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.
The aim of the study was to evaluate the spectrum of upper limb functional activities and imaging finding in a cohort of patients affected by Duchenne muscular dystrophy. Thirty-one patients of age ...between 5 and 29 years were included in the study (17 ambulant and 14 non-ambulant). They were all assessed using the Performance of Upper Limb (PUL) test and muscle MRI of shoulder, arm and forearm in order to establish if the functional scores obtained at shoulder, mid and distal level related to specific patterns of involvement in each upper limb segment on muscle MRI. At shoulder level, latissimus dorsi, serratus anterior, infraspinatus and subscapularis were always involved, even in patients with full functional scores at shoulder level. Diffuse and severe involvement of all muscles was found in the patients with a PUL shoulder functional score of ≤ 5. At arm level biceps brachii, brachialis and triceps were generally concordantly involved or spared. Some degree of involvement could already be detected in patients with reduced scores on the PUL mid domain. They were generally severely involved in patients with functional scores less than 6 at mid-level. At distal level supinator and pronator muscles were often involved, followed by brachioradialis and, less frequently, by the muscles of the flexor compartment. The extensor muscles were generally completely spared. A diffuse and severe involvement was found only in patients who had very low scores (8 or below) on the PUL distal domain. The integrated use of functional scales and imaging allowed to establish patterns of involvement at each level, and the functional scores that were more frequently associated with diffuse and severe involvement.
Background and Objectives: The aim of this study was to evaluate longitudinal changes using both upper limb muscle Magnetic Resonance Imaging (MRI) at shoulder, arm and forearm levels and Performance ...of upper limb (PUL) in ambulant and non-ambulant Duchenne Muscular Dystrophy (DMD) patients. We also wished to define whether baseline muscle MRI could help to predict functional changes after one year. Materials and Methods: Twenty-seven patients had both baseline and 12month muscle MRI and PUL assessments one year later. Results: Ten were ambulant (age range 5–16 years), and 17 non ambulant (age range 10–30 years). Increased abnormalities equal or more than 1.5 point on muscle MRI at follow up were found on all domains: at shoulder level 12/27 patients (44%), at arm level 4/27 (15%) and at forearm level 6/27 (22%). Lower follow up PUL score were found in 8/27 patients (30%) at shoulder level, in 9/27 patients (33%) at mid-level whereas no functional changes were found at distal level. There was no constant association between baseline MRI scores and follow up PUL scores at arm and forearm levels but at shoulder level patients with moderate impairment on the baseline MRI scores between 16 and 34 had the highest risk of decreased function on PUL over a year. Conclusions: Our results confirmed that the integrated use of functional scales and imaging can help to monitor functional and MRI changes over time.
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.
The aim of the study was to retrospectively evaluate the consistency of longitudinal findings on intellectual functioning in DMD boys and their relationship to behavioral and neuropsychiatric ...difficulties. The cohort included 70 patients of age 3 to 17 years with at least two assessments using the Wechsler scales. CBCL and clinical observation of behavior were also performed. Changes in total intelligence quotient were interpreted as stable or not stable using the reliable-change method. On the first assessment 43/70 had normal quotients, 18 borderline, 5 mild, and 4 moderate intellectual disability, while 27/70 had no behavioral disorders, 17 had abnormal CBCL, and 26 patients had clear signs of attention deficits despite normal CBCL. The remaining seven were untestable. The mean total intelligence quotient change in the cohort was -2.99 points (SD: 12.29). Stable results on TIQ were found in 63% of the paired assessments. A third of the consecutive cognitive assessments showed a difference of more than 11 points with changes up to 42 points. Boys with no behavioral/attention disorder had smaller changes than those with attention (
= 0.007) and behavioral disorders (
= 0.002). Changes in IQ may occur in Duchenne and are likely to be associated with behavioral or attention deficits.
We report the clinical case of a nine-year-old girl who presented with progressive motor neuropathy, revealed via the detection of a higher delay in F-wave recording using digitalized nerve ...conduction/electromyography. Since the lupus anticoagulant (LAC) positivity, detected using diluted Russell viper venom time (dRVVT), switched to persistent serological anticardiolipin immunoglobulin G (IgG) positivity, a possible non-thrombotic antiphospholipid antibody (aPL)-related clinical manifestation was suspected, and intravenous immunoglobulin treatment (IVIG) was started. The IVIG treatment was well tolerated and the complete resolution of motor impairment was obtained after the third IVIG infusion. Our findings suggest that it could be useful to check for antiphospholipid antibodies in children with a rapid onset of progressive neurological signs in order to provide the beneficial use of IVIG in the treatment of pediatric aPL neurological conditions.
