JAK Inhibition in Aicardi-Goutières Syndrome: a Monocentric Multidisciplinary Real-World Approach Study.

The paradigm type I interferonopathy Aicardi-Goutières syndrome (AGS) is most typically characterized by severe neurological involvement. AGS is considered an immune-mediated disease, poorly responsive to conventional immunosuppression. Premised on a chronic enhancement of type I interferon signaling, JAK1/2 inhibition has been trialed in AGS, with clear improvements in cutaneous and systemic disease manifestations. Contrastingly, treatment efficacy at the level of the neurological system has been less conclusive. Here, we report our real-word approach study of JAK1/2 inhibition in 11 patients with AGS, providing extensive assessments of clinical and radiological status; interferon signaling, including in cerebrospinal fluid (CSF); and drug concentrations in blood and CSF. Over a median follow-up of 17 months, we observed a clear benefit of JAK1/2 inhibition on certain systemic features of AGS, and reproduced results reported using the AGS neurologic severity scale. In contrast, there was no change in other scales assessing neurological status; using the caregiver scale, only patient comfort, but no other domain of everyday-life care, was improved. Serious bacterial infections occurred in 4 out of the 11 patients. Overall, our data lead us to conclude that other approaches to treatment are urgently required for the neurologic features of AGS. We suggest that earlier diagnosis and adequate central nervous system penetration likely remain the major factors determining the efficacy of therapy in preventing irreversible brain damage, implying the importance of early and rapid genetic testing and the consideration of intrathecal drug delivery.

Movement disorders in valine métabolism diseases caused by HIBCH and ECHS1 deficiencies.

BACKGROUND AND PURPOSE: HIBCH and ECHS1 genes encode two enzymes implicated in the critical steps of valine catabolism, 3-hydroxyisobutyryl-coenzyme A (CoA) hydrolase (HIBCH) and short-chainenoyl-CoA hydratase (ECHS1), respectively. HIBCH deficiency (HIBCHD) and ECHS1 deficiency (ECHS1D) generate rare metabolic dysfunctions, often revealed by neurological symptoms. The aim of this study was to describe movement disorders spectrum in patients with pathogenic variants in ECHS1 and HIBC. METHODS: We reviewed a series of 18 patients (HIBCHD: 5; ECHS1D: 13) as well as 105 patients from the literature. We analysed the detailed phenotype of HIBCHD (38 patients) and ECHS1D (85 patients), focusing on MDs. RESULTS: The two diseases have a very similar neurological phenotype, with an early onset before 10 years of age for three clinical presentations: neonatal onset, Leigh-like syndrome (progressive onset or acute neurological decompensation), and isolated paroxysmal dyskinesia. Permanent or paroxysmal MDs were recorded in 61% of HIBCHD patients and 72% of ECHS1D patients. Patients had a variable combination of either isolated or combined MD, and dystonia was the main MD. These continuous MDs included dystonia, chorea, parkinsonism, athetosis, myoclonus, tremors, and abnormal eye movements. Patients with paroxysmal dyskinesia (HIBCHD: 4; ECHS1D: 9) usually had pure paroxysmal dystonia with normal clinical examination and no major impairment in psychomotor development. No correlation could be identified between clinical pattern (especially MD) and genetic pathogenic variants. CONCLUSIONS: Movement disorders, including abnormal ocular movements, are a hallmark of HIBCHD and ECHS1D. MDs are not uniform; dystonia is the most frequent, and various types of MD are combined in single patient.

An Integrated Clinical-Biological Approach to Identify Interindividual Variability and Atypical Phenotype-Genotype Correlations in Myopathies: Experience on A Cohort of 156 Families.

