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Background: Limb girdle muscular dystrophy type 2A (LGMD2A) is characterised by wide variability in clinical features and rate of progression. Patients with two null mutations usually have a rapid course, but in the remaining cases (two missense mutations or compound heterozygote mutations) prognosis is uncertain. Methods: We conducted what is to our knowledge the first systematic histopathological, biochemical and molecular investigation of 24 LGMD2A patients, subdivided according to rapid or slow disease progression, to determine if some parameters could correlate with disease progression. Results: We found that muscle histopathology score and the extent of regenerating and degenerating fibres could be correlated with the rate of disease course when the biochemical and molecular data do not offer sufficient information. Comparison of clinical and muscle histopathological data between LGMD2A and four other types of LGMD (LGMD2B–E) also gave another important and novel result. We found that LGMD2A has significantly lower levels of dystrophic features (ie degenerating and regenerating fibres) and higher levels of chronic changes (ie lobulated fibres) compared with other LGMDs, particularly LGMD2B. These results might explain the observation that atrophic muscle involvement seems to be a clinical feature peculiar to LGMD2A patients. Conclusions: Distinguishing patterns of muscle histopathological changes in LGMD2A might reflect the effects of a disease-specific pathogenetic mechanism and provide clues complementary to genetic data.

Limb girdle muscular dystrophy (LGMD) type 2A (LGMD2A) is caused by mutations in the CAPN3 gene encoding for calpain‐3, a muscle specific protease. While a large number of CAPN3 gene mutations have already been described in calpainopathy patients, the diagnosis has recently shifted from molecular genetics towards biochemical assay of defective protein. However, an estimate of sensitivity and specificity of protein analysis remains to be established. Thus, we first correlated protein and molecular data in our large LGMD2A patient population. By a preliminary immunoblot screening for calpain‐3 protein of 548 unclassified patients with various phenotypes (LGMD, myopathy, or elevated levels of serum creatine kinase [hyperCKemia]), we selected 208 cases for CAPN3 gene mutation analysis: 69 had protein deficiency and 139 had normal expression. Mutation search was conducted using SSCP, denaturing high performance liquid chromatography (DHPLC), amplification refractory mutation system (ARMS‐PCR), and direct sequencing methods. We identified 58 LGMD2A mutant patients: 46 (80%) had a variable degree of protein deficiency and 12 (20%) had normal amount of calpain‐3. We calculated that the probability of having LGMD2A is very high (84%) when patients show a complete calpain‐3 deficiency and progressively decreases with the amount of protein; this new data offers an important tool for genetic counseling when only protein data are available. A total of 37 different CAPN3 gene mutations were detected, 10 of which are novel. In our population, 87% of mutant alleles were concentrated in seven exons (exons 1, 4, 5, 8, 10, 11, and 21) and 61% correspond to only eight mutations, indicating the regions where future molecular analysis could be restricted. This study reports the largest collection of LGMD2A patients so far in which both protein and gene mutations were obtained to draw genotype–protein–phenotype correlations and provide insights into a critical protein domain. Hum Mutat 24:52–62, 2004. © 2004 Wiley‐Liss, Inc.

Introduction Late‐onset Pompe disease (LOPD) is characterized by a progressive myopathy resulting from a deficiency of acid α‐glucosidase enzyme activity. Enzyme replacement therapy has been shown to be effective, but long‐term treatment results vary. Avalglucosidase alfa demonstrated non‐inferiority to alglucosidase alfa in a phase 3 study, allowing in France compassionate access for advanced LOPD patients unresponsive to alglucosidase alfa. Methods Data from the French Pompe registry were analyzed for patients who benefited from a switch to avalglucosidase alfa with at least 1 year of follow‐up. Respiratory (forced vital capacity [FVC]) and motor functions (Six‐Minute Walk Test [6MWT]) were assessed before and 1 year after switching. Individual changes in FVC and 6MWT were expressed as slopes and statistical analyses were performed to compare values. Results Twenty‐nine patients were included (mean age 56 years, 11 years of prior treatment). The FVC and 6MWT values remained stable. The individual analyses showed a stabilization of motor worsening: –1 m/year on the 6MWT after the switch versus –63 m/year the year before the switch (i.e., a worsening of 33%/year before vs. an improvement of 3%/year later). Respiratory data were not statistically different. Discussion At the group level, gait parameters improved slightly with a stabilization of previous worsening, but respiratory parameters showed limited changes. At the individual level, results were discordant, with some patients with a good motor or respiratory response and some with further worsening. Conclusion Switching to avalglucosidase alfa demonstrated varied responses in advanced LOPD patients with failing alglucosidase alfa therapy, with a general improvement in motor stabilization.

