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Aim: To investigate the timing of type 1 myotonic dystrophy (DM1) diagnosis in parents of affected children and describe children's perinatal characteristics and developmental outcomes., Method: This was a descriptive case series of children with congenital myotonic dystrophy (CDM) and childhood-onset myotonic dystrophy (ChDM). Parental timing of DM1 diagnosis and the perinatal, motor, and cognitive outcomes of paediatric patients were recorded., Results: A total of 139 children followed by 12 highly specialized tertiary care neuromuscular centres in Italy and one tertiary neuromuscular centre in the USA were included: 105 children with CDM and 34 children with ChDM (mean age 8 years 8 months and 12 years 2 months respectively; 49 males and 17 males respectively). Seventy (50%) parents were diagnosed with adult-onset DM1 after the affected child was diagnosed. Only 12 (17%) of the 69 parents known to be affected had prenatal testing. Of the 105 children with CDM, 98% had maternally inherited CDM, 36% were born preterm, 83% required a stay in the neonatal intensive care unit for more than 48 hours, 84% and 79% had ambulation and speech delay, and 84% had an IQ lower than 70. Of the 34 children with ChDM, 59% had paternally inherited ChDM, 91% were born at term, and 36% had an IQ lower than 70., Interpretation: Delay in diagnosing DM1 affects family planning. The prenatal and perinatal outcomes of the affected offspring emphasize the need for proactive counselling as parents may be reluctant to conduct prenatal testing., (© 2024 The Author(s). Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Behçet's Disease (BD), also recognized as Behçet Syndrome, manifests uniquely in pediatric populations as Pediatric Behçet's Disease (PBD), characterized by multisystemic inflammatory symptoms including recurrent oral and genital aphthae, and diverse ocular, vascular, and neurological involvements. This review elucidates the prevalence, burden, and management strategies of headaches in children with PBD, focusing on both primary headaches, such as migraine and tension-type headaches, and secondary headaches linked to systemic disease manifestations. It explores the pathophysiological underpinnings specific to PBD-related headaches and discusses the intricate relationship between systemic inflammatory processes and neurological symptoms. By examining the literature from 2004 to 2024, this study highlights the high frequency of headache in PBD patients, underscoring its diagnostic and clinical significance. We aim to provide a detailed understanding of headache management in PBD, emphasizing tailored therapeutic strategies that address the unique challenges faced by this patient population. This review also underscores the importance of comprehensive clinical evaluations to optimize outcomes and mitigate long-term sequelae, proposing that awareness and understanding of headache in PBD can significantly enhance both diagnosis and management.