Diagnosis of myopathies is challenged by the high genetic heterogeneity and clinical overlap of the various etiologies. We previously reported a Next-Generation Sequencing strategy to identify genetic etiology in patients with undiagnosed Limb-Girdle Muscular Dystrophies, Congenital Myopathies, Congenital Muscular Dystrophies, Distal Myopathies, Myofibrillar Myopathies, and hyperCKemia or effort intolerance, using a large gene panel including genes classically associated with other entry diagnostic categories. In this study, we report the comprehensive clinical-biological strategy used to interpret NGS data in a cohort of 156 pediatric and adult patients, that included Copy Number Variants search, variants filtering and interpretation according to ACMG guidelines, segregation studies, deep phenotyping of patients and relatives, transcripts and protein studies, and multidisciplinary meetings. Genetic etiology was identified in 74 patients, a diagnostic yield (47.4%) similar to previous studies. We identified 18 patients (10%) with causative variants in different genes (ACTA1, RYR1, NEB, TTN, TRIP4, CACNA1S, FLNC, TNNT1, and PAPBN1) that resulted in milder and/or atypical phenotypes, with high intrafamilial variability in some cases. Mild phenotypes could mostly be explained by a less deleterious effect of variants on the protein. Detection of inter-individual variability and atypical phenotype-genotype associations is essential for precision medicine, patient care, and to progress in the understanding of the molecular mechanisms of myopathies.

Palliative Care in SMA Type 1: A Prospective Multicenter French Study Based on Parents' Reports.

Spinal muscular atrophy type 1 (SMA-1) is a severe neurodegenerative disorder, which in the absence of curative treatment, leads to death before 1 year of age in most cases. Caring for these short-lived and severely impaired infants requires palliative management. New drugs (nusinersen) have recently been developed that may modify SMA-1 natural history and thus raise ethical concerns about the appropriate level of care for patients. The national Hospital Clinical Research Program (PHRC) called "Assessment of clinical practices of palliative care in children with Spinal Muscular Atrophy Type 1 (SMA-1)" was a multicenter prospective study conducted in France between 2012 and 2016 to report palliative practices in SMA-1 in real life through prospective caregivers' reports about their infants' management. Thirty-nine patients were included in the prospective PHRC (17 centers). We also studied retrospective data regarding management of 43 other SMA-1 patients (18 centers) over the same period, including seven treated with nusinersen, in comparison with historical data from 222 patients previously published over two periods of 10 years (1989-2009). In the latest period studied, median age at diagnosis was 3 months [0.6-10.4]. Seventy-seven patients died at a median 6 months of age[1-27]: 32% at home and 8% in an intensive care unit. Eighty-five percent of patients received enteral nutrition, some through a gastrostomy (6%). Sixteen percent had a non-invasive ventilation (NIV). Seventy-seven percent received sedative treatment at the time of death. Over time, palliative management occurred more frequently at home with increased levels of technical supportive care (enteral nutrition, oxygenotherapy, and analgesic and sedative treatments). No statistical difference was found between the prospective and retrospective patients for the last period. However, significant differences were found between patients treated with nusinersen vs. those untreated. Our data confirm that palliative care is essential in management of SMA-1 patients and that parents are extensively involved in everyday patient care. Our data suggest that nusinersen treatment was accompanied by significantly more invasive supportive care, indicating that a re-examination of standard clinical practices should explicitly consider what treatment pathways are in infants' and caregivers' best interest. This study was registered on clinicaltrials.gov under the reference NCT01862042 (https://clinicaltrials.gov/ct2/show/study/NCT01862042?cond=SMA1&rank=8).

A novel pathogenic variant of NEFL responsible for deafness associated with peripheral neuropathy discovered through next-generation sequencing and review of the literature.

Neurofilaments are neuron-specific intermediate filaments essential for the radial growth of axons during development and the maintenance of axonal diameter. Pathogenic variants of Neurofilament Light (NEFL) are associated with CMT1F, CMT2E, and CMTDIG and have been observed in less than 1% of Charcot-Marie-Tooth (CMT) cases, resulting in the reporting of 35 variants in 173 CMT patients to date. However, only six variants have been reported in 17 patients with impaired hearing. No genotype-phenotype correlations have yet been established. Here, we report an additional case: a 69-year-old female, who originally presented with axonal sensory and motor neuropathy at the age of 45, associated with moderate sensorineural hearing loss, with a slight slope at high frequencies. Next-generation sequencing identified a novel pathogenic variant: c.269A > G, p.(Glu90Gly). Hearing impairment is often linked to CMT due to pathogenic variants of NEFL, especially p.(Glu90Lys) and p.(Asn98Ser), and in our case p.(Glu90Gly). These pathogenic variants are all located at hot spots, in the head domain and the two ends of the rod domain of the protein.

A large multicenter study of pediatric myotonic dystrophy type 1 for evidence-based management.