To report the long-term progression in a cohort of patients with type II spinal muscular atrophy (SMA) assessed with the Hammersmith Functional Motor Scale-Expanded.
Seventy-three patients (age ...2.6-25 years) were included in the study. Twenty-eight of the 73 were first assessed before the age of 5 years and had been followed up for ≈5 years or longer. We observed an overall progression that was not linear. A piecewise regression analysis showed an improvement of scores in the younger patients with a point of slope change at ≈5 years of age, a decline between 5 and 13 years of age, and stability/slower decline after that.
Patients with the lowest scores at baseline had the earliest onset of scoliosis and a higher need for noninvasive ventilation compared to those with higher scores. Our results confirm that on the long-term follow-up all patients with type II SMA show a clear and progressive decline.
The severity of functional impairment at baseline can help to predict the magnitude of changes over time and the overall progression, including onset of scoliosis and need for noninvasive ventilation.
The aim of this Phase 1/2, 2-part, multicenter trial was to report clinical safety and efficacy of long-term golodirsen treatment among ambulatory patients with exon 53 skip-amenable Duchenne ...muscular dystrophy (DMD). Part 1 was a 12-week, randomized, double-blind, placebo-controlled, dose-titration study followed by 9-week safety review. Part 2 was a 168-week, open-label evaluation of golodirsen 30 mg/kg. Part 1 primary endpoint was safety. Part 2 primary endpoints were dystrophin protein expression and 6-minute walk test (6MWT); secondary endpoints were percent predicted forced vital capacity (FVC%p) and safety.
Post hoc
ambulation analyses used mutation-matched external natural history controls. All patients from Part 1 (golodirsen,
n
= 8; placebo,
n
= 4) plus 13 additional patients entered Part 2; 23 completed the study. Adverse events were generally mild, nonserious, and unrelated to golodirsen, with no safety-related discontinuations or deaths. Golodirsen increased dystrophin protein (16.0-fold;
P
< 0.001) and exon skipping (28.9-fold;
P
< 0.001). At 3 years, 6MWT change from baseline was −99.0 m for golodirsen-treated patients versus −181.4 m for external controls (
P
= 0.067), and loss of ambulation occurred in 9% versus 26% (
P
= 0.21). FVC%p declined 8.4% over 3 years in golodirsen-treated patients, comparing favorably with literature-reported rates. This study provides evidence for golodirsen biologic activity and long-term safety in a declining DMD population and suggests functional benefit versus external controls. Clinical Trial Registration number: NCT02310906.
Introduction: The aim of the study was to assess 12 month changes in upper limb function in patients affected by spinal muscular atrophy type 2 and 3. Methods: Longitudinal 12 month data was ...collected in 114 patients, 60 type 2 and 54 type 3, using the Revised Upper Limb Module. Results: The 12 month changes ranged between ‐7 and 9 (mean: ‐0.41; SD: 2.93). The mean changes were not significantly different between the three spinal muscular atrophy groups (‐0.45 in type 2, ‐0.23 in non‐ambulant type 3 and ‐0.34 in ambulant type 3, p = 0.96) and the relationship between 12 month change and age classes was not significantly different among the three types of SMA patients. Discussion: Our results confirm that the Module explores a wide range of functional abilities and can be used in ambulant and non‐ambulant patients of different ages in conjunction with other functional scales. Muscle Nerve 59:426–430, 2019
Neonatal screening for SMA has allowed the identification of infants who may present with early clinical signs. Our aim was to establish whether the presence and the severity of early clinical signs ...have an effect on the development of motor milestones. Infants identified through newborn screening were prospectively assessed using a structured neonatal neurological examination and an additional module developed for the assessment of floppy infants. As part of the follow-up, all infants were assessed using the HINE-2 to establish developmental milestones. Only infants with at least 24 months of follow-up were included. Normal early neurological examination (
n
= 11) was associated with independent walking before the age of 18 months while infants with early clinical signs of SMA (
n
= 4) did not achieve ambulation (duration follow-up 33.2 months). Paucisymptomatic patients (
n
= 3) achieved ambulation, one before the age of 18 months and the other 2 between 22 and 24 months.
Conclusion
: Our findings suggest that early clinical signs may contribute to predict motor milestones development.
What is Known:
• There is increasing evidence of heterogeneity among the SMA newborns identified via NBS.
• The proposed nosology describes a clinically silent disease, an intermediate category (‘paucisymptomatic’) and ‘symptomatic SMA’.
What is New:
• The presence of minimal clinical signs at birth does not prevent the possibility to achieve independent walking but this may occur with some delay.
• The combination of genotype at SMN locus and clinical evaluation may better predict the possibility to achieve milestones.
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