Journal of neuromuscular diseases最新文献

Background: FSHD is an inherited myopathy with complex epigenetic pathogenesis and no causal treatment. Inflammation is thought to contribute to muscle pathology, but its nature remains unclear.

Objective: To characterize inflammatory infiltrates and morphological changes in MRI-guided FSHD muscle biopsies compared to healthy controls (HC).

Methods: We performed turbo inversion recovery magnitude (TIRM) and DIXON MRI on 43 genetically confirmed FSHD patients (50 ± 12 years, 51% men) to assess inflammation and fatty infiltration. From 24 patients with at least one TIRM + leg muscle, two MRI-guided biopsies (TIRM + and TIRM-) were obtained. Needle biopsies from 8 HC (36 ± 12 years, 62% men) served as controls. Samples underwent hematoxylin-phloxine staining and immunodetection of CD3, CD4, CD8, CD56, CD68, HLA-ABC, HLA-DR, and MAC. Electron microscopy provided ultrastructural analysis.

Results: TIRM + FSHD samples showed significantly higher histopathology and inflammation grades than paired TIRM- and HC samples. Inflammatory infiltrates, mainly CD8 + lymphocytes and CD68 + macrophages, were present in 67% of TIRM + and 20% of TIRM- muscles. Electron microscopy revealed frequent myofibrillar disorganization in TIRM + samples.

Conclusion: Our findings validate TIRM hyperintensity as a biomarker for active disease, correlating with histopathology and inflammation. The incidence of inflammation in FSHD appears underestimated, highlighting its role in disease pathogenesis. These results support targeting inflammation as a potential therapeutic strategy in FSHD.

BackgroundSince 2018, World Duchenne Organization, Dutch Duchenne Parent Project, and Duchenne Data Foundation have been championing efforts to make Duchenne-related data reusable in combination with data contained in other registries. Transforming human language into a coded language that machines can understand ("FAIRification"; FAIR, Findable, Accessible, Interoperable, Reusable) offers a solution.PurposeTo recount and reflect on the process and challenges encountered during the FAIRification of a patient-registry, the Duchenne Data Platform.MethodsThe FAIRification plan was developed by a multidisciplinary team that was coordinated by a FAIR project manager. It focused on FAIRifying common data elements for rare disease registrations and patient-related outcome data. Protecting patient privacy and autonomy were at the forefront throughout the process. FAIR data transformation was accomplished through a combination of open-source and custom-written software. Data access for federated exploration was enabled through a privacy-preserving "data-visiting" approach.ResultsThe plan consisted of 10 main steps and addressed social, legal, ethical, and technical issues. Proof-of-concept testing for interoperability between the Duchenne Data Platform and four other registries demonstrated that FAIR data discovery and reuse was possible. Misconceptions about FAIR data persist, which act as barriers to scaling-up community-level FAIR efforts. Suggestions for overcoming these barriers are provided.ConclusionsData visiting and federated analyses between registries is possible. Actions to help mitigate hesitation to implement FAIR in practice include seeking out existing FAIR training opportunities, addressing misconceptions as needed, contacting FAIR experts for advice and using the open-source resources that we have shared.

Introduction: Popeye domain containing 3 (POPDC3) gene encodes a protein involved in membrane trafficking and is highly expressed in skeletal muscles. POPDC3 pathogenic variants are associated with LGMDR26. Only a few reports of POPDC3 LGMD exist worldwide and none from India. Herein, we describe the first case of POPDC3 LGMD26.

Methods: This is a case report from a neurology referral center in India. All the clinical, laboratory and electrophysiological data were collected from the medical records.

Results: A 34-year-old man born to non-consanguineous parents presented with progressive proximal weakness of lower limbs from 22 years of age. He developed calf muscle pain and recurrent falls on walking for 7 years. He had atrophy of calves (medial gastrocnemius more than lateral) along with weakness of hip extensor, adductors and knee flexors and normal upper limb power, resembling Miyoshi myopathy. Serum creatine kinase ranged from 3524 to 6531 U/L. Muscle MRI showed selective atrophy of gluteus maximus, quadriceps femoris, semimembranosus and gastrocnemius with sparing of rectus femoris, gracilis and sartorius. Muscle biopsy done elsewhere and reported to show dystrophic features and immunohistochemistry showed positive staining for dystrophins and sarcoglycans. Clinically the possibility of LGMDR2/Dysferlinopathy, was considered and whole exome sequencing was done which revealed a novel homozygous pathogenic nonsense premature termination codon (PTC) variant (NM_022361.5) c.316C > T (NP_079130.2:) p.Arg106Ter) in exon 2 of POPDC3 gene.

