This table is published annually in the December issue. Its purpose is to provide the reader of Neuromuscular Disorders with an updated list of monogenic neuromuscular diseases due to a primary ...defect residing in the nuclear genome. It comprises diseases in which the causative gene is known or at least localized on a chromosome, if not yet identified. Diseases for which the locus has not been mapped or which are due to defects involving mitochondrial genes are not included.
Thousands of mutations are identified yearly. Although many directly affect protein expression, an increasing proportion of mutations is now believed to influence mRNA splicing. They mostly affect ...existing splice sites, but synonymous, non-synonymous or nonsense mutations can also create or disrupt splice sites or auxiliary cis-splicing sequences. To facilitate the analysis of the different mutations, we designed Human Splicing Finder (HSF), a tool to predict the effects of mutations on splicing signals or to identify splicing motifs in any human sequence. It contains all available matrices for auxiliary sequence prediction as well as new ones for binding sites of the 9G8 and Tra2-β Serine-Arginine proteins and the hnRNP A1 ribonucleoprotein. We also developed new Position Weight Matrices to assess the strength of 5′ and 3′ splice sites and branch points. We evaluated HSF efficiency using a set of 83 intronic and 35 exonic mutations known to result in splicing defects. We showed that the mutation effect was correctly predicted in almost all cases. HSF could thus represent a valuable resource for research, diagnostic and therapeutic (e.g. therapeutic exon skipping) purposes as well as for global studies, such as the GEN2PHEN European Project or the Human Variome Project.
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.
Pathogenic variants in
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
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
-related dystrophies in humans, which should be taken into consideration for future clinical trials.
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;
< 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.
To monitor treatment effects in patients with congenital myopathies and congenital muscular dystrophies, valid outcome measures are necessary. The Motor Function Measure (MFM) was examined for ...robustness, and changes are proposed for better adequacy.
Observational study based on data previously collected from several cohorts.
Nineteen departments of physical medicine or neuromuscular consultation in France, Belgium, and the United States.
Patients (N=289) aged 5 to 77 years.
None.
A Rasch analysis examined the robustness of the MFM across the disease spectrum. The 3 domains of the scale (standing position and transfers, axial and proximal motor function, and distal motor function) were independently examined with a partial credit model.
The original 32-item MFM did not sufficiently fit the Rasch model expectations in either of its domains. Switching from a 4- to a 3-category response scale in 18 items restored response order in 16. Various additional checks suggested the removal of 7 items. The resulting Rasch-scaled Motor Function Measure with 25 items for congenital disorders of the muscle (Rs-MFM25(CDM)) demonstrated a good fit to the Rasch model. Domain 1 was well targeted to the whole severity spectrum-close mean locations for items and persons (0 vs 0.316)-whereas domains 2 and 3 were better targeted to severe cases. The reliability coefficients of the Rs-MFM25(CDM) suggested sufficient ability for each summed score to distinguish between patient groups (0.9, 0.8, and 0.7 for domains 1, 2, and 3, respectively). A sufficient agreement was found between results of the Rasch analysis and physical therapists' opinions.
The Rs-MFM25(CDM) can be considered a clinically relevant linear scale in each of its 3 domains and may be soon reliably used for assessment in congenital disorders of the muscle.
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