Cognitive impairment in adult myotonic dystrophies : a longitudinal study

The clinical relevance and extent of cognitive impairment in adult myotonic dystrophy type 1 (DM1) and 2 (DM2) is still unclear. The aim of this study was to determine whether previously reported cognitive abnormalities progress over time and if this occurs in DM2 as it does in DM1. Fifty-six patients with DM1 and 29 patients with DM2 were subjected to muscle strength assessment, and to a complete battery of neuropsychological tests. Repeated assessment was performed in 20 DM1 and 13 DM2 over time (DM1 mean follow-up: 7.3\ub12.7 years; DM2 mean follow- up: 9.5\ub12.4 years). Muscle strength and test scores for frontal lobe functions worsened significantly over time (p<0.01), in both DM1 and DM2. DM2 is a progressive muscle disorder, although less severe than DM1. In both DM1 and DM2 frontal cognitive impairment (attentional) worsens over time but does not extend to additional areas of cognition

Characterization of pulmonary function in 10â18 year old patients with Duchenne muscular dystrophy

Pulmonary function loss in patients with Duchenne muscular dystrophy (DMD) is progressive and leads to pulmonary insufficiency. The purpose of this study in 10â18 year old patients with DMD is the assessment of the inter-correlation between pulmonary function tests (PFTs), their reliability and the association with the general disease stage measured by the Brooke score. Dynamic PFTs (peak expiratory flow [PEF], forced vital capacity [FVC], forced expiratory volume in one second [FEV1]) and maximum static airway pressures (MIP, MEP) were prospectively collected from 64 DMD patients enrolled in the DELOS trial (ClinicalTrials.gov, number NCT01027884). Baseline PEF percent predicted (PEF%p) was <80% and patients had stopped taking glucocorticoids at least 12 months prior to study start. At baseline PEF%p, FVC%p and FEV1%p correlated well with each other (Spearman's rho: PEF%pâFVC%p: 0.54; PEF%pâFEV1%p: 0.72; FVC%pâFEV1%p: 0.91). MIP%p and MEP%p correlated well with one another (MIP%pâMEP%p: 0.71) but less well with PEF%p (MIP%pâPEF%p: 0.40; MEP%pâPEF%p: 0.41) and slightly better with FVC%p (MIP%pâFVC%p: 0.59; MEP%pâFVC%p: 0.74). The within-subject coefficients of variation (CV) for successive measures were 6.97% for PEF%p, 6.69% for FVC%p and 11.11% for FEV1%p, indicating that these parameters could be more reliably assessed compared to maximum static airway pressures (CV for MIP%p: 18.00%; MEP%p: 15.73%). Yearly rates of PFT decline (placebo group) were larger in dynamic parameters (PEF%p: â8.9% [SD 2.0]; FVC%p: â8.7% [SD 1.1]; FEV1%p: â10.2% [SD 2.0]) than static airway pressures (MIP%p: â4.5 [SD 1.3]; MEP%p: â2.8 [SD 1.1]). A considerable drop in dynamic pulmonary function parameters was associated with loss of upper limb function (transition from Brooke score category 4 to category 5). In conclusion, these findings expand the understanding of the reliability, correlation and evolution of different pulmonary function measures in DMD patients who are in the pulmonary function decline phase

Idebenone reduces respiratory complications in patients with Duchenne muscular dystrophy

In Duchenne muscular dystrophy (DMD), progressive loss of respiratory function leads to restrictive pulmonary disease and places patients at significant risk for severe respiratory complications. Of particular concern are ineffective cough, secretion retention and recurrent respiratory tract infections. In a Phase 3 randomized controlled study (DMD Long-term Idebenone Study, DELOS) in DMD patients 10–18 years of age and not taking concomitant glucocorticoid steroids, idebenone (900 mg/day) reduced significantly the loss of respiratory function over a 1-year study period. In a post-hoc analysis of DELOS we found that more patients in the placebo group compared to the idebenone group experienced bronchopulmonary adverse events (BAEs): placebo: 17 of 33 patients, 28 events; idebenone: 6 of 31 patients, 7 events. The hazard ratios (HR) calculated “by patient” (HR 0.33, p = 0.0187) and for “all BAEs” (HR 0.28, p = 0.0026) indicated a clear idebenone treatment effect. The overall duration of BAEs was 222 days (placebo) vs. 82 days (idebenone). In addition, there was also a difference in the use of systemic antibiotics utilized for the treatment of BAEs. In the placebo group, 13 patients (39.4%) reported 17 episodes of antibiotic use compared to 7 patients (22.6%) reporting 8 episodes of antibiotic use in the idebenone group. Furthermore, patients in the placebo group used systemic antibiotics for longer (105 days) compared to patients in the idebenone group (65 days). This post-hoc analysis of DELOS indicates that the protective effect of idebenone on respiratory function is associated with a reduced risk of bronchopulmonary complications and a reduced need for systemic antibiotics

Clinical and molecular characterization of a cohort of patients with novel nucleotide alterations of the Dystrophin gene detected by direct sequencing

