International retrospective natural history study of LMNA-related congenital muscular dystrophy

Laminopaties; Distròfia muscular; Múscul estriatLaminopatías; Distrofia muscular; Músculo estriadoLaminopathies; Muscular dystrophy; Striated muscleMuscular dystrophies due to heterozygous pathogenic variants in LMNA gene cover a broad spectrum of clinical presentations and severity with an age of onset ranging from the neonatal period to adulthood. The natural history of these conditions is not well defined, particularly in patients with congenital or early onset who arguably present with the highest disease burden. Thus the definition of natural history endpoints along with clinically revelant outcome measures is essential to establishing both clinical care planning and clinical trial readiness for this patient group. We designed a large international cross-sectional retrospective natural history study of patients with genetically proven muscle laminopathy who presented with symptoms before two years of age intending to identify and characterize an optimal clinical trial cohort with pertinent motor, cardiac and respiratory endpoints. Quantitative statistics were used to evaluate associations between LMNA variants and distinct clinical events. The study included 151 patients (median age at symptom onset 0.9 years, range: 0.0–2.0). Age of onset and age of death were significantly lower in patients who never acquired independent ambulation compared to patients who achieved independent ambulation. Most of the patients acquired independent ambulation (n = 101, 66.9%), and subsequently lost this ability (n = 86; 85%). The age of ambulation acquisition (median: 1.2 years, range: 0.8–4.0) and age of ambulation loss (median: 7 years, range: 1.2–38.0) were significantly associated with the age of the first respiratory interventions and the first cardiac symptoms. Respiratory and gastrointestinal interventions occurred during first decade while cardiac interventions occurred later. Genotype–phenotype analysis showed that the most common mutation, p.Arg249Trp (20%), was significantly associated with a more severe disease course. This retrospective natural history study of early onset LMNA-related muscular dystrophy confirms the progressive nature of the disorder, initially involving motor symptoms prior to onset of other symptoms (respiratory, orthopaedic, cardiac and gastrointestinal). The study also identifies subgroups of patients with a range of long-term outcomes. Ambulatory status was an important mean of stratification along with the presence or absence of the p.Arg249Trp mutation. These categorizations will be important for future clinical trial cohorts. Finally, this study furthers our understanding of the progression of early onset LMNA-related muscular dystrophy and provides important insights into the anticipatory care needs of LMNA-related respiratory and cardiac manifestations.This work was supported by the AFM-Telethon, the Institut National de la Santé et de la Recherche Médicale (INSERM) and Sorbonne Université (R.B.Y., G.B.), intramural funds of the National Institute of Neurological Disorders and Stroke, National Institutes of Health (C.G.B.), Cure-CMD (A.R., G.B., R.B.Y.), The Andres Marcio Fondation (G.B., R.B.Y). and the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular and the Fashion Industries Guild Endowed Fellowship for the Undiagnosed Diseases Program (T.M.P)

Muscle imaging in laminopathies: Synthesis study identifies meaningful muscles for follow-up

Introduction: Particular fibroadipose infiltration patterns have been recently described by muscle imaging in congenital and later onset forms of LMNA-related muscular dystrophies (LMNA-RD). Methods: Scores for fibroadipose infiltration of 23 lower limb muscles in 34 patients with LMNA-RD were collected from heat maps of 2 previous studies. Scoring systems were homogenized. Relationships between muscle infiltration and disease duration and age of onset were modeled with random forests. Results: The pattern of infiltration differs according to disease duration but not to age of disease onset. The muscles whose progression best predicts disease duration were semitendinosus, biceps femoris long head, gluteus medius, and semimembranosus. Discussion: In LMNA-RD, our synthetic analysis of lower limb muscle infiltration did not find major differences between forms with different ages of onset but allowed the identification of muscles with characteristic infiltration during disease progression. Monitoring of these specific muscles by quantitative MRI may provide useful imaging biomarkers in LMNA-RD. Muscle Nerve 58:812-817, 201

Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome

Background: Genomics enables individualized diagnosis and treatment, but large challenges remain to functionally interpret rare variants. To date, only one causative variant has been described for KCNK9 imprinting syndrome (KIS). The genotypic and phenotypic spectrum of KIS has yet to be described and the precise mechanism of disease fully understood. Methods: This study discovers mechanisms underlying KCNK9 imprinting syndrome (KIS) by describing 15 novel KCNK9 alterations from 47 KIS-affected individuals. We use clinical genetics and computer-assisted facial phenotyping to describe the phenotypic spectrum of KIS. We then interrogate the functional effects of the variants in the encoded TASK3 channel using sequence-based analysis, 3D molecular mechanic and dynamic protein modeling, and in vitro electrophysiological and functional methodologies. Results: We describe the broader genetic and phenotypic variability for KIS in a cohort of individuals identifying an additional mutational hotspot at p.Arg131 and demonstrating the common features of this neurodevelopmental disorder to include motor and speech delay, intellectual disability, early feeding difficulties, muscular hypotonia, behavioral abnormalities, and dysmorphic features. The computational protein modeling and in vitro electrophysiological studies discover variability of the impact of KCNK9 variants on TASK3 channel function identifying variants causing gain and others causing loss of conductance. The most consistent functional impact of KCNK9 genetic variants, however, was altered channel regulation. Conclusions: This study extends our understanding of KIS mechanisms demonstrating its complex etiology including gain and loss of channel function and consistent loss of channel regulation. These data are rapidly applicable to diagnostic strategies, as KIS is not identifiable from clinical features alone and thus should be molecularly diagnosed. Furthermore, our data suggests unique therapeutic strategies may be needed to address the specific functional consequences of KCNK9 variation on channel function and regulation

Multiomic investigations in neuromuscular diseases

Les maladies neuromusculaires pédiatriques sont relatives à des atteintes du muscle, de la jonction neuromusculaire, du nerf périphérique et de la corne antérieure. La multitude de sites, ainsi que l'hétérogénéité et la rareté de ces troubles, rendent leur diagnostic et leur traitement difficiles. Par conséquent, les efforts conjoints des chercheurs et des cliniciens sont nécessaires pour diagnostiquer et traiter les patients avec plus de précision en utilisant des outils de la biologie des systèmes. Cette approche permet d’analyser différents types de biomolécules et permet, ainsi, d’étudier de manière exhaustive les changements moléculaires en tenant compte des caractéristiques individuelles du patient (contexte clinique, environnement…). Il y a actuellement une recherche très active dans le domaine des maladies neuromusculaires qui a abouti à la mise à disposition de traitements innovants nécessitant une meilleure identification et stratification des patients pour améliorer la prise en charge. Les objectifs de cette thèse sont d'appliquer les techniques omiques afin d’étudier les deux maladies neuromusculaires les plus courantes (l'amyotrophie spinale infantile (SMA) et la myopathie de Duchenne), d'explorer leurs mécanismes physiopathologiques, d'identifier des biomarqueurs de diagnostic potentiels et de mieux stratifier les patients. Le second objectif est d’identifier des biomarqueurs pour suivre la réponse au traitement dans la SMA. Une étude métabolomique sur des biopsies musculaires de patients atteints de la maladie de Duchenne a révélé des changements significatifs dans les métabolismes énergétique et phospholipidique. Par ailleurs, l’étude métabolomique des plasma et LCR de patients SMA a confirmé la présence d'un remodelage métabolique profond chez les patients SMA. De plus, nous avons démontré que ces altérations sont plus prononcées dans le phénotype sévère. L’étude protéomique de ces échantillons est en cours. En conclusion, les outils de biologie des systèmes sont pertinents pour l'étude des maladies neuromusculaires car ils permettent la découverte de biomarqueurs, la compréhension de la physiopathologie et l'identification de nouvelles cibles thérapeutiques.Pediatric neuromuscular disorders encompass all childhood onset diseases affecting the muscle, the neuromuscular junction, peripheral nerve, and the anterior horn cell. The multitude of sites as well as the heterogeneity and rarity of these disorders, make their diagnosis and treatment challenging. Therefore, joint efforts of researchers and clinicians are mandatory to diagnose and treat patients more accurately using integrative systems biology tools. Such appealing approach uses high-throughput technologies to comprehensively study multilayered molecular changes. It is valuable in the neuromuscular diseases field where innovative treatments are being produced. The objectives of this thesis were to apply omics techniques to study the two most common neuromuscular disorders (Spinal muscular atrophy and Duchenne muscular dystrophy) and explore their pathophysiological mechanisms, identify potential diagnosis biomarkers, and better stratify patients. The second objective was to find biomarkers for response to treatment in SMA. Metabolomics study on muscle biopsies of Duchenne patients revealed significant changes in energy and phospholipid metabolisms. SMA metabolic profiling investigations in plasma and CSF confirmed the presence of profound metabolic remodeling in SMA patients. Moreover, we demonstrated that these alterations are more pronounced in the severe phenotype. SMA proteomics studies are ongoing. In conclusion, systems biology tools are powerful for the study of neuromuscular diseases as they allow the discovery of biomarkers, the understanding of the physiopathology and the identification of new therapeutic targets

