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.

Nivolumab serum concentration in metastatic melanoma patients could be related to outcome and enhanced immune activity: a gene profiling retrospective analysis.

BACKGROUND: Nivolumab is an anti-PD-1 antibody approved for treating metastatic melanoma (MM), for which still limited evidence is available on the correlation between drug exposure and patient outcomes. METHODS: In this observational retrospective study, we assessed whether nivolumab concentration is associated with treatment response in 88 patients with MM and if the patient's genetic profile plays a role in this association. RESULTS: We observed a statistically significant correlation between nivolumab serum concentration and clinical outcomes, measured as overall and progression-free survival. Moreover, patients who achieved a clinical or partial response tended to have higher levels of nivolumab than those who reached stable disease or had disease progression. However, the difference was not statistically significant. In particular, patients who reached a clinical response had a significantly higher concentration of nivolumab and presented a distinct genetic signature, with more marked activation of ICOS and other genes involved in effector T-cells mediated proinflammatory pathways. CONCLUSIONS: In conclusion, these preliminary results show that in patients with MM, nivolumab concentration correlates with clinical outcomes and is associated with an increased expression of ICOS and other genes involved in the activation of T effectors cells.

PD-L1+ neutrophils as novel biomarkers for stage IV melanoma patients treated with nivolumab.

Melanoma displays a rising incidence, and the mortality associated with metastatic form remains high. Monoclonal antibodies that block programmed death (PD-1) and PD Ligand 1 (PD-L1) network have revolutionized the history of metastatic disease. PD-L1 is expressed on several immune cells and can be also expressed on human neutrophils (PMNs). The role of peripheral blood PMNs as predictive biomarkers in anti-PD-1 therapy of melanoma is largely unknown. In this study, we aimed to determine activation status and PD-L1 expression on human neutrophils as possible novel biomarkers in stage IV melanoma patients (MPs). We found that PMNs from MPs displayed an activated phenotype and increased PD-L1 levels compared to healthy controls (HCs). Patients with lower PD-L1+ PMN frequencies displayed better progression-free survival (PFS) and overall survival (OS) compared to patients with high PD-L1+ PMN frequencies. Multivariate analysis showed that PD-L1+ PMNs predicted patient outcome in BRAF wild type MP subgroup but not in BRAF mutated MPs. PD-L1+ PMN frequency emerges as a novel biomarker in stage IV BRAF wild type MPs undergoing anti-PD-1 immunotherapy. Our findings suggest further evaluation of the role of neutrophil subsets and their mediators in melanoma patients undergoing immunotherapy.

Age, corticosteroid treatment and site of mutations affect motor functional changes in young boys with Duchenne Muscular Dystrophy.

The aim of this study was to establish the possible effect of age, corticosteroid treatment and brain dystrophin involvement on motor function in young boys affected by Duchenne Muscular Dystrophy who were assessed using the North Star Ambulatory Assessment between the age of 4 and 7 years. The study includes 951 North Star assessments from 226 patients. Patients were subdivided according to age, to the site of mutation and therefore to the involvement of different brain dystrophin isoforms and to corticosteroids duration. There was a difference in the maximum North Star score achieved among patients with different brain dystrophin isoforms (p = 0.007). Patients with the involvement of Dp427, Dp140 and Dp71, had lower maximum NSAA scores when compared to those with involvement of Dp427 and Dp140 or of Dp427 only. The difference in the age when the maximum score was achieved in the different subgroups did not reach statistical significance. Using a linear regression model on all assessments we found that each of the three variables, age, site of mutation and corticosteroid treatment had an influence on the NSAA values and their progression over time. A second analysis, looking at 12-month changes showed that within this time interval the magnitude of changes was related to corticosteroid treatment but not to site of mutation. Our findings suggest that each of the considered variables appear to play a role in the progression of North Star scores in patients between the age of 4 and 7 years and that these should be carefully considered in the trial design of boys in this age range.

Genetic modifiers of upper limb function in Duchenne muscular dystrophy.