Background: Diaphragmatic sleep disordered breathing (dSDB) has been recently identified as sleep dysfunction secondary to diaphragmatic weakness in Duchenne muscular dystrophy (DMD). However, scoring criteria for the identification of dSDB are missing.This study aimed to define and validate dSDB scoring criteria and to evaluate whether dSDB severity correlates with respiratory progression in DMD., Methods: Scoring criteria for diaphragmatic apnoea (dA) and hypopnoeas (dH) have been defined by the authors considering the pattern observed on cardiorespiratory polygraphy (CR) and the dSDB pathophysiology.10 sleep professionals (physiologists, consultants) blinded to each other were involved in a two-round Delphi survey to rate each item of the proposed dSDB criteria (Likert scale 1-5) and to recognise dSDB among other SDB. The scorers' accuracy was tested against the authors' panel.Finally, CR previously conducted in DMD in clinical setting were rescored and diaphragmatic Apnoea-Hypopnoea Index (dAHI) was derived. Pulmonary function (forced vital capacity per cent of predicted, FVC%pred), overnight oxygen saturation (SpO2) and transcutaneous carbon dioxide (tcCO2) were correlated with dAHI., Results: After the second round of Delphi, raters deemed each item of dA and dH criteria as relevant as 4 or 5. The agreement with the panel in recognising dSDB was 81%, kappa 0.71, sensitivity 77% and specificity 85%.32 CRs from DMD patients were reviewed. dSDB was previously scored as obstructive. The dAHI negatively correlated with FVC%pred (r=-0.4; p<0.05). The total number of dA correlated with mean overnight tcCO2 (r 0.4; p<0.05)., Conclusions: dSDB is a newly defined sleep disorder that correlates with DMD progression. A prospective study to evaluate dSDB as a respiratory measure for DMD in clinical and research settings is planned., Competing Interests: Competing interests: FT reports participation to Scientific Advisory boards for Roche UK and teaching initiatives for Biogen UK, Avexis UK, Roche UK and Italy, Breas UK. MD, DR, AAZ and FA report no disclosures. FM reports participation in Scientific Advisory boards and teaching initiatives for Biogen, Roche and Novartis. He is a member of the Rare Disease Scientific Advisory Board for Pfizer. He is involved as an investigator in clinical trials from Novartis, Biogen and Roche. In addition, he is the principal investigator of the SMA REACH UK clinical network, partially funded by Biogen., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: Nusinersen has shown significant functional motor benefit in the milder types of spinal muscular atrophy (SMA). Less is known on the respiratory outcomes in patients with nusinersen-treated SMA. The aim of this study was to describe changes in respiratory function in pediatric patients with SMA type 2 and 3 on regular treatment with nusinersen within the iSMAc international cohort and to compare their trajectory with the natural history (NH) data published by the consortium in 2020., Methods: This is a 5-year retrospective observational study of pediatric SMA type 2 and nonambulant type 3 (age ≤18 years) treated with nusinersen. The primary objective was to compare the slopes of decline in forced vital capacity % predicted (FVC% pred.), FVC, and age when FVC dropped below 60% between the treated patients and a control group from the natural history cohort. Data on peak cough flow and the use of noninvasive ventilation (NIV) and cough assist were collected., Results: Data were available for 69 treated patients, 53 were SMA type 2 and 16 type 3. The mean (SD) age at first injection was 8.5 (3.2) and 9.7 (3.7) years, respectively. The median (interquartile range) treatment duration was 1 (0.7; 1.9) and 1.2 (0.9; 1.9) years, respectively. At the time of the first nusinersen injection, 24 of 52 (46%) patients with SMA type 2 and 2 of 16 (13%) patients with SMA type 3 were on NIV. Forty-three of 53 (81%) and 4 of 16 (25%) patients used cough device. FVC% pred. in treated patients with SMA type 2 declined annually by 2.3% vs 3.9% in NH ( p = 0.08) and in treated patients with type 3 by 2.6% vs 3.4% NH ( p = 0.59). Patients treated reached FVC <60% later than untreated (12.1 vs 10 years, p = 0.05). A higher percentage of treated vs untreated patients maintained FVC% pred. equal/above their baseline after 12 (65% vs 36%) and 24 (50% vs 24%) months, respectively. NIV use among treated did not significantly change throughout 1-year follow-up., Discussion: This study included the largest real-world cohort of pediatric patients with milder SMA types. The results suggest a positive role of nusinersen in delaying the respiratory decline in patients treated longer than 1 year when compared with natural history. Larger cohorts and longer observation are planned., Classification of Evidence: This study provided Class III evidence that nusinersen slows progression for patients with SMA types 2 and 3 compared with a natural history cohort., Competing Interests: F. Trucco reports participation to Scientific Advisory Boards for Roche UK and teaching initiatives for Biogen, Avexis, Roche, and BREAS. D. Ridout, I. Hughes, Z. Zolkipli-Cunningham, and M. Main report no disclosures. M. Scoto reports participation in Scientific Advisory Boards and teaching initiatives for Avexis, Biogen, and Roche. She is involved as an investigator in clinical trials from Avexis, Biogen, and Roche. In addition, she is the co-principal investigator of the SMA REACH UK clinical network, partially funded by Biogen and Roche. F. Muntoni reports participation in Scientific Advisory Boards and teaching initiatives for Biogen, Roche, and Novartis. He is member of the Rare Disease Scientific Advisory Board for Pfizer. He is involved as an investigator in clinical trials from Novartis, Biogen, and Roche. In addition, he is the principal investigator of the SMA REACH UK clinical network, partially funded by Biogen and Roche. E. Mercuri reports participation in Scientific Advisory Boards and teaching initiatives for Biogen, Roche, Scholar Rock, and Novartis. He is involved as an investigator in clinical trials from Novartis, Biogen, Scholar Rock, and Roche. In addition, he is the principal investigator of the Italian registry participating in iSMAc, partially funded by Biogen, Roche, and Novartis. R. Finkel reports participation in Medical and Scientific Advisory Boards on SMA topics with Novartis, Biogen, Ionis, Roche, Cure SMA, SMA Europe, SMA REACH UK, SMA Foundation, and MDA. Finkel participates as an investigator in SMA-related clinical trials sponsored or supported by Novartis, Biogen, Ionis, Roche, and Scholar Rock. Dr. D. De Vivo reports participation as a consultant in Medical and Scientific Advisory Boards and as an investigator with Novartis, Biogen, Ionis, Roche, PTC, Santhera, Scholar Rock, Sanofi, GliaPharm, Fulcrum Therapeutics, Sarepta, NS Pharma, SMA Foundation, Cure SMA, DoD, NIH, Glut1 Deficiency Foundation, and Hope for Children Research Foundation. B. Darras has served as an ad hoc Scientific Advisory Board member for Novartis, Biogen, Cytokinetics, Vertex, Genentech, Roche, and Sarepta; Steering Committee chair for Roche; and Data Safety Monitoring Board member for Amicus Inc. He has no financial interests in these companies. He has received research support from the NIH/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, the Spinal Muscular Atrophy Foundation, CureSMA, and Working on Walking Fund and has received grants from Ionis Pharmaceuticals, Inc, for the ENDEAR, CHERISH, CS2/CS12 studies; from Biogen for CS11; and from Cytokinetics, Sarepta Pharmaceuticals, PTC Therapeutics, Fibrogen, and Summit. O. Mayer reports participation in Advisory Boards for Roche, Biogen, and PTC Therapeutics. He is participating in SMA REACH and iSMAC, partially funded by Biogen. C. Bruno reports participation in Scientific Advisory Boards on SMA topics with Novartis, Biogen, and Roche and participates as a principal investigator in SMA-related clinical trials sponsored by Novartis, Biogen, Ionis, and Roche. S. Messina reports participation in Scientific Advisory Boards and teaching initiatives for Novartis, Biogen, and Roche. She is involved as an investigator in clinical trials from Novartis, Biogen, Scholar Rock, and Roche. M. Pane reports participation in Scientific Advisory Boards and teaching initiatives for Novartis and Biogen. V.A. Sansone provides intellectual support in Advisory Boards and teaching activities for Biogen, Santhera, Sarepta, PTC, Dyne, Triplet, and Novartis. A. D'Amico reports participation in Scientific Advisory Board for Novartis, Roche, and Novartis and teaching initiatives for Biogen. She is also involved as an investigator in clinical trials from Novartis, Biogen, and Roche. In addition, she is an investigator of the Italian registry participating in iSMAc, partially funded by Biogen. E.S. Bertini reports participation in Scientific Advisory Boards for Novartis, Roche, Novartis, and PTC and teaching initiatives for Biogen. He is also involved as an investigator in clinical trials from Novartis, Biogen, Roche, and Novartis. In addition, he is an investigator of the Italian registry participating in iSMAc, partially funded by Biogen. C. Marini-Bettolo reports participation in Scientific Advisory Boards and teaching initiatives for Novartis, Biogen, and Roche. She is involved as an investigator in clinical trials from Novartis. In addition, she is principal investigator for the UK SMA patient registry funded by SMA UK. A. Childs reports participation in Advisory Boards for Novartis, Roche, Biogen, Santhera, and PTC Therapeutics. She is principal investigator for clinical trials supported by Sarepta, Santhera, and PTC Therapeutics. She is participating in SMA REACH and iSMAC, partially funded by Biogen. M. Ong reports participation in Advisory Boards or received consultation fees for Novartis, Roche, Biogen, and CSL Behring. She is participating in SMA REACH and iSMAC, partially funded by Biogen. Dr. A. Mayhew reports participation in Scientific Advisory Boards and teaching initiatives for Biogen and Roche. She is involved as an evaluator at site and acts as an independent consultant to train evaluators in clinical trials from Novartis, Biogen, and Roche. In addition, she is the principal investigator at Newcastle for the SMA REACH UK clinical network, partially funded by Biogen and by SMA UK. J. Montes reports participation as a consultant and on Scientific Advisory Boards for Biogen, Ionis, Roche, and Scholar Rock. G. Coratti reports consultant activities for Novartis, Biogen, Roche, Biologix, and Genesis Pharma. She is involved as a clinical evaluator in clinical trials from Novartis, Biogen, Scholar Rock, and Roche. R. De Sanctis reports consultant activities for Biogen and Roche. He is involved as a clinical evaluator in clinical trials from Novartis, Biogen, Scholar Rock, and Roche. L. Servais reports consultancy/board attendance/lectures for Novartis, Biogen, Roche, Scholar Rock, and BioHaven. A. Majumdar reports participation in Advisory Boards for Novartis, Roche, Biogen, Santhera, and PTC Therapeutics. He is principal investigator for clinical trials supported by Wave Therapeutics. He is participating in SMA REACH and iSMAC, partially funded by Biogen. D. Parasuraman reports participation in Advisory Boards for Roche, Biogen, Sarepta and has had support from PTC Therapeutics. He is principal investigator for clinical trials supported by Roche. He is participating in SMA REACH and iSMAC, partially funded by Biogen. V. Gowda reports participation in Advisory Boards or received consultation fees for Novartis, Roche, Biogen, PTC therapeutics, Wave Life Sciences, Pfizer, and Sarepta Therapeutics. She is participating in SMA REACH and iSMAC, partially funded by Biogen. FT, CB, EB, AD, EM, and MP are members of the ERN NMD (European Reference Networks). Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (© 2024 American Academy of Neurology.)