Explorations Multi-omiques dans les maladies neuromusculaires

Pediatric neuromuscular disorders encompass all childhood onset diseases affecting the muscle, the neuromuscular junction, peripheral nerve, and the anterior horn cell. The multitude of sites as well as the heterogeneity and rarity of these disorders, make their diagnosis and treatment challenging. Therefore, joint efforts of researchers and clinicians are mandatory to diagnose and treat patients more accurately using integrative systems biology tools. Such appealing approach uses high-throughput technologies to comprehensively study multilayered molecular changes. It is valuable in the neuromuscular diseases field where innovative treatments are being produced. The objectives of this thesis were to apply omics techniques to study the two most common neuromuscular disorders (Spinal muscular atrophy and Duchenne muscular dystrophy) and explore their pathophysiological mechanisms, identify potential diagnosis biomarkers, and better stratify patients. The second objective was to find biomarkers for response to treatment in SMA. Metabolomics study on muscle biopsies of Duchenne patients revealed significant changes in energy and phospholipid metabolisms. SMA metabolic profiling investigations in plasma and CSF confirmed the presence of profound metabolic remodeling in SMA patients. Moreover, we demonstrated that these alterations are more pronounced in the severe phenotype. SMA proteomics studies are ongoing. In conclusion, systems biology tools are powerful for the study of neuromuscular diseases as they allow the discovery of biomarkers, the understanding of the physiopathology and the identification of new therapeutic targets.Les maladies neuromusculaires pédiatriques sont relatives à des atteintes du muscle, de la jonction neuromusculaire, du nerf périphérique et de la corne antérieure. La multitude de sites, ainsi que l'hétérogénéité et la rareté de ces troubles, rendent leur diagnostic et leur traitement difficiles. Par conséquent, les efforts conjoints des chercheurs et des cliniciens sont nécessaires pour diagnostiquer et traiter les patients avec plus de précision en utilisant des outils de la biologie des systèmes. Cette approche permet d’analyser différents types de biomolécules et permet, ainsi, d’étudier de manière exhaustive les changements moléculaires en tenant compte des caractéristiques individuelles du patient (contexte clinique, environnement…). Il y a actuellement une recherche très active dans le domaine des maladies neuromusculaires qui a abouti à la mise à disposition de traitements innovants nécessitant une meilleure identification et stratification des patients pour améliorer la prise en charge. Les objectifs de cette thèse sont d'appliquer les techniques omiques afin d’étudier les deux maladies neuromusculaires les plus courantes (l'amyotrophie spinale infantile (SMA) et la myopathie de Duchenne), d'explorer leurs mécanismes physiopathologiques, d'identifier des biomarqueurs de diagnostic potentiels et de mieux stratifier les patients. Le second objectif est d’identifier des biomarqueurs pour suivre la réponse au traitement dans la SMA. Une étude métabolomique sur des biopsies musculaires de patients atteints de la maladie de Duchenne a révélé des changements significatifs dans les métabolismes énergétique et phospholipidique. Par ailleurs, l’étude métabolomique des plasma et LCR de patients SMA a confirmé la présence d'un remodelage métabolique profond chez les patients SMA. De plus, nous avons démontré que ces altérations sont plus prononcées dans le phénotype sévère. L’étude protéomique de ces échantillons est en cours. En conclusion, les outils de biologie des systèmes sont pertinents pour l'étude des maladies neuromusculaires car ils permettent la découverte de biomarqueurs, la compréhension de la physiopathologie et l'identification de nouvelles cibles thérapeutiques