Genetic modifiers of Duchenne muscular dystrophy (DMD) are variants located in genes different from the disease-causing gene DMD, but associated with differences in disease onset, progression, or response to treatment. Modifiers described so far have been tested mainly for associations with ambulatory function, while their effect on upper limb function, which is especially relevant for quality of life and independence in non-ambulatory patients, is unknown. We tested genotypes at several known modifier loci (SPP1, LTBP4, CD40, ACTN3) for association with Performance Upper Limb version 1.2 score in an Italian multicenter cohort, and with Brooke scale score in the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS), using generalized estimating equation (GEE) models of longitudinally collected data, with age and glucocorticoid treatment as covariates. CD40 rs1883832, previously linked to earlier loss of ambulation, emerged as a modifier of upper limb function, negatively affecting shoulder and distal domains of PUL (p = 0.023 and 0.018, respectively) in the Italian cohort, as well as of Brooke score (p = 0.018) in the CINRG-DNHS. These findings will be useful for the design and interpretation of clinical trials in DMD, especially for non-ambulatory populations.

Clinical Categorization Algorithm (CLICAL) and Machine Learning Approach (SRF-CLICAL) to Predict Clinical Benefit to Immunotherapy in Metastatic Melanoma Patients: Real-World Evidence from the Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy.

The real-life application of immune checkpoint inhibitors (ICIs) may yield different outcomes compared to the benefit presented in clinical trials. For this reason, there is a need to define the group of patients that may benefit from treatment. We retrospectively investigated 578 metastatic melanoma patients treated with ICIs at the Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale" of Napoli, Italy (INT-NA). To compare patients' clinical variables (i.e., age, lactate dehydrogenase (LDH), neutrophil-lymphocyte ratio (NLR), eosinophil, BRAF status, previous treatment) and their predictive and prognostic power in a comprehensive, non-hierarchical manner, a clinical categorization algorithm (CLICAL) was defined and validated by the application of a machine learning algorithm-survival random forest (SRF-CLICAL). The comprehensive analysis of the clinical parameters by log risk-based algorithms resulted in predictive signatures that could identify groups of patients with great benefit or not, regardless of the ICI received. From a real-life retrospective analysis of metastatic melanoma patients, we generated and validated an algorithm based on machine learning that could assist with the clinical decision of whether or not to apply ICI therapy by defining five signatures of predictability with 95% accuracy.

Test-retest reliability of the Performance of Upper Limb (PUL) module for muscular dystrophy patients.

The Performance of the Upper Limb (PUL) module is an externally-assessed clinical scale, initially designed for the Duchenne muscular dystrophy population. It provides an upper extremity functional score suitable for both weaker ambulatory and non-ambulatory phases up to the severely impaired patients. It is capable of characterizing overall progression and severity of disease and of tracking the stereotypical proximal-to-distal progressive loss of upper limb function in muscular dystrophy. Since the PUL module has been validated only with Duchenne patients, its use also for Becker and Limb-Girdle muscular dystrophy patients has been here evaluated, to verify its reliability and extend its use. In particular, two different assessors performed this scale on 32 dystrophic subjects in two consecutive days. The results showed that the PUL module has high reliability, both absolute and relative, based on the calculation of Pearson's r (0.9942), Intraclass Correlation Coefficient (0.9943), Standard Error of Measurement (1.36), Minimum Detectable Change (3.77), and Coefficient of Variation (3%). The Minimum Detectable Change, in particular, can be used in clinical trials to perform a comprehensive longitudinal evaluation of the effects of interventions with the lapse of time. According to this analysis, an intervention is effective if the difference in the PUL score between subsequent evaluation points is equal or higher than 4 points; otherwise, the observed effect is not relevant. Inter-rater reliability with ten different assessors was evaluated, and it has been demonstrated that deviation from the mean is lower than calculated Minimum Detectable Change. The present work provides evidence that the PUL module is a reliable and valid instrument for measuring upper limb ability in people with different forms of muscular dystrophy. Therefore, the PUL module might be extended to other pathologies and reliably used in multicenter settings.

Interpretation of the Epigenetic Signature of Facioscapulohumeral Muscular Dystrophy in Light of Genotype-Phenotype Studies.