Conclusion: This is the first report of POPDC3- LGMDR26 from India detected among a large cohort (461 genetically confirmed cases). POPDC3 gene variations should be considered in distal onset LGMDs with markedly elevated serum creatine kinase levels.

Background: The phenotypic variability of C9orf72-associated disease is broadening, including atypical and non-motor presentations. C9orf72-associated neurodegeneration has only rarely been associated with primary lateral sclerosis (PLS), and even more rarely with ocular motor apraxia.

Objectives: Describe a family with C9orf72 mutation presenting with frontotemporal dementia (FTD) and atypical PLS phenotypes and discuss the implications regarding 1) where PLS lies on the ALS-FTD spectrum, and 2) how C9orf72 mutations influence PLS clinically.

Methods: Chart review.

Results: A 52-year-old male experiencing 4 months of progressive right lower leg spasticity with a family history of FTD was referred to us. Within 15 months, he was anarthric and required a powered wheelchair. He developed acquired ocular motor apraxia, consistent with supranuclear ophthalmoplegia. He later developed laryngeal dystonia which led to his death. Ten years later, his 67-year-old brother presented with 8 months of progressive spastic dysarthria, hyperreflexia, right foot drop, and right facial weakness. Genetic testing revealed heterozygous C9orf72 hexanucleotide repeat expansion.

Conclusions: This family's presentation expands on sparse reports of C9orf72-associated PLS. The proband showcases a severity of ocular motor deficits not yet reported in PLS, extending ocular motor findings in MND. These deficits also provide clinical evidence of degeneration outside the motor cortex/spinal cord in PLS. The symptomatology (laryngeal dystonia, rapid progression) clinically overlaps with ALS/FTD, suggesting PLS may lie on the ALS-FTD spectrum. The severity and atypicality of this case also support suggestions that C9orf72 mutations amplify the spectrum/severity of disease observed in TDP-43 proteinopathies.

We described ambulatory Duchenne muscular dystrophy (DMD) progression, across multiple functional measures, via previously established prognostic groups for loss of ambulation (LoA) and health states. Patients closer to vs. farther from LoA had greater declines in some measures (e.g., 6-min walk distance) and less change in others (e.g., timed rise from floor velocity) due to floor effects. Patients in the late vs. early ambulatory health state were concordantly shifted towards higher LoA risk. Findings further characterize health states and prognostic factors in ambulatory DMD and highlight the importance of multiple measures of function to fully characterize disease progression.

Background: Although genetically-engineered mouse models are revolutionizing our understanding of numerous human diseases, some of them fail to reproduce or to mimic the human condition or even exhibit distinct disease features depending on the mouse genetic background, on the environment conditions, and/or on unknown parameters.

Objective: Experiments aimed at further characterizing the muscle defects associated with the I-T substitution at position 4898 of the human type 1 ryanodine receptor (RyR1) protein sequence, responsible for central core disease in affected patients, to use this model for therapeutic development. RyR1 is a cationic channel in the sarcoplasmic reticulum membrane that is responsible for the Ca²⁺ release flux that triggers muscle contraction. The above I-T change was previously described to alter RyR1 channel permeation so as to produce muscle weakness.

Methods: We used the corresponding I4895T mouse model, previously shown unviable in the homozygous form, and with heterozygous animals suffering from depressed RyR1-mediated Ca²⁺ flux and muscle force production. We performed a full characterization, at the molecular level of the RYR1 gene and transcript, and at the functional level at the isolated fiber or whole animal levels.

Results: We found no significant deficit in the heterozygous animals, from force and activity parameters at the whole organism level, to contraction of isolated muscles and Ca²⁺ release in single isolated muscle fibers.

Conclusions: Our results prompt the need for caution when using this model, and point to its potential limited relevance for preclinical studies.

Introduction: Duchenne muscular dystrophy (DMD) is a progressive disorder. This study evaluates upper limb function in DMD patients using the Performance of Upper Limb 2.0 (PUL 2.0) over 36-months.

Methods: Data were collected between 2011 and 2024. Patients with at least 36 months of follow-up were included. Mixed-effects models accounting for repeated measures evaluated 36-month PUL 2.0 changes by entry item and ambulatory status. The entry item assesses the overall upper limb function of the patient. Ambulant patients were defined as those able to walk 10 meters independently, transitioning patients as those who lost ambulation during the duration of the study and non-ambulant as those who had already lost ambulation at baseline.

