the spinal cord, multiple organs, including cardiac, skeletal, and gastrointestinal, are negatively aﬀected as well. 2,3
Many studies have demonstrated the important role played by tumor necrosis factor alpha (TNF- α ) in regulating muscle size through apoptosis . The MAPK14 (p38) gene belongs to TNF-α/p38 MAPK pathway and regulates MAP kinase interacting serine/threonine kinase (MNK1/ 2). MNK2 is down-regulated in patients with SMA I, like IL-32, a positive regulator of p38 and TNF-α. Finally TXN, a negative regulator of MEKK5 (ASK1) that is upstream of p38, is even more up-regulated in SMA I samples. Consid- ering all these data and the notion that MNK1/2 phospho- rylates eIF4E , we monitored the TNF-α/p38 MAPK pathway looking for TRAF2 and MAPK14 (p38). SMA I muscles showed an under-expression of p38 that may be the protein synthesis regulator. In SMA III there was instead a general up-regulation of these genes.
The natural history of SMA pulmonary compromise parallels progressive respiratory failure. Individuals with SMA 1 or 2 develop inspiratory and expiratory respiratory muscle weakness. Individuals with SMA type 1 also develop bulbar muscle weakness and resulting dysphagia. Ineffective cough is a result of respiratory muscle weakness and contributes to repeated respiratory infections. The next phase is development of rapid eye movement (REM)-related sleep-disordered breathing. Gradual progression results in sleep-disordered breathing during REM and non-REM sleep followed by ventilatory failure during the day and at night. Without intervention, respiratory failure will result in death.
Most of the patients in our study consistently had values out of the expected range in several blood analytes. We believe that many of these abnormalities are an expected consequence of severe generalized muscleatrophy and bone disease. For example, low creatinine concentrations in these participants were expected because creatinine is a product of creatine metabolism, and creatine is mainly present in muscle. 22 Importantly, analysis of urine sedi- ment revealed granular casts and/or amorphous crystals and generalized aminoaciduria in the majority of partic- ipants with SMA type 1 (table 1). These elements being found in urine are associated with acute and chronic kidney injury with potential calcium oxalate deposition within the renal tubules. This process may lead to obstruction of the urine ﬂow in the tubules while the intratubular crystals develop an inﬂammatory reaction with the renal inter- stitium and promote acute kidney dysfunction. 23,24 Overall, the clinical laboratory data in these participants strongly suggest that the majority had impaired kidney
Whereas nutrition is commonly difficult from the beginning in patients with SMA type I, the difficulties are less frequent and constrictive in the other SMA types. Nevertheless, exami- nation is needed in all SMA patients. The primary problems are limited mouth opening with cumulative chewing difficul- ties and reduced bite force. Increased fatigue of masticatory muscles and swallowing difficulties result in a higher risk for aspiration and consequent pneumonia. A first consensus statement on standard of care in spinal muscular atrophy 52
Background: Hereditary proximal spinal muscular atrophy (SMA) is a severe neuromuscular disease of childhood caused by homozygous loss of function of the survival motor neuron (SMN) 1 gene. The presence of a second, nearly identical SMN gene (SMN2) in the human genome ensures production of residual levels of the ubiquitously expressed SMN protein. Alpha-motor neurons in the ventral horns of the spinal cord are most vulnerable to reduced SMN concentrations but the development or function of other tissues may also be affected, and cardiovascular abnormalities have frequently been reported both in patients and SMA mouse models.
Conclusion. We found that there was improvement in survival in SMA patients as compared with other studies. Assistance or supervision was needed for the majority of SMA patients for both mobility and self-care domains. With improvement in survival as a result of medical advances, assessment of the most current or the best-ever functional status at a designated age might be an impor- tant criterion for classification of SMA. Pediatrics 2004; 114:e548–e553. URL: www.pediatrics.org/cgi/doi/10.1542/ peds.2004-0668; spinal muscular atrophy, Functional In- dependence Measure for Children, Chinese children.
