JAK inhibition in Aicardi-Goutières syndrome: a monocentric multidisciplinary real-world approach study

International audienceThe 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

Expression des métalloprotéases dans les médulloblastomes

BORDEAUX2-BU Santé (330632101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Benign nocturnal alternating hemiplegia of childhood: two cases with positive evolution

Benign nocturnal alternating hemiplegia (BNAH) of childhood is distinct from the classic form of malignant alternating hemiplegia of childhood [1]. It is characterized by hemiplegic attacks occurring exclusively during sleep [2]. It can be misdiagnosed as migraine, nocturnal frontal lobe epilepsy, benign rolandic epilepsy, Panayiotopoulos syndrome, or sleep-related movement disorder [1-4]. Only nine patients have been described to date, with typically, a normal development [1,5-7]. In order to insist about the benignity of the affection, we report two cases: a new three-year-old boy suffering from BNAH and a patient already published to show positive evolution at fourteen years of age. BNAH is a rare disorder but may be underdiagnosed. Making an early diagnosis can help to describe to the parents the good prognosis without treatment

CHN1 and duane retraction syndrome: Expanding the phenotype to cranial nerves development disease

Duane retraction syndrome is a congenital eye movement disorder characterized by a failure of abducens nerve to develop normally, resulting in restriction or absence of abduction, adduction, or both, and narrowing of the palpebral fissure and retraction of the globe on attempted adduction. There is a genetic heterogeneity in Duane retraction syndrome (DURS). DURS maps to chromosome 8q13 in some patients, and pathogenic variants in CHN1 and MAFB genes are known to lead to DURS. We report here a child and his father with Duane retraction syndrome, associated to swallowing difficulties and unilateral trapeze aplasia. A whole exome sequencing revealed a heterozygous missense variant in CHN1 gene. This gene encodes GTPase-activating protein and is involved in the assembly of neuronal locomotor circuits. A patient with a 8q deletion has previously been described with a Duane retraction syndrome associated to trapeze aplasia. We provide an additional description to support the role in cranial nerves development of the CHN1 gene

Quel suivi pour les traitements innovants ?

Suivre les bénéfices et la tolérance d’une thérapie innovante constitue un exercice relativement récent dans le champ des maladies neuromusculaires. Fonction respiratoire, capacités musculaires et fonctionnelles, qualité de vie, effets indésirables, pour chaque paramètre à évaluer s’esquisse un panel de mesures idéales

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

International audienceNeurofilaments 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

Expanding the Spectrum of Neurological Manifestations in Cutis Laxa, Autosomal Recessive, Type IIIA

International audienceCutis laxa is a heterogeneous group of diseases, characterized by abundant and wrinkled skin and a variable degree of intellectual disability. Cutis laxa, autosomal recessive, type IIIA and autosomal dominant 3 syndromes are caused by autosomal recessive or de novo pathogenic variants in ALDH18A1. Autosomal recessive variants are known to lead to the most severe neurological phenotype, and very few patients have been described.We describe a 13-month-old patient with cutis laxa, autosomal recessive, type IIIA, with an extremely severe phenotype, including novel neurological findings. This description enlarges the neurological spectrum associated to cutis laxa, autosomal recessive, type IIIA, and provides an additional description of this syndrome

Confirmatory validation of the french version of the Duchenne Muscular Dystrophy module of the pediatric quality of life inventory (PedsQLTM3.0DMDfv)

Duchenne Muscular Dystrophy (DMD) is a neuromuscular disease that inevitably leads to total loss of autonomy. The new therapeutic strategies aim to both improve survival and optimise quality of life. Evaluating quality of life is nevertheless a major challenge. No DMD-specific quality of life scale to exists in French. We therefore produced a French translation of the English Duchenne Muscular Dystrophy module of the Pediatric Quality of Life Inventory (PedsQL TM DMD) following international recommendations. The study objective was to carry out a confirmatory validation of the French version of the PedsQL TM DMD for paediatric patients with DMD, using French multicentre descriptive cross-sectional data. The sample consisted of 107 patients. Internal consistency was acceptable for proxyassessments, with Cronbach's alpha coefficients above 0.70, except for the Treatment dimension. For self-assessments, internal consistency was acceptable only for the Daily Activities dimension. Our results showed poor metric qualities for the French version of the PedsQL TM DMD based on a sample of about 100 children, but these results remained consistent with those of the original validation. This confirms the interest of its use in clinical practice