Detecting early signs in Duchenne muscular dystrophy: comprehensive review and diagnostic implications

Despite the early onset of clinical signs suggestive of Duchenne muscular dystrophy (DMD), a diagnosis is often not made until four years of age or older, with a diagnostic delay of up to two years from the appearance of the first symptoms. As disease-modifying therapies for DMD become available that are ideally started early before irreversible muscle damage occurs, the importance of avoiding diagnostic delay increases. Shortening the time to a definite diagnosis in DMD allows timely genetic counseling and assessment of carrier status, initiation of multidisciplinary standard care, timely initiation of appropriate treatments, and precise genetic mutation characterization to assess suitability for access to drugs targeted at specific mutations while reducing the emotional and psychological family burden of the disease. This comprehensive literature review describes the early signs of impairment in DMD and highlights the bottlenecks related to the different diagnostic steps. In summary, the evidence suggests that the best mitigation strategy for improving the age at diagnosis is to increase awareness of the early symptoms of DMD and encourage early clinical screening with an inexpensive and sensitive serum creatine kinase test in all boys who present signs of developmental delay and specific motor test abnormality at routine pediatrician visits

Novel Splicing Mutation in MTM1 Leading to Two Abnormal Transcripts Causes Severe Myotubular Myopathy

Myotubular myopathy; Novel mutation; SplicingMiopatía miotubular; Nueva mutación; EmpalmeMiopatia miotubular; Nova mutació; EmpalmamentX-linked myotubular myopathy (XLMTM) is a severe form of centronuclear myopathy, characterized by generalized weakness and respiratory insufficiency, associated with pathogenic variants in the MTM1 gene. NGS targeted sequencing on the DNA of a three-month-old child affected by XLMTM identified the novel hemizygous MTM1 c.1261-5T>G intronic variant, which interferes with the normal splicing process, generating two different abnormal transcripts simultaneously expressed in the patient’s muscular cells. The first aberrant transcript, induced by the activation of a cryptic splice site in intron 11, includes four intronic nucleotides upstream of exon 12, resulting in a shift in the transcript reading frame and introducing a new premature stop codon in the catalytic domain of the protein (p.Arg421SerfsTer7). The second aberrant MTM1 transcript, due to the lack of recognition of the 3′ acceptor splice site of intron 11 from the spliceosome complex, leads to the complete skipping of exon 12. We expanded the genotypic spectrum of XLMTM underlying the importance of intron–exons boundaries sequencing in male patients affected by XLMTM

Implicit learning deficit in children with Duchenne muscular dystrophy: Evidence for a cerebellar cognitive impairment?

This study aimed at comparing implicit sequence learning in individuals affected by Duchenne Muscular Dystrophy without intellectual disability and age-matched typically developing children. A modified version of the Serial Reaction Time task was administered to 32 Duchenne children and 37 controls of comparable chronological age. The Duchenne group showed a reduced rate of implicit learning even if in the absence of global intellectual disability. This finding provides further evidence of the involvement of specific aspects of cognitive function in Duchenne muscular dystrophy and on its possible neurobiological substrate

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 naive 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 naive 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 naive 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. (C) 2015 The Authors. Published by Elsevier B.V

Timed rise from floor as a predictor of disease progression in Duchenne muscular dystrophy: An observational study

The role of timed items, and more specifically, of the time to rise from the floor, has been reported as an early prognostic factor for disease progression and loss of ambulation. The aim of our study was to investigate the possible effect of the time to rise from the floor test on the changes observed on the 6MWT over 12 months in a cohort of ambulant Duchenne boys.A total of 487 12-month data points were collected from 215 ambulant Duchenne boys. The age ranged between 5.0 and 20.0 years (mean 8.48 ±2.48 DS).The results of the time to rise from the floor at baseline ranged from 1.2 to 29.4 seconds in the boys who could perform the test. 49 patients were unable to perform the test at baseline and 87 at 12 month The 6MWT values ranged from 82 to 567 meters at baseline. 3 patients lost the ability to perform the 6mwt at 12 months. The correlation between time to rise from the floor and 6MWT at baseline was high (r = 0.6, p<0.01).Both time to rise from the floor and baseline 6MWT were relevant for predicting 6MWT changes in the group above the age of 7 years, with no interaction between the two measures, as the impact of time to rise from the floor on 6MWT change was similar in the patients below and above 350 m. Our results suggest that, time to rise from the floor can be considered an additional important prognostic factor of 12 month changes on the 6MWT and, more generally, of disease progression

Language Development in Preschool Duchenne Muscular Dystrophy Boys

Background: the present study aims to assess language in preschool-aged Duchenne muscular dystrophy (DMD) boys with normal cognitive quotients, and to establish whether language difficulties are related to attentional aspects or to the involvement of brain dystrophin isoforms. Methods: 20 children aged between 48 and 72 months were assessed with language and attention assessments for preschool children. Nine had a mutation upstream of exon 44, five between 44 and 51, four between 51 and 63, and two after exon 63. A control group comprising 20 age-matched boys with a speech language disorder and normal IQ were also used. Results: lexical and syntactic comprehension and denomination were normal in 90% of the boys with Duchenne, while the articulation and repetition of long words, and sentence repetition frequently showed abnormal results (80%). Abnormal results were also found in tests assessing selective and sustained auditory attention. Language difficulties were less frequent in patients with mutations not involving isoforms Dp140 and Dp71. The profile in Duchenne boys was different form the one observed in SLI with no cognitive impairment. Conclusion: The results of our observational cross-sectional study suggest that early language abilities are frequently abnormal in preschool Duchenne boys and should be assessed regardless of their global neurodevelopmental quotient