Significant inconsistencies in respiratory care provision for Duchenne muscular dystrophy (DMD) are reported across different specialist neuromuscular centres in the UK. The absence of robust clinical evidence and expert consensus is a barrier to the implementation of care recommendations in public healthcare systems as is the need to increase awareness of key aspects of care for those living with DMD. Here, we provide evidenced-based and/or consensus-based best practice for the respiratory care of children and adults living with DMD in the UK, both as part of routine care and in an emergency., Methodology: Initiated by an expert working group of UK-based respiratory physicians (including British Thoracic Society (BTS) representatives), neuromuscular clinicians, physiotherapist and patient representatives, draft guidelines were created based on published evidence, current practice and expert opinion. After wider consultation with UK respiratory teams and neuromuscular services, consensus was achieved on these best practice recommendations for respiratory care in DMD., Result: The resulting recommendations are presented in the form of a flow chart for assessment and monitoring, with additional guidance and a separate chart setting out key considerations for emergency management. The recommendations have been endorsed by the BTS., Conclusions: These guidelines provide practical, reasoned recommendations for all those managing day-to-day and acute respiratory care in children and adults with DMD. The hope is that this will support patients and healthcare professionals in accessing high standards of care across the UK., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Obstructive sleep disordered breathing (SDB) is prevalent in patients with Spinal Muscular Atrophy (SMA) and possibly reduced by disease modifying treatment (DMT) such as nusinersen. We hypothesized that some obstructive events may in fact be pseudo-obstructive, reflecting the imbalance of chest wall weakness with preserved diaphragmatic function, rather than true upper airway obstruction. If confirmed, these events could represent SMA-specific outcome measures. We aimed to report on the pattern observed in respiratory polygraphies (PG) in paediatric patients with SMA type 2 resembling obstructive SDB. We defined pseudo-obstructive SDB and assessed its changes throughout disease progression., Methods: Retrospective review of 18 PG of 6 SMA type 2 patients naïve from DMT across 3 timepoints (first study, one-year follow-up, latest study)., Results: At first study patients aged 3-13 years. Four patients were self-ventilating in room air and one of them required non-invasive ventilation (NIV) after the 1-year study. Two patients were on NIV since the first study. The features of pseudo-obstructive SDB included a. paradoxical breathing before, after, and throughout the event, b. the absence of increased respiratory rate during the event, c. the absence of compensatory breath after the event with a return to baseline breathing. Pseudo-obstructive events were progressively more prevalent over time. The derived pseudo-obstructive AHI increased at each timepoint in all patients self-ventilating, whilst it dropped after NIV initiation/adjustments., Conclusions: Pseudo-obstructive SDB is prevalent in SMA type 2. Its number progresses along with the disease and is treatable with NIV. Prospective studies in larger SMA cohorts are planned., Competing Interests: Declaration of competing interest Dr. F. Trucco reports participation to Scientific Advisory boards for Roche UK and teaching initiatives for Biogen, Avexis, Roche, Breas. S. Dastagir and DR Hui-Leng Tan have nothing to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Spinal muscular atrophy (SMA) type 1 is a severe condition leading to early respiratory failure. Treatment options have become available, yet respiratory outcome measures in SMA type 1 are limited. The aim of this study was to assess the respiratory pattern in SMA type 1 patients via structured light plethysmography (SLP). SLP measures the thoraco-abdominal movements by projecting a light grid onto the anterior thoraco-abdominal surface., Methods: Cross-sectional study of consecutive children with SMA type 1. All children underwent motor assessment (CHOP-INTEND) and one-minute tidal breathing recording by SLP in supine position while self-ventilating in room air. The Respiratory rate , the abdominal vs. chest contribution to breath ( Relative Expired Abdomen% , Relative Expired Chest% ) and the severity of thoraco-abdominal paradox ( Phase Angle ) were acquired., Results: Nineteen patients were included, median (IQR) age 2.3 years (1.4-7.9). Their respiratory pattern captured via SLP showed a raised median (IQR) respiratory rate per age of 33.5 bpm (26.6-41.7), a prevalent abdominal contribution to tidal breathing with median (IQR) Relative Expired Abdomen 77% (68-90) vs. Chest 23% (10-32). Thoracoabdominal paradox was detected (median Phase Angle 48.70°) and its severity correlated negatively with CHOP-INTEND (r -0.8, p < 0.01)., Conclusions: SLP captured and quantified the respiratory features of infants and children with SMA type 1.

Bulbar and jaw muscles are impaired in patients with Spinal Muscular Atrophy (SMA) but the assessment of their severity and progression are limited by the lack of age-appropriate and disease-specific measures. We investigated mastication and swallowing in children and adults with SMA, sitters and walkers. In a 2-year multicentre cross-sectional prospective study, lip and tongue strength (Iowa Oral Performance Instrument), chewing and swallowing (Test of Masticating and Swallowing Solids), active mouth opening (aMMO) were compared to age-appropriate normative data. The perceived burden of oro-bulbar involvement (SMA-Health Index) was recorded. 78 patients were included, 45 children (median age 7.4 years),22 adults (median age 26.8 years) on nusinersen and 11 untreated (median age 32.7 years). Forty-three percent children had reduced mouth opening, 50% had prolonged total time to eat. These issues were more prominent in sitters than in walkers (p = 0.019, p = 0.014). Sixty-six percent needed increased swallows for bolus clearance. Nusinersen treated adults had median aMMO, tongue strength and total time at TOMASS values within normal range (z score: -1.40, -1.22, -1.32, respectively) whereas untreated adults had reduced aMMO (z score: -2.68) and tongue strength (z score: -2.20). Only a minority of children (2/17) and treated adults (5/21) reported burden in swallowing or mastication compared to all untreated adults (5/5). After 16 months, mastication and swallowing were stable in treated children and adults, whether sitters or walkers. The reported multimodal approach to assess oro-bulbar functions demonstrate that swallowing and mastication are impaired in SMA despite patients' perception. These results suggest a trend towards stabilization of oro-bulbar function in patients on long-term treatment with nusinersen., (© 2023. The Author(s).)

Introduction: Pyruvate dehydrogenase complex (PDH) deficiency (Online Mendelian Inheritance in Man # 312170) is a relatively common mitochondrial disorder, caused by mutations in the X-linked PDHA1 gene and presenting with a variable phenotypic spectrum, ranging from severe infantile encephalopathy to milder chronic neurological disorders.Isolated peripheral neuropathy as predominant clinical presentation is uncommon., Results: We report on a patient, now 21 years old, presenting at the age of 2 years with recurrent symmetric weakness as first symptom of a PDH deficiency. Neurophysiological evaluation proving a sensory-motor polyneuropathy with conduction blocks and presence of elevated cerebrospinal fluid proteins, suggested a chronic inflammatory demyelinating polyneuropathy. The evidence of high serum lactate and the alterations in oxidative metabolism in muscle biopsy pointed toward the final diagnosis. After starting nutritional supplements, no further episodes occurred. A hemizygous mutation in PDHA1 (p.Arg88Cys) was identified. This mutation has been previously described in five patients with a similar phenotype. A three-dimensional reconstruction demonstrated that mutations affecting this arginine destabilize the interactions between the subunits of the E1 complex., Conclusion: We summarize the clinical and genetic characteristics of one patient with PDH deficiency presenting isolated peripheral nervous system involvement. This study highlights that the diagnosis of PDH deficiency should be considered in children with unexplained peripheral neuropathy, even with features suggestive of acquired forms, especially in case of early onset and limited response to treatment. A simple analysis of lactic acid could help to target the diagnosis.In addition, we suggest that the residue Arg88 is the most frequently involved in this specific phenotype of PDH deficiency., Competing Interests: None declared., (Thieme. All rights reserved.)

Background and Objectives: The decline of respiratory function in Duchenne muscular dystrophy (DMD) is associated with sleep disordered breathing (SDB) and alteration of nocturnal gas exchange, first manifesting as nocturnal hypoventilation (NH). However, the correlation between the pulmonary function measured by spirometry (PFT) and the onset of SDB with or without NH is unclear. The aims of this study are to identify the prevalence and features of SDB and to investigate the relationship between lung function determined by forced vital capacity (FVC) and sleep abnormalities in a large pediatric DMD population., Methods: This was a retrospective, single-center cohort study. FVC% predicted (FVC%) was calculated using predicted equations from the Global Lung Function Initiative. NH was defined by transcutaneous (tc) CO2 &gt;50 mm Hg for &gt;25% of total sleep time (TST), borderline NH by a mean tcCO2 between 45 and 50 mm Hg or tcCO2&gt;50 mm Hg for ≤25% of TST, and clinically meaningful obstructive sleep apnea (OSA) by obstructive apnea-hypopnea index &gt;5. The sensitivity, specificity, and positive and negative predictive values of FVC &lt; 50% to indicate the presence of nocturnal hypoventilation were calculated., Results: One hundred thirty-four patients underwent 284 sleep studies and 1222 PFT. The mean (SD) age at the first and the last sleep study was 12.9 (2.7) and 14.3 (2.6) years, respectively. Borderline NH (n = 31) was detected in both ambulant and early-nonambulant participants, while 100% of NH cases (n = 14) were nonambulant. NH was detected in 4 of the 14 patients despite an FVC &gt;50%. Seventeen of the 26 patients with OSA presented with concomitant NH or borderline NH. FVC &lt;50% was associated with NH indicating a sensitivity and specificity of 73% and 86%, respectively. Positive and negative predictive values were 32% and 97%, respectively. PFT showed a nonlinear, sudden FVC% decline in 18% of cases., Discussion: FVC% &lt;50 was associated with NH in close to a third of patients. CO2 elevation can be associated with obstructive/pseudo-obstructive events and was also observed in early nonambulant cases or in the presence of FVC &gt;50%. These results are relevant for the clinical management of SDB., (© 2022 American Academy of Neurology.)

