The initial molecular response predicts the deep molecular response but not treatment-free remission maintenance in a real-world chronic myeloid leukemia cohort.

In chronic myeloid leukemia, the identification of early molecular predictors of stable treatment-free remission (TFR) after tyrosine kinase inhibitor (TKI) discontinuation is challenging. The predictive values of residual disease (BCR::ABL1 quantification) at months 3 and 6 and more recently, BCR::ABL1 transcript halving time (HT) have been described, but no study compared the predictive value of different early parameters. Using a real-world cohort of 408 patients, we compared the performance of the ELTS score, BCR::ABL1 HT, and residual disease at month 3 and 6 to predict the molecular response, achievement of the TKI discontinuation criteria, and TFR maintenance. The performances of BCR::ABL1 HT and residual disease at month 3 were similar. Residual disease at month 6 displayed the best performance for predicting the optimal response (area under the ROC curve between 0.81 and 0.92; cut-off values: 0.11% for MR4 at month 24 and 0.12% for MR4.5 at month 48). Conversely, no early parameter predicted reaching the TKI discontinuation criteria and TFR maintenance. We obtained similar results when patients were divided in subgroups by first-line treatment (imatinib vs second generation TKI, 2G-TKI). We identified a relationship between ELTS score, earlier milestones and TFR maintenance only in the 2G-TKI group. In conclusion, this first comparative study of early therapeutic response parameters showed that they are excellent indicators of TKI efficacy (BCR::ABL1 transcript reduction) and best responders. Conversely, they did not predict the achievement of the TKI discontinuation criteria and TFR maintenance, suggesting that other parameters are involved in TFR maintenance.

EURO-NMD registry: federated FAIR infrastructure, innovative technologies and concepts of a patient-centred registry for rare neuromuscular disorders.

BACKGROUND: The EURO-NMD Registry collects data from all neuromuscular patients seen at EURO-NMD's expert centres. In-kind contributions from three patient organisations have ensured that the registry is patient-centred, meaningful, and impactful. The consenting process covers other uses, such as research, cohort finding and trial readiness. RESULTS: The registry has three-layered datasets, with European Commission-mandated data elements (EU-CDEs), a set of cross-neuromuscular data elements (NMD-CDEs) and a dataset of disease-specific data elements that function modularly (DS-DEs). The registry captures clinical, neuromuscular imaging, neuromuscular histopathology, biological and genetic data and patient-reported outcomes in a computer-interpretable format using selected ontologies and classifications. The EURO-NMD registry is connected to the EURO-NMD Registry Hub through an interoperability layer. The Hub provides an entry point to other neuromuscular registries that follow the FAIR data stewardship principles and enable GDPR-compliant information exchange. Four national or disease-specific patient registries are interoperable with the EURO-NMD Registry, allowing for federated analysis across these different resources. CONCLUSIONS: Collectively, the Registry Hub brings together data that are currently siloed and fragmented to improve healthcare and advance research for neuromuscular diseases.

Characteristics of Patients With Late-Onset Pompe Disease in France: Insights From the French Pompe Registry in 2022.

BACKGROUND AND OBJECTIVES: The French Pompe disease registry was created in 2004 for study of the natural course of the disease in patients. It rapidly became a major tool for assessing the long-term efficacy of enzyme replacement therapy (ERT) after the market release of alglucosidase-alfa. METHODS: Approximately 10 years after publication of the baseline characteristics of the 126 initial patients of the French Late-Onset Pompe Disease registry, we provide here an update of the clinical and biological features of patients included in this registry. RESULTS: We describe 210 patients followed at 31 hospital-based French neuromuscular or metabolic centers. The median age at inclusion was 48.67 ± 14.91 years. The first symptom was progressive lower limb muscle weakness, either isolated (50%) or associated with respiratory symptoms (18%), at a median age of 38 ± 14.9 years. At inclusion, 64% of the patients were able to walk independently and 14% needed a wheelchair. Positive associations were found between motor function measure, manual motor test, and 6-minute walk test (6MWT) results, and these parameters were inversely associated with the time taken to sit up from a lying position at inclusion. Seventy-two patients had been followed for at least 10 years in the registry. Thirty-three patients remained untreated a median of 12 years after symptom onset. The standard ERT dose was administered for 177 patients. DISCUSSION: This update confirms previous findings for the adult population included in the French Pompe disease registry, but with a lower clinical severity at inclusion, suggesting that this rare disease is now diagnosed earlier; thanks to greater awareness among physicians. The 6MWT remains an important method for assessing motor performance and walking ability. The French Pompe disease registry provides an exhaustive, nationwide overview of Pompe disease and can be used to assess individual and global responses to future treatments.

