Spinal muscular atrophy with oculomotor palsy, epilepsy, and cerebellar hypoperfusion

Oka, Akira; Matsushita, Yuko; Sakakihara, Yoichi; Momose, Tomohiro; Yanaginasawa, Masayoshi

doi:10.1016/0887-8994(95)00058-n

Cited by 9 publications

(7 citation statements)

References 21 publications

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“…Finally, data presented here support sporadic reports in the literature detailing low-level cytopathological changes in the brain of human SMA patients (15,(29)(30)(31)(32)(33)(34)(35)(36), suggesting that pathological changes in the nervous system of human patients with the severest forms of SMA may extend beyond the neuromuscular system. Taken together, these findings suggest that detailed neuropathological and/or neuroimaging studies on human patients with the severest forms of SMA are now required to accurately determine the long-term effects of low SMN levels on human brain development.…”

Section: Discussionsupporting

confidence: 89%

SMN deficiency disrupts brain development in a mouse model of severe spinal muscular atrophy

Wishart

Huang

Murray

et al. 2010

Human Molecular Genetics

114

104

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Reduced expression of the survival motor neuron (SMN) gene causes the childhood motor neuron disease spinal muscular atrophy (SMA). Low levels of ubiquitously expressed SMN protein result in the degeneration of lower motor neurons, but it remains unclear whether other regions of the nervous system are also affected. Here we show that reduced levels of SMN lead to impaired perinatal brain development in a mouse model of severe SMA. Regionally selective changes in brain morphology were apparent in areas normally associated with higher SMN levels in the healthy postnatal brain, including the hippocampus, and were associated with decreased cell density, reduced cell proliferation and impaired hippocampal neurogenesis. A comparative proteomics analysis of the hippocampus from SMA and wild-type littermate mice revealed widespread modifications in expression levels of proteins regulating cellular proliferation, migration and development when SMN levels were reduced. This study reveals novel roles for SMN protein in brain development and maintenance and provides the first insights into cellular and molecular pathways disrupted in the brain in a severe form of SMA.

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Section: Discussionsupporting

confidence: 89%

SMN deficiency disrupts brain development in a mouse model of severe spinal muscular atrophy

Wishart

Huang

Murray

et al. 2010

Human Molecular Genetics

114

104

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“…Moreover, it has been recognized by neuropathologists for many years that specific regions of the brain such as the thalamus show neuronal loss in severe SMA patients, although this has been assumed to be subclinical (Shishikura et al, 1983; Yohannan et al, 1991; Oka et al, 1995; Hayashi et al, 1998; Araki et al, 2003; Ito et al, 2004). …”

Section: Is Motor Neuron Specificity In Sma Absolute or Relative?mentioning

confidence: 99%

The contribution of mouse models to understanding the pathogenesis of spinal muscular atrophy

Sleigh

Gillingwater

Talbot

2011

Disease Models &Amp; Mechanisms

111

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Spinal muscular atrophy (SMA), which is caused by inactivating mutations in the survival motor neuron 1 (SMN1) gene, is characterized by loss of lower motor neurons in the spinal cord. The gene encoding SMN is very highly conserved in evolution, allowing the disease to be modeled in a range of species. The similarities in anatomy and physiology to the human neuromuscular system, coupled with the ease of genetic manipulation, make the mouse the most suitable model for exploring the basic pathogenesis of motor neuron loss and for testing potential treatments. Therapies that increase SMN levels, either through direct viral delivery or by enhancing full-length SMN protein expression from the SMN1 paralog, SMN2, are approaching the translational stage of development. It is therefore timely to consider the role of mouse models in addressing aspects of disease pathogenesis that are most relevant to SMA therapy. Here, we review evidence suggesting that the apparent selective vulnerability of motor neurons to SMN deficiency is relative rather than absolute, signifying that therapies will need to be delivered systemically. We also consider evidence from mouse models suggesting that SMN has its predominant action on the neuromuscular system in early postnatal life, during a discrete phase of development. Data from these experiments suggest that the timing of therapy to increase SMN levels might be crucial. The extent to which SMN is required for the maintenance of motor neurons in later life and whether augmenting its levels could treat degenerative motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), requires further exploration.

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“…Four class IV studies reported on four patients with SMA type 1. A case report of a 7-year-old patient described diffuse cerebral atrophy, dilation of the 3rd and lateral ventricles, and significant white matter atrophy as well as a hypoplastic corpus callosum [ 15 ]. T2-weighted images revealed high intensity areas around the posterior horns of the lateral ventricles.…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, Ito et al reported high intensity areas around the posterior horns of the lateral ventricles based on T2-weighted and FLAIR (fluid attenuated inversion recovery) images and found high intensity areas in anterolateral portions of the bilateral thalami [ 16 ]. Moreover, lesions in the thalamus and cerebellum were observed in one patient [ 17 ]; however, the cerebellum and brainstem were normal in another patient [ 15 ]. No brain abnormalities were reported in another case of a newborn with type 1 SMA; yet postmortem examination revealed neurodegeneration in cortical and subcortical brain structures [ 18 ].…”

Section: Resultsmentioning

confidence: 99%

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Brain Magnetic Resonance Imaging (MRI) in Spinal Muscular Atrophy: A Scoping Review

Nancy

Andrea

Behlim

et al. 2023

JND

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Background: 5q Spinal Muscular Atrophy (SMA) is a prototypical lower motor neuron disorder. However, the characteristic early motor impairment raises the question on the scope of brain involvement with implications for further investigations on the brain as a potential therapeutic target. Objective: To review changes across the SMA clinical spectrum reported on brain magnetic resonance imaging (MRI). Methods: We conducted a scoping review of existing literature on PubMed and EMBASE. Two reviewers searched and retrieved relevant articles on magnetic resonance brain imaging in individuals with SMA censoring to April 2022. Full-text articles published in peer-reviewed journals or abstracts accepted to conferences in English and French were included. Results: Twelve articles were identified describing a total of 39 patients [age range: 11 days to 41 years old, type 0 (n = 5), type 1 (n = 4), type 2 (n = 2), type 3 (n = 22), type 4 (n = 6)]. All reported structural changes and did not explore other MRI modalities. In individuals with infantile onset SMA, cortical and subcortical brain abnormalities in white matter, basal ganglia, thalamus, hippocampus, and high intensity areas around lateral ventricles and thalami were reported over time. In individuals with later-onset SMA, reduced cerebellar and lobular volume were observed as well as increased grey matter density in motor areas. Conclusions: Limited data on brain imaging in SMA highlights both cortical and subcortical involvement in SMA, supporting the hypothesis that changes are not restricted to lower motor neuron pathways. Further studies are needed to determine the extent and prevalence of structural and functional brain changes across SMA types.

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Spinal muscular atrophy with oculomotor palsy, epilepsy, and cerebellar hypoperfusion

Cited by 9 publications

References 21 publications

SMN deficiency disrupts brain development in a mouse model of severe spinal muscular atrophy

SMN deficiency disrupts brain development in a mouse model of severe spinal muscular atrophy

The contribution of mouse models to understanding the pathogenesis of spinal muscular atrophy

Brain Magnetic Resonance Imaging (MRI) in Spinal Muscular Atrophy: A Scoping Review

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