Aim: To correlate the North Star Ambulatory Assessment (NSAA) and timed rise from floor (TRF) recorded at age of expected peak with age at loss of ambulation (LOA) in Duchenne muscular dystrophy (DMD)., Method: Male children with DMD enrolled in the UK North Start Network database were included according to the following criteria: follow-up longer than 3 years, one NSAA record between 6 years and 7 years 6 months (baseline), at least one visit when older than 8 years. Data about corticosteroid treatment, LOA, genotype, NSAA, and TRF were analysed. Age at LOA among the different groups based on NSAA and TRF was determined by log-rank tests. Cox proportional hazard models were used for multivariable analysis., Results: A total of 293 patients from 13 different centres were included. Mean (SD) age at first and last visit was 5 years 6 months (1 year 2 months) and 12 years 8 months (2 years 11 months) (median follow-up 7 years 4 months). Higher NSAA and lower TRF at baseline were associated with older age at LOA (p<0.001). Patients scoring NSAA 32 to 34 had a probability of 0.61 of being ambulant when older than 13 years compared with 0.34 for those scoring 26 to 31. In multivariable analysis, NSAA, TRF, and corticosteroid daily regimen (vs intermittent) were all independently associated with outcome (p=0.01)., Interpretation: Higher functional abilities at peak are associated with older age at LOA in DMD. This information is important for counselling families. These baseline measures should also be considered when designing clinical trials., (© 2022 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Objective: Rapid implementation of home sleep studies during the first UK COVID-19 'lockdown'-completion rates, family feedback and factors that predict success., Design: We included all patients who had a sleep study conducted at home instead of as inpatient from 30 March 2020 to 30 June 2020. Studies with less than 4 hours of data for analysis were defined 'unsuccessful'., Results: 137 patients were included. 96 underwent home respiratory polygraphy (HRP), median age 5.5 years. 41 had oxycapnography (O 2 /CO 2 ), median age 5 years. 56% HRP and 83% O 2 /CO 2 were successful. A diagnosis of autism predicted a lower success rate (29%) as did age under 5 years., Conclusion: Switching studies rapidly from an inpatient to a home environment is possible, but there are several challenges that include a higher failure rate in younger children and those with neurodevelopmental disorders., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction/aims: Mutations amenable to skipping of specific exons have been associated with different motor progression in Duchenne muscular dystrophy (DMD). Less is known about their association with long-term respiratory function. In this study we investigated the features of respiratory progression in four DMD genotypes relevant in ongoing exon-skipping therapeutic strategies., Methods: This was a retrospective longitudinal study including DMD children followed by the UK NorthStar Network and international AFM Network centers (May 2003 to October 2020). We included boys amenable to skip exons 44, 45, 51, or 53, who were older than 5 years of age and ambulant at first recorded visit. Subjects who were corticosteroid-naive or enrolled in interventional clinical trials were excluded. The progression of respiratory function (absolute forced vital capacity [FVC] and calculated as percent predicted [FVC%]) was compared across the four subgroups (skip44, skip45, skip51, skip53)., Results: We included 142 boys in the study. Mean (standard deviation) age at first visit was 8.6 (2.5) years. Median follow-up was 3 (range, 0.3-8.3) years. In skip45 and skip51, FVC% declined linearly from the first recorded visit. From the age of 9 years, FVC% declined linearly in all genotypes. Skip44 had the slowest (2.7%/year) and skip51 the fastest (5.9%/year) annual FVC% decline. The absolute FVC increased progressively in skip44, skip45, and skip51. In skip53, FVC started declining from 14 years of age., Discussion: The progression of respiratory dysfunction follows different patterns for specific genotype categories. This information is valuable for prognosis and for the evaluation of exon-skipping therapies., (© 2021 Wiley Periodicals LLC.)

Disease course of feeding difficulties in spinal muscular atrophy type 2 is not well documented. Disease-modifying therapies rapidly change the trajectory of motor function and survival in spinal muscular atrophy, but effects on co-morbidities like bulbar function are unknown. We analysed data concerning feeding problems and their standard of care treatment in 146 patients with spinal muscular atrophy type 2. Data were collected from two separate cohorts: one single-centre retrospective chart review study from the United Kingdom (London), and one prospective questionnaire-based multicentre study from Italy. Cumulatively feeding difficulties were present in 88 patients (60%) in these 2 cohorts. Median age at onset of problems was 6.5years (range 0-16.5 years). Eighty-two patients (60%) showed periods of underweight according to age adjusted body mass index, and thirty-six patients (25%) showed malnourishment with a significant drop on their weight curves. Enteral feeding was indicated in 23 out of 72 patients in the UK cohort (32%) because of weight loss, oropharyngeal dysphagia or aspiration. Gastrostomy and its placement was generally well tolerated, uncomplicated in 96%, never reversed and performed without Nissen fundoplication in 66% of patients. After gastrostomy chest infections improved in 80% and nutritional status (e.g., Body Mass Index) in 84% of patients. These results show that feeding difficulties are a common problem in spinal muscular atrophy type 2. Treatment strategies should be tailor-made on the symptoms and needs of the individual patient., Competing Interests: Declaration of Competing Interest This work was supported by the SMA REACH UK (grant number 540606, supported by SMA UK and MDUK) and by the Italian Association of SMA Families (Famiglie SMA, 2015–2016 contribution) and Fondazione Telethon (Application GUP15014, 2015, Italy)., (Copyright © 2020. Published by Elsevier B.V.)

