P3.8 Cardiac involvement in patients with spinal muscular atrophies

Palladino, Alberto; Passamano, Luigia; Scutifero, Marianna; Gregorio, M.G. Di; Spina, Francesco; Torre, Vito; Luca, Fabio De; Nigro, Gerardo; Politano, Luisa

doi:10.1016/j.nmd.2011.06.902

Cited by 25 publications

(38 citation statements)

References 17 publications

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“…and other organ systems in the pathogenesis of SMA have been called into question (30), cardiac defects are seldom part of the clinical presentation of SMA types I, II, and III (47). Cardiac defects are, however, the cause of death in both the severe SMA mouse models (29,48) and milder models.…”

Section: Discussionmentioning

confidence: 99%

Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

Bogdanik

Osborne

Davis

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Clinical presentation of spinal muscular atrophy (SMA) ranges from a neonatal-onset, very severe disease to an adult-onset, milder form. SMA is caused by the mutation of the Survival Motor Neuron 1 (SMN1) gene, and prognosis inversely correlates with the number of copies of the SMN2 gene, a human-specific homolog of SMN1. Despite progress in identifying potential therapies for the treatment of SMA, many questions remain including how late after onset treatments can still be effective and what the target tissues should be. These questions can be addressed in part with preclinical animal models; however, modeling the array of SMA severities in the mouse, which lacks SMN2, has proven challenging. We created a new mouse model for the intermediate forms of SMA presenting with a delay in neuromuscular junction maturation and a decrease in the number of functional motor units, all relevant to the clinical presentation of the disease. Using this new model, in combination with clinical electrophysiology methods, we found that administering systemically SMN-restoring antisense oligonucleotides (ASOs) at the age of onset can extend survival and rescue the neurological phenotypes. Furthermore, these effects were also achieved by administration of the ASOs late after onset, independent of the restoration of SMN in the spinal cord. Thus, by adding to the limited repertoire of existing mouse models for type II/III SMA, we demonstrate that ASO therapy can be effective even when administered after onset of the neurological symptoms, in young adult mice, and without being delivered into the central nervous system.

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Section: Discussionmentioning

confidence: 99%

Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

Bogdanik

Osborne

Davis

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…To fully evaluate these factors a large animal model of SMA with correction is needed. Rodent models have a relative permeable blood brain barrier at early time points and distinct phenotypes such as tail necrosis and cardiac defects that are not associated with the human pathology and thus cannot give the required information 17, 28, 29 . Models of SMA can be created by knockdown of SMN and in this case it is important to consider the degree of knockdown.…”

Section: Introductionmentioning

confidence: 99%

A large animal model of spinal muscular atrophy and correction of phenotype

Duqué

Arnold

Odermatt

et al. 2015

Annals of Neurology

119

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Objectives Spinal muscular atrophy (SMA) is caused by reduced levels of SMN which results in motoneuron loss. Therapeutic strategies to increase SMN levels including drug compounds, antisense oligonucleotides or scAAV9 gene therapy have proved effective in mice. We wished to determine whether reduction of SMN in postnatal motoneurons resulted in SMA in a large animal model, whether SMA could be corrected after development of muscle weakness and the response of clinically relevant biomarkers. Methods Using intrathecal delivery of scAAV9 expressing a shRNA targeting pig SMN1, SMN was knocked down in motoneurons postnatally to SMA levels. This resulted in an SMA phenotype representing the first large animal model of SMA. Restoration of SMN was performed at different time points with scAAV9 expressing human SMN (scAAV9-SMN) and electrophysiology measures and pathology were performed. Results Knockdown of SMN in postnatal motoneurons results in overt proximal weakness, fibrillations on electromyography (EMG) indicating active denervation, and reduced compound muscle action potential (CMAP) and motor unit number estimates (MUNE), like human SMA. Neuropathology showed loss of motoneurons and motor axons. Pre-symptomatic delivery of scAAV9-SMN prevented SMA symptoms indicating all changes are SMN dependent. Delivery of scAAV9-SMN after symptom onset had a marked impact on phenotype, electrophysiological measures and pathology. Interpretation High SMN levels are critical in postnatal motoneurons and reduction of SMN results in a SMA phenotype which is SMN dependent. Importantly, clinically relevant biomarkers including CMAP and MUNE are responsive to SMN restoration and abrogation of phenotype can be achieved even after symptom onset.

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“…Those patients with a high risk of malignant hyperthermia require coordination of care with anesthesiology before any procedure requiring sedation . Cardiovascular involvement can range from mild tachycardia, to fatal arrhythmias or cardiomyopathy . Screening for cardiac complications in pediatric neuromuscular disorders is recommended at baseline and at regular intervals in collaboration with cardiology…”

Section: Pediatric Considerations In Multidisciplinary Care Models Fomentioning

confidence: 99%

Developing multidisciplinary clinics for neuromuscular care and research

et al. 2017

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Multidisciplinary care is considered the standard of care for both adult and pediatric neuromuscular disorders and has been associated with improved quality of life, resource utilization, and health outcomes. Multidisciplinary care is delivered in multidisciplinary clinics that coordinate care across multiple specialties by reducing travel burden and streamlining care. In addition, the multidisciplinary care setting facilitates the integration of clinical research, patient advocacy, and care innovation (e.g., telehealth). Yet, multidisciplinary care requires substantial commitment of staff time and resources. We calculated personnel costs in our ALS clinic in 2015 and found an average cost per patient visit of $580, of which only 45% was covered by insurance reimbursement. In this review, we will describe classic and emerging concepts in multidisciplinary care models for adult and pediatric neuromuscular disease. We will then explore the financial impact of multidisciplinary care with emphasis on sustainability and metrics to demonstrate quality and value. Muscle Nerve 56: 848–858, 2017

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P3.8 Cardiac involvement in patients with spinal muscular atrophies

Cited by 25 publications

References 17 publications

Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

A large animal model of spinal muscular atrophy and correction of phenotype

Developing multidisciplinary clinics for neuromuscular care and research

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