Type 0 Spinal Muscular Atrophy: Further Delineation of Prenatal and Postnatal Features in 16 Patients

Grotto, Sarah; Cuisset, Jean‐Marie; Marret, Stéphane; Drunat, Séverine; Faure, Patricia; Audebert‐Bellanger, Séverine; Desguerre, Isabelle; Flurin, V.; Grebille, Anne-Gaëlle; Guerrot, Anne‐Marie; Journel, Hubert; Morin, Gilles; Plessis, Ghislaine; Renolleau, Sylvain; Roume, J.; Simon‐Bouy, Brigitte; Touraine, Renaud; Willems, Marjolaine; Frébourg, Thierry; Verspyck, É.; Saugier-Veber, Pascale

doi:10.3233/jnd-160177

Cited by 68 publications

(79 citation statements)

References 49 publications

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“…; Grotto et al. ). Taken together, thinning of the walls and enlargement of the ventricles in the SMA heart is strikingly similar to dilated cardiomyopathy (DCM), where the heart becomes enlarged and cannot pump blood efficiently, evidenced by blood pooling.…”

Section: Discussionmentioning

confidence: 97%

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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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Section: Discussionmentioning

confidence: 97%

“…; Grotto et al. ). Together these findings do not immediately suggest a common or consistent aetiology.…”

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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“…Congenital fractures of long bones have been reported in some perinatal‐manifesting neuromuscular diseases, such as SMA and primary myopathies . These fractures are rare and are attributed to fetal akinesia or hypokinesia, where the decrease of mechanical use affects bone development .…”

Section: Discussionmentioning

confidence: 99%

The new neuromuscular disease related with defects in the ASC‐1 complex: report of a second case confirms ASCC1 involvement

et al. 2017

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Next-generation sequencing technology aided the identification of the underlying genetic cause in a female newborn with a severe neuromuscular disorder. The patient presented generalized hypotonia, congenital bone fractures, lack of spontaneous movements and poor respiratory effort. She died within the first days of life. Karyotyping and screening for several genes related with neuromuscular diseases all tested negative. A male sibling was subsequently born with the same clinical presentation. Whole-exome sequencing was performed with variant filtering assuming a recessive disease model. Analysis focused on genes known to be related firstly with congenital myopathies, extended to muscle diseases and finally to other neuromuscular disorders. No disease-causing variants were identified. A similar disorder was described in patients with recessive variants in two genes: TRIP4 (three families) and ASCC1 (one family), both encoding subunits of the nuclear activating signal cointegrator 1 (ASC-1) complex. Our patient was also found to have a homozygous frameshift variant (c.157dupG, p.Glu53Glyfs*19) in ASCC1 , thereby representing the second known case. This confirms ASCC1 involvement in a severe neuromuscular disease lying within the spinal muscular atrophy or primary muscle disease spectra.

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“…ANN NEUROL 2019;86:458-462 S pinal muscular atrophy (SMA) is characterized by loss of lower motor neurons in the spinal cord and somatic motor nuclei in the brainstem, leading to progressive proximal weakness. 5 Their clinical manifestations are beyond the neuromuscular phenotype and include congenital heart defects, dysautonomia with bradycardia, arthrogryposis, vascular necrosis, and craniofacial muscle involvement, 5 which support that severe extreme SMA phenotypes should be considered in the context of a multiorgan disease. 1 The incidence rate is 1 in 6,000 to 11,000 live births, with a high frequency of carriers depending on the population (1:20, 1:40, or 1:67 individuals).…”

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confidence: 99%

“…2 SMA represents a continuous spectrum of muscular weakness ranging from compromised neonates to adults with minimal manifestations and has been classified clinically into 3 main types based on the age of onset and the maximal function achieved. 5 Involvement of the central nervous system is poorly documented in patients with SMA. 4 Most of these latter patients die in the first weeks of life.…”

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confidence: 99%

Severe brain involvement in 5q spinal muscular atrophy type 0

Mendonça

Rocha²,

Lozano-Arango

et al. 2019

Annals of Neurology

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Type 0 Spinal Muscular Atrophy: Further Delineation of Prenatal and Postnatal Features in 16 Patients

Cited by 68 publications

References 49 publications

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

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

The new neuromuscular disease related with defects in the ASC‐1 complex: report of a second case confirms ASCC1 involvement

Severe brain involvement in 5q spinal muscular atrophy type 0

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