Real-world therapeutic response and tyrosine kinase inhibitor discontinuation in chronic phase-chronic myeloid leukemia: data from the French observatory.

Guidelines for tyrosine kinase inhibitor (TKI)-treated chronic phase-chronic myeloid leukemia (CML) management are essentially based on data from clinical research trials; however, real-world data should be valuable for optimizing such recommendations. Here, we analyzed the data collected in the French CML Observatory database, a multicenter real-world cohort (n = 646), using a first-line "intention-to-treat" analysis strategy. This cohort included patients treated with first-line imatinib (n = 484), nilotinib (n = 103), dasatinib (n = 17), imatinib and interferon (n = 9), or second-generation (2G)-TKIs and interferon (n = 29). The cumulative incidence of major molecular response (MMR), MR4, MR4.5 and MR5 confirmed the faster response kinetics with 2G-TKIs. Multivariate analysis identified being a woman and residual disease at month 6 as the main predictive factors of deep molecular response (DMR). Moreover, 30% of patients met the criteria for treatment discontinuation (5 years of treatment and ≥ 2 years of DMR), but only 38% of them stopped treatment. Among the 92 patients who actually discontinued treatment due to optimal response, 31.5% relapsed (48% of them after > 6 months of TKI discontinuation). Multivariate analysis identified age and TKI duration as factors positively correlated with treatment-free remission maintenance. Late (> 6 months) relapses were more frequent in patients with the e14a2 BCR::ABL transcript. Relapse rate was higher in patients who stopped TKI before than after 5 years of treatment (52.6% vs 26%; p = 0.040). These results advocate caution concerning early treatment withdrawal, including in patients receiving 2G-TKIs. This still recruiting database is a valuable source of information for the real-world follow-up of patients with CML.

Macroglossia: A potentially severe complication of late-onset Pompe disease.

BACKGROUND: Pompe disease is a rare neuromuscular disorder caused by a deficiency of a lysosomal enzyme, acid α-glucosidase. Macroglossia is a classic clinical sign of several inherited myopathies and has also been reported to occur progressively in late-onset Pompe disease (LOPD). METHODS: We describe patients with LOPD and macroglossia included in the French national Pompe disease registry. Clinical, functional, and radiological data were collected during periodic follow-up and analyzed retrospectively. These cases were compared with 15 previously reported cases. RESULTS: Five patients, three females and two males, aged 71-88 years, were included in this study. All but one of the patients suffered from symptoms related to macroglossia before the diagnosis of Pompe disease. Three had localized tongue atrophy and one had significant localized tongue hypertrophy which led to glossectomy 10 years before diagnosis. Two patients had severe dysphagia, one of whom underwent gastrostomy for enteral nutritional support. One patient experienced the persistence of numerous sleep apneas despite nocturnal bilevel positive airway pressure (BiPAP) ventilation. All our patients had dysarthria, and two required speech therapy. Four patients had a tongue hypersignal on magnetic resonance imaging (MRI) T1 sequences. CONCLUSIONS: Detection of macroglossia should be part of the clinical diagnosis and follow-up of patients with LOPD, with a careful evaluation of its main consequences. Macroglossia can have severe functional impacts on speech, swallowing, and sleep. Whole-body MRI with facial sections may facilitate the early diagnosis of Pompe disease with the "bright tongue sign".

Implementation of Motor Function Measure score percentile curves - Predicting motor function loss in Duchenne muscular dystrophy.

