SMN1
Survival motor neuron protein (Component of gems 1) (Gemin-1) [SMN] [SMNT]
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Spinal muscular atrophy [SMA] is the most common genetic cause of childhood mortality, primarily from the most severe form SMA type 1. It is a severe, progressive motor neurone disease, affecting the lower brainstem nuclei and the spinal cord. There is a graded level of severity with SMA children from a practical viewpoint described as "Non-sitters", "Sitters" and less commonly, "Ambulant" correlating with SMA Type 0/Type 1, Type 2 and Type 3 respectively. Children with SMA Type 0 have a severe neonatal form whilst those with SMA Type 1 develop hypoventilation, pulmonary aspiration, recurrent lower respiratory tract infections, dysphagia and failure to thrive before usually succumbing to respiratory failure and death before the age of 2 years. The recent introduction of the antisense oligonucleotide nusinersen into clinical practice in certain countries, following limited trials of less than two years duration, has altered the treatment landscape and improved the outlook considerably for SMN1 related SMA. Approximately 70% of infants appear to have a clinically significant response to nusinersen with improved motor function. It appears the earlier the treatment is initiated the better the response. There are other rarer genetic forms of SMA that are not treated with nusinersen. Clinical expectations will change although it is unclear as yet what the extent of response will mean in terms of screening initiatives [e.g., newborn screening], "preventative strategies" to maintain respiratory wellbeing, timing of introduction of respiratory supports, and prolonged life expectancy for the subcategory of children with treated SMA type 1. This article provides a review of the strategies available for supporting children with respiratory complications of SMA, with a particular emphasis on SMA Type 1.
MeSH Terms
- Early Medical Intervention
- Humans
- Hypoventilation
- Life Expectancy
- Oligonucleotides
- Phenotype
- Physical Therapy Modalities
- Pneumonia
- Respiration, Artificial
- Respiratory Aspiration
- Respiratory Insufficiency
- Respiratory Therapy
- Spinal Muscular Atrophies of Childhood
Keywords
- Airway clearance
- Invasive ventilation
- Non-invasive ventilation
- Pneumonia
- Respiratory failure
- Spinal muscular atrophy
Spinal muscular atrophy (SMA) is caused by homozygous inactivation of the SMN1 gene. The SMN2 copy number modulates the severity of SMA. The 0SMN1/1SMN2 genotype, the most severe genotype compatible with life, is expected to be associated with the most severe form of the disease, called type 0 SMA, defined by prenatal onset. The aim of the study was to review clinical features and prenatal manifestations in this rare SMA subtype. SMA patients with the 0SMN1/1SMN2 genotype were retrospectively collected using the UMD-SMN1 France database. Data from 16 patients were reviewed. These 16 patients displayed type 0 SMA. At birth, a vast majority had profound hypotonia, severe muscle weakness, severe respiratory distress, and cranial nerves involvement (inability to suck/swallow, facial muscles weakness). They showed characteristics of fetal akinesia deformation sequence and congenital heart defects. Recurrent episodes of bradycardia were observed. Death occurred within the first month. At prenatal stage, decreased fetal movements were frequently reported, mostly only by mothers, in late stages of pregnancy; increased nuchal translucency was reported in about half of the cases; congenital heart defects, abnormal amniotic fluid volume, or joint contractures were occasionally reported. Despite a prenatal onset attested by severity at birth and signs of fetal akinesia deformation sequence, prenatal manifestations of type 0 SMA are not specific and not constant. As illustrated by the frequent association with congenital heart defects, type 0 SMA physiopathology is not restricted to motor neuron, highlighting that SMN function is critical for organogenesis.
