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Congenital heart defects in spinal muscular atrophy type I: A clinical report of two siblings and a review of the literature

A newborn girl presented with asphyxia, joint contractures and diminished spontaneous movements. Echocardiography showed hypoplastic left heart. Spinal muscular atrophy type I (SMA I) was diagnosed by detecting a homozygous deletion in the survival motor neuron 1 gene (SMN1). In the first trimester of a subsequent pregnancy, SMA I, hypoplastic left heart, and contractures were identified again. Congenital heart defects (CHD) have now been reported in 20 patients with SMA I, including three previously reported siblings and our two siblings, leading us to hypothesize that SMA I/CHD represents a unique phenotype of SMA I rather than a coincidental association. The homozygous SMN1 deletion may play a role in the development of CHD when it occurs in the presence of mutations or polymorphisms in other genes important for cardiac development. (C) 2008 Wiley-Liss, Inc

Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice

Proximal spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. Traditionally, SMA has been described as a motor neuron disease; however, there is a growing body of evidence that arrhythmia and/or cardiomyopathy may present in SMA patients at an increased frequency. Here, we ask whether SMA model mice possess such phenotypes. We find SMA mice suffer from severe bradyarrhythmia characterized by progressive heart block and impaired ventricular depolarization. Echocardiography further confirms functional cardiac deficits in SMA mice. Additional investigations show evidence of both sympathetic innervation defects and dilated cardiomyopathy at late stages of disease. Based upon these data, we propose a model in which decreased sympathetic innervation causes autonomic imbalance. Such imbalance would be characterized by a relative increase in the level of vagal tone controlling heart rate, which is consistent with bradyarrhythmia and progressive heart block. Finally, treatment with the histone deacetylase inhibitor trichostatin A, a drug known to benefit phenotypes of SMA model mice, produces prolonged maturation of the SMA heartbeat and an increase in cardiac size. Treated mice maintain measures of motor function throughout extended survival though they ultimately reach death endpoints in association with a progression of bradyarrhythmia. These data represent the novel identification of cardiac arrhythmia as an early and progressive feature of murine SMA while providing several new, quantitative indices of mouse health. Together with clinical cases that report similar symptoms, this reveals a new area of investigation that will be important to address as we move SMA therapeutics towards clinical success

Anesthesia and spinal muscle atrophy.

Spinal muscle atrophy (SMA) is autosomal recessive and one of the most common inherited lethal diseases in childhood. The spectrum of symptoms of SMA is continuous and varies from neonatal death to progressive symmetrical muscle weakness first appearing in adulthood. The disease is produced by degeneration of spinal motor neurons and can be described in three or more categories: SMA I with onset of symptoms before 6 months of age; SMAII with onset between 6 and 18 months and SMA III, which presents later in childhood. Genetics: The disease is in more than 95% of cases caused by a homozygous deletion in survival motor neuron gene 1 (SMN1). Pathophysiology: The loss of full-length functioning SMN protein leads to a degeneration of anterior spinal motor neurons which causes muscle weakness. Anesthetic risks: Airway: Tracheal intubation can be difficult. Respiration: Infants with SMA I almost always need postoperative respiratory support. Patients with SMA II sometimes need support, while SMA III patients seldom need support. Circulation: Circulatory problems during anesthesia are rare. Anesthetic drugs: Neuromuscular blockers: Patients with SMA may display increased sensitivity to and prolonged effect of nondepolarizing neuromuscular blockers. Intubation without muscle relaxation should be considered. Succinylcholine should be avoided. Opioids: These should be titrated carefully. Anesthetic techniques: All types of anesthetic technique have been used. Although none is absolutely contraindicated, none is perfect: anesthesia must be individualized. Conclusion: The perioperative risks can be considerable and are mainly related to the respiratory system, from respiratory failure to difficult/impossible intubation