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by incomplete penetrance and intra-familial clinical variability. The disease has been associated with the genetic and epigenetic features of the D4Z4 repetitive elements at 4q35. Recently, D4Z4 hypomethylation has been proposed as a reliable marker in the FSHD diagnosis. We exploited the Italian Registry for FSHD, in which FSHD families are classified using the Clinical Comprehensive Evaluation Form (CCEF). A total of 122 index cases showing a classical FSHD phenotype (CCEF, category A) and 110 relatives were selected to test with the receiver operating characteristic (ROC) curve, the diagnostic and predictive value of D4Z4 methylation. Moreover, we performed DNA methylation analysis in selected large families with reduced penetrance characterized by the co-presence of subjects carriers of one D4Z4 reduced allele with no signs of disease or presenting the classic FSHD clinical phenotype. We observed a wide variability in the D4Z4 methylation levels among index cases revealing no association with clinical manifestation or disease severity. By extending the analysis to family members, we revealed the low predictive value of D4Z4 methylation in detecting the affected condition. In view of the variability in D4Z4 methylation profiles observed in our large cohort, we conclude that D4Z4 methylation does not mirror the clinical expression of FSHD. We recommend that measurement of this epigenetic mark must be interpreted with caution in clinical practice.

Genetic modifiers of respiratory function in Duchenne muscular dystrophy.

OBJECTIVE: Respiratory insufficiency is a major complication of Duchenne muscular dystrophy (DMD). Its progression shows considerable interindividual variability, which has been less thoroughly characterized and understood than in skeletal muscle. We collected pulmonary function testing (PFT) data from a large retrospective cohort followed at Centers collaborating in the Italian DMD Network. Furthermore, we analyzed PFT associations with different DMD mutation types, and with genetic variants in SPP1, LTBP4, CD40, and ACTN3, known to modify skeletal muscle weakness in DMD. Genetic association findings were independently validated in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). METHODS AND RESULTS: Generalized estimating equation analysis of 1852 PFTs from 327 Italian DMD patients, over an average follow-up time of 4.5 years, estimated that forced vital capacity (FVC) declined yearly by -4.2%, forced expiratory volume in 1 sec by -5.0%, and peak expiratory flow (PEF) by -2.9%. Glucocorticoid (GC) treatment was associated with higher values of all PFT measures (approximately + 15% across disease stages). Mutations situated 3' of DMD intron 44, thus predicted to alter the expression of short dystrophin isoforms, were associated with lower (approximately -6%) PFT values, a finding independently validated in the CINRG-DNHS. Deletions amenable to skipping of exon 51 and 53 were independently associated with worse PFT outcomes. A meta-analysis of the two cohorts identified detrimental effects of SPP1 rs28357094 and CD40 rs1883832 minor alleles on both FVC and PEF. INTERPRETATION: These findings support GC efficacy in delaying respiratory insufficiency, and will be useful for the design and interpretation of clinical trials focused on respiratory endpoints in DMD.

Mental health and coping strategies in families of children and young adults with muscular dystrophies.

BACKGROUND: Living with a progressive disease as muscular dystrophy (MD) can be challenging for the patient and the entire family from both emotional and practical point of view. We aimed to extend our previously published data about mental health in patients with MDs, also investigating coping profiles of both themselves and their parents. Furthermore, we wanted to verify whether psychological adaptation of patients can be predicted by coping strategies, taking also into account physical impairment, cognitive level and socioeconomic status. METHODS: 112 patients with MDs, aged 2-32 were included. Their emotional and behavioural features were assessed through parent- and self-report Achenbach System for Empirically Based Assessment questionnaires and Strength and Difficulties Questionnaires. Development and Well-Being Assessment or Autism Diagnostic Observation Schedule were administered to confirm suspected diagnoses. Coping profile of both parents and patients was assessed through the self-administered New Italian Version of the Coping Orientation to the Problems Experienced questionnaire and its relationship with emotional/behavioural outcome was examined in linear regression analyses. RESULTS: High prevalence of intellectual disability and autism spectrum disorders was confirmed in Duchenne MD. Despite the high rate of internalizing symptomatology, we did not report higher rate of psychopathological disorders compared to general population. Parents tend to rely more on positive reinterpretation and less on disengagement coping. Avoidance coping, whether used by parents or patients, and ID, predicted increased emotional/behavioural problems. CONCLUSIONS: Psychosocial interventions should address problems of anxiety and depression that people with MDs frequently experience, even through fostering parents' and childrens' engagement coping over disengagement coping.

