Development of electrocardiogram intervals during growth of FVB/N neonate mice

<p>Abstract</p> <p>Background</p> <p>Electrocardiography remains the best diagnostic tool and therapeutic biomarker for a spectrum of pediatric diseases involving cardiac or autonomic nervous system defects. As genetic links to these disorders are established and transgenic mouse models produced in efforts to understand and treat them, there is a surprising lack of information on electrocardiograms (ECGs) and ECG abnormalities in neonate mice. This is likely due to the trauma and anaesthesia required of many legacy approaches to ECG recording in mice, exacerbated by the fragility of many mutant neonates. Here, we use a non-invasive system to characterize development of the heart rate and electrocardiogram throughout the growth of conscious neonate FVB/N mice.</p> <p>Results</p> <p>We examine ECG waveforms as early as two days after birth. At this point males and females demonstrate comparable heart rates that are 50% lower than adult mice. Neonatal mice exhibit very low heart rate variability. Within 12 days of birth PR, QRS and QTc interval durations are near adult values while heart rate continues to increase until weaning. Upon weaning FVB/N females quickly develop slower heart rates than males, though PR intervals are comparable between sexes until a later age. This suggests separate developmental events may contribute to these gender differences in electrocardiography.</p> <p>Conclusions</p> <p>We provide insight with a new level of detail to the natural course of heart rate establishment in neonate mice. ECG can now be conveniently and repeatedly used in neonatal mice. This should serve to be of broad utility, facilitating further investigations into development of a diverse group of diseases and therapeutics in preclinical mouse studies.</p

Spinal motor neuron loss occurs through a p53-and-p21-independent mechanism in the Smn

Spinal muscular atrophy (SMA) is a pediatric neuromuscular disease caused by genetic deficiency of the survival motor neuron (SMN) protein. Pathological hallmarks of SMA are spinal motor neuron loss and skeletal muscle atrophy. The molecular mechanisms that elicit and drive preferential motor neuron degeneration and death in SMA remain unclear. Transcriptomic studies consistently report p53 pathway activation in motor neurons and spinal cord tissue of SMA mice. Recent work has identified p53 as an inducer of spinal motor neuron loss in severe Δ7 SMA mice. Additionally, the cyclin-dependent kinase inhibitor P21 (Cdkn1a), an inducer of cell cycle arrest and mediator of skeletal muscle atrophy, is consistently increased in motor neurons, spinal cords, and other tissues of various SMA models. p21 is a p53 transcriptional target but can be independently induced by cellular stressors. To ascertain whether p53 and p21 signaling pathways mediate spinal motor neuron death in milder SMA mice, and how they affect the overall SMA phenotype, we introduced Trp53 and P21 null alleles onto the Sm

In Search of a Cure: The Development of Therapeutics to Alter the Progression of Spinal Muscular Atrophy

Until the recent development of disease-modifying therapeutics, spinal muscular atrophy (SMA) was considered a devastating neuromuscular disease with a poor prognosis for most affected individuals. Symptoms generally present during early childhood and manifest as muscle weakness and progressive paralysis, severely compromising the affected individual’s quality of life, independence, and lifespan. SMA is most commonly caused by the inheritance of homozygously deleted SMN1 alleles with retention of one or more copies of a paralog gene, SMN2, which inversely correlates with disease severity. The recent advent and use of genetically targeted therapies have transformed SMA into a prototype for monogenic disease treatment in the era of genetic medicine. Many SMA-affected individuals receiving these therapies achieve traditionally unobtainable motor milestones and survival rates as medicines drastically alter the natural progression of this disease. This review discusses historical SMA progression and underlying disease mechanisms, highlights advances made in therapeutic research, clinical trials, and FDA-approved medicines, and discusses possible second-generation and complementary medicines as well as optimal temporal intervention windows in order to optimize motor function and improve quality of life for all SMA-affected individuals

Friedreich’s Ataxia: Clinical Presentation of a Compound Heterozygote Child with a Rare Nonsense Mutation and Comparison with Previously Published Cases

Friedreich’s ataxia is a neurodegenerative disorder associated with a GAA trinucleotide repeat expansion in intron 1 of the frataxin (FXN) gene. It is the most common autosomal recessive cerebellar ataxia, with a mean age of onset at 16 years. Nearly 95-98% of patients are homozygous for a 90-1300 GAA repeat expansion with only 2-5% demonstrating compound heterozygosity. Compound heterozygous individuals have a repeat expansion in one allele and a point mutation/deletion/insertion in the other. Compound heterozygosity and point mutations are very rare causes of Friedreich’s ataxia and nonsense mutations are a further rarity among point mutations. We report a rare compound heterozygous Friedrich’s ataxia patient who was found to have one expanded GAA FXN allele and a nonsense point mutation in the other. We summarize the four previously published cases of nonsense mutations and compare the phenotype to that of our patient. We compared clinical information from our patient with other nonsense FXN mutations reported in the literature. This nonsense mutation, to our knowledge, has only been described once previously; interestingly the individual was also of Cuban ancestry. A comparison with previously published cases of nonsense mutations demonstrates some common clinical characteristics

Spinal motor neuron loss occurs through a p53-and-p21-independent mechanism in the Smn

Spinal muscular atrophy (SMA) is a pediatric neuromuscular disease caused by genetic deficiency of the survival motor neuron (SMN) protein. Pathological hallmarks of SMA are spinal motor neuron loss and skeletal muscle atrophy. The molecular mechanisms that elicit and drive preferential motor neuron degeneration and death in SMA remain unclear. Transcriptomic studies consistently report p53 pathway activation in motor neurons and spinal cord tissue of SMA mice. Recent work has identified p53 as an inducer of spinal motor neuron loss in severe Δ7 SMA mice. Additionally, the cyclin-dependent kinase inhibitor P21 (Cdkn1a), an inducer of cell cycle arrest and mediator of skeletal muscle atrophy, is consistently increased in motor neurons, spinal cords, and other tissues of various SMA models. p21 is a p53 transcriptional target but can be independently induced by cellular stressors. To ascertain whether p53 and p21 signaling pathways mediate spinal motor neuron death in milder SMA mice, and how they affect the overall SMA phenotype, we introduced Trp53 and P21 null alleles onto the Sm

Characterization of a commonly used mouse model of SMA reveals increased seizure susceptibility and heightened fear response in FVB/N mice.

The SMN2 transgenic mouse, Tg(SMN2)89Ahmb, has emerged as the most widely used in spinal muscular atrophy (SMA) research. Here we clone the genomic integration site of the transgene and demonstrate it to be in intron 4 of the metabotropic glutamate receptor 7 (mGluR7) gene. We found that the integration of this transgene significantly reduced both mGluR7 mRNA and protein levels (24% and 9%, respectively). To determine if phenotypes associated with mGluR7 knockout mice were present in Tg(SMN2)89Ahmb containing mice, we subjected mice homozygous for the transgene to open field and seizure susceptibility tests. When compared to wild type FVB/N mice, Tg(SMN2)89Ahmb(tg/tg) mice exhibited significantly longer times in finding a safe wall-adjacent square (+54s if Smn(+/+), +90s if Smn(+/-)), as well as a significantly higher frequency of generalized seizure in response to a subthreshold dose of pentylenetrazol (0.11 vs 0.45). These findings aid in explaining the sudden unexpected death that occurs within SMA mouse colonies that contain a homozygous Tg(SMN2)89Ahmb transgene. This should be taken into account in pre-clinical studies that utilize this transgene, especially in therapy-treated SMA mice that have extended survival