Results: A total of 219 patients provided 684 paired 36-month assessments. Ambulatory status significantly affected total, shoulder, elbow, and distal scores at baseline. The largest 36-month decline in total scores was found in the 58 transitioning patients (11.62 points, 95%CI = -12.40, 10.84), followed by non-ambulant and ambulant subgroups (n = 116 and n = 86 respectively). The largest declines were seen in patients with baseline entry score of 4 (-11.97, 95% CI = -13.48, -10.46) and 5 (-11.55, 95% CI = -12.46, -10.63), with smaller declines for other entry scores.ConclusionsThe 36-month analysis confirms a clear trend of functional decline across time points, with the transitioning group exhibiting the greatest changes in upper limb function. These findings provide valuable insights for designing trials and offer a reference for long-term comparison of treatment efficacy in both experimental and real-world setting.

Background: Pediatric neuromuscular diseases (NMDs) do not only affect patients themselves, they also exert an impact on parents. However, the impact that parents experience on their own personal lives remains largely understudied.

Objective: This study introduced the construct of parental illness intrusiveness in a NMD population by addressing two objectives. First, to increase our insight in the levels of parental intrusiveness in the NMD population, these parents were compared to parents of youth with type 1 diabetes (T1D). Second, we aimed to increase our understanding of parental illness intrusiveness within the NMD sample by exploring its associations with parental demographical characteristics, parental depressive symptoms and quality of life, and disease- and child characteristics.

Methods: A total of 56 parents of youth with a NMD (aged 12-25) and a 2:1 matched sample of parents of youth with T1D completed questionnaires on parental illness intrusiveness, parental depressive symptoms, parental quality of life, and perceived patient physical functioning. For Objective 1, ANOVAs were conducted to compare parents in the NMD sample to parents in the T1D sample. For Objective 2, ANOVAs and correlational analyses were used.

Results: First, parents in the NMD sample reported significantly more illness intrusiveness, but not depressive symptoms as compared to parents in the T1D sample. Second, parental illness intrusiveness correlated positively with parental depressive symptoms and perceived patient physical impairment, and negatively with parental quality of life.

Conclusions: Compared to parents of a child with T1D, parents in the NMD population may experience more impact of their child's disease in their personal life. Parents of youth with higher physical impairment may be particularly at risk for experiencing difficulties among a wide array of personal life domains.

Introduction: Spinal Muscular Atrophy (SMA) is a rare neuromuscular disease. With the discovery of disease-modifying therapies, more infantile onset SMA patients will live to adulthood. The purpose of this study was to explore SMA patients' experience with adult care and their transition from pediatric care.

Methods: This was a convergent parallel mixed-methods design including a quantitative cross-sectional survey and qualitative interviews. A purposive sample of 20 participants was recruited. Quantitative data were collected using the Family Experiences with Care Coordination (FECC) survey. Qualitative data were collected using semi-structured interviews. Participants' experiences before, during, and after their transition to adult care were explored. Themes from interviews were identifiedResults:The mean age of participants was 40.5; 10 were male, 15 had SMA type 2, and 5 had SMA type 3. The FECC found that 7 patients had a care coordinator, 0 had a shared care or emergency plan, and 1 had a written transition plan. Three themes emerged from the semi-structured interviews: 1) a disjointed pediatric to adult care transition period 2) physically inaccessible adult healthcare settings and requirements for constant self-advocacy, and 3) suggestions for improving care including: multidisciplinary care teams and increased preparation of pediatric patients for the transition to adult care.

Discussion: The patient experiences captured in this study demonstrate the lack of transition plans and support for SMA patients when graduating to adult care. With more SMA patients anticipated to survive to adulthood, this problem will be exacerbated. Multi-disciplinary SMA pediatric to adult transition programs are necessary.

Biallelic mutations in XPNPEP3 gene, encoding a mitochondrial peptidase, mainly cause nephronophthisis, but associated muscle involvement remains poorly described. We report here a 44-year-old male presenting since childhood with exercise intolerance and recurrent rhabdomyolysis. Electroneuromyography revealed a sensory axonal neuropathy and brain MRI showed white matter lesions in the posterior cranial fossa. Muscle biopsy revealed ragged-red fibers, COX negative fibers and abnormal mitochondria in electron microscopy. Whole genome sequencing identified a homozygous frameshift variant in the XPNPEP3 gene. Our results expand the spectrum associated with XPNPEP3 variants, including metabolic myopathy with subclinical central and peripheral nervous system involvement.