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Duchenne muscular dystrophy (DMD) is a common and severe X-linked myopathy, characterized by muscle degeneration due to altered or absent dystrophin. DMD has no effective cure, and the underlying molecular mechanisms remain incompletely understood. The aim of this study is to investigate the metabolic changes in DMD using mass spectrometry-based imaging. Nine human muscle biopsies from DMD patients and nine muscle biopsies from control individuals were subjected to untargeted MSI using matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometry. Both univariate and pattern recognition techniques have been used for data analysis. This study revealed significant changes in 34 keys metabolites. Seven metabolites were decreased in the Duchenne biopsies compared to control biopsies including adenosine triphosphate, and glycerophosphocholine. The other 27 metabolites were increased in the Duchenne biopsies, including sphingomyelin, phosphatidylcholines, phosphatidic acids and phosphatidylserines. Most of these dysregulated metabolites are tightly related to energy and phospholipid metabolism. This study revealed a deep metabolic remodelling in phospholipids and energy metabolism in DMD. This systems-based approach enabled exploring the metabolism in DMD in an unprecedented holistic and unbiased manner with hypothesis-free strategies.

Mutations in genes required for the glycosylation of α-dystroglycan lead to muscle and brain diseases known as dystroglycanopathies. However, the precise structure and biogenesis of the assembled glycan are not completely understood. Here we report that three enzymes mutated in dystroglycanopathies can collaborate to attach ribitol phosphate onto α-dystroglycan. Specifically, we demonstrate that isoprenoid synthase domain-containing protein (ISPD) synthesizes CDP-ribitol, present in muscle, and that both recombinant fukutin (FKTN) and fukutin-related protein (FKRP) can transfer a ribitol phosphate group from CDP-ribitol to α-dystroglycan. We also show that ISPD and FKTN are essential for the incorporation of ribitol into α-dystroglycan in HEK293 cells. Glycosylation of α-dystroglycan in fibroblasts from patients with hypomorphic ISPD mutations is reduced. We observe that in some cases glycosylation can be partially restored by addition of ribitol to the culture medium, suggesting that dietary supplementation with ribitol should be evaluated as a therapy for patients with ISPD mutations. Mutations in genes required for the glycosylation of α-dystroglycan lead to dystroglycanopathies. Here, the authors show that three of these enzymes (ISPD, FKTN and FKRP) work together to attach ribitol phosphate to α-dystroglycan.

BackgroundLAMA2-related muscular dystrophy (LAMA2-RD) encompasses a group of recessive muscular dystrophies caused by mutations in the LAMA2 gene, which codes for the alpha-2 chain of laminin-211 (merosin). Diagnosis is straightforward in the classic congenital presentation with no ambulation and complete merosin deficiency in muscle biopsy, but is far more difficult in milder ambulant individuals with partial merosin deficiency.ObjectiveTo investigate the diagnostic utility of muscle imaging in LAMA2-RD using whole-body magnetic resonance imaging (WBMRI).Results27 patients (2–62 years, 21–80% with acquisition of walking ability and 6 never ambulant) were included in an international collaborative study. All carried two pathogenic mutations, mostly private missense changes. An intronic variant (c.909 + 7A > G) was identified in all the Chilean cases. Three patients (two ambulant) showed intellectual disability, epilepsy, and brain structural abnormalities. WBMRI T1w sequences or T2 fat-saturated images (Dixon) revealed abnormal muscle fat replacement predominantly in subscapularis, lumbar paraspinals, gluteus minimus and medius, posterior thigh (adductor magnus, biceps femoris, hamstrings) and soleus. This involvement pattern was consistent for both ambulant and non-ambulant patients. The degree of replacement was predominantly correlated to the disease duration, rather than to the onset or the clinical severity. A “COL6-like sandwich sign” was observed in several muscles in ambulant adults, but different involvement of subscapularis, gluteus minimus, and medius changes allowed distinguishing LAMA2-RD from collagenopathies. The thigh muscles seem to be the best ones to assess disease progression.ConclusionWBMRI in LAMA2-RD shows a homogeneous pattern of brain and muscle imaging, representing a supportive diagnostic tool.