The Motor Function Measure is a standardized scoring system to evaluate motor function and monitor disease progression in neuromuscular diseases such as Duchenne muscular dystrophy. There are no available reference percentile curves for this measure. The aim of this analysis was to generate Motor Function Measure percentile curves for ambulant and non-ambulant patients affected by Duchenne Muscular Dystrophy, providing the opportunity to better evaluate the status and progression of an individual patient compared to other patients in the same age group. Data of patients aged between 6 and 15 years (819 measurements) was obtained from the international Motor Function Measure database. Age-dependent percentile curves were estimated using a "Generalized additive model for location, scale and shape" as suggested by the World Health Organisation Multicentre Growth Reference Study Group. Percentile curves for the Motor Function Measure total score and its sub-scores for patients with and without treatment with glucocorticoids are presented. Mean scores decline with age. Patients treated with glucocorticoids have higher mean values compared to glucocorticoid-naïve patients at the same age. The percentile curves with the online tool extend the clinical utility of the Motor Function Measure by facilitating the interpretation of individual standing and disease progression.

CRB1-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor CRB1 Isoforms.

Pathogenic variants in CRB1 lead to diverse recessive retinal disorders from severe Leber congenital amaurosis to isolated macular dystrophy. Until recently, no clear phenotype-genotype correlation and no appropriate mouse models existed. Herein, we reappraise the phenotype-genotype correlation of 50 patients with regards to the recently identified CRB1 isoforms: a canonical long isoform A localized in Müller cells (12 exons) and a short isoform B predominant in photoreceptors (7 exons). Twenty-eight patients with early onset retinal dystrophy (EORD) consistently had a severe Müller impairment, with variable impact on the photoreceptors, regardless of isoform B expression. Among them, two patients expressing wild type isoform B carried one variant in exon 12, which specifically damaged intracellular protein interactions in Müller cells. Thirteen retinitis pigmentosa patients had mainly missense variants in laminin G-like domains and expressed at least 50% of isoform A. Eight patients with the c.498_506del variant had macular dystrophy. In one family homozygous for the c.1562C>T variant, the brother had EORD and the sister macular dystrophy. In contrast with the mouse model, these data highlight the key role of Müller cells in the severity of CRB1-related dystrophies in humans, which should be taken into consideration for future clinical trials.

Retinitis Punctata Albescens and RLBP1-Allied Phenotypes: Phenotype-Genotype Correlation and Natural History in the Aim of Gene Therapy.

Purpose: To identify relevant criteria for gene therapy based on clinical and genetic characteristics of rod-cone dystrophy associated with RLBP1 pathogenic variants in a large cohort comprising children and adults. Design: Retrospective cohort study. Participants: Patients with pathogenic variants in RLBP1 registered in a single French reference center specialized in inherited retinal dystrophies. Methods: Clinical, multimodal imaging, and genetic findings were reviewed. Main Outcome Measures: Age of onset; visual acuity; ellipsoid line length; nasal, temporal, and foveal retinal thickness; and pathogenic variants and related phenotypes, including Newfoundland rod-cone and Bothnia dystrophies (NFRCDs), were reappraised. Results: Twenty-one patients (15 families) were included. The most frequent form was NFRCD with 12 patients (8 families) homozygous for the recurrent deletion of exons 7 through 9 in RLBP1 and 5 patients (4 families) with biallelic protein-truncating variants (2 novel: p.Gln16∗ and p.Tyr251∗). A novel combination of the p.Arg234Trp Bothnia variant with a nonsense variant in trans led to Bothnia dystrophy in 2 sisters. One proband carrying the p.Met266Lys Bothnia variant and in trans p.Arg121Trp and a second, with the p.Arg9Cys and p.Tyr111∗ combination, both demonstrated mild retinitis punctata albescens. Independently of genotype, all patients showed a visual acuity of worse than 20/200, an ellipsoid line width of less than 1000 µm, and a mean foveal thickness of less than 130 to 150 µm, with loss of both the interdigitation and ellipsoid lines. Conclusions: The eligibility for RLBP1 gene therapy first should be determined according to the biallelic variant combination using a robust classification as proposed herein. An ellipsoid line width of more than 1200 µm and a central thickness of more than 130 to 150 µm with detectable ellipsoid and interdigitation lines should be 2 prerequisite imaging indicators for gene therapy.