Nusinersen treatment and cerebrospinal fluid neurofilaments: An explorative study on Spinal Muscular Atrophy type 3 patients.

The antisense oligonucleotide Nusinersen has been recently licensed to treat spinal muscular atrophy (SMA). Since SMA type 3 is characterized by variable phenotype and milder progression, biomarkers of early treatment response are urgently needed. We investigated the cerebrospinal fluid (CSF) concentration of neurofilaments in SMA type 3 patients treated with Nusinersen as a potential biomarker of treatment efficacy. The concentration of phosphorylated neurofilaments heavy chain (pNfH) and light chain (NfL) in the CSF of SMA type 3 patients was evaluated before and after six months since the first Nusinersen administration, performed with commercially available enzyme-linked immunosorbent assay (ELISA) kits. Clinical evaluation of SMA patients was performed with standardized motor function scales. Baseline neurofilament levels in patients were comparable to controls, but significantly decreased after six months of treatment, while motor functions were only marginally ameliorated. No significant correlation was observed between the change in motor functions and that of neurofilaments over time. The reduction of neurofilament levels suggests a possible early biochemical effect of treatment on axonal degeneration, which may precede changes in motor performance. Our study mandates further investigations to assess neurofilaments as a marker of treatment response.

Multiparametric quantitative MRI assessment of thigh muscles in limb-girdle muscular dystrophy 2A and 2B.

INTRODUCTION: The aim of this study was to apply quantitative MRI (qMRI) to assess structural modifications in thigh muscles of subjects with limb girdle muscular dystrophy (LGMD) 2A and 2B with long disease duration. METHODS: Eleven LGMD2A, 9 LGMD2B patients and 11 healthy controls underwent a multi-parametric 3T MRI examination of the thigh. The protocol included structural T1-weighted images, DIXON sequences for fat fraction calculation, T2 values quantification and diffusion MRI. Region of interest analysis was performed on 4 different compartments (anterior compartment, posterior compartment, gracilis, sartorius). RESULTS: Patients showed high levels of fat infiltration as measured by DIXON sequences. Sartorius and anterior compartment were more infiltrated in LGMD2B than LGMD2A patients. T2 values were mildly reduced in both disorders. Correlations between clinical scores and qMRI were found. CONCLUSIONS: qMRI measures may help to quantify muscular degeneration, but careful interpretation is needed when fat infiltration is massive. Muscle Nerve 58: 550-558, 2018.

Measurement of respiratory function decline in patients with Duchenne muscular dystrophy: a conjoint analysis.

AIM: In Duchenne muscular dystrophy (DMD), little attention has been paid to severity of respiratory function decline (RFD) based on disease progression. We performed a conjoint analysis among 123 Italian clinicians to generate a scale for RFD in DMD patients. METHODS: Before the interview, 11 attributes were selected by discussion among experts. 32 'patient profiles' were generated. Each physician assessed the severity of RFD for each profile. Each level/attribute was assigned an estimated usefulness to understand its impact on RFD. RESULTS: The identified attributes were forced vital capacity, forced vital capacity decline, dysphagia, type of ventilation and peak cough flow. These results allowed the development of a scale for RFD severity. CONCLUSION: This scale can stratify DMD patients according to the severity of their RFD.

Assessing mental health in boys with Duchenne muscular dystrophy: Emotional, behavioural and neurodevelopmental profile in an Italian clinical sample.

