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Motor neuron death in patients with spinal muscular atrophy is related to abnormal RNA editing of two specific proteins, which leads to the activation of a key cell death pathway and neurodegeneration, a study suggests. Genes, which are composed of DNA sequences, are transcribed into molecules called RNA. In turn, RNA molecules are used as templates to make proteins, which carry out various functions in a cell. SMA is a neurodegenerative disease characterized by widespread RNA dysfunction, leading to the abnormal production of various proteins. RNA dysfunction in SMA patients is the result of a mutation in the gene that provides instructions to make the survival motor neuron protein, which is a major regulator of RNA splicing. RNA splicing is a process by which RNA molecules are edited to produce the final RNA product. When an RNA molecule is initially made, it is composed of alternating regions known as exons or introns. Through the use of RNA splicing, the intros of the RNA molecules are cut out and the exons are joined together. These exons are a vital part of the RNA molecule that actually contain the instructions used to make the protein. A deficiency in SMN leads to significant RNA dysfunction. One of the hallmarks of SMA is the progressive loss of spinal motor neurons, and researchers have been trying to understand the cause behind the excessive death of these motor neurons in patients. Studies using mouse models of SMA have shown that motor neuron death can be attributed to the p53-dependent pathway, which is activated by high levels of a protein called p53. The role of p53 in cells is to stop them from dividing and trigger the pathways that result in cell death. The molecular mechanisms that link a deficiency in the SMN protein to p53 activation and motor neuron death in SMA are currently unknown. Normally, p53 expression is kept at low levels in the cell by Mdm2 and Mdm4, proteins that negatively regulate p53. Therefore, researchers hypothesized that p53 activation in SMA involves a dysregulation of Mdm2 and Mdm4 due to abnormal RNA splicing caused by an SMN deficiency. Using both cellular and animal models, researchers in this study showed that a deficiency in the SMN protein “disrupts the balance between inclusion and exclusion of key regulatory exons in Mdm2 and Mdm4.” Specifically, they observed that exon 3 of Mdm2 and exon 7 of Mdm4 are not included in the final RNA molecules for these proteins in SMN-deficient cells. This dysfunction in RNA splicing activity causes problems in the biological activity of Mdm2 and Mdm4, and p53 becomes active. In fact, prior studies have shown that irregular RNA splicing of these specific exons is associated with an increase in p53 activity. Therefore, researchers conclude that their findings mechanistically link dysregulation of alternative splicing induced by SMN deficiency with motor neuron death, the key hallmark of SMA.