To confirm the origin of the observed peaks, we PCR amplified the CAG expanded repeats and cloned and then sequenced the products, which revealed a single peak suggesting that sequencing produces no artifacts (figure 4A). We then reamplified the cloned product by PCR and observed the appearance only of peaks corresponding to smaller size repeats, thus confirming (1) that PCR amplification indeed contributes to gen- erating smaller repeats by slippage, and (2) that the larger size peaks represent genuine somatic instability (figure 4A). Therefore, we considered only the peaks (1) corresponding to amplicons larger than the major peak, and (2) that had an area of . 2% of the major peak. The number of peaks determined by somatic mosaicism in blood is fewer than that observed in other tissues, making the count of these not very informative. To grade the mosaicism in this setting, we calculated an MI by summing the area of all extra peaks and dividing by the area of the major peak (figure 4B). CAG repeat number and MI showed a positive correlation (p 5 0.0014) (figure 4C), confirm- ing results obtained in skin and muscle tissues. 21 We
clinical development for SMA. Key outcomes of clin- ical trials largely concern motor function, muscle mass, and strength [11 – 13]. The Hammersmith Func- tional Motor Scale (HFMS) and its expanded version (HFMSE) are designed to measure motor capabilities of non-ambulant SMA type 2 and ambulatory type 3 patients. Both measures have been used in the clinical setting, natural history studies , and as outcomes in some trials, including in one of the pivotal trials for Spinraza [15 – 17]. The 33 items on the HFMSE concern an individual ’ s capacity to perform actions such as sitting on a chair without support, rolling over from prone to supine position or the reverse, lifting the head from supine, getting up from lying, four-point kneeling, propping on arms, standing and
gene, is the leading genetic cause of infant mortality. SMN protein is present at high levels in both axons and growth cones, and loss of its function disrupts axonal extension and path ﬁ nding. SMN is known to associate with the RNA-binding protein hnRNP-R, and together they are responsible for the transport and/or local trans- lation of β -actin mRNA in the growth cones of motor neurons. However, the full complement of SMN-interacting proteins in neu- rons remains unknown. Here we used mass spectrometry to iden- tify HuD as a novel neuronal SMN-interacting partner. HuD is a neuron-speciﬁc RNA-binding protein that interacts with mRNAs, including candidate plasticity-related gene 15 (cpg15). We show that SMN and HuD form a complex in spinal motor axons, and that both interact with cpg15 mRNA in neurons. CPG15 is highly expressed in the developing ventral spinal cord and can promote motor axon branching and neuromuscular synapse formation, sug- gesting a crucial role in the development of motor axons and neu- romuscular junctions. Cpg15 mRNA previously has been shown to localize into axonal processes. Here we show that SMN de ﬁ ciency reduces cpg15 mRNA levels in neurons, and, more importantly, cpg15 overexpression partially rescues the SMN-de ﬁ ciency pheno- type in zebraﬁsh. Our results provide insight into the function of SMN protein in axons and also identify potential targets for the study of mechanisms that lead to the SMA pathology and related neuromuscular diseases.
SCCSA and lower motor neuron degeneration by relating motor- evoked potential amplitude of the adductor digiti minimi and deltoid, respectively, with cord atrophy at spinal levels C8 and C5 (here, it was not possible to study the C8 spinal level; see “Limi- tations” section). However, combining advanced image process- ing and better MR imaging pulse sequences is promising to inves- tigate the effect of GM atrophy on muscle-specific deficits in the low thoracic and lumbar cord. 23 The ability to isolate lower motor
Traumatic spinal cord injury (SCI) usually leads to permanent clin- ical impairment and is a life changing event (Dietz and Curt, 2006). Currently there is no ‘cure’ for paralysis. However, recent discoveries, such as anti-Nogo-A antibody treatment (Schwab, 2002), have the potential to translate into therapies with patient benefit (Freund et al., 2006), but their efficacy depends on care- fully designed clinical trials. Consequently, there is a prescient need to develop non-invasive biomarkers, which quantify the impact of SCI upon the structural integrity and functional reorgan- ization of sensorimotor systems and the ensuing clinical impair- ment. For example, in other diseases such as multiple sclerosis, changes in whole-brain volume, which reflect the development of atrophy, have been used to quantify treatment effects (Barkhof et al., 2010).
AAV9-UBA1 rescues neuromuscular and systemic pathology in SMA mice. Given that AAV9-UBA1 treatment had a beneficial effect on the gross phenotype of SMA mice, we next analyzed the effect of increasing UBA1 levels on late-stage (P9) neuromuscular and organ pathology. In the neuromuscular system, AAV9-UBA1– treated SMA mice displayed a significant improvement in spinal motor neuron survival (Figure 5, A and B), a reversal of NMJ pathology (Figure 5, C and D, and Supplemental Figure 4, A and C), and restored muscle fiber diameters (Figure 5, E and F, and Supplemental Figure 4, B and D). The gross appearance of the heart was noticeably improved in AAV9-UBA1–treated SMA mice (Figure 6A), as reflected in an increased heart length (Figure 6B), heart weight (Figure 6C), and heart-weight-to-body-weight ratio (Figure 6D). H&E anal- ysis of liver pathology in SMA mice revealed an increased number of nucleated cells and megakaryocytes (Figure 6E). Ly76/DAPI immunohistochemistry showed that SMA mouse livers have an accumulation of erythrocytes and nucleated erythrocyte precursors (Figure 6, E–G). AAV9-UBA1 treatment ameliorated mega- karyocyte numbers (Figure 6E), Ly76 + erythrocyte accumulation (Figure 6, E and F), and nucleated Ly76 +