Objective: To describe the respiratory trajectories and their correlation with motor function in an international pediatric cohort of patients with type 2 and nonambulant type 3 spinal muscular atrophy (SMA)., Methods: This was an 8-year retrospective observational study of patients in the International SMA Consortium (iSMAc) natural history study. We retrieved anthropometrics, forced vital capacity (FVC) absolute, FVC percent predicted (FVC%P), and noninvasive ventilation (NIV) requirement. Hammersmith Functional Motor Scale (HFMS) and revised Performance of Upper Limb (RULM) scores were correlated with respiratory function. We excluded patients in interventional clinical trials and on nusinersen commercial therapy., Results: There were 437 patients with SMA: 348 with type 2 and 89 with nonambulant type 3. Mean age at first visit was 6.9 (±4.4) and 11.1 (±4) years. In SMA type 2, FVC%P declined by 4.2%/y from 5 to 13 years, followed by a slower decline (1.0%/y). In type 3, FVC%P declined by 6.3%/y between 8 and 13 years, followed by a slower decline (0.9%/y). Thirty-nine percent with SMA type 2% and 9% with type 3 required NIV at a median age 5.0 (1.8-16.6) and 15.1 (13.8-16.3) years. Eighty-four percent with SMA type 2% and 80% with type 3 had scoliosis; 54% and 46% required surgery, which did not significantly affect respiratory decline. FVC%P positively correlated with HFMS and RULM scores in both subtypes., Conclusions: In SMA type 2 and nonambulant type 3, lung function declines differently, with a common leveling after age 13 years. Lung and motor function correlated in both subtypes. Our data further define the milder SMA phenotypes and provide information to benchmark the long-term efficacy of new treatments for SMA., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Corticosteroids (CSs) have prolonged survival and respiratory function in boys with Duchenne muscular dystrophy (DMD) when compared with CSs-naïve boys., Research Question: The differential impact of frequently used CSs and their regimens on long-term (> 5 years) cardiorespiratory progression in children with DMD is unknown., Study Design and Methods: This was a retrospective longitudinal study including children with DMD followed at Dubowitz Neuromuscular Centre, Great Ormond Street Hospital London, England, from May 2000 to June 2017. Patients enrolled in any interventional clinical trials were excluded. We collected patients' anthropometrics and respiratory (FVC, FVC % predicted and absolute FVC, and noninvasive ventilation requirement [NIV]) and cardiac (left ventricular shortening function [LVFS%]) function. CSs-naïve patients had never received CSs. Patients who were treated with CSs took either deflazacort or prednisolone, daily or intermittently (10 days on/10 days off) for > 1 month. Average longitudinal models were fitted for yearly respiratory (FVC % predicted) and cardiac (LVFS%) progression. A time-to-event analysis to FVC % predicted < 50%, NIV start, and cardiomyopathy (LVFS% < 28%) was performed in CS-treated (daily and intermittent) vs CS-naïve patients., Results: There were 270 patients, with a mean age at baseline of 6.2 ± 2.3 years. The median follow-up time was 5.6 ± 3.5 years. At baseline, 263 patients were ambulant. Sixty-six patients were treated with CSs daily, 182 patients underwent CSs intermittent > 60% treatment, and 22 were CS-naïve patients. Yearly FVC % predicted declined similarly from 9 years (5.9% and 6.9% per year, respectively; P = .27) in the CSs-daily and CSs-intermittent groups. The CSs-daily group declined from a higher FVC % predicted than the CSs-intermittent group (P < .05), and both reached FVC % predicted < 50% and NIV requirement at a similar age, > 2 years later than the CS-naïve group. LVFS% declined by 0.53% per year in the CSs-treated group irrespective of the CSs regimen, significantly slower (P < .01) than the CSs-naïve group progressing by 1.17% per year. The age at cardiomyopathy was 16.6 years in the CSs-treated group (P < .05) irrespective of regimen and 13.9 years in the CSs-naïve group., Interpretation: CSs irrespective of the regimen significantly improved respiratory function and delayed NIV requirement and cardiomyopathy., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: Paediatric obstructive sleep apnoea is associated with systemic inflammation and co-morbidities. We assessed whether sleep disordered breathing (SDB) due to neuromuscular weakness was associated with elevated airway and systemic pro-inflammatory cytokines., Methods: Consecutive neuromuscular children (age 5-18years) underwent overnight full polysomnography and morning collection of serum and breath condensate, analysed for cytokines (Interleukin-10, Interleukin-6, Interleukin-1β, Tumour Necrosis Factorα, high-sensitivity C-Reactive Protein, Intercellular and Vascular Adhesion Molecules ICAM-1, VCAM-1). Cytokine levels were related to Oxygen desaturation index (ODI), desaturation>4%/h, and levels of transcutaneous carbon dioxide overnight (tcCO2≥6.7 kPa > 2% sleep)., Results: A total of 23 patients were included, median age 12.6 years (IQR 8.7-14.6). ODI>3/h was associated with higher breath and serum IL-6 (p = 0.02). Children with elevated CO 2 overnight had higher ICAM-1 and VCAM-1. CO 2 levels correlated with serum ICAM-1 (rs0.570, p = 0.026) and VCAM-1 (rs0.76, p = 0.001)., Discussion: SDB in neuromuscular children is associated with raised serum IL-6, VCAM-1, ICAM-1. This may predispose these children to future cardiovascular and other co-morbidities., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Soybean yield is limited primarily by abiotic constraints. No transgenic soybean with improved abiotic stress tolerance is commercially available. We transformed soybean plants with genetic constructs able to express the sunflower transcription factor HaHB4, which confers drought tolerance to Arabidopsis and wheat. One line (b10H) carrying the sunflower promoter was chosen among three independent lines because it exhibited the best performance in seed yield, and was evaluated in the greenhouse and in 27 field trials in different environments in Argentina. In greenhouse experiments, transgenic plants showed increased seed yield under stress conditions together with greater epicotyl diameter, larger xylem area, and increased water use efficiency compared with controls. They also exhibited enhanced seed yield in warm and dry field conditions. This response was accompanied by an increase in seed number that was not compensated by a decrease in individual seed weight. Transcriptome analysis of plants from a field trial with maximum difference in seed yield between genotypes indicated the induction of genes encoding redox and heat shock proteins in b10H. Collectively, our results indicate that soybeans transformed with HaHB4 are expected to have a reduced seed yield penalty when cultivated in warm and dry conditions, which constitute the best target environments for this technology., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

Objective: Respiratory insufficiency is a major complication of Duchenne muscular dystrophy (DMD). Its progression shows considerable interindividual variability, which has been less thoroughly characterized and understood than in skeletal muscle. We collected pulmonary function testing (PFT) data from a large retrospective cohort followed at Centers collaborating in the Italian DMD Network. Furthermore, we analyzed PFT associations with different DMD mutation types, and with genetic variants in SPP1, LTBP4, CD40, and ACTN3, known to modify skeletal muscle weakness in DMD. Genetic association findings were independently validated in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS)., Methods and Results: Generalized estimating equation analysis of 1852 PFTs from 327 Italian DMD patients, over an average follow-up time of 4.5 years, estimated that forced vital capacity (FVC) declined yearly by -4.2%, forced expiratory volume in 1 sec by -5.0%, and peak expiratory flow (PEF) by -2.9%. Glucocorticoid (GC) treatment was associated with higher values of all PFT measures (approximately + 15% across disease stages). Mutations situated 3' of DMD intron 44, thus predicted to alter the expression of short dystrophin isoforms, were associated with lower (approximately -6%) PFT values, a finding independently validated in the CINRG-DNHS. Deletions amenable to skipping of exon 51 and 53 were independently associated with worse PFT outcomes. A meta-analysis of the two cohorts identified detrimental effects of SPP1 rs28357094 and CD40 rs1883832 minor alleles on both FVC and PEF., Interpretation: These findings support GC efficacy in delaying respiratory insufficiency, and will be useful for the design and interpretation of clinical trials focused on respiratory endpoints in DMD., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: The McGill score is used to stratify severity of oximetry in children referred for investigation of obstructive sleep apnoea (OSA) to identify those with more severe disease and prioritize treatment. We hypothesized that its positive predictive value (PPV) and negative predictive value (NPV) in detecting OSA differs significantly between children with medical conditions and otherwise healthy children., Methods: We performed a two-year retrospective analysis of children referred for investigation of OSA who underwent a cardiorespiratory (CR) polygraphy study. McGill score was calculated from the oximetry trace blinded to polygraphy results. We looked at two definitions of OSA: Obstructive Apnoea Hypopnoea Index (oAHI) ≥1 and ≥ 5. McGill sensitivity, specificity, PPV and NPV were calculated. McGill score = 1 was considered normal or inconclusive, >1 abnormal., Results: We studied 312 children, 190 males (61%), median age 4.5 (2.4-7.9) years. 129 were otherwise healthy and 183 had associated medical conditions. The PPV of the McGill score was significantly lower in children with medical conditions than otherwise healthy children. The NPV was similar in both groups of children., Conclusions: The higher number of false positives in children with medical conditions may be due to non-obstructive causes such as central apnoeas. Children with underlying lung disease are also more likely to desaturate following a brief apnoea or hypopnoea. Children with co-morbidities who have an abnormal McGill score should not be assumed to have OSA and need more detailed sleep studies to determine the reason for the oxygen desaturations., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Research, production, and use of genetically modified (GM) crops have split the world between supporters and opponents. Up to now, this technology has been limited to the control of weeds and pests, whereas the second generation of GM crops is expected to assist farmers in abiotic stress tolerance or improved nutritional features. Aiming to analyze this subject holistically, in this presentation we address an advanced technology for drought-tolerant GM crops, upscaling from molecular details obtained in the laboratory to an extensive network of field trials as well as the impact of the introduction of this innovation into the market. Sunflower has divergent transcription factors, which could be key actors in the drought response orchestrating several signal transduction pathways, generating an improved performance to deal with water deficit. One of such factors, HaHB4, belongs to the homeodomain-leucine zipper family and was first introduced in Arabidopsis. Transformed plants had improved tolerance to water deficits, through the inhibition of ethylene sensitivity and not by stomata closure. Wheat and soybean plants expressing the HaHB4 gene were obtained and cropped across a wide range of growing conditions exhibiting enhanced adaptation to drought-prone environments, the most important constraint affecting crop yield worldwide. The performance of wheat and soybean, however, differed slightly across mentioned environments; whereas the improved behavior of GM wheat respect to controls was less dependent on the temperature regime (cool or warm), differences between GM and wild-type soybeans were remarkably larger in warmer compared to cooler conditions. In both species, these GM crops are good candidates to become market products in the near future. In anticipation of consumers' and other stakeholders' interest, spectral analyses of field crops have been conducted to differentiate these GM crops from wild type and commercial cultivars. In this paper, the potential impact of the release of such market products is discussed, considering the perspectives of different stakeholders., (Copyright © 2020 González, Rigalli, Miranda, Romagnoli, Ribichich, Trucco, Portapila, Otegui and Chan.)

