Cardiac Involvement in Werdnig-Hoffmann’s Spinal Muscular At rophy

Finsterer, Josef; Stöllberger, Claudia

doi:10.1159/000006968

Cited by 19 publications

(16 citation statements)

References 11 publications

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“…While previous clinical reports of SMA I patients did not explicitly determine if the cardiac defects were secondary to respiratory distress; recently, however, congenital heart anomalies are being described more frequently upon autopsy and include: dilated right ventricle, atrial and ventricular septal defects. The most common congenital heart defect is an anomalous development of the heart, referred to as hypoplastic left heart syndrome [123,129,120]. Analysis performed by Rudnik-Schoneborn and collaborators support a crucial role for SMN protein in cardiac development.…”

Section: Other Cell Types Outside the Central Nervous System Involmentioning

confidence: 99%

Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

Simone

Ramirez

Bucchia

et al. 2015

Cell. Mol. Life Sci.

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Spinal Muscular Atrophy (SMA) is a genetic neurological disease that causes infant mortality; no effective therapies are currently available. SMA is due to homozygous mutations and/or deletions in the Survival Motor Neuron 1 (SMN1) gene and subsequent reduction of the SMN protein, leading to the death of motor neurons. However, there is increasing evidence that in addition to motor neurons, other cell types are contributing to SMA pathology. In this review, we will discuss the involvement of non-motor neuronal cells, located both inside and outside the central nervous system, in disease onset and progression. These contribution of non-motor neuronal cells to disease pathogenesis has important therapeutic implications: in fact, even if SMN restoration in motor neurons is needed, it has been shown that optimal phenotypic amelioration in animal models of SMA requires a more widespread SMN correction. It will be crucial to take this evidence into account before clinical translation of the novel therapeutic approaches that are currently under development.

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Section: Other Cell Types Outside the Central Nervous System Involmentioning

confidence: 99%

Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

Simone

Ramirez

Bucchia

et al. 2015

Cell. Mol. Life Sci.

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“…Congenital heart defects, including atrial septal defects, ventricular septal defects and hypoplastic aortic arch, are the most common structural defects observed in SMA patients (Møller et al 1990;B€ urglen et al 1995;Mulleners et al 1996;Jong et al 1998;El-Matary et al 2004;Cook et al 2006;Sarnat & Trevenen, 2007;Vaidla et al 2007;Menke et al 2008;Araujo et al 2009;Grotto et al 2016;Krupickova et al 2017). However, pulmonary hypertension, ventricular enlargement, systolic murmurs and cardiomyopathies have also been reported (Tanaka et al 1976(Tanaka et al , 1977Kimura et al 1980;Møller et al 1990;Distefano et al 1994;Elkohen et al 1996;Finsterer & St€ ollberger, 1999;El-Matary et al 2004;Collado-Ortiz et al 2007;Vaidla et al 2007;Menke et al 2008;Kuru et al 2009). In the case of arrhythmias, bradycardias are most predominant in children with SMA, although heart block and ECG tremors have also been noted (Tanaka et al 1976;Kimura et al 1980;Dawood & Moosa, 1983;Coletta et al 1989;Finsterer & St€ ollberger, 1999;Arai et al 2005;Hachiya et al 2005;Takahashi et al 2006;Rudnik-Sch€ oneborn et al 2008;Roos et al 2009;Haliloglu et al 2015;…”

Section: Introductionmentioning

confidence: 97%

Developmental and degenerative cardiac defects in the Taiwanese mouse model of severe spinal muscular atrophy

