Microvasculopathy in spinal muscular atrophy is driven by a reversible autonomous endothelial cell defect

Zhou, Haïyan; Hong, Ying; Scoto, Mariacristina; Thomson, Alison K.; Pead, Emma; MacGillivray, Tom; Hernandez‐Gerez, Elena; Catapano, Francesco; Meng, Jinhong; Zhang, Qiang; Hunter, Gillian; Shorrock, Hannah K.; Ng, Thomas K; Hamida, Abedallah; Sanson, M.; Baranello, Giovanni; Howell, Kevin; Gillingwater, Thomas H.; Brogan, Paul; Thompson, Dorothy; Parson, Simon H.; Muntoni, Francesco

doi:10.1172/jci153430

Cited by 5 publications

(2 citation statements)

References 85 publications

(119 reference statements)

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“…This would be particularly relevant for the newly aging demographics of treated SMA patients ( 10 , 13 ), and has implications for adverse drug reactions involving the liver, such as with gene therapy. Furthermore, these data add to accumulating evidence demonstrating cell-intrinsic defects in response to SMN depletion, including muscle ( 56 ), pancreas ( 57 ), Schwann cells ( 58 , 59 ), and endothelial cells ( 60 ).…”

Section: Discussionsupporting

confidence: 55%

Hepatocyte-intrinsic SMN deficiency drives metabolic dysfunction and liver steatosis in spinal muscular atrophy

Leow,

Ng,

Wang

et al. 2024

Journal of Clinical Investigation

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Spinal Muscular Atrophy (SMA) is typically characterized as a motor neuron disease, but extraneuronal phenotypes are present in almost every organ in severely affected patients and animal models. Extra-neuronal phenotypes were previously underappreciated as patients with severe SMA phenotypes usually died in infancy; however, with current treatments for motor neurons increasing patient lifespan, impaired function of peripheral organs may develop into significant future comorbidities and lead to new treatment-modified phenotypes. Fatty liver is seen in SMA animal models , but generalizability to patients and whether this is due to hepatocyteintrinsic Survival Motor Neuron (SMN) protein deficiency and/or subsequent to skeletal muscle denervation is unknown. If liver pathology in SMA is SMN-dependent and hepatocyteintrinsic, this suggests SMN repleting therapies must target extra-neuronal tissues and motor neurons for optimal patient outcome. Here we showed that fatty liver is present in SMA and that SMA patient-specific iHeps were susceptible to steatosis. Using proteomics, functional studies and CRISPR/Cas9 gene editing, we confirmed that fatty liver in SMA is a primary SMN-dependent hepatocyte-intrinsic liver defect associated with mitochondrial and other hepatic metabolism implications. These pathologies require monitoring and indicate need for systematic clinical surveillance and additional and/or combinatorial therapies to ensure continued SMA patient health.

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Section: Discussionsupporting

confidence: 55%

Hepatocyte-intrinsic SMN deficiency drives metabolic dysfunction and liver steatosis in spinal muscular atrophy

Leow,

Ng,

Wang

et al. 2024

Journal of Clinical Investigation

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“…There is conflicting evidence concerning whether Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infects neuronal cells, with some studies reporting neuronal invasion [ 10 ], while others report no evidence of direct infection [ 11 , 12 ]. Additional studies suggest that a diffuse microvasculopathy may ensue with endothelial compromise, micro-infarctions, subsequent micro-hemorrhages, and microglial conglomerates with innate immune activation [ 13 – 15 ]. Nonetheless, CNS manifestations could also arise from secondary effects, such as from respiratory distress, cardiovascular stress, sepsis, hypercoagulation, and host-mediated immune responses triggered by SARS-CoV-2 infection.…”

Section: Introductionmentioning

confidence: 99%

Long-term outcomes of hospitalized patients with SARS-CoV-2/COVID-19 with and without neurological involvement: 3-year follow-up assessment