Introduction: Tele-monitoring (TM) has proved effective in the home management of adult ventilator-dependent neuromuscular disease (NMD) patients. We aimed to evaluate a 2-year longitudinal multicentre TM trial designed for young ventilated NMD patients in terms of feasibility, home management of exacerbations and caregivers' burden., Methods: The TM trial protocol included patients' weekly scheduled overnight home-recording of SpO 2 , heart rate and ventilation and their transmission to each TM centre the following morning. Overnight data were reviewed by non-physicians and calls to families made to assess clinical condition. If clinical conditions (assessed by a scoring system) or overnight parameters worsened, either unscheduled transmissions or calls were activated and managed by non-physicians or medical team according to severity. Hospitalisations were compared with those of TM patients prior to TM start and with those of age-disease-severity-matched controls. Scores from the Caregiver Burden Inventory (CBI) questionnaire pre- and post-TM were compared., Results: Forty-eight patients were enrolled, 30 males, median age 16.4 years (interquartile range (IQR) 8.9-22.1), median ventilation/day 10.5 h (IQR 8-16). Exacerbations in TM patients did not differ (59 versus 53; p  = 0.15) from controls. Hospitalisations were significantly reduced in TM patients when compared with those prior to TM (11 versus 24, p  = 0.04) and to controls (11 versus 21, p  = 0.03). Median hospitalisation length was significantly lower in TM patients than controls (6 versus 7 days, p  = 0.03 ) . Caregivers satisfaction was excellent whereas no significant changes in CBI were seen (32.5 versus 35.5, p  = 0.06)., Discussion: TM was effective in improving the home management of respiratory exacerbations in young ventilated NMD patients and overall well tolerated.

Mandibular hypoplasia, deafness, and progeroid features, with concomitant lipodystrophy, define a multisystem disorder named MDPL syndrome. MDPL has been associated with heterozygous mutations in POLD1 gene resulting in loss of DNA polymerase δ activity. In this study, we report clinical, genetic, and cellular studies of a 13-year-old Pakistani girl, presenting growth retardation, sensorineural deafness, altered distribution of subcutaneous adipose tissue, and insulin resistance. We performed Sanger sequencing of POLD1 gene in the proband and the healthy parents. Fibroblasts obtained from dermal biopsy were evaluated for the specific hallmarks of cellular senescence and for their response to the DNA-induced damage. Patient carried the recurrent heterozygous de novo in frame deletion (c.1812&#95;1814delCTC, p.Ser605del ) within POLD1 gene, previously detected in 16 MDPL patients. In patient's fibroblasts we observed severe nuclear envelope anomalies, presence of micronuclei, accumulation of prelamin A, altered cell growth, and cellular senescence. In addition, we observed a persistence of DNA damage after cisplatin exposure, compared to control cells. In conclusion, the MDPL nuclear and cellular findings resemble features observed in other progeroid syndromes and familial lipodystrophies. Although further investigations will be necessary, these information could be used to establish targeted therapeutic approaches.

Study Objectives: Obstructive sleep apnoea (OSAS) in children with Down syndrome (DS) is now well recognized, but other forms of sleep disordered breathing (SDB) in this population are less well described. Anecdotally, respiratory support for SDB treatment in this population is not easily tolerated. We aimed to characterize the types of SDB in children with DS referred to a tertiary respiratory center and to assess the effectiveness and adherence to respiratory support., Methods: Retrospective study of DS patients <18 years old under follow-up at a tertiary respiratory center. Anthropometrics, comorbidities, sleep study results, and details of respiratory support were collected. Satisfactory adherence to oxygen (O 2 ), Continuous Positive Airway Pressure (CPAP), or bilevel noninvasive ventilation (NIV) was defined as use >4 h/night for >50% nights., Results: Sixty patients were included, median age 1.5 (0.7-5.3) years; 49 (82%) had congenital heart disease, 16 (27%) pulmonary hypertension, 28 (47%) gastroesophageal reflux, 38 (63%) swallowing impairment; 16/17 who underwent CT scanning had evidence of aspiration. Forty-two had SDB: 27 (61%) OSAS (10 mild, 5 moderate, 12 severe), 11 (25%) central apnoeas, 19 (32%) nocturnal hypoventilation. Twenty-six had baseline saturations <95%. Lower SpO 2 correlated with pulmonary hypertension (r 2  = 0.1, P = 0.04). Thirty-nine (65%) patients started respiratory support (14 O 2 , 18 CPAP, 7 NIV) and 22 (56%) have regularly used it. After a 1.9 years follow up 11/24 had satisfactory adherence to CPAP/NIV (average use 8 h/night)., Conclusions: Our results confirm the high prevalence of OSAS in children with DS. A significant number also have low baseline saturations, central apnoeas, and nocturnal hypoventilation. Contrary to popular belief, more than half of children with DS had satisfactory adherence to respiratory support., (© 2018 Wiley Periodicals, Inc.)

