ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for similar to 40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6). Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot-Marie-Tooth disease type 2H on chromosome 8q13-21.1 was excluded by linkage analysis. Pedigrees originated in Italy, Brazil, Canada, England, Iran, and Japan. Interestingly, we identified 15 ALS5/SPG11/KIAA1840 mutations in 12 families (two sequence variants were never reported before, p.Gln198* and p.Pro2212fs*5). No large deletions/duplications were detected in these patients. The novel mutations seemed to be pathogenic since they co-segregated with the disease in all pedigrees and were absent in 300 unrelated controls. Furthermore, in silico analysis predicted their pathogenic effect. Our results indicate that ALS5/SPG11/KIAA1840 is the causative gene of a wide spectrum of clinical features, including autosomal recessive axonal Charcot-Marie-Tooth disease

Long-term miR-669a therapy alleviates chronic dilated cardiomyopathy in dystrophic mice.

BACKGROUND: Dilated cardiomyopathy (DCM) is a leading cause of chronic morbidity and mortality in muscular dystrophy (MD) patients. Current pharmacological treatments are not yet able to counteract chronic myocardial wastage, thus novel therapies are being intensely explored. MicroRNAs have been implicated as fine regulators of cardiomyopathic progression. Previously, miR-669a downregulation has been linked to the severe DCM progression displayed by Sgcb-null dystrophic mice. However, the impact of long-term overexpression of miR-669a on muscle structure and functionality of the dystrophic heart is yet unknown. METHODS AND RESULTS: Here, we demonstrate that intraventricular delivery of adeno-associated viral (AAV) vectors induces long-term (18 months) miR-669a overexpression and improves survival of Sgcb-null mice. Treated hearts display significant decrease in hypertrophic remodeling, fibrosis, and cardiomyocyte apoptosis. Moreover, miR-669a treatment increases sarcomere organization, reduces ventricular atrial natriuretic peptide (ANP) levels, and ameliorates gene/miRNA profile of DCM markers. Furthermore, long-term miR-669a overexpression significantly reduces adverse remodeling and enhances systolic fractional shortening of the left ventricle in treated dystrophic mice, without significant detrimental consequences on skeletal muscle wastage. CONCLUSIONS: Our findings provide the first evidence of long-term beneficial impact of AAV-mediated miRNA therapy in a transgenic model of severe, chronic MD-associated DCM

Spastic paraplegia type 4: A novel SPAST splice site donor mutation and expansion of the phenotype variability

Mutations in SPG4/SPAST are the most frequent molecular aetiology in the autosomal dominant form of hereditary spastic paraplegia (HSP). Loss-of-function and haploinsufficiency in SPAST have been demonstrated and the pure form of spastic paraplegia is a main clinical manifestation. This study is to explore the novel SPAST splice site donor variant, c.1004+3A>C, in seven patients from two families, one from Italy and the other from Japan. Exon 6 is skipped out by the variant, leading to a premature termination of translation, p.Gly290Trpfs*5. Measurement of SPAST transcripts in lymphocytes demonstrated a reduction through nonsense-mediated mRNA decay (NMD). Intra- and inter-familial phenotypic variations were observed, including age-at-onset, severity of spasticity, and scoliosis. Our study demonstrated further evidence of allelic heterogeneity in SPG4, dosage effects through NMD, and broad clinical features of the SPAST mutation

Book embeddings of k-framed graphs and k-map graphs

An embedding of a graph in a book, called book embedding, consists of a linear ordering of its vertices along the spine of the book and an assignment of its edges to the pages of the book, so that no two edges on the same page cross. The book thickness of a graph is the minimum number of pages over all its book embeddings. For planar graphs, a fundamental result is due to Yannakakis, who proposed an algorithm to compute embeddings of planar graphs in books with four pages. Our main contribution is a technique that generalizes this result to a much wider family of nonplanar graphs, namely to k-map graphs. In fact, our technique can deal with any nonplanar graph having a biconnected skeleton of crossingfree edges whose faces have bounded degree. We prove that this family of graphs has book thickness bounded in k, and as a corollary, we obtain the first constant upper bound for the book thickness of optimal 2-planar graphs. (c) 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons .org /licenses /by /4 .0/)

One-year outcomes of surgical aortic valve replacement: A single, high-volume center experience

Background. The introduction of transcatheter aortic valve replacement (AVR) mandates attention to outcomes after surgical AVR (SAVR). The aim of this study was to assess 1-year outcomes in a contemporary large cohort of patients undergoing AVR. Methods. Data from 520 patients who underwent isolated SAVR between October 2016 and April 2019 were prospectively collected. Results. The mean age of the study population was 72.8 ± 10.1 years and the average EuroSCORE II was 1.8 ± 1.5%. SAVR was performed using minimally invasive approaches (MI-AVR) in 306 patients (58.9%). However, the rate of MI-AVR considerably increased over the observational period from 47.9% to 86.7% (p<0.001). MI-AVR patients received rapid deployment valves in 40% of cases, minimally invasive extracorporeal circulation system in 34.4% and ultra fast track anesthetic management with table extubation in 38.2%. Overall 30-day mortality was 0.4% (n=2). The rates of postoperative stroke and atrioventricular block requiring pacemaker implantation were 0.6% (n=3) and 3.8% (n=20), respectively. At 1 year, the estimated survival, stroke and rehospitalization rates were 97.3%, 1% and 4.5%, respectively. Overall, the estimated incidence of the composite endpoint - death, stroke and rehospitalization - was 7%. Conclusions. Contemporary SAVR in a high-volume center yields excellent clinical outcomes with very low mortality and morbidity. In this setting, the extensive use of minimally invasive approaches combined with the modern techniques and technologies demonstrated to improve clinical outcomes and increase patient and family satisfaction

One-year outcomes of surgical aortic valve replacement: A single, high-volume center experience

Background. The introduction of transcatheter aortic valve replacement (AVR) mandates attention to outcomes after surgical AVR (SAVR). The aim of this study was to assess 1-year outcomes in a contemporary large cohort of patients undergoing AVR. Methods. Data from 520 patients who underwent isolated SAVR between October 2016 and April 2019 were prospectively collected. Results. The mean age of the study population was 72.8 \ub1 10.1 years and the average EuroSCORE II was 1.8 \ub1 1.5%. SAVR was performed using minimally invasive approaches (MI-AVR) in 306 patients (58.9%). However, the rate of MI-AVR considerably increased over the observational period from 47.9% to 86.7% (p&lt;0.001). MI-AVR patients received rapid deployment valves in 40% of cases, minimally invasive extracorporeal circulation system in 34.4% and ultra fast track anesthetic management with table extubation in 38.2%. Overall 30-day mortality was 0.4% (n=2). The rates of postoperative stroke and atrioventricular block requiring pacemaker implantation were 0.6% (n=3) and 3.8% (n=20), respectively. At 1 year, the estimated survival, stroke and rehospitalization rates were 97.3%, 1% and 4.5%, respectively. Overall, the estimated incidence of the composite endpoint - death, stroke and rehospitalization - was 7%. Conclusions. Contemporary SAVR in a high-volume center yields excellent clinical outcomes with very low mortality and morbidity. In this setting, the extensive use of minimally invasive approaches combined with the modern techniques and technologies demonstrated to improve clinical outcomes and increase patient and family satisfaction