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.

NGLY1 deficiency is the first recognized autosomal recessive disorder of N-linked deglycosylation (NGLY1-CDDG). This severe multisystemic disease is still poorly known and, to date, most cases have been diagnosed through whole exome or genome sequencing. The aim of this study is to provide the clinical, biochemical and molecular description of the first NGLY1-CDDG patient from France along with a literature review. The index case presented with developmental delay, acquired microcephaly, hypotonia, alacrimia, feeding difficulty, and dysmorphic features. Given the complex clinical picture and the multisystemic involvement, a trio-based exome sequencing was conducted and urine oligosaccharides were assessed using mass spectrometry. The exome sequencing revealed a novel variant in the NGLY1 gene in a homozygous state. NGLY1 deficiency was confirmed by the identification of the Neu5Ac1Hex1GlcNAc1-Asn oligosaccharide in the urine of the patient. Literature review revealed the association of some key clinical and biological features such as global developmental delay—hypertransaminasemia, movement disorders, feeding difficulties and alacrima/hypolacrima.

Introduction: LMNA-related muscular dystrophy is a rare entity that produce “laminopathies” such as Emery–Dreifuss muscular dystrophy (EDMD), limb–girdle muscular dystrophy type 1B (LGMD1B), and LMNA-related congenital muscular dystrophy (L-CMD). Heart failure, malignant arrhythmias, and sudden death may occur. No consensus exists on cardiovascular management in pediatric laminopathies. The aim was to perform an exhaustive cardiologic follow-up in pediatric patients diagnosed with LMNA-related muscular dystrophy. Methods: Baseline cardiac work-up consisted of clinical assessment, transthoracic Doppler echocardiography, 12-lead electrocardiogram, electrophysiological study, and implantation of a long-term implantable cardiac loop recorder (ILR). Results: We enrolled twenty-eight pediatric patients diagnosed with EDMD (13 patients), L-CMD (11 patients), LGMD1B (2 patients), and LMNA-related mild weakness (2 patients). Follow-up showed dilated cardiomyopathy (DCM) in six patients and malignant arrhythmias in five (four concomitant with DCM) detected by the ILR that required implantable cardioverter defibrillator (ICD) implantation. Malignant arrhythmias were detected in 20% of our cohort and early-onset EDMD showed worse cardiac prognosis. Discussion: Patients diagnosed with early-onset EDMD are at higher risk of DCM, while potentially life-threatening arrhythmias without DCM appear earlier in L-CMD patients. Early onset neurologic symptoms could be related with worse cardiac prognosis. Specific clinical guidelines for children are needed to prevent sudden death.

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.

Diagnosis of lysosomal disorders (LDs) may be hampered by their clinical heterogeneity, phenotypic overlap, and variable age at onset. Conventional biological diagnostic procedures are based on a series of sequential investigations and require multiple sampling. Early diagnosis may allow for timely treatment and prevent clinical complications. In order to improve LDs diagnosis, we developed a capture-based next generation sequencing (NGS) panel allowing the detection of single nucleotide variants (SNVs), small insertions and deletions, and copy number variants (CNVs) in 51 genes related to LDs. The design of the LD panel covered at least coding regions, promoter region, and flanking intronic sequences for 51 genes. The validation of this panel consisted in testing 21 well-characterized samples and evaluating analytical and diagnostic performance metrics. Bioinformatics pipelines have been validated for SNVs, indels and CNVs. The clinical output of this panel was tested in five novel cases. This capture-based NGS panel provides an average coverage depth of 474× which allows the detection of SNVs and CNVs in one comprehensive assay. All the targeted regions were covered above the minimum required depth of 30×. To illustrate the clinical utility, five novel cases have been sequenced using this panel and the identified variants have been confirmed using Sanger sequencing or quantitative multiplex PCR of short fluorescent fragments (QMPSF). The application of NGS as first-line approach to analyze suspected LD cases may speed up the identification of alterations in LD-associated genes. NGS approaches combined with bioinformatics analyses, are a useful and cost-effective tool for identifying the causative variations in LDs.

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.