OBJECTIVE: To evaluate through a comprehensive protocol, the psychopathological profile of DMD boys. The primary aim of this observational study was to describe the emotional and behavioural profile and the neurodevelopmental problems of Italian boys with Duchenne Muscular Dystrophy (DMD); the secondary aim was to explore the relation between psychopathological profile and DMD genotype. METHOD: 47 DMD boys, aged 2-18, were included in the study and assessed through structured and validated tools including Wechsler scales or Griffiths for cognitive ability, Child Behavior Check List (CBCL), Youth Self Report (YSR) and Strengths and Difficulties Questionnaire (SDQ) for emotional and behavioural features. Patients "at risk" based on questionnaires scores were evaluated by a clinical structured interview using Development and Well Being Assessment (DAWBA) or Autism Diagnostic Observation Schedule (ADOS), as required. RESULTS: The 47 enrolled patients, defined with a Full Scale Intelligence Quotient (FSIQ) of 80.38 (one SD below average), and presenting a large and significant difference in FSIQ in relation to the site of mutation along the dystrophin gene (distal mutations associated with a more severe cognitive deficit), were showing Internalizing Problems (23.4%) and Autism Spectrum Disorders (14.8%). Interestingly, an association of internalizing problems with distal deletion of the DMD gene is documented. CONCLUSION: Even though preliminary, these data show that the use of validated clinical instruments, that focus on the impact of emotional/behaviour problems on everyday life, allows to carefully identify clinically significant psychopathology.

A novel clinical tool to classify facioscapulohumeral muscular dystrophy phenotypes.

Based on the 7-year experience of the Italian Clinical Network for FSHD, we revised the FSHD clinical form to describe, in a harmonized manner, the phenotypic spectrum observed in FSHD. The new Comprehensive Clinical Evaluation Form (CCEF) defines various clinical categories by the combination of different features. The inter-rater reproducibility of the CCEF was assessed between two examiners using kappa statistics by evaluating 56 subjects carrying the molecular marker used for FSHD diagnosis. The CCEF classifies: (1) subjects presenting facial and scapular girdle muscle weakness typical of FSHD (category A, subcategories A1-A3), (2) subjects with muscle weakness limited to scapular girdle or facial muscles (category B subcategories B1, B2), (3) asymptomatic/healthy subjects (category C, subcategories C1, C2), (4) subjects with myopathic phenotype presenting clinical features not consistent with FSHD canonical phenotype (D, subcategories D1, D2). The inter-rater reliability study showed an excellent concordance of the final four CCEF categories with a κ equal to 0.90; 95 % CI (0.71; 0.97). Absolute agreement was observed for categories C and D, an excellent agreement for categories A [κ = 0.88; 95 % CI (0.75; 1.00)], and a good agreement for categories B [κ = 0.79; 95 % CI (0.57; 1.00)]. The CCEF supports the harmonized phenotypic classification of patients and families. The categories outlined by the CCEF may assist diagnosis, genetic counseling and natural history studies. Furthermore, the CCEF categories could support selection of patients in randomized clinical trials. This precise categorization might also promote the search of genetic factor(s) contributing to the phenotypic spectrum of disease.

Long-term follow-up of a patient with 5q31.3 microdeletion syndrome and the smallest de novo 5q31.2q31.3 deletion involving PURA.

BACKGROUND: Purine-rich element binding protein A (PURA, MIM 600473), is considered the crucial phenocritical gene for an emerging 5q31.3 microdeletion syndrome. To date, at least seven affected individuals with overlapping 5q31.2q31.3 deletions, varying in size from 2.6 to 5 Mb, have been reported sharing neurologic features such as severe developmental delay, neonatal hypotonia, early feeding difficulties, respiratory distress and EEG abnormalities. The recent finding that de novo PURA point mutations are indeed sufficient to cause the severe neurological symptoms also observed in patients with 5q31.2q31.3 deletion further reinforces the gene's causative role in 5q31.3 microdeletion syndrome. CASE PRESENTATION: The present patient, aged 26 years, is the oldest reported individual and carries the smallest de novo 5q31.2q31.3 microdeletion encompassing PURA (360 kb). Her clinical history summarizes the mainly neurodevelopmental phenotype described in children with 5q31.3 microdeletion syndrome. In addition, our patient exhibited a remarkable deterioration of clinical symptoms, starting at the beginning of adolescence, pubertal delay and primary amenorrhea. While epileptic seizures were successfully treated during her life, feeding problems showed a poor outcome, her respiratory problems increased and eventually became severe enough to cause her death. CONCLUSION: The clinical and molecular findings reported here provide further evidence that 5q31.3 microdeletion syndrome is a clinically discernible PURA-related disorder and describe the previously unreported natural evolution of the disease in a 26 years old patient.