MeSH Terms
- Arthrogryposis
- Autonomic Nervous System Diseases
- Cranial Nerve Diseases
- Female
- Genotype
- Heart Defects, Congenital
- Homozygote
- Humans
- Infant, Newborn
- Life Expectancy
- Male
- Muscle Hypotonia
- Reflex, Abnormal
- Respiratory Distress Syndrome, Newborn
- Spinal Muscular Atrophies of Childhood
- Survival of Motor Neuron 1 Protein
- Survival of Motor Neuron 2 Protein
- Ultrasonography, Prenatal
Keywords
- Spinal muscular atrophy
- congenital heart defect
- fetal akinesia deformation sequence
- human SMN2 protein
- prenatal ultrasonography
The development of antisense oligonucleotide therapy is an important advance in the identification of corrective therapy for neuromuscular diseases, such as spinal muscular atrophy (SMA). Because of difficulties of delivering single-stranded oligonucleotides to the CNS, current approaches have been restricted to using invasive intrathecal single-stranded oligonucleotide delivery. Here, we report an advanced peptide-oligonucleotide, Pip6a-morpholino phosphorodiamidate oligomer (PMO), which demonstrates potent efficacy in both the CNS and peripheral tissues in severe SMA mice following systemic administration. SMA results from reduced levels of the ubiquitously expressed survival motor neuron (SMN) protein because of loss-of-function mutations in the SMN1 gene. Therapeutic splice-switching oligonucleotides (SSOs) modulate exon 7 splicing of the nearly identical SMN2 gene to generate functional SMN protein. Pip6a-PMO yields SMN expression at high efficiency in peripheral and CNS tissues, resulting in profound phenotypic correction at doses an order-of-magnitude lower than required by standard naked SSOs. Survival is dramatically extended from 12 d to a mean of 456 d, with improvement in neuromuscular junction morphology, down-regulation of transcripts related to programmed cell death in the spinal cord, and normalization of circulating insulin-like growth factor 1. The potent systemic efficacy of Pip6a-PMO, targeting both peripheral as well as CNS tissues, demonstrates the high clinical potential of peptide-PMO therapy for SMA.
MeSH Terms
- Aging
- Alleles
- Amino Acid Sequence
- Biomarkers
- Cell Line
- Humans
- Movement
- Muscular Atrophy, Spinal
- Neuromuscular Junction
- Oligonucleotides
- Peptides
- Phenotype
- RNA Splicing
- Survival Analysis
- Survival of Motor Neuron 2 Protein
Keywords
- antisense oligonucleotide
- cell-penetrating peptide
- spinal muscular atrophy
- splice switching oligonucleotide
- survival motor neuron
Spinal Muscular Atrophy (SMA) is due to the loss of the survival motor neuron gene 1 (SMN1), resulting in motor neuron (MN) degeneration, muscle atrophy and loss of motor function. While SMN2 encodes a protein identical to SMN1, a single nucleotide difference in exon 7 causes most of the SMN2-derived transcripts to be alternatively spliced resulting in a truncated and unstable protein (SMNΔ7). SMA patients retain at least one SMN2 copy, making it an important target for therapeutics. Many of the existing SMA models are very severe, with animals typically living less than 2 weeks. Here, we present a novel intermediate mouse model of SMA based upon the human genomic SMN2 gene. Genetically, this model is similar to the well-characterized SMNΔ7 model; however, we have manipulated the SMNΔ7 transgene to encode a modestly more functional protein referred to as SMN read-through (SMN(RT)). By introducing the SMN(RT) transgene onto the background of a severe mouse model of SMA (SMN2( / );Smn(-/-)), disease severity was significantly decreased based upon a battery of phenotypic parameters, including MN pathology and a significant extension in survival. Importantly, there is not a full phenotypic correction, allowing for the examination of a broad range of therapeutics, including SMN2-dependent and SMN-independent pathways. This novel animal model serves as an important biological and therapeutic model for less severe forms of SMA and provides an in vivo validation of the SMN(RT) protein.
MeSH Terms
- Animals
- Body Weight
- Brain
- Disease Models, Animal
- Exons
- Gene Expression Regulation
- Humans
- Longevity
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Muscular Atrophy, Spinal
- Phenotype
- Promoter Regions, Genetic
- RNA
- RNA Splicing
- Spinal Cord
- Survival of Motor Neuron 1 Protein
- Survival of Motor Neuron 2 Protein