Young children with spinal muscular atrophy show improvements in motor function after six-months of treatment with Spinraza, a German study shows. The response to Spinraza strongly correlated with the age when treatment began, with children treated before seven months of age responding better to the therapy. These findings support the need for early detection of SMA by screening newborns, study authors emphasized. Spinraza, developed by Biogen, is the first FDA-approved drug for SMA. SMA arises due to mutations in the survival motor neuron 1 (SMN1) gene, which is key to the function and survival of the nerves that control muscles. Some patients, however, maintain a copy of a gene called SMN2, a gene nearly identical to SMN1 that can give rise to a shorter version of the SMN protein. Spinraza boosts the amount of the SMN protein by increasing the levels of full-length messenger RNA (mRNA), the mediator between gene and protein, generated by the SMN2 gene. Spinraza is administered via intrathecal injection — directly to the cerebrospinal fluid around the spinal cord, where motor neurons of SMA individuals degenerate due to insufficient levels of SMN protein. The therapy was approved in the U.S. in December 2016 to treat SMA types 1–3 in children and adults, and learned approval in Europe in June 2017. Prior to the EU’s approval, a group of children in Germany with SMA type 1 was given access to Spinraza for seven months, under an Expanded Access Program (EAP). The children had different ages and were at different stages of the disease, representing a more heterogenous group than those in previous trials. Researchers analyzed data from 61 children treated with Spinraza in seven centers under the EAP. Children enrolled in the study developed the first symptoms of SMA before the age of 6 months and had no ability to sit independently. Moreover, 38 children had less than two copies of the SMN2 gene, and 20 children had more than three copies. In three children, the SMN2 copy number was unknown. Previous studies showed that a higher number of SMN2 correlates with longer survival and inversely with disease severity. Administration of Spinraza was performed on days 1, 15, 30, 60 and 180. Researchers measured the treatment outcomes by assessing primarily the changes from the beginning of the study in the score of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders, also known as (CHOP INTEND), which measures motor function. The CHOP-INTEND scores range from 0 to 64 points and previous studies have reported that children with SMA type 1 have a mean value of 21.4 points. The test was performed at the beginning of the study, then after 60 days, and at the end of treatment. Additionally, they assessed changes in scores in section 2 of the Hammersmith Infant Neurological Examination (HINE) scale, another test measuring motor function, whose scores range between zero and 26. The HINE-2 was performed routinely at every patient visit. At baseline, children’s mean CHOP INTEND score was 22.3 and after six months of treatment the mean score improved to 31.2, which was an increase of nine points. Specifically, eight children improved by one to four points, and 17 children improved by five to nine points. Sixteen children improved by more than 10 points (between 10 and 14 points), and 11 children underwent an increase on the CHOP INTEND by more than 15 points. Children with less than two copies of the SMN2 gene had lower scores in the CHOP INTEND at the beginning of the trial. The changes in scores after treatment were comparable to children with more than three SMN2 copies, scores of 8.1 and 8.2, respectively. Treatment was more effective in younger children (aged below 7 months) compared to older ones — an improvement of 14.4 vs. 7.0, respectively. These results suggest there is a “critical therapeutic time window for delivery of SMN-targeted therapies. The implementation of newborn screening for SMA is crucial to allow pre-symptomatic diagnosis." Regarding the motor response, 19 children improved by more than two points in HINE-2 motor milestones —  15 children increased their score by two to four points, and four children by more than five points. Four children (6.6%) achieved full head control, and 2 children (3.3%) were able to sit independently. After six months of treatment, the parents of 28 children reported a marked improvement in motor function, while three parents noticed no benefit, and one a slight worsening. Respiratory function was improved in 16 children, with a marked improvement in four of them. Overall, these findings “indicate that even in advanced stages of the disease, Spinraza can lead to improvement of motor function as measured by CHOP INTEND. Moreover, the results support early diagnosis and access to Spinraza as early as possible as a key factor to improve the outcomes of children with SMA. Researchers now will evaluate whether increasing the treatment period with Spinraza enhances the therapy’s benefits and patients' quality of life. The data will be collected within the SMArtCARE project, a “real-world data” registry of SMA patients.

Spinal muscular atrophy (SMA) patients can be more prone to a life-threatening metabolic imbalance called ketoacidosis, which causes the blood to become acidic, a case report highlights. In patients with neuromuscular diseases like SMA, physicians should be particularly suspicious of this complication so that…

Spinal muscular atrophy (SMA) has been added to the Recommended Uniform Screening Panel (RUSP) for newborns in the United States, opening the door to newborn screening for SMA at the state level, the Muscular Dystrophy Association (MDA) reports on its website. The decision adding SMA to recommended screenings…

Lowering the levels of a protein called CHP1, together with Spinraza (nusinersen) treatment, may help to improve responses to therapy in spinal muscular atrophy (SMA) patients, a study in a mouse model of the disease suggests. Because CHP1 is independent…

A population-based study conducted in the state of New York demonstrates the feasibility and benefits of newborn screening for spinal muscular atrophy (SMA). Supported by these findings, researchers recommend adding SMA genetic tests to the national recommended uniform screening panel. The study, “Pilot study of population-based newborn…

A key player in a pathway known as the cell’s “cleaning system” could be a promising target for alternative approaches to treating spinal muscular atrophy (SMA), a mouse study suggests. The study, “Blocking p62-dependent SMN degradation ameliorates spinal muscular atrophy disease phenotypes,”…