Upper Limb Changes in DMD Patients Amenable to Skipping Exons 44, 45, 51 and 53: A 24-Month Study

Introduction: The Performance of Upper Limb version 2.0 (PUL 2.0) is increasingly used in Duchenne Muscular Dystrophy (DMD) to study longitudinal functional changes of motor upper limb function in ambulant and non-ambulant patients. The aim of this study was to evaluate changes in upper limb functions in patients carrying mutations amenable to skipping exons 44, 45, 51 and 53. Methods: All DMD patients were assessed using the PUL 2.0 for at least 2 years, focusing on 24-month paired visits in those with mutations eligible for skipping exons 44, 45, 51 and 53. Results: 285 paired assessments were available. The mean total PUL 2.0 12-month change was -0.67 (2.80), -1.15 (3.98), -1.46 (3.37) and -1.95 (4.04) in patients carrying mutations amenable to skipping exon 44, 45, 51 and 53, respectively. The mean total PUL 2.0 24-month change was -1.47 (3.73), -2.78 (5.86), -2.95 (4.56) and -4.53 (6.13) in patients amenable to skipping exon 44, 45, 51 and 53, respectively. The difference in PUL 2.0 mean changes among the type of exon skip class for the total score was not significant at 12 months but was significant at 24 months for the total score (p 0.05). Conclusions: Our results expand the information on upper limb function changes detected by the PUL 2.0 in a relatively large group of DMD patients with distinct exon-skipping classes. This information can be of help when designing clinical trials or in the interpretation of the real world data including non-ambulant patients

Health-related quality of life and functional changes in DMD: A 12-month longitudinal cohort study

In Duchenne muscular dystrophy (DMD) little has been reported on the association between clinical outcome measures and patient health-related quality of life (HRQOL) tools. Our study evaluated the relationship between 12 month changes on the Generic Core Scales (GCS), the Multidimensional Fatigue Scale and the Neuromuscular Module of the PedsQL\u2122 with several outcome measures (6 minute walk test, North Star Ambulatory Assessment and timed items) in ambulatory DMD. Ninety-eight ambulatory DMD in a multicentric setting were included in the study. At baseline, the PedsQL\u2122 inventories correlated with almost all the functional measures On the Child Self-Report there was a significant decrease between baseline and 12 months on the PedsQL\u2122 GCS and its first domain, in parallel with the decrement in the functional outcome measures. Correlation between the 12 month changes on the PedsQL\u2122 inventories and functional measures were almost all negligible. Similar results were obtained on the Parent Proxy-Report.In conclusion, PedsQL\u2122 correlates with the level of impairment at baseline, but this does not hold true when 12 month changes are considered. Further studies comparing different tools are needed to better elucidate the complexity of the relationship between HRQOL and functional performances

Long-term natural history data in Duchenne muscular dystrophy ambulant patients with mutations amenable to skip exons 44, 45, 51 and 53

The aim of this international collaborative effort was to report 36-month longitudinal changes using the 6MWT in ambulant patients affected by Duchenne muscular dystrophy amenable to skip exons 44, 45, 51 or 53

Ambulatory function in spinal muscular atrophy: Age-related patterns of progression

Individuals with spinal muscular atrophy (SMA) type 3 are able to walk but they have weakness, gait impairments and fatigue. Our primary study objective was to examine longitudinal changes in the six-minute walk test (6MWT) and to evaluate whether age and SMA type 3 subtype are associated with decline in ambulatory function. Data from three prospective natural history studies were used. Seventy-three participants who performed the 6MWT more than once, at least 6 months apart, were included; follow-up ranged from 0.5–9 years. Only data from patients who completed the 6MWT were included. The mean age of the participants was 13.5 years (range 2.6–49.1), with 52 having disease onset before age 3 years (type 3A). At baseline, type 3A participants walked a shorter distance on average (257.1 m) than type 3B participants (390.2 m) (difference = 133.1 m, 95% confidence interval [CI] 71.8–194.3, p < 0.001). Distance walked was weakly associated with age (r = 0.25, p = 0.04). Linear mixed effects models were used to estimate the mean annual rate of change. The overall mean rate of change was -7.8 m/year (95% CI -13.6 –-2.0, p = 0.009) and this did not differ by subtype (type 3A: -8.5 m/year, type 3B: -6.6 m/year, p = 0.78), but it did differ by age group (< 6: 9.8 m/year; 6–10: -7.9 m/year; 11–19: -20.8 m/year; ≥ 20: -9.7 m/year; p = 0.005). Our results showed an overall decline on the 6MWT over time, but different trajectories were observed depending on age. Young ambulant SMA patients gain function but in adolescence, patients lose function. Future clinical trials in ambulant SMA patients should consider in their design the different trajectories of ambulatory function over time, based on age