<p>Abstract</p> <p>Background</p> <p>Duchenne and Becker Muscular dystrophies (DMD/BMD) are allelic disorders caused by mutations in the dystrophin gene, which encodes a sarcolemmal protein responsible for muscle integrity. Deletions and duplications account for approximately 75% of mutations in DMD and 85% in BMD. The implementation of techniques allowing complete gene sequencing has focused attention on small point mutations and other mechanisms underlying complex rearrangements.</p> <p>Methods</p> <p>We selected 47 patients (41 families; 35 DMD, 6 BMD) without deletions and duplications in <it>DMD </it>gene (excluded by multiplex ligation-dependent probe amplification and multiplex polymerase chain reaction analysis). This cohort was investigated by systematic direct sequence analysis to study sequence variation. We focused our attention on rare mutational events which were further studied through transcript analysis.</p> <p>Results</p> <p>We identified 40 different nucleotide alterations in DMD gene and their clinical correlates; altogether, 16 mutations were novel. DMD probands carried 9 microinsertions/microdeletions, 19 nonsense mutations, and 7 splice-site mutations. BMD patients carried 2 nonsense mutations, 2 splice-site mutations, 1 missense substitution, and 1 single base insertion. The most frequent stop codon was TGA (n = 10 patients), followed by TAG (n = 7) and TAA (n = 4). We also analyzed the molecular mechanisms of five rare mutational events. They are two frame-shifting mutations in the <it>DMD </it>gene 3'end in BMD and three novel splicing defects: IVS42: c.6118-3C>A, which causes a leaky splice-site; c.9560A>G, which determines a cryptic splice-site activation and c.9564-426 T>G, which creates pseudoexon retention within IVS65.</p> <p>Conclusion</p> <p>The analysis of our patients' sample, carrying point mutations or complex rearrangements in <it>DMD </it>gene, contributes to the knowledge on phenotypic correlations in dystrophinopatic patients and can provide a better understanding of pre-mRNA maturation defects and dystrophin functional domains. These data can have a prognostic relevance and can be useful in directing new therapeutic approaches, which rely on a precise definition of the genetic defects as well as their molecular consequences.</p

A wearable device for breathing frequency monitoring: A pilot study on patients with muscular dystrophy

Patients at risk of developing respiratory dysfunctions, such as patients with severe forms of muscular dystrophy, need a careful respiratory assessment, and periodic follow-up visits to monitor the progression of the disease. In these patients, at-home continuous monitoring of respiratory activity patterns could provide additional understanding about disease progression, allowing prompt clinical intervention. The core aim of the present study is thus to investigate the feasibility of using an innovative wearable device for respiratory monitoring, particularly breathing frequency variation assessment, in patients with muscular dystrophy. A comparison of measurements of breathing frequency with gold standard methods showed that the device based on the inertial measurement units (IMU-based device) provided optimal results in terms of accuracy errors, correlation, and agreement. Participants positively evaluated the device for ease of use, comfort, usability, and wearability. Moreover, preliminary results confirmed that breathing frequency is a valuable breathing parameter to monitor, at the clinic and at home, because it strongly correlates with the main indexes of respiratory function

Alterazioni proteine tau liquorali e quoziente intellettivo (QI) nelle Distrofie Miotonichew di tipo 1 (DM1) e di tipo 2 (DM2).

PREMESSE: La significativit\ue0 clinica delle alterazioni delle proteine tau dimostrata nella DM1 non \ue8 chiara ed \ue8 ancora da dimostrare nella DM2. OBIETTIVI: (i) Determinare le proteine liquorali tau nei pazienti con DM1 e DM2; (ii) Stabilire se i livelli di proteine tau correlano con i livelli di QI. METODI: 24 DM1 (50.3\ub112.2 anni;CTG:600-800n) e 9 DM2 (56.3\ub113.1 anni) sono stati sottoposti a: (i) bilancio muscolare (scala MRC);(ii)Wais-R (QI);(iii) determinazione liquorale di tau totale (t-tau), tau fosforilata (p-tau), ed Abeta(1-42) (ELISA; Innogenetics, Belgio). I risultati sono stati confrontati con 16 controlli sani di pari et\ue0, sesso e grado di educazione. RISULTATI:(i) I livelli medi di t-tau e p-tau sono significativamente diversi nei DM1 rispetto ai controlli (p< 0.05);(ii) I livelli medi di t-tau sono superiori alla norma solo in 6/24 DM1; (ii) I livelli di p-tau sono superiori alla norma in quasi tutti i DM1 (22/24, 91%) ma solo in 6/9 DM2 (66%);(iii) 2/24 DM1 (12.5%) e 1/9 DM2 (22%) hanno valori di QI < 79 e 1/24 DM1 e 1/9 DM2 hanno QI < 69;(iv) I livelli di tau ed i valori di QI sono indipendenti dal grado di ipostenia. CONCLUSIONI: Tali dati preliminari confermano ulteriormente che l\u2019interessamento cognitivo nelle forme adulte di DM \ue8 indiscusso. Sottolineano tuttavia che \ue8 necessario correlare i dati con aspetti neuropsicologici maggiormente compromessi (funzioni visuo-spaziali, frontali) e con il grado di atrofia corticale e sofferenza della bianca mediante studi quantitativi di RM