Background and Objectives Mortality in Late‐Onset Pompe Disease (LOPD) has been associated with the rapid progression of respiratory and motor impairment. However, an in‐depth approach to the exact causes of death in these patients is still lacking. Methods In this retrospective cohort study, we analyzed the cause of death and the comorbidities of all deceased patients from the French Late‐Onset Pompe Disease registry. Results By the time of the last extraction, 60 patients diagnosed with LOPD and monitored were registered as deceased in the French national registry, out of a total of 260 patients included. The median age of death was 70.5 years, while the median age of diagnosis was 58 years. The causes of death were divided into disease‐related, accounting for 46.6% of deaths, and non‐disease‐related, comprising 28.3% of total deaths. Fifteen patients (25%) died of an unknown cause. The most frequent etiology of disease‐related death was respiratory failure (n = 14), while for the non‐disease‐related group, malignant neoplasm was the most common (n = 8). Patients in the non‐disease‐related death group had significantly higher forced vital capacity (FVC) values compared to those in the disease‐related death group (54.7% vs. 38%). Treatment‐wise, the median period elapsed from diagnosis to ERT introduction was higher in the disease‐related group. Discussion This is the first study to focus on the specific causes of death of LOPD patients. The majority of the LOPD deaths in the French registry were attributed to respiratory failure and malignant neoplasms.

Background Diagnostic wandering and impasse are major challenges for rare disease management. This study describes the characteristics of patients with rare neuromuscular diseases (RNMDs) without a diagnosis being managed by the French national network for RNMDs (FILNEMUS). Methods Data for RNMD patients managed by FILNEMUS centers between January 2017 and November 2022 were extracted from the French National Rare Disease Database (BNDMR). A network‐wide, standardized, and quality‐controlled process was established to collect additional data for patients without a diagnosis. The demographic and socioeconomic characteristics of these patients were then compared with patients with a confirmed diagnosis. Results 13.5% of patients evaluated (n = 5696/42,256) had no confirmed diagnosis. Comparison with 25,682 managed in the same centers and during the same periods with a confirmed diagnosis revealed that socioeconomic characteristics and region of residence did not influence diagnostic status. However, lack of a confirmed diagnosis was more common in patients aged > 50 years, and older patients had longer periods between first symptom onset and first interaction with an expert center. Evaluation of medical records identified eight RNMDs associated with increased risk of diagnostic wandering and impasse. Conclusions The FILNEMUS national network of expert centers has enabled equality of care for RNMD patients across France, but further measures are needed to promote more rapid referral to these centers, reduce times to first consultation, and maintain patient engagement in the diagnostic process, particularly for later‐onset RNMDs. Between 2017 and 2022, 13.5% of the 42,256 FILNEMUS patients (n = 5696) still lacked a confirmed diagnosis. Socio‐economic status and postcode are off the hook, but crossing the 50‐year mark sharply lengthens the gap between first symptoms and expert evaluation. Eight neuromuscular diseases top the “whodunnit” list, highlighting the need for nimbler diagnostic pathways especially for the silver‐haired sleuths among us.

Background and purpose The Rasch‐Built Pompe‐Specific Activity (R‐PAct) scale is a patient‐reported outcome measure specifically designed to quantify the effects of Pompe disease on daily life activities, developed for use in Dutch‐ and English‐speaking countries. This study aimed to validate the R‐PAct for use in other countries. Methods Four other language versions (German, French, Italian, and Spanish) of the R‐PAct were created and distributed among Pompe patients (≥16 years old) in Germany, France, Spain, Italy, and Switzerland and pooled with data of newly diagnosed patients from Australia, Belgium, Canada, the Netherlands, New Zealand, the USA, and the UK and the original validation cohort (n = 186). The psychometric properties of the scale were assessed by exploratory factor analysis and Rasch analysis. Results Data for 520 patients were eligible for analysis. Exploratory factor analysis suggested that the items separated into two domains: Activities of Daily Living and Mobility. Both domains independently displayed adequate Rasch model measurement properties, following the removal of one item (\"Are you able to practice a sport?\") from the Mobility domain, and can be added together to form a \"higher order\" factor as well. Differential item functioning (DIF)‐by‐language assessment indicated DIF for several items; however, the impact of accounting for DIF was negligible. We recalibrated the nomogram (raw score interval‐level transformation) for the updated 17‐item R‐PAct scale. The minimal detectable change value was 13.85 for the overall R‐PAct. Conclusions After removing one item, the modified‐R‐PAct scale is a valid disease‐specific patient‐reported outcome measure for patients with Pompe disease across multiple countries.

Drug delivery in diffuse intrinsic pontine glioma is significantly limited by the blood-brain barrier (BBB). Focused ultrasound (FUS), when combined with the administration of microbubbles can effectively open the BBB permitting the entry of drugs across the cerebrovasculature into the brainstem. Given that the utility of FUS in brainstem malignancies remains unknown, the purpose of our study was to determine the safety and feasibility of this technique in a murine pontine glioma model. A syngeneic orthotopic model was developed by stereotactic injection of PDGF-B + PTEN −/− p53 −/− murine glioma cells into the pons of B6 mice. A single-element, spherical-segment 1.5 MHz ultrasound transducer driven by a function generator through a power amplifier was used with concurrent intravenous microbubble injection for tumor sonication. Mice were randomly assigned to control, FUS and double-FUS groups. Pulse and respiratory rates were continuously monitored during treatment. BBB opening was confirmed with gadolinium-enhanced MRI and Evans blue. Kondziela inverted screen testing and sequential weight lifting measured motor function before and after sonication. A subset of animals were treated with etoposide following ultrasound. Mice were either sacrificed for tissue analysis or serially monitored for survival with daily weights. FUS successfully caused BBB opening while preserving normal cardiorespiratory and motor function. Furthermore, the degree of intra-tumoral hemorrhage and inflammation on H&E in control and treated mice was similar. There was also no difference in weight loss and survival between the groups ( p  > 0.05). Lastly, FUS increased intra-tumoral etoposide concentration by more than fivefold. FUS is a safe and feasible technique for repeated BBB opening and etoposide delivery in a preclinical pontine glioma model.