Explorations Multi-omiques dans les maladies neuromusculaires

Pediatric neuromuscular disorders encompass all childhood onset diseases affecting the muscle, the neuromuscular junction, peripheral nerve, and the anterior horn cell. The multitude of sites as well as the heterogeneity and rarity of these disorders, make their diagnosis and treatment challenging. Therefore, joint efforts of researchers and clinicians are mandatory to diagnose and treat patients more accurately using integrative systems biology tools. Such appealing approach uses high-throughput technologies to comprehensively study multilayered molecular changes. It is valuable in the neuromuscular diseases field where innovative treatments are being produced. The objectives of this thesis were to apply omics techniques to study the two most common neuromuscular disorders (Spinal muscular atrophy and Duchenne muscular dystrophy) and explore their pathophysiological mechanisms, identify potential diagnosis biomarkers, and better stratify patients. The second objective was to find biomarkers for response to treatment in SMA. Metabolomics study on muscle biopsies of Duchenne patients revealed significant changes in energy and phospholipid metabolisms. SMA metabolic profiling investigations in plasma and CSF confirmed the presence of profound metabolic remodeling in SMA patients. Moreover, we demonstrated that these alterations are more pronounced in the severe phenotype. SMA proteomics studies are ongoing. In conclusion, systems biology tools are powerful for the study of neuromuscular diseases as they allow the discovery of biomarkers, the understanding of the physiopathology and the identification of new therapeutic targets.Les maladies neuromusculaires pédiatriques sont relatives à des atteintes du muscle, de la jonction neuromusculaire, du nerf périphérique et de la corne antérieure. La multitude de sites, ainsi que l'hétérogénéité et la rareté de ces troubles, rendent leur diagnostic et leur traitement difficiles. Par conséquent, les efforts conjoints des chercheurs et des cliniciens sont nécessaires pour diagnostiquer et traiter les patients avec plus de précision en utilisant des outils de la biologie des systèmes. Cette approche permet d’analyser différents types de biomolécules et permet, ainsi, d’étudier de manière exhaustive les changements moléculaires en tenant compte des caractéristiques individuelles du patient (contexte clinique, environnement…). Il y a actuellement une recherche très active dans le domaine des maladies neuromusculaires qui a abouti à la mise à disposition de traitements innovants nécessitant une meilleure identification et stratification des patients pour améliorer la prise en charge. Les objectifs de cette thèse sont d'appliquer les techniques omiques afin d’étudier les deux maladies neuromusculaires les plus courantes (l'amyotrophie spinale infantile (SMA) et la myopathie de Duchenne), d'explorer leurs mécanismes physiopathologiques, d'identifier des biomarqueurs de diagnostic potentiels et de mieux stratifier les patients. Le second objectif est d’identifier des biomarqueurs pour suivre la réponse au traitement dans la SMA. Une étude métabolomique sur des biopsies musculaires de patients atteints de la maladie de Duchenne a révélé des changements significatifs dans les métabolismes énergétique et phospholipidique. Par ailleurs, l’étude métabolomique des plasma et LCR de patients SMA a confirmé la présence d'un remodelage métabolique profond chez les patients SMA. De plus, nous avons démontré que ces altérations sont plus prononcées dans le phénotype sévère. L’étude protéomique de ces échantillons est en cours. En conclusion, les outils de biologie des systèmes sont pertinents pour l'étude des maladies neuromusculaires car ils permettent la découverte de biomarqueurs, la compréhension de la physiopathologie et l'identification de nouvelles cibles thérapeutiques