OBJECTIVE: To genotypically and phenotypically characterize a large pediatric myotonic dystrophy type 1 (DM1) cohort to provide a solid frame of data for future evidence-based health management. METHODS: Among the 2,697 patients with genetically confirmed DM1 included in the French DM-Scope registry, children were enrolled between January 2010 and February 2016 from 24 centers. Comprehensive cross-sectional analysis of most relevant qualitative and quantitative variables was performed. RESULTS: We studied 314 children (52% females, with 55% congenital, 31% infantile, 14% juvenile form). The age at inclusion was inversely correlated with the CTG repeat length. The paternal transmission rate was higher than expected, especially in the congenital form (13%). A continuum of highly prevalent neurodevelopmental alterations was observed, including cognitive slowing (83%), attention deficit (64%), written language (64%), and spoken language (63%) disorders. Five percent exhibited autism spectrum disorders. Overall, musculoskeletal impairment was mild. Despite low prevalence, cardiorespiratory impairment could be life-threatening, and frequently occurred early in the first decade (25.9%). Gastrointestinal symptoms (27%) and cataracts (7%) were more frequent than expected, while endocrine or metabolic disorders were scarce. CONCLUSIONS: The pedDM-Scope study details the main genotype and phenotype characteristics of the 3 DM1 pediatric subgroups. It highlights striking profiles that could be useful in health care management (including transition into adulthood) and health policy planning.

A Reliable Targeted Next-Generation Sequencing Strategy for Diagnosis of Myopathies and Muscular Dystrophies, Especially for the Giant Titin and Nebulin Genes.

Myopathies and muscular dystrophies (M-MDs) are genetically heterogeneous diseases, with >100 identified genes, including the giant and complex titin (TTN) and nebulin (NEB) genes. Next-generation sequencing technology revolutionized M-MD diagnosis and revealed high frequency of TTN and NEB variants. We developed a next-generation sequencing diagnostic strategy targeted to the coding sequences of 135 M-MD genes. Comparison of two targeted capture technologies (SeqCap EZ Choice library capture kit and Nextera Rapid Capture Custom Enrichment kit) and of two whole-exome sequencing kits (SureSelect V5 and TruSeq RapidExome capture) revealed best coverage with the SeqCap EZ Choice protocol. A marked decrease in coverage was observed with the other kits, affecting mostly the first exons of genes and the repeated regions of TTN and NEB. Bioinformatics analysis strategy was fine-tuned to achieve optimal detection of variants, including small insertions/deletions (INDELs) and copy number variants (CNVs). Analysis of a cohort of 128 patients allowed the detection of 52 substitutions, 13 INDELs (including a trinucleotide repeat expansion), and 3 CNVs. Two INDELs were localized in the repeated regions of NEB, suggesting that these mutations may be frequent but underestimated. A large deletion was also identified in TTN that is, to our knowledge, the first published CNV in this gene.

Genetic and clinical specificity of 26 symptomatic carriers for dystrophinopathies at pediatric age.

The molecular basis underlying the clinical variability in symptomatic Duchenne muscular dystrophy (DMD) carriers are still to be precised. We report 26 cases of early symptomatic DMD carriers followed in the French neuromuscular network. Clinical presentation, muscular histological analysis and type of gene mutation, as well as X-chromosome inactivation (XCI) patterns using DNA extracted from peripheral blood or muscle are detailed. The initial symptoms were significant weakness (88%) or exercise intolerance (27%). Clinical severity varied from a Duchenne-like progression to a very mild Becker-like phenotype. Cardiac dysfunction was present in 19% of the cases. Cognitive impairment was worthy of notice, as 27% of the carriers are concerned. The muscular analysis was always contributive, revealing muscular dystrophy (83%), mosaic in immunostaining (81%) and dystrophin abnormalities in western blot analysis (84%). In all, 73% had exonic deletions or duplications and 27% had point mutations. XCI pattern was biased in 62% of the cases. In conclusion, we report the largest series of manifesting DMD carriers at pediatric age and show that exercise intolerance and cognitive impairment may reveal symptomatic DMD carriers. The complete histological and immunohistological study of the muscle is the key of the diagnosis leading to the dystrophin gene analysis. Our study shows also that cognitive impairment in symptomatic DMD carriers is associated with mutations in the distal part of the DMD gene. XCI study does not fully explain the mechanisms as well as the wide spectrum of clinical phenotype, though a clear correlation between the severity of the phenotype and inactivation bias was observed.