Researchers in a mouse model of spinal muscular atrophy have discovered why certain nerve cells, called ocular motor neurons, are able to resist the damage and degeneration linked to the disease. SMA is caused by mutations in the SMN1 gene, considerably lowering the amount of the SMN protein produced. SMN, present in all cells, is necessary for the survival of motor nerve cells, or motor neurons, which are progressively lost during disease progression. In SMA, spinal motor neurons — nerve cells in the spinal cord that control skeletal muscle movements, including the arms and legs — are those mainly affected. Their loss leads to weakness and atrophy of skeletal muscles, affecting voluntary movement. For unknown reasons, certain types of cranial motor neurons in the brainstem — the region at the base of the brain that connects with the spinal cord — show partial or even no damage in SMA patients. Among cranial motor neurons, those that control the muscles of the tongue are affected to some extent, and those controlling the eyes — called ocular motor neurons — are resistant to SMA-associated degeneration. Understanding why ocular motor neurons are spared in SMA may help in developing new treatment approaches, particularly gene therapies, and in preventing progressive motor neuron loss. Using a mouse model of SMA, researchers conducted a comprehensive analysis of vulnerable and resistant nerve cell groups at several stages of the disease. They used an approach called LCM-seq that couples laser microdissection of cells from frozen tissues with analysis of gene expression. Dissected nerve cells came from the spinal cord and brainstem regions of healthy mice and  mice at different stages of SMA: a pre-symptomatic stage, an early symptomatic stage (damage restricted to some regions of the spinal cord), and a symptomatic stage (clear motor dysfunction and extensive loss of spinal motor nerve cells). Researchers found 251 genes highly associated with SMA, from which 113 genes (45%) were differentially expressed to a significant degree in both disease-vulnerable and -resistant types of motor neurons from the SMA mice. In response to low SMN protein levels, all motor nerve cells showed significant expression of genes associated with stress-responses and cell death, independent of their vulnerability to SMA. To understand how — despite activated cell death signals — ocular motor neurons were able to resist damage due to SMA, the researchers compared the expression patterns of these resistant ocular motor neurons with those of vulnerable spinal motor neurons. They found signs of nerve cell dysfunction upon loss of SMN in the vulnerable neurons. But the resistant neurons rapidly and selectively adapted: they increased the expression of genes that are associated with cell survival, with protection from oxidative stress and cell death, and with regeneration and/or maintenance of communication signals between nerve cells and muscle cells. “We show that ocular motor neurons present unique disease-adaptation mechanisms that could explain their resilience,” the researchers wrote. They also noted these cell-specific mechanisms “present compelling targets for future gene therapy studies aimed towards preserving vulnerable motor neurons,” in the context of motor nerve cell diseases.

Walking ability in type 3 SMA patients is significantly impaired during adolescence, according to recent research. Type 3 SMA, also known as Kugelberg-Welander disease, is a milder form of SMA. Muscle weakness in type 3 SMA mainly affects patients’ limb movements, and children are generally able to stand and walk. These abilities decrease over time, however. Symptoms usually appear between 18 months and early teens. Symptom onset before age 3 is classified as type 3A SMA, and onset at later ages as type 3B — considered a milder SMA subtype. However, while SMA is thought to be a largely stable disorder, recent studies have highlighted different rates of progression based on age and function. In patients who cannot walk, gross motor function improves until about age 5, then worsens until about age 15, followed by a relatively stable phase in late adolescence and adulthood. While ambulatory patients have a similar disease progression to that of non-ambulatory patients, a more specific assessment may be necessary to identify changes in walking function. Researchers used data from three prospective natural history studies to evaluate changes in walking ability in 73 individuals with type 3 SMA who were able to walk without support for at least 10 meters. The team used the  the six-minute walk test, a valid and reliable functional assessment that measures the distance a person can walk in six minutes. While the 6MWT was initially developed to evaluate functional exercise capacity in heart- and lung-associated diseases, it has become a valuable and reliable test to measure functional walking ability in SMA patients. The study showed that the ability to walk strongly deteriorated during adolescence with a loss of 20.8 meters per year, and slowly declined again through adulthood with a loss of 9.7 meters per year. The age around puberty appeared to be the most vulnerable period in ambulant patients, with researchers hypothesizing that weight gain and growth associated with puberty could contribute toward a greater decline in walking capacity. The study authors emphasized that when designing future clinical trials with SMA patients, it is important to understand the natural history of the disease and identify disease trajectories as measured by the 6MWT to better interpret patients' response to treatment.

Taking care of a child with spinal muscular atrophy (SMA) significantly affects several aspects of  families’ lives, including finances, career choices, social life, and mental health, according to an Australian study. The study, “Financial, opportunity and psychosocial costs of spinal muscular atrophy: an exploratory qualitative analysis…