Mosquitoes are vectors of many human diseases. In particular, Aedes ægypti (Linnaeus) is the main vector for Chikungunya, Dengue, and Zika viruses in Latin America and it represents a global threat. Public health policies that aim at combating this vector require dependable and timely information, which is usually expensive to obtain with field campaigns. For this reason, several efforts have been done to use remote sensing due to its reduced cost. The present work includes the temporal modeling of the oviposition activity (measured weekly on 50 ovitraps in a north Argentinean city) of Aedes ægypti (Linnaeus), based on time series of data extracted from operational earth observation satellite images. We use are NDVI, NDWI, LST night, LST day and TRMM-GPM rain from 2012 to 2016 as predictive variables. In contrast to previous works which use linear models, we employ Machine Learning techniques using completely accessible open source toolkits. These models have the advantages of being non-parametric and capable of describing nonlinear relationships between variables. Specifically, in addition to two linear approaches, we assess a support vector machine, an artificial neural networks, a K-nearest neighbors and a decision tree regressor. Considerations are made on parameter tuning and the validation and training approach. The results are compared to linear models used in previous works with similar data sets for generating temporal predictive models. These new tools perform better than linear approaches, in particular nearest neighbor regression (KNNR) performs the best. These results provide better alternatives to be implemented operatively on the Argentine geospatial risk system that is running since 2012., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective Nocturnal hypoventilation (NH) is a complication of respiratory involvement in neuromuscular disorders (NMD) that can evolve into symptomatic daytime hypercapnia if not treated proactively with non-invasive ventilation. This study aimed to assess whether NH can be detected in the absence of other signs of nocturnal altered gas exchange. Methods We performed nocturnal transcutaneous coupled (tc) pCO 2 /SpO 2 monitoring in 46 consecutive cases of paediatric-onset NMD with a restrictive respiratory defect (forced vital capacity < 60%). Nocturnal hypoventilation was defined as tcPCO 2  > 50 mmHg for > 25% of recorded time, and hypoxemia as tcSpO 2  < 88% for > 5 minutes. Daytime symptoms and bicarbonate were recorded after overnight monitoring. Results Twenty-nine of 46 consecutive patients showed NH. Twenty-three patients did not have nocturnal hypoxemia and 18 were clinically asymptomatic. In 20 patients, PaCO 2 in daytime blood samples was normal. Finally, 13/29 patients with NH had isolated nocturnal hypercapnia without nocturnal hypoxia, clinical NH symptoms, or daytime hypercapnia. Conclusions Paediatric patients with NMD can develop NH in the absence of clinical symptoms or significant nocturnal desaturation. Therefore, monitoring of NH should be included among nocturnal respiratory assessments of these patients as an additional tool to determine when to commence non-invasive ventilation.

Mutations in the guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) gene encoding a key enzyme of the glycosylation pathway have been described in families with congenital (CMD) and limb girdle (LGMD) muscular dystrophy with reduced alpha-dystroglycan (α-DG) at muscle biopsy.Patients typically display a combined phenotype of muscular dystrophy, brain malformations, and generalized epilepsy. However, a wide spectrum of clinical severity has been described ranging from classical CMD presentation to children with mild, yet progressive LGMD with or without intellectual disability. Cardiac involvement, including a long QT interval and left ventricular dilatation, has also been described in four cases.Two missense mutations in GMPPB gene, one novel and one already reported, have been identified in a 21-year-old man presenting with elevated CK (38,650 UI/L; normal values <150 UI/L) without overt muscle weakness. Major complaints included limb myalgia, exercise intolerance, and several episodes of myoglobinuria consistent with a form of metabolic myopathy. Muscle biopsy showed only minimal alterations, whereas a marked reduction of glycosylated α-DG was evident.This case further expands the phenotypic spectrum of GMPPB mutations and highlights the importance of exhaustive molecular characterization of patients with reduced glycosylation of α-DG at muscle biopsy.

Despite all the advances in diagnosis and management of Duchenne muscular dystrophy over the past 50 years, the average age at diagnosis in most countries in the world around is still around 4-5 years. This retrospective study investigates the age at diagnosis in Italy in the past 10 years. We report findings from 384 boys who were diagnosed with DMD from 2005 to 2014. The mean age at first medical contact, which raised the suspicion of DMD, was 31 months. The mean age at diagnosis was 41 months. The finding that more frequently brought to suspect a DMD was the incidental finding of consistent elevated creatine kinase serum level detected during routine assessments in children undergoing general anesthesia or with intercurrent illness. This was followed by motor delay and signs of muscle weakness. Initial concerns were raised by general pediatricians (29%), specialists at tertiary centers (35%) or first level hospitals (23%). In children presenting incidental elevated creatine kinase values the diagnosis was achieved earlier than in children presenting a developmental delay. The mean age at diagnosis in our cohort was about 10-12 months lower than that reported in other countries., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant inherited disorder characterized by selective weakness of face and upper arms and girdle. Respiratory involvement in FSHD has been described mainly in the most severely affected patients. In this work we tested the respiratory function by spirometry in 12 patients affected by FSHD with onset before 18 years. Spirometry results were correlated with motor involvement and compared to aged matched group of Becker patients. Of note FSHD patients present a peculiar pattern characterized by a flat shape in flow-volume loop. Respiratory volumes correlate with clinical severity and expiratory phase is specifically affected in comparison to other muscular dystrophies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Female carriers of Duchenne muscular dystrophy (DMD), although usually asymptomatic, develop muscle weakness up to 17% of the time, and a third present cardiac abnormalities or cognitive impairment. Clinical features of DMD carriers during childhood are poorly known., Patients: We describe a cohort of pediatric DMD carriers, providing clinical, genetic, and histopathologic features, with a mean follow-up of 7 years., Results: Fifteen females with a DMD mutation (age range 5 to 18 years) were included. Seven patients (46%) presented with clinically evident symptoms and signs such as limb girdle weakness, abnormal gait, and exercise intolerance. The other eight patients (53%) were evaluated because of an incidental finding of elevated level of creatine kinase. Creatine kinase level was elevated in all, ranging from 392 to 13,000 U/L. Calf hypertrophy was observed in eight patients (53%). No patient developed respiratory or cardiac involvement. The most frequent complication was scoliosis (46%). Four patients (29%) also presented minor learning disabilities or behavioral problems. We performed electromyography in half of patients, showing myopathic pattern in four (53%). Muscle biopsy revealed a mosaic reduction of dystrophin in nine available cases. DMD gene mutations were mostly deletions (71%), resulting in loss of reading frame in five patients (36%). The three patients who experienced the most severe disease course were affected either by a nonsense or frameshift mutation., Conclusions: Our analysis suggests that DMD gene mutations may be suspected in a female child with persistently elevated levels of creatine kinase. Evidence of scoliosis, calf hypertrophy, or myopathic pattern at electromyography may also be helpful, and muscle biopsy is always indicative. DMD carriers should be followed for subtle orthopedic and psychiatric complications during childhood., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Mitochondrial disorders are a heterogeneous group of diseases sharing a defect of the oxidative phosphorylation system. Point mutations in the mitochondrial DNA are a common cause of mitochondrial disorders and frequently affect the sequences encoding mitochondrial transfer RNAs. The m.3271T>C mutation in the mitochondrial tRNA(Leu(UUR)) is traditionally reported in patients with clinical features of the mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome and in mitochondrial diabetes. Here we describe the clinical, pathological, and molecular features of an Italian child and his asymptomatic mother, carrying the m.3271T>C mutation in the mitochondrial tRNA(Leu(UUR)) gene, in association with an unusual clinical phenotype dominated by hypertrophic cardiomyopathy and provide review literature of cases with this mutation. To the best of our knowledge, there are no reports describing the association of this mutation with cardiomyopathy, and our cases suggest that the m.3271T>C mutation has to be taken into account in the diagnostic approach of maternally inherited cardiomyopathies., (Copyright © 2015. Published by Elsevier Inc.)

Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) is a novel mitochondrial disease caused by mutations in EARS2, which encodes the mitochondrial glutamyl-tRNA synthetase (mtGluRS). A distinctive brain MRI pattern is the hallmark of the disease.A 6-year-old boy presented at 3 months with feeding difficulties and muscle hypotonia. Brain MRI, at 8 months, showed hyperintensity of the deep cerebral and cerebellar white matter, thalamus, basal ganglia, brainstem, and thin corpus callosum. From the second year of life onward, the child reported global clinical improvement, parallel to partial resolution of brain MRI pattern. However, the last neuroimaging assessment revealed novel lesions within the left caudate and pallidum nuclei. DNA genomic sequencing analysis identified a novel EARS2 mutation.This case expands the clinical and neuroradiological phenotype of LTBL presenting intermediate clinical manifestations between the severe and milder forms of the disease and previously unreported brain MRI features.