et al. 2018

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Spinal muscular atrophy (SMA), an autosomal recessive disease caused by a decrease in levels of the survival motor neuron (SMN) protein, is the most common genetic cause of infant mortality. Although neuromuscular pathology is the most severe feature of SMA, other organs and tissues, including the heart, are also known to be affected in both patients and animal models. Here, we provide new insights into changes occurring in the heart, predominantly at pre- and early symptomatic ages, in the Taiwanese mouse model of severe SMA. Thinning of the interventricular septum and dilation of the ventricles occurred at pre- and early symptomatic ages. However, the left ventricular wall was significantly thinner in SMA mice from birth, occurring prior to any overt neuromuscular symptoms. Alterations in collagen IV protein from birth indicated changes to the basement membrane and contributed to the abnormal arrangement of cardiomyocytes in SMA hearts. This raises the possibility that developmental defects, occurring prenatally, may contribute to cardiac pathology in SMA. In addition, cardiomyocytes in SMA hearts exhibited oxidative stress at pre-symptomatic ages and increased apoptosis during early symptomatic stages of disease. Heart microvasculature was similarly decreased at an early symptomatic age, likely contributing to the oxidative stress and apoptosis phenotypes observed. Finally, an increased incidence of blood retention in SMA hearts post-fixation suggests the likelihood of functional defects, resulting in blood pooling. These pathologies mirror dilated cardiomyopathy, with clear consequences for heart function that would likely contribute to potential heart failure. Our findings add significant additional experimental evidence in support of the requirement to develop systemic therapies for SMA capable of treating non-neuromuscular pathologies.

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“…Therefore, vagal hypertonia induced bradycardia has also been considered [10]. Furthermore, palpitations, ST-segment abnormalities, couplets, diastolic dysfunction, and right ventricular overload have been reported in SMA patients [11,12]. Distal necrosis has also been documented in severe SMA, occasionally with atrial septal defects and asymmetric left ventricular hypertrophy [13,14].…”

Section: Introductionmentioning

confidence: 99%

Partial restoration of cardio-vascular defects in a rescued severe model of spinal muscular atrophy

Shababi

Habibi

et al. 2012

Journal of Molecular and Cellular Cardiology

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Spinal muscular atrophy (SMA) is a leading genetic cause of infantile death. Loss of a gene called Survival Motor Neuron 1 (SMN1) and, as a result, reduced levels of the Survival Motor Neuron (SMN) protein leads to SMA development. SMA is characterized by the loss of functional motor neurons in the spinal cord. However, accumulating evidence suggest the contribution of other organs to the composite SMA phenotype and disease progression. A growing number of congenital heart defects have been identified in severe SMA patients. Consistent with the clinical cases, we have recently identified developmental and functional heart defects in two SMA mouse models, occurring at embryonic stage in a severe SMA model and shortly after birth in a less severe model (SMNΔ7). Our goal was to examine the late stage cardiac abnormalities in untreated SMNΔ7 mice and to determine whether gene replacement therapy restores cardiac structure/function in rescued SMNΔ7 model. To reveal the extent of the cardiac structural/functional repair in the rescued mice, we analyzed the heart of untreated and treated SMNΔ7 model using self-complementary Adeno-associated virus (serotype 9) expressing the full-length SMN cDNA. We examined the characteristics of the heart failure such as remodeling, fibrosis, oxidative stress, and vascular integrity in both groups. Our results clearly indicate that fibrosis, oxidative stress activation, vascular remodeling, and a significant decrease in the number of capillaries exist in the SMA heart. The cardiac structural defects were improved drastically in the rescued animals, however, the level of impairment was still significant compared to the age-matched wildtype littermates. Furthermore, functional analysis by in vivo cardiac magnetic resonance imaging (MRI) revealed that the heart of the treated SMA mice still exhibit functional defects. In conclusion, cardiac abnormalities are only partially rescued in post-birth treated SMA animals and these abnormalities may contribute to the premature death of vector-treated SMA animals with seemingly rescued motor function but an average life span of less than 70 days as reported in several studies.

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Cardiac Involvement in Werdnig-Hoffmann’s Spinal Muscular At rophy

Cited by 19 publications

References 11 publications

Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

Developmental and degenerative cardiac defects in the Taiwanese mouse model of severe spinal muscular atrophy

Partial restoration of cardio-vascular defects in a rescued severe model of spinal muscular atrophy

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