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

Menke, Leonie A.; Poll-Thé, Bwee Tien; Clur, S. A.; Bilardo, C. M.; Wal, Allard C. van der; Lemmink, Henny H.; Cobben, Jan Maarten

doi:10.1002/ajmg.a.32233

Cited by 48 publications

(40 citation statements)

References 32 publications

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“…42,43,64 In humans, cardiac involvement has been described in the form of congenital malformations (predominantly SMA type I) and case reports of cardiomyopathy (predominantly SMA type III). 41,44,[65][66][67] The question remains whether our observations are due to autonomous nerve involvement or muscle development or affection. We found that motoneuron endplate size in the TVA muscle from affected late-stage animals was smaller than that in P0 animals reflecting progressive neurodegeneration.…”

Section: Discussionmentioning

confidence: 92%

“…The remaining 50% are healthy SMA carriers (Smn þ / À ; SMN2 tg/0 ) and used as controls. 30 Recent reports suggest that abnormal heart development in mice and human [41][42][43][44] as well as defects in skeletal muscle 45 and skeletal muscle vasculature 46 of mice are part of the phenotype and that SMA may be not a pure motoneuron disease. In addition, decreased levels of hepatic insulin-like growth factor binding protein acid labile subunit 18 possibly account for some of the dwarfism observed consistently across different SMA mouse models.…”

Section: Introductionmentioning

confidence: 99%

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Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585

et al. 2012

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Spinal muscular atrophy (SMA) is the leading genetic cause of early childhood death worldwide and no therapy is available today. Many drugs, especially histone deacetylase inhibitors (HDACi), increase SMN levels. As all HDACi tested so far only mildly ameliorate the SMA phenotype or are unsuitable for use in humans, there is still need to identify more potent drugs. Here, we assessed the therapeutic power of the pan-HDACi JNJ-26481585 for SMA, which is currently used in various clinical cancer trials. When administered for 64 h at 100 nM, JNJ-26481585 upregulated SMN levels in SMA fibroblast cell lines, including those from non-responders to valproic acid. Oral treatment of Taiwanese SMA mice and control littermates starting at P0 showed no overt extension of lifespan, despite mild improvements in motor abilities and weight progression. Many treated and untreated animals showed a very rapid decline or unexpected sudden death. We performed exploratory autopsy and histological assessment at different disease stages and found consistent abnormalities in the intestine, heart and lung and skeletal muscle vasculature of SMA animals, which were not prevented by JNJ-26481585 treatment. Interestingly, some of these features may be only indirectly caused by a-motoneuron function loss but may be major life-limiting factors in the course of disease. A better understanding of -primary or secondary -non-neuromuscular organ involvement in SMA patients may improve standard of care and may lead to reassessment of how to investigate SMA patients clinically.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585

et al. 2012

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“…Of therapeutic relevance, increasing the excitability of motor circuits through the pharmacological inhibition of K + channels ameliorated SMA in animal models [93]. Further evidence of the wider impact of SMN deficiency in disease pathogenesis comes from abnormalities in Schwann cells, skeletal muscle, heart, bone, pancreas, liver, hippocampus, thalamus, and the vascular system [94][95][96][97][98][99][100][101]. Controversy remains over the relative contribution of organ systems other than the motor neuron in SMN1-related SMA pathogenesis.…”

Section: Insights Into Smn1-related Sma Pathogenesismentioning

confidence: 99%

The Genetics of Spinal Muscular Atrophy: Progress and Challenges

2015

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Spinal muscular atrophies (SMAs) are a group of inherited disorders characterized by motor neuron loss in the spinal cord and lower brainstem, muscle weakness, and atrophy. The clinical and genetic phenotypes incorporate a wide spectrum that is differentiated based on age of onset, pattern of muscle involvement, and inheritance pattern. Over the past several years, rapid advances in genetic technology have accelerated the identification of causative genes and provided important advances in understanding the molecular and biological basis of SMA and insights into the selective vulnerability of the motor neuron. Common pathophysiological themes include defects in RNA metabolism and splicing, axonal transport, and motor neuron development and connectivity. Together these have revealed potential novel treatment strategies, and extensive efforts are being undertaken towards expedited therapeutics. While a number of promising therapies for SMA are emerging, defining therapeutic windows and developing sensitive and relevant biomarkers are critical to facilitate potential success in clinical trials. This review incorporates an overview of the clinical manifestations and genetics of SMA, and describes recent advances in the understanding of mechanisms of disease pathogenesis and development of novel treatment strategies.

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“…Additional clinical reports of individuals and siblings have also described an association between SMA type 1 disease severity and heart abnormalities [131][132][133]. It has thus been proposed that the combination of SMA and congenital heart defects may be exclusive to type 1 SMA [131].…”

Section: Cardiac Musclementioning

confidence: 99%

“…It has thus been proposed that the combination of SMA and congenital heart defects may be exclusive to type 1 SMA [131].…”

Section: Cardiac Musclementioning

confidence: 99%

The many faces of SMN: deciphering the function critical to spinal muscular atrophy pathogenesis

2010

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Spinal muscular atrophy (SMA) is the leading genetic cause of infant death, affecting 1 in 6000-10,000 live births. SMA is an autosomal recessive disorder characterized by the degeneration of a-motor neurons, and lower limb and proximal muscle weakness and wasting. SMA is the result of the deletion of or mutations in the survival motor neuron (SMN)1 gene. Currently, our understanding of how loss of the widely expressed SMN leads to the selective pathogenesis observed in SMA is limited. Here, we discuss the known nuclear and cytoplasmic functions of the SMN protein and how they relate to the SMA pathology reported in motor neurons, striated muscle and at neuromuscular junctions. While a vast amount of work in various cell and animal models has increased our knowledge of the many functions of the SMN protein, we have yet to come to a full understanding of which role(s) are central to SMA pathogenesis.Keywords n actin dynamics n neurodegeneration n preclinical models n snRNP assembly n spinal muscular atrophy n survival motor neuron ReviewFor reprint orders, please contact: reprints@futuremedicine.com

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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

Cited by 48 publications

References 32 publications

Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585

Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585

The Genetics of Spinal Muscular Atrophy: Progress and Challenges

The many faces of SMN: deciphering the function critical to spinal muscular atrophy pathogenesis

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