先天性ミオパチー

Biallelic variants in the RDH11 gene, a retinol dehydrogenase involved in the visual cycle and systemic retinoid homeostasis, were initially implicated in a rare condition characterized by retinal dystrophy, early-onset cataract, neurodevelopmental anomalies and myopathy, through single-family reports, with this association more recently being confirmed in a larger study. Here, we further establish the pathogenic role of RDH11 by presenting a large multi-center cohort, comprising eight individuals from seven unrelated families. Comprehensive genetic analysis identified homozygous variants in all affected subjects, including two novel variants, strongly supporting loss-of-function as the primary disease mechanism. Detailed clinical phenotyping defined a consistent and severe multisystem disorder. Ophthalmologically, the hallmark features include bilateral congenital or early-childhood cataracts requiring surgical intervention, accompanied by retinitis pigmentosa (RP). In terms of extra-ocular involvement, the cohort exhibited a high prevalence of neurodevelopmental delay, including intellectual disability, autistic spectrum disorder and learning difficulties. These features were frequently accompanied by congenital microcephaly, intrauterine and postnatal growth restriction, facial dysmorphisms, and dental anomalies. By significantly expanding both the mutational and phenotypic spectrum of RDH11-related disease, our findings provide independent replication of this gene-disease association and definitively support RDH11 as a bona fide syndromic RP gene.

OBJECTIVE: To review the clinical research progress of craniofacial duplication, improve clinicians' recognition of this disease, and provide theoretical basis and practical references for its precise diagnosis and individualized treatment. METHODS: Recent domestic and international literature on craniofacial duplication as well as the diagnosis and treatment experiences of clinical cases in our team were reviewed. A comprehensive elaboration was conducted from embryonic development, etiological hypotheses, clinical classification, imaging manifestations, multidisciplinary diagnosis and treatment strategies, and prognostic follow-up. Special focus was placed on summarizing clinical features of jaw duplication, characteristics of occlusal disorder, and sequential orthodontic-orthognathic combined therapy. RESULTS: Craniofacial duplication is an extremely rare congenital craniofacial developmental malformation with highly heterogeneous phenotypes, involving multiple structures including lips, oral cavity, maxilla, and mandible. It is often complicated by cleft lip and palate, cervical vertebral fusion, hypertelorism, muscular dysfunction and other deformities, severely impairing patients' mastication, phonation, deglutition, and facial aesthetics. Due to its extremely low incidence, scattered reported cases, and unclear pathogenesis, unified diagnostic criteria and therapeutic specifications have not been established worldwide. Developmental disorders of pharyngeal arches and cranial neural crest cells at embryonic weeks 4-8 are the core pathogenic trigger. The five etiological hypotheses have limited evidence levels, and no single theory can explain all clinical subtypes. The PAX7 gene variant identified by our team only serves as a genetic clue without functional verification to confirm its pathogenicity. The modified Hamberis 3-type classification and Sun 4-type mandibular duplication classification can clearly define the lesion scope, with matched surgical procedures, orthodontic regimens and recurrence risks for each subtype. Cone-beam computed tomography (CBCT) combined with three-dimensional reconstruction acts as the gold standard for diagnosis, and multidisciplinary sequential therapy can ameliorate facial appearance and oral function. Nevertheless, long-term follow-up data are scarce, and clinical management mainly relies on individualized experiences of clinicians. CONCLUSION: Craniofacial duplication features complicated pathogenesis characterized by duplicated jaws, lips, and dental arches, with dysregulated development of embryonic pharyngeal arches and cranial neural crest cells as the core inducement. CBCT three-dimensional reconstruction enables accurate diagnosis, and multidisciplinary sequential therapy represents the optimal intervention strategy. Shortcomings including scarce clinical cases, unidentified pathogenic genes, absent standardized therapeutic protocols and insufficient long-term follow-up evidence remain prominent. Future research directions include constructing a multi-center case registry, conducting functional research on pathogenic genes, popularizing digital diagnosis and treatment techniques, and formulating standardized diagnostic and therapeutic guidelines. For pediatric patients with suspected malformations, CBCT examination should be performed as early as possible, and the principle of early diagnosis, early planning and early intervention shall be followed to restore oral function and optimize maxillofacial appearance.