Benefits of glucocorticoids in non-ambulant boys/men with Duchenne muscular dystrophy: A multicentric longitudinal study using the Performance of Upper Limb test.

The aim of this study was to establish the possible effect of glucocorticoid treatment on upper limb function in a cohort of 91 non-ambulant DMD boys and adults of age between 11 and 26 years. All 91 were assessed using the Performance of Upper Limb test. Forty-eight were still on glucocorticoid after loss of ambulation, 25 stopped steroids at the time they lost ambulation and 18 were GC naïve or had steroids while ambulant for less than a year. At baseline the total scores ranged between 0 and 74 (mean 41.20). The mean total scores were 47.92 in the glucocorticoid group, 36 in those who stopped at loss of ambulation and 30.5 in the naïve group (p < 0.001). The 12-month changes ranged between -20 and 4 (mean -4.4). The mean changes were -3.79 in the glucocorticoid group, -5.52 in those who stopped at loss of ambulation and -4.44 in the naïve group. This was more obvious in the patients between 12 and 18 years and at shoulder and elbow levels. Our findings suggest that continuing glucocorticoids throughout teenage years and adulthood after loss of ambulation appears to have a beneficial effect on upper limb function.

Early Neurodevelopmental Findings Predict School Age Cognitive Abilities in Duchenne Muscular Dystrophy: A Longitudinal Study.

OBJECTIVE: Neurodevelopmental and cognitive difficulties are known to occur frequently in boys with Duchenne muscular dystrophy but so far none of the published studies have reported both early neurodevelopmental assessments and cognitive tests in the same cohort. The aim of the present longitudinal study was to establish the correlation between early neurodevelopmental assessments performed in preschool boys and the cognitive scales performed at school age or later. METHODS: We performed cognitive tests at school age (mean age 5.7 year ±1.7 SD) (69 months+19 SD) in a cohort of Duchenne boys, previously assessed using the Griffiths scales before the age of 4 years (mean age when the Griffiths scales were performed 30 months ±8.9 SD). RESULTS: The range of total Developmental quotients on the Griffiths ranged between 56 and 116 (mean 89 ± 15.6 SD). The total Intelligence Quotients on the Wechsler scales ranged between 35 and 119 (mean 87 ± 17.2 SD). There was a significant correlation between the findings on the two scales. P = <0.0001. When we subdivided the cohort according to site of mutations, there was a difference between boys with mutations upstream exon 44 and those with mutations in exon 44-45 affecting Dp140 on both Developmental and Intelligence Quotient (p 0.01 and p 0,003 respectively). CONCLUSIONS: Our results confirm that Duchenne boys tend to slightly underperform on both neurodevelopmental and cognitive assessments. Early neurodevelopmental findings correlated with the cognitive results obtained at school age with a clear concordance between subscales exploring similar domains on the two scales.

Reliability of the Performance of Upper Limb assessment in Duchenne muscular dystrophy.

The Performance of Upper Limb was specifically designed to assess upper limb function in Duchenne muscular dystrophy. The aim of this study was to assess (1) a cohort of typically developing children from the age of 3years onwards in order to identify the age when the activities assessed in the individual items are consistently achieved, and (2) a cohort of 322 Duchenne children and young adults to establish the range of findings at different ages. We collected normative data for the scale validation on 277 typically developing subjects from 3 to 25years old. A full score was consistently achieved by the age of 5years. In the Duchenne cohort there was early involvement of the proximal muscles and a proximal to distal progressive involvement. The scale was capable of measuring small distal movements, related to activities of daily living, even in the oldest and weakest patients. Our data suggest that the assessment can be reliably used in both ambulant and non ambulant Duchenne patients in a multicentric setting and could therefore be considered as an outcome measure for future trials.