Eligulashvili,

Gordon,

Lee

et al. 2024

PLoS Med

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Background Acute neurological manifestation is a common complication of acute Coronavirus Disease 2019 (COVID-19) disease. This retrospective cohort study investigated the 3-year outcomes of patients with and without significant neurological manifestations during initial COVID-19 hospitalization. Methods and findings Patients hospitalized for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection between 03/01/2020 and 4/16/2020 in the Montefiore Health System in the Bronx, an epicenter of the early pandemic, were included. Follow-up data was captured up to 01/23/2023 (3 years post-COVID-19). This cohort consisted of 414 patients with COVID-19 with significant neurological manifestations and 1,199 propensity-matched patients (for age and COVID-19 severity score) with COVID-19 without neurological manifestations. Neurological involvement during the acute phase included acute stroke, new or recrudescent seizures, anatomic brain lesions, presence of altered mentation with evidence for impaired cognition or arousal, and neuro-COVID-19 complex (headache, anosmia, ageusia, chemesthesis, vertigo, presyncope, paresthesias, cranial nerve abnormalities, ataxia, dysautonomia, and skeletal muscle injury with normal orientation and arousal signs). There were no significant group differences in female sex composition (44.93% versus 48.21%, p = 0.249), ICU and IMV status, white, not Hispanic (6.52% versus 7.84%, p = 0.380), and Hispanic (33.57% versus 38.20%, p = 0.093), except black non-Hispanic (42.51% versus 36.03%, p = 0.019). Primary outcomes were mortality, stroke, heart attack, major adverse cardiovascular events (MACE), reinfection, and hospital readmission post-discharge. Secondary outcomes were neuroimaging findings (hemorrhage, active and prior stroke, mass effect, microhemorrhages, white matter changes, microvascular disease (MVD), and volume loss). More patients in the neurological cohort were discharged to acute rehabilitation (10.39% versus 3.34%, p < 0.001) or skilled nursing facilities (35.75% versus 25.35%, p < 0.001) and fewer to home (50.24% versus 66.64%, p < 0.001) than matched controls. Incidence of readmission for any reason (65.70% versus 60.72%, p = 0.036), stroke (6.28% versus 2.34%, p < 0.001), and MACE (20.53% versus 16.51%, p = 0.032) was higher in the neurological cohort post-discharge. Per Kaplan–Meier univariate survival curve analysis, such patients in the neurological cohort were more likely to die post-discharge compared to controls (hazard ratio: 2.346, (95% confidence interval (CI) [1.586, 3.470]; p < 0.001)). Across both cohorts, the major causes of death post-discharge were heart disease (13.79% neurological, 15.38% control), sepsis (8.63%, 17.58%), influenza and pneumonia (13.79%, 9.89%), COVID-19 (10.34%, 7.69%), and acute respiratory distress syndrome (ARDS) (10.34%, 6.59%). Factors associated with mortality after leaving the hospital involved the neurological cohort (odds ratio (OR): 1.802 (95% CI [1.237, 2.608]; p = 0.002)), discharge disposition (OR: 1.508 (95% CI [1.276, 1.775]; p < 0.001)), congestive heart failure (OR: 2.281 (95% CI [1.429, 3.593]; p < 0.001)), higher COVID-19 severity score (OR: 1.177 (95% CI [1.062, 1.304]; p = 0.002)), and older age (OR: 1.027 (95% CI [1.010, 1.044]; p = 0.002)). There were no group differences in radiological findings, except that the neurological cohort showed significantly more age-adjusted brain volume loss (p = 0.045) than controls. The study’s patient cohort was limited to patients infected with COVID-19 during the first wave of the pandemic, when hospitals were overburdened, vaccines were not yet available, and treatments were limited. Patient profiles might differ when interrogating subsequent waves. Conclusions Patients with COVID-19 with neurological manifestations had worse long-term outcomes compared to matched controls. These findings raise awareness and the need for closer monitoring and timely interventions for patients with COVID-19 with neurological manifestations, as their disease course involving initial neurological manifestations is associated with enhanced morbidity and mortality.

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Necrotizing Enterocolitis following Onasemnogene Abeparvovec for Spinal Muscular Atrophy: A Case Series

Gaillard,

Gu,

Neil Knierbein

2023

The Journal of Pediatrics

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Microvasculopathy in spinal muscular atrophy is driven by a reversible autonomous endothelial cell defect

Cited by 5 publications

References 85 publications

Hepatocyte-intrinsic SMN deficiency drives metabolic dysfunction and liver steatosis in spinal muscular atrophy

Hepatocyte-intrinsic SMN deficiency drives metabolic dysfunction and liver steatosis in spinal muscular atrophy

Long-term outcomes of hospitalized patients with SARS-CoV-2/COVID-19 with and without neurological involvement: 3-year follow-up assessment

Necrotizing Enterocolitis following Onasemnogene Abeparvovec for Spinal Muscular Atrophy: A Case Series

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