Filamin C (FLNC) contributes to 1%-8% of adult-onset cardiomyopathy (CMP), with a high prevalence of end-stage heart failure and sudden cardiac death, particularly for FLNC truncating variants (FLNCtv), rendering it one of the high-risk CMP genes. Outcome data and genotype-phenotype correlation in children are scarce. We conducted a retrospective cohort study of children (< 18 years) with CMP features and a (likely) pathogenic FLNC variant, identified via literature search or in the Belgian Pediatric Cardiology Registry (BePCaR), to evaluate cardiovascular outcomes and genotype-phenotype correlations. Seventy-four individuals (56.8% male, median age 4.5 years) from 57 families were included. Restrictive CMP was the most prevalent phenotype. Half of the patients experienced major adverse cardiovascular events, including heart transplantation (20.3%) and death (13.5%). Hypertrophic CMP was exclusively associated with ROD2 domain variants. Mortality was significantly higher in FLNCtv carriers versus non-truncating carriers (26.9% vs. 6.3%, p = 0.019), and multivariate analysis identified FLNCtv as an independent predictor of adverse outcome (OR = 6.4, 95% CI: [1.36, 29.80]). Extracardiac manifestations occurred in 32.4%, predominantly in RCM patients, with myopathy-associated variants clustering in exons 21 and 41. Pathogenic FLNC variants associate with early-onset CMP and poor prognosis, underscoring the need for early genetic screening, risk stratification, and personalized follow-up to improve outcome.

BACKGROUND: Autosomal dominant centronuclear myopathy (ADCNM), most commonly caused by mutations in the dynamin 2 (DNM2) gene, is a rare congenital myopathy characterized by progressive muscle weakness and atrophy. Myostatin, a key negative regulator of skeletal muscle mass, has shown therapeutic potential in several models of neuromuscular diseases. We hypothesized that inhibiting myostatin could counteract muscle deconditioning in ADCNM and evaluated the therapeutic potential of both genetic and pharmacological myostatin inhibition strategies in a mouse model of ADCNM. METHODS: Knockin-dnm2R465W/+ (KI) mice were first crossed with knockout-myostatin mice (KO) to generate double mutant (KIKO) mice carrying both the R465W missense mutation and the myostatin gene deletion. In a second experiment, KI mice received intraperitoneal injections of a soluble activin type IIB receptor fused to IgG1 Fc fragment (sActRIIB-Fc) at 5 mg kg-1 twice weekly starting at 4 weeks of age for 4 weeks. Muscle structure, molecular pathways and functional analysis were performed in tibialis anterior muscle. RESULTS: MRI and immunohistochemical analyses showed that KI mice exhibited impaired postnatal muscle growth between 1 and 2 months of age, resulting in persistent muscle hypotrophy (-15%, p < 0.05). This defect was associated with a significant reduction in the number of satellite cells (-53%, p < 0.001 at 1 month and -68%, p < 0.01 at 2 months), the central accumulation of dense NADH-TR staining in more than 20% of muscle fibres, an upregulation of atrophy-related E3 ligases mRNA (Trim63 + 50%, p < 0.001 and +87%, p < 0.001; Fbxo32 + 39% p < 0.05 and +95%, p < 0.001 at 1 and 2 months of age, respectively) and impaired autophagy. Genetic deletion of myostatin in KIKO mice fully restored muscle mass and normalized muscle function to wild-type conditions. Pharmacological inhibition with sActRIIB-Fc also robustly restored muscle mass to wild-type values, primarily via activation of the Akt-mTOR pathway. However, this anabolic effect was transient, as muscle mass returned to baseline 5 weeks after treatment cessation. Importantly, despite increased muscle mass, sActRIIB-Fc treatment did not improve muscle force and key pathological features, including defects in proteostasis, mitochondrial organization and excitation-contraction coupling. CONCLUSIONS: These findings establish the proof of concept that myostatin inhibition counteracts skeletal muscle growth defect in ADCNM, which may be combined with other drugs to better address the multifactorial nature of muscle weakness in ADCNM.

Mutations in the Ky gene are the underlying cause of Myofibrillar Myopathy-7 (MFM-7), a rare progressive muscle weakness disease of childhood onset. A defining characteristic of the KY protein is the presence of a conserved transglutaminase-like domain, but unequivocal evidence of its enzymatic function remains to be established. To investigate the functional relevance of the predicted KY catalytic triad we use here in vitro enzymatic assays, structural modeling and in vivo rescue experiments in ky/ky mice. While structural modelling shows a striking conservation of the catalytic pocket architecture, our results show that recombinant KY proteins showed no detectable enzymatic activity under the assay conditions used. Moreover, while deletion of transglutaminase-like domain prevents phenotype rescue, replacements of the predicted catalytic residues do not impair the protein's ability to rescue fibre size in ky/ky muscle, indicating that the predicted catalytic residues are dispensable for fibre size rescue in these assays. Proteomic analyses identified KY-associated protein complexes involved in protein quality control, including core components of the Chaperone-Assisted Selective Autophagy machinery. In agreement, basal autophagic flux is significantly reduced in both KY-deficient C2C12 cells and ky/ky muscle fibres. Collectively, our data suggests that the TGN/PROT domain facilitates critical molecular associations at the sarcomeric Z-disc through a mechanism independent of catalysis and that impaired autophagic flux may contribute to the muscle phenotype.