Ischemic stroke on SARS‐CoV2 vasculitis in a healthy young girl

Abstract Background and Aims In France, we noted the fifth wave of SARS‐CoV2 pandemic, characterized by presence of Omicron variant. This variant is very contagious, but less often aggressive, especially in pediatric population. Methods We report a case of a 10‐year‐old girl, previously healthy, not yet vaccinated for SARS‐CoV2, presented to our emergency department for left hemiparesis associated with headache and vomiting, without any signs of respiratory tract infection. Results Cerebral CT and MRI showed an ischemic stroke of right sylvian artery. Magnetic resonance angiography performed upon resurgence of new symptoms was in favor of vasculitis on the right internal carotid and right sylvian artery. PCR SARS‐CoV2 was positive for Omicron variant. She fully recovered after few days and was treated with acetylsalicylic acid and intravenous corticosteroids. Conclusion We report this case to raise awareness on the possible complications related to SARS‐CoV2 infection and we highly recommend vaccination in this age group

Diagnosis and Management of Glioblastoma: A Comprehensive Perspective

Glioblastoma is the most common malignant brain tumor in adults. The current management relies on surgical resection and adjuvant radiotherapy and chemotherapy. Despite advances in our understanding of glioblastoma onset, we are still faced with an increased incidence, an altered quality of life and a poor prognosis, its relapse and a median overall survival of 15 months. For the past few years, the understanding of glioblastoma physiopathology has experienced an exponential acceleration and yielded significant insights and new treatments perspectives. In this review, through an original R-based literature analysis, we summarize the clinical presentation, current standards of care and outcomes in patients diagnosed with glioblastoma. We also present the recent advances and perspectives regarding pathophysiological bases as well as new therapeutic approaches such as cancer vaccination and personalized treatments

Pontocerebellar Hypoplasia Type 1D: A Case Report and Comprehensive Literature Review

Pontocerebellar hypoplasia (PCH) is an autosomal recessive, neurodegenerative disorder with multiple subtypes leading to severe neurodevelopmental disabilities. PCH type 1 D is linked to alterations in the EXOSC9 gene. EXOSC9 is a component of the RNA exosome, an evolutionarily conserved ribonuclease complex essential for RNA degradation and processing. The clinical phenotype is characterized by cerebellar and pontine hypoplasia associated with motor neuronopathy. To date, nine patients have been reported in the literature with PCH1D. We report the case of an infant with PCH type 1D due to two variants in the EXOCS9 gene (NM_001034194.1: c.41T>C-p.Leu14Pro) and a novel variant (c.643C>T-p.Arg212*). This report thoroughly reviews the literature PCH1D and highlights the crucial role of the exosome in cellular homeostasis

An Atypical Case of Head Tremor and Extensive White Matter in an Adult Female Caused by 3-Hydroxy-3-methylglutaryl-CoA Lyase Deficiency

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) Lyase deficiency (HMGLD) (OMIM 246450) is an autosomal recessive genetic disorder caused by homozygous or compound heterozygous variants in the HMGCL gene located on 1p36.11. Clinically, this disorder is characterized by a life-threatening metabolic intoxication with a presentation including severe hypoglycemia without ketosis, metabolic acidosis, hyper-ammoniemia, hepatomegaly and a coma. HMGLD clinical onset is within the first few months of life after a symptomatic free period. In nonacute periods, the treatment is based on a protein- and fat-restricted diet. L-carnitine supplementation is recommended. A late onset presentation has been described in very few cases, and only two adult cases have been reported. The present work aims to describe an incidental discovery of an HMGLD case in a 54-year-old patient and reports a comprehensive review of clinical and biological features in adult patients to raise awareness about the late-onset presentation of this disease