Long-term benefit of enzyme replacement therapy with alglucosidase alfa in adults with Pompe disease: Prospective analysis from the French Pompe Registry.

Despite a wide clinical spectrum, the adult form of Pompe disease is the most common one, and represents more than 90% of diagnosed patients in France. Since the marketing of enzyme replacement therapy (alglucosidase alfa, Myozyme), all reports to date in adults demonstrated an improvement of the walking distance, and a trend toward stabilization of respiratory function, but the majority of these studies were less than 5 years of duration. We report here the findings from 158 treated patients included in the French Pompe Registry, who underwent regular clinical assessments based on commonly used standardized tests (6-minute walking test, MFM scale, sitting vital capacity, MIP and MEP). For longitudinal analyses, the linear mixed effects models were used to assess trends in primary endpoints over time under ERT. A two-phase model better described the changes in distance traveled in the 6-minute walk test and MFM. 6MWT showed an initial significant increase (1.4% ± 0.5/year) followed by a progressive decline (-2.3%/year), with a cut-off point at 2.2 years. A similar pattern was observed in total MFM score (6.6% ± 2.3/year followed by a - 1.1%/year decline after 0.5 years). A single-phase decline with a slope of -0.9 ± 0.1%/year (P < .001) was observed for FVC, and MEP remained stable over the all duration of follow-up. This study provides further evidence that ERT improves walking abilities and likely stabilizes respiratory function in adult patients with Pompe disease, with a ceiling effect for the 6MWT in the first 3 years of treatment.

Immunoglobulin Abnormalities in Gaucher Disease: an Analysis of 278 Patients Included in the French Gaucher Disease Registry.

Gaucher disease (GD) is a rare lysosomal autosomal-recessive disorder due to deficiency of glucocerebrosidase; polyclonal gammopathy (PG) and/or monoclonal gammopathy (MG) can occur in this disease. We aimed to describe these immunoglobulin abnormalities in a large cohort of GD patients and to study the risk factors, clinical significance, and evolution. Data for patients enrolled in the French GD Registry were studied retrospectively. The risk factors of PG and/or MG developing and their association with clinical bone events and severe thrombocytopenia, two markers of GD severity, were assessed with multivariable Cox models and the effect of GD treatment on gammaglobulin levels with linear/logarithmic mixed models. Regression of MG and the occurrence of hematological malignancies were described. The 278 patients included (132 males, 47.5%) were followed up during a mean (SD) of 19 (14) years after GD diagnosis. PG occurred in 112/235 (47.7%) patients at GD diagnosis or during follow-up and MG in 59/187 (31.6%). Multivariable analysis retained age at GD diagnosis as the only independent risk factor for MG (> 30 vs. ≤30 years, HR 4.71, 95%CI [2.40-9.27]; p < 0.001). Risk of bone events or severe thrombocytopenia was not significantly associated with PG or MG. During follow-up, non-Hodgkin lymphoma developed in five patients and multiple myeloma in one. MG was observed in almost one third of patients with GD. Immunoglobulin abnormalities were not associated with the disease severity. However, prolonged surveillance of patients with GD is needed because hematologic malignancies may occur.

The DM-scope registry: a rare disease innovative framework bridging the gap between research and medical care.