Topotecan is cytotoxic to glioma cells but is clinically ineffective because of drug delivery limitations. Systemic delivery is limited by toxicity and insufficient brain penetrance, and, to date, convection-enhanced delivery (CED) has been restricted to a single treatment of restricted duration. To address this problem, we engineered a subcutaneously implanted catheter-pump system capable of repeated, chronic (prolonged, pulsatile) CED of topotecan into the brain and tested its safety and biological effects in patients with recurrent glioblastoma. We did a single-centre, open-label, single-arm, phase 1b clinical trial at Columbia University Irving Medical Center (New York, NY, USA). Eligible patients were at least 18 years of age with solitary, histologically confirmed recurrent glioblastoma showing radiographic progression after surgery, radiotherapy, and chemotherapy, and a Karnofsky Performance Status of at least 70. Five patients had catheters stereotactically implanted into the glioma-infiltrated peritumoural brain and connected to subcutaneously implanted pumps that infused 146 μM topotecan 200 μL/h for 48 h, followed by a 5–7-day washout period before the next infusion, with four total infusions. After the fourth infusion, the pump was removed and the tumour was resected. The primary endpoint of the study was safety of the treatment regimen as defined by presence of serious adverse events. Analyses were done in all treated patients. The trial is closed, and is registered with ClinicalTrials.gov, NCT03154996. Between Jan 22, 2018, and July 8, 2019, chronic CED of topotecan was successfully completed safely in all five patients, and was well tolerated without substantial complications. The only grade 3 adverse event related to treatment was intraoperative supplemental motor area syndrome (one [20%] of five patients in the treatment group), and there were no grade 4 adverse events. Other serious adverse events were related to surgical resection and not the study treatment. Median follow-up was 12 months (IQR 10–17) from pump explant. Post-treatment tissue analysis showed that topotecan significantly reduced proliferating tumour cells in all five patients. In this small patient cohort, we showed that chronic CED of topotecan is a potentially safe and active therapy for recurrent glioblastoma. Our analysis provided a unique tissue-based assessment of treatment response without the need for large patient numbers. This novel delivery of topotecan overcomes limitations in delivery and treatment response assessment for patients with glioblastoma and could be applicable for other anti-glioma drugs or other CNS diseases. Further studies are warranted to determine the effect of this drug delivery approach on clinical outcomes. US National Institutes of Health, The William Rhodes and Louise Tilzer Rhodes Center for Glioblastoma, the Michael Weiner Glioblastoma Research Into Treatment Fund, the Gary and Yael Fegel Foundation, and The Khatib Foundation.

Introduction: Down Syndrome Regression Disorder (DSRD) is a neuropsychiatric condition causing insomnia, catatonia, encephalopathy, and obsessive-compulsive behavior in otherwise healthy individuals with Down syndrome (DS). Smaller cohorts have identified heterogenous diagnostic abnormalities which have predicted immunotherapy responsiveness although pattern analysis in a large cohort has never been performed. Methods: A multi-center, retrospective study of individuals with DSRD was performed. Individuals met international consensus criteria for DRSD and were aged 10–30 years. Clinical, demographic, and diagnostic data was extracted for all individuals. Serum studies were compared to a group of individuals with DS only. Results: A total of 164 individuals with DSRD were identified. Individuals with DSRD were more likely to have a positive antinuclear antibody, low complement 3, abnormal cytokines, and elevated ferritin levels. In a minority of individuals, EEG (30%), MRI (33%) and cerebrospinal fluid (CSF) (21%) were abnormal. Individuals with CSF abnormalities demonstrated greater disease severity at diagnosis on the BFCRS and NPI-Q ( p  = 0.02 and p  < 0.001). Abnormalities in cytokines ( p  = 0.03), neuroimaging ( p  < 0.001), and CSF ( p  = 0.02) were predictive of immunotherapy responsiveness. When MRI and LP were both abnormal or when EEG, MRI and LP were all abnormal, the odds of immunotherapy responsiveness approached 100% ( p  = 0.01, 95%CI: 1.75–105.1, OR: 13.56 and p  = 0.02, 95%CI: 1.37–86.87, OR: 10.91, respectively). Conclusions: In a population of individuals diagnosed with DSRD, abnormalities in serum cytokine levels, neuroimaging findings, and CSF analysis emerged as indicators of disease severity and responsiveness to immunotherapy.