We report a 14-year-old-boy with markedly elevated serum creatine kinase (CK) levels, in whom massive triglyceride storage was found in peripheral blood leukocytes and in muscle biopsy. Sequencing PNPLA2, the gene encoding the adipose triglyceride lipase (ATGL) and responsible for the neutral lipid storage disease with myopathy (NLSDM), we identified two heterozygous mutations, including a previously reported nonsense and a novel missense mutation in the patatin domain of the gene. Lipid storage myopathy can be clinically silent in childhood and presenting only with hyperCKemia., (Copyright © 2012 Elsevier Inc. All rights reserved.)

*Amaranthus tuberculatus represents one of the most dramatic cases of weed invasion documented in the midwestern USA. The species is infamous for evolving resistance to multiple herbicides, and predicting whether these resistances may be transferred to widespread weeds of the Amaranthus hybridus aggregate is a matter of epidemiological concern. Here, we explore the patterns of genetic exchange between Amaranthus tuberculatus and A. hybridus in an effort to understand whether allele introgression occurs throughout the genome and if fecundity penalties are associated with genetic exchange. *We evaluated 192 homoploid BC(1)s at 197 amplified fragment length polymorphism (AFLP) loci, as well as two loci associated with herbicide resistance: ALS and PPO. We also assessed the fecundity of each genotype by evaluation of seed production or pollen development. *It was discovered that genetic exchange between the species is unidirectional. Whereas A. hybridus alleles transfer with little or no penalty to A. tuberculatus, the reciprocal exchange is significantly distorted and potentially of limited evolutionary consequence. *Our previous hypothesis suggesting unidirectional introgression at ALS owing to circumstantial linkage is now modified to account for the more generalized distortion of genetic exchange observed in this study.

The synthesis and potent antiprotozoal activity of 14-hydroxylunularin, a natural hydroxybibenzyl bryophyte constituent is reported. 14-hydroxylunularin was highly active in vitro assays against culture and intracellular forms of Leishmania spp. and Trypanosoma. cruzi, in absence of cytotoxicity against mammalian cells. Preliminary structure-activity relationship studies showed that the reported bioactivity depends on hybridization at the carbon-carbon bridge, position and number of free hydroxy group on the aromatic rings. The reported results were also in agreement with the in silico prediction using Non-Stochastic Quadratic Fingerprints-based algorithms. The same compound also showed antiprotozoal activity in Leishmania spp. infected mice by oral and subcutaneous administration routes, with an optimal treatment of a daily subcutaneous administration of 10 mg/kg of body weight for 15 days. This study suggested that 14-hydroxylunularin may be chosen as a new candidate in the development of leishmanicidal therapy.

We describe the clinical features, muscle pathology features, and molecular studies of seven patients with Chanarin-Dorfman syndrome (CDS) or neutral lipid storage disease and ichthyosis (NLSDI), a multisystem triglyceride storage disease with massive accumulation of lipid droplets in muscle fibers. All patients presented with congenital ichthyosiform erythroderma, cytoplasmic lipid droplets in blood cells, mild to severe hepatomegaly, and increased serum CK levels and liver enzymes. Three patients showed muscle symptoms and three had steathorrea. Molecular analysis identified five mutations, three of which are novel. These findings expand the clinical and mutational spectrum and underline the genetic heterogeneity of this disease.

Herbicide resistance is an evolutionary event resulting from intense herbicide selection over genetically diverse weed populations. In South America, orchard, cereal and legume cropping systems show a strong dependence on glyphosate to control weeds. The goal of this report is to review the current knowledge on cases of evolved glyphosate-resistant weeds in South American agriculture. The first reports of glyphosate resistance include populations of highly diverse taxa (Lolium multiflorum Lam., Conyza bonariensis L., C. canadensis L.). In all instances, resistance evolution followed intense glyphosate use in fruit fields of Chile and Brazil. In fruit orchards from Colombia, Parthenium hysterophorus L. has shown the ability to withstand high glyphosate rates. The recent appearance of glyphosate-resistant Sorghum halepense L. and Euphorbia heterophylla L. in glyphosate-resistant soybean fields of Argentina and Brazil, respectively, is of major concern. The evolution of glyphosate resistance has clearly taken place in those agroecosystems where glyphosate exerts a strong and continuous selection pressure on weeds. The massive adoption of no-till practices together with the utilization of glyphosate-resistant soybean crops are factors encouraging increase in glyphosate use. This phenomenon has been more evident in Argentina and Brazil. The exclusive reliance on glyphosate as the main tool for weed management results in agroecosystems biologically more prone to glyphosate resistance evolution., (Copyright (c) 2007 Society of Chemical Industry.)

Drugs that target mitotic spindle proteins have been proven useful for tackling tumor growth. Eg5, a kinesin-5 family member, represents a potential target, since its inhibition leads to prolonged mitotic arrest through the activation of the mitotic checkpoint and apoptotic cell death. Monastrol, a specific dihydropyrimidine inhibitor of Eg5, shows stereo-specificity, since predominantly the (S)-, but not the (R)-, enantiomer has been shown to be the biologically active compound in vitro and in cell-based assays. Here, we solved the crystal structure (2.7A) of the complex between human Eg5 and a new keto derivative of monastrol (named mon-97), a potent antimitotic inhibitor. Surprisingly, we identified the (R)-enantiomer bound in the active site, and not, as for monastrol, the (S)-enantiomer. The absolute configuration of this more active (R)-enantiomer has been unambiguously determined via chemical correlation and x-ray analysis. Unexpectedly, both the R- and the S-forms inhibit Eg5 ATPase activity with IC(50) values of 110 and 520 nM (basal assays) and 150 nm and 650 nm (microtubule-stimulated assays), respectively. However, the difference was large enough for the protein to select the (R)- over the (S)-enantiomer. Taken together, these results show that in this new monastrol family, both (R)- and (S)-enantiomers can be active as Eg5 inhibitors. This considerably broadens the alternatives for rational drug design.

Acetolactate synthase (ALS) catalyzes the first common step in the biosynthesis of branched-chain amino acids in plants and is the target of several herbicides. ALS inhibitors have enjoyed popularity as herbicides due to numerous attributes, although their current adequacy in weed control programs is hampered by herbicide resistance. Most cases of ALS-inhibitor resistance have resulted from selection of an altered target site. The study herein reports on an alanine by threonine amino acid substitution at position 122 of ALS as the basis for imidazolinone-specific resistance in an A. hybridus population from Illinois. In vitro inhibition of enzymatic activity (I(50)) required 1000-fold greater concentration of imazethapyr in the resistant population compared with a susceptible control. This mutation represents the second ALS alteration associated with herbicide resistance in a natural A. hybridus population.

Several studies in vitro and in vivo suggest that the nitric oxide (NO) production is impaired in diabetes mellitus. Reduced levels of NO could contribute to vascular alteration facilitating platelet-vascular wall interaction, adhesion of monocytes to endothelium, vascular smooth muscle proliferation and by decreasing endothelium-dependent vasodilation. In this study we evaluated the activity of the constitutive nitric oxide synthase (cNOS) in platelets of patients with insulin-dependent diabetes mellitus (IDDM) and with non-insulin-dependent diabetes mellitus (NIDDM). When compared to that of normal subjects, cNOS activity is significantly lower in patients with IDDM and with NIDDM (1.57 +/- 0.25 vs. 0.66 +/- 0.10 fmol/min/10(9) PLTs and 1.57 +/- 0.25 vs. 0.67 +/- 0.08, respectively; p<0.005). These data demonstrate that the platelet cNOS activity is decreased in diabetes mellitus.