BACKGROUND: The relevance of registries as a key component for developing clinical research for rare diseases (RD) and improving patient care has been acknowledged by most stakeholders. As recent studies pointed to several limitations of RD registries our challenge was (1) to improve standardization and data comparability; (2) to facilitate interoperability between existing RD registries; (3) to limit the amount of incomplete data; (4) to improve data quality. This report describes the innovative concept of the DM-Scope Registry that was developed to achieve these objectives for Myotonic Dystrophy (DM), a prototypical example of highly heterogeneous RD. By the setting up of an integrated platform attractive for practitioners use, we aimed to promote DM epidemiology, clinical research and patients care management simultaneously. RESULTS: The DM-Scope Registry is a result of the collaboration within the French excellence network established by the National plan for RDs. Inclusion criteria is all genetically confirmed DM individuals, independently of disease age of onset. The dataset includes social-demographic data, clinical features, genotype, and biomaterial data, and is adjustable for clinical trial data collection. To date, the registry has a nationwide coverage, composed of 55 neuromuscular centres, encompassing the whole disease clinical and genetic spectrum. This widely used platform gathers almost 3000 DM patients (DM1 n = 2828, DM2 n = 142), both children (n = 322) and adults (n = 2648), which accounts for > 20% of overall registered DM patients internationally. The registry supported 10 research studies of various type i.e. observational, basic science studies and patient recruitment for clinical trials. CONCLUSION: The DM-Scope registry represents the largest collection of standardized data for the DM population. Our concept improved collaboration among health care professionals by providing annual follow-up of quality longitudinal data collection. The combination of clinical features and biomolecular materials provides a comprehensive view of the disease in a given population. DM-Scope registry proves to be a powerful device for promoting both research and medical care that is suitable to other countries. In the context of emerging therapies, such integrated platform contributes to the standardisation of international DM research and for the design of multicentre clinical trials. Finally, this valuable model is applicable to other RDs.

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.

Late-onset Pompe disease in France: molecular features and epidemiology from a nationwide study.

Pompe disease (PD) is caused by a deficiency of lysosomal acid α-glucosidase resulting from mutations in the GAA gene. The clinical spectrum ranges from a rapidly fatal multisystemic disorder (classic PD, onset < 1 year) to a milder adult onset myopathy. The aims of this study were to characterize the GAA mutations, to establish the disease epidemiology, and to identify potential genotype-phenotype correlations in French late-onset PD patients (onset ≥ 2 years) diagnosed since the 1970s. Data were collected from the two main laboratories involved in PD diagnosis and from the French Pompe registry. Two hundred forty-six patients (130 females and 116 males) were included, with a mean age at diagnosis of 43 years. Eighty-three different mutations were identified in the GAA gene, among which 28 were novel. These variants were spread all over the sequence and included 42 missense (one affecting start codon), 8 nonsense, 15 frameshift, 14 splice mutations, 3 small in-frame deletions, and one large deletion. The common c.-32-13T>G mutation was detected in 151/170 index cases. Other frequent mutations included the exon 18 deletion, the c.525del, and the missense mutations c.1927G>A (p.Gly643Arg) and c.655G>A (p.Gly219Arg). Patients carrying the c.-32-13T>G mutation had an older mean age at onset than patients non-exhibiting this mutation (36 versus 25 years). Patients with the same genotype had a highly variable age at onset. We estimated the frequency of late-onset PD in France around 1/69,927 newborns. In conclusion, we characterized the French cohort of late-onset PD patients through a nationwide study covering more than 40 years.

Is Going Beyond Rasch Analysis Necessary to Assess the Construct Validity of a Motor Function Scale?

OBJECTIVE: To examine whether a Rasch analysis is sufficient to establish the construct validity of the Motor Function Measure (MFM) and discuss whether weighting the MFM item scores would improve the MFM construct validity. DESIGN: Observational cross-sectional multicenter study. SETTING: Twenty-three physical medicine departments, neurology departments, or reference centers for neuromuscular diseases. PARTICIPANTS: Patients (N=911) aged 6 to 60 years with Charcot-Marie-Tooth disease (CMT), facioscapulohumeral dystrophy (FSHD), or myotonic dystrophy type 1 (DM1). INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): Comparison of the goodness-of-fit of the confirmatory factor analysis (CFA) model vs that of a modified multidimensional Rasch model on MFM item scores in each considered disease. RESULTS: The CFA model showed good fit to the data and significantly better goodness of fit than the modified multidimensional Rasch model regardless of the disease (P<.001). Statistically significant differences in item standardized factor loadings were found between DM1, CMT, and FSHD in only 6 of 32 items (items 6, 27, 2, 7, 9 and 17). CONCLUSIONS: For multidimensional scales designed to measure patient abilities in various diseases, a Rasch analysis might not be the most convenient, whereas a CFA is able to establish the scale construct validity and provide weights to adapt the item scores to a specific disease.