Sudden Death in High School Athletes: A Case Series Examining the Influence of Sickle Cell Trait.

ABSTRACT: Athletes with sickle cell trait (SCT) have up to a 37-fold increased risk of exercise-related death. Exertional collapse associated with sickle cell trait (ECAST) is uncommon but can lead to exercise-related death due to exertional sickling. We present a case series of fatal ECAST in high school athletes aged 14 to 16 years. All 3 athletes experienced collapse during practice sessions with muscle pain or weakness. Upon evaluation at the hospital, the athletes had a significant metabolic acidosis that did not respond as expected to fluid resuscitation. Admitting diagnoses for the athletes included exertional heat stroke or dehydration. All 3 athletes had profound rhabdomyolysis leading to acute renal failure, worsening metabolic acidosis, and hyperkalemia. They rapidly progressed to disseminated intravascular coagulation, multiorgan system failure, and death. The autopsies of all 3 athletes showed extensive sickle cell vaso-occlusion involving the spleen liver, and muscles. Final clinical and pathologic diagnosis supported ECAST with fatal exertional rhabdomyolysis. Exertional collapse associated with sickle cell trait is an uncommon but potentially deadly condition that is often underrecognized or misdiagnosed as exertional heat stroke. The development of ECAST is thought to be multifactorial with exercise intensity, recent illness, and exercising conditions (ie, heat and altitude). Prevention should be the primary goal for athletes with SCT through exercise modification, education of precipitation factors, and cessation of exercise with recent illness. Athletes with suspected ECAST should undergo aggressive resuscitation with a low threshold for early transfer to a tertiary care facility for further management and potential hemodialysis.

Impaired prenatal motor axon development necessitates early therapeutic intervention in severe SMA.

Gene replacement and pre-mRNA splicing modifier therapies represent breakthrough gene targeting treatments for the neuromuscular disease spinal muscular atrophy (SMA), but mechanisms underlying variable efficacy of treatment are incompletely understood. Our examination of severe infantile onset human SMA tissues obtained at expedited autopsy revealed persistence of developmentally immature motor neuron axons, many of which are actively degenerating. We identified similar features in a mouse model of severe SMA, in which impaired radial growth and Schwann cell ensheathment of motor axons began during embryogenesis and resulted in reduced acquisition of myelinated axons that impeded motor axon function neonatally. Axons that failed to ensheath degenerated rapidly postnatally, specifically releasing neurofilament light chain protein into the blood. Genetic restoration of survival motor neuron protein (SMN) expression in mouse motor neurons, but not in Schwann cells or muscle, improved SMA motor axon development and maintenance. Treatment with small-molecule SMN2 splice modifiers beginning immediately after birth in mice increased radial growth of the already myelinated axons, but in utero treatment was required to restore axonal growth and associated maturation, prevent subsequent neonatal axon degeneration, and enhance motor axon function. Together, these data reveal a cellular basis for the fulminant neonatal worsening of patients with infantile onset SMA and identify a temporal window for more effective treatment. These findings suggest that minimizing treatment delay is critical to achieve optimal therapeutic efficacy.

Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy.

The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increased SMN expression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, but SMN may have variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power.

Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy.

To define alterations of neuronal connectivity that occur during motor neuron degeneration, we characterized the function and structure of spinal circuitry in spinal muscular atrophy (SMA) model mice. SMA motor neurons show reduced proprioceptive reflexes that correlate with decreased number and function of synapses on motor neuron somata and proximal dendrites. These abnormalities occur at an early stage of disease in motor neurons innervating proximal hindlimb muscles and medial motor neurons innervating axial muscles, but only at end-stage disease in motor neurons innervating distal hindlimb muscles. Motor neuron loss follows afferent synapse loss with the same temporal and topographical pattern. Trichostatin A, which improves motor behavior and survival of SMA mice, partially restores spinal reflexes, illustrating the reversibility of these synaptic defects. Deafferentation of motor neurons is an early event in SMA and may be a primary cause of motor dysfunction that is amenable to therapeutic intervention.