1-Deoxysphingolipids Lone, M.A.; Santos, T.; Alecu, I. ...
Biochimica et biophysica acta. Molecular and cell biology of lipids,
04/2019, Letnik:
1864, Številka:
4
Journal Article
Recenzirano
Sphingolipids (SLs) are fundamental components of eukaryotic cells. 1-Deoxysphingolipids differ structurally from canonical SLs as they lack the essential C1-OH group. Consequently, ...1-deoxysphingolipids cannot be converted to complex sphingolipids and are not degraded over the canonical catabolic pathways. Pathologically elevated 1-deoxySLs are involved in several disease conditions. Within this review, we will provide an up-to-date overview on the metabolic, physiological and pathophysiological aspects of this enigmatic class of “headless” sphingolipids.
•1-deoxysphingolipids are formed by serine –palmitoyltransferase through the alternate use of alanine instead of its regular substrate serine•1-deoxysphinganine induces mitochondrial fragmentation and dysfunction•1-deoxysphingolipids impair cytoskeletal dynamics and regulation•Pathologically elevated 1-deoxysphingolipids cause the hereditary neuropathy HSAN1•l-Serine supplementation was shown clinically to be an effective therapy in HSAN1
AP-4-associated hereditary spastic paraplegia (AP-4-HSP: SPG47, SPG50, SPG51, SPG52) is an emerging cause of childhood-onset hereditary spastic paraplegia and mimic of cerebral palsy. This study aims ...to define the spectrum of brain MRI findings in AP-4-HSP and to investigate radioclinical correlations.
We performed a systematic qualitative and quantitative analysis of 107 brain MRI studies from 76 individuals with genetically confirmed AP-4-HSP and correlation with clinical findings including surrogates of disease severity.
We define AP-4-HSP as a disorder of gray and white matter and demonstrate that abnormal myelination is common and that metrics of reduced white matter volume correlate with severity of motor symptoms. We identify a common diagnostic imaging signature consisting of (1) a thin splenium of the corpus callosum, (2) an absent or thin anterior commissure, (3) characteristic signal abnormalities of the forceps minor ("ears of the grizzly sign"), and (4) periventricular white matter abnormalities. The presence of 2 or more of these findings has a sensitivity of ∼99% for detecting AP-4-HSP; the combination of all 4 is found in ∼45% of cases. Compared to other HSPs with a thin corpus callosum, the absent anterior commissure appears to be specific to AP-4-HSP. Our analysis identified a subset of patients with polymicrogyria, underscoring the role of AP-4 in early brain development. These patients displayed a higher prevalence of seizures and status epilepticus, many at a young age.
Our findings define the MRI spectrum of AP-4-HSP, providing opportunities for early diagnosis, identification of individuals at risk for complications, and a window into the role of the AP-4 complex in brain development and neurodegeneration.
This study assessed the characteristics and the relationship between symptoms in any part of the 24-hour (24-h) day, physical activity level (PAL), and other clinical and functional outcomes in ...stable COPD patients.
Out of the 2162 patients enrolled in the SPACE study (The Symptoms and Physical Activity in COPD patients in Europe, clinicaltrials.gov NCT03031769), 406 (18.8%) were recruited from Romania. Here, we present the Romanian cohort results. Eligible patients were adults with age at least 40 years, confirmed diagnosis of stable COPD, current or former smokers with a smoking history of minimum 10 pack-years. The 24-h respiratory symptoms were assessed using Early Morning Symptoms of COPD Instrument (EMSCI), Evaluating Respiratory Symptoms in COPD (E-RS™: COPD) and Nighttime Symptoms of COPD Instrument (NiSCI). During clinical interview, patients self-evaluated PAL through Exercise as Vital Sign (EVS) and Yale Physical Activity Survey (YPAS). Physicians assessed PAL through their clinical judgment.
For each combination of 2 between the early morning (EM), daytime (DT) and night-time (NT) symptoms of the 24-h day, there was a significant association (p < 0.001 for each). All symptoms significantly correlated with exacerbation history (p < 0.001 for EM and NT, p=0.002 for DT), and number of severe exacerbations (p < 0.001 for DT, p=0.001 for EM and p=0.026 for NT, respectively). The 24-h symptoms correlated negatively and significantly with PAL (p < 0.001), irrespective of the assessment used. Self-reported PAL negatively correlated with dyspnea, symptom burden, severity of disease and number of exacerbations (p < 0.001). Patients spent an average (standard deviation) of 25.8 (21.0) hours/week performing physical activity. Physicians overestimated their patients' daily PAL.
A negative and significant correlation between the 24-h day symptoms and PAL was identified in stable COPD patients. Physicians need to routinely assess PAL using adequate tools and start educating inactive COPD patients to optimize their disease outcomes.
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