Transition and management of patients with Duchenne Muscular Dystrophy: a narrative review based on Italian experts' opinion and real-world experience.

Objectives: Duchenne Muscular Dystrophy (DMD) is a severe, progressive, X-linked disorder resulting in muscle wasting, progressive functional loss and cardiomyopathy. Therapeutic strategies feature glucocorticoid corticosteroids plus gene therapy/stop codon read-through, plus standards of care. Prolonged survival, delayed loss of ambulation (LoA), and innovative treatment prescriptions pose new clinical challenges, including identification of new outcome measures/targets and implementation of continuity of care. Methods: We report on the results of an Italian experts' meeting held in Rome, Italy on 20th April 2022. We aimed to: discuss challenges linked to transitioning from the ambulatory to the non-ambulatory phase, and from pediatric to adult care; collect experience on the importance of ongoing care and treatment in advanced disease stages and on the need to measure clinically relevant outcomes during disease progression after LoA. Results: Following LoA the main management focus shifts to cardiac, respiratory, orthopaedics, nutrition and upper limbs function. More data on clinical needs, available treatments, standards of care, frequency of follow-up, and transition should be collected in order to facilitate management optimisation. Shared protocols should be developed, especially to improve patients' management in the acute setting. Conclusions: Transition from paediatric to adult services and from the ambulatory to the non-ambulatory phase require a multidisciplinary approach and the Identification of clinically meaningful outcome measures, which should be described in long-term longitudinal studies.

The IAAM LTBP4 Haplotype is Protective Against Dystrophin-Deficient Cardiomyopathy.

Background: Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMD mutation type and location, and variants in other genes. Methods and Results: We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS). Using generalized estimating equation (GEE) models, we estimated the yearly rate of decrease of EF (-0.80%) and SF (-0.41%), while EDV increase was not significantly associated with age. Utilizing a multivariate generalized estimating equation (GEE) model we observed that mutations preserving the expression of the C-terminal Dp71 isoform of dystrophin were correlated with decreased EDV (-11.01 mL/m2, p = 0.03) while for dp116 were correlated with decreased EF (-4.14%, p = <0.001). The rs10880 genotype in the LTBP4 gene, previously shown to prolong ambulation, was also associated with increased EF and decreased EDV (+3.29%, p = 0.002, and -10.62 mL/m2, p = 0.008) with a recessive model. Conclusions: We quantitatively describe the progression of systolic dysfunction progression in DMD, confirm the effect of distal dystrophin isoform expression on the dystrophin-deficient heart, and identify a strong effect of LTBP4 genotype of DCM in DMD.

Continuitiy of care with ataluren in Duchenne Muscular Dystrophy patients with nonsense mutations after loss of ambulation. Personal experience.

Duchenne Muscular Dystrophy (DMD) includes predictable phases requiring dedicated standard treatments. Therapeutic strategies feature corticosteroids or the more recent gene therapy/stop codon read-through. Ataluren (Translarna®) is an oral drug promoting the readthrough of premature stop codons caused by nonsense mutation (nm) in order to produce full-length dystrophin. It was licensed by EMA in 2014 for ambulatory patients with nmDMD aged ≥ 5 years. Our aim is to report data on long-term ataluren use in Italian patients with nmDMD, with emphasis on continuity of the treatment after loss of ambulation (LoA). Four DMD patients aged between 16 and 24 years who lost ambulation between 12 and 14 years continued to take ataluren after LoA. The oldest patient, aged 24 years, is still taking a few steps. Even in those experiencing motor decline, PUL-test performances were stable and respiratory function satisfactory in all; two patients developed severe cardiomyopathy, stable in one. Therapeutic continuity with ataluren should be offered to all nmDMD patients after LoA given its favourable safety and efficacy profile. However, further research is recommended to identify additional clinically meaningful outcomes and treatment goals following LoA.