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1.  The genetic basis of undiagnosed muscular dystrophies and myopathies 
Neurology  2016;87(1):71-76.
Objective:
To apply next-generation sequencing (NGS) for the investigation of the genetic basis of undiagnosed muscular dystrophies and myopathies in a very large cohort of patients.
Methods:
We applied an NGS-based platform named MotorPlex to our diagnostic workflow to test muscle disease genes with a high sensitivity and specificity for small DNA variants. We analyzed 504 undiagnosed patients mostly referred as being affected by limb-girdle muscular dystrophy or congenital myopathy.
Results:
MotorPlex provided a complete molecular diagnosis in 218 cases (43.3%). A further 160 patients (31.7%) showed as yet unproven candidate variants. Pathogenic variants were found in 47 of 93 genes, and in more than 30% of cases, the phenotype was nonconventional, broadening the spectrum of disease presentation in at least 10 genes.
Conclusions:
Our large DNA study of patients with undiagnosed myopathy is an example of the ongoing revolution in molecular diagnostics, highlighting the advantages in using NGS as a first-tier approach for heterogeneous genetic conditions.
doi:10.1212/WNL.0000000000002800
PMCID: PMC4932234  PMID: 27281536
2.  Burden, professional support, and social network in families of children and young adults with muscular dystrophies 
Muscle & Nerve  2015;52(1):13-21.
ABSTRACT
Introduction: This study explores burden and social and professional support in families of young patients with muscular dystrophies (MDs) in Italy. Methods: The study was carried out on 502 key relatives of 4‐ to 25‐year‐old patients suffering from Duchenne, Becker, or Limb‐Girdle MD who were living with at least 1 adult relative. Results: A total of 77.1% of relatives reported feelings of loss, 74.0% had feelings of sadness, and 59.1% had constraints in leisure activities. Burden was higher among relatives of patients with higher disability and who spent more daily hours in caregiving. Practical difficulties were higher among relatives who perceived lower help in patient emergencies and less practical support by their social network. Psychological burden was higher in those relatives who were unemployed, those with poorer support in emergencies, and those with lower social contacts. Conclusions: Caring for patients with MDs may be demanding for relatives even in the early stages of these disorders, especially when social support is poor and the patient's disability increases. Muscle Nerve 52: 13–21, 2015
doi:10.1002/mus.24503
PMCID: PMC5029774  PMID: 25363165
caregiving; family burden; muscular dystrophy; professional support; social network
3.  Revised North Star Ambulatory Assessment for Young Boys with Duchenne Muscular Dystrophy 
PLoS ONE  2016;11(8):e0160195.
The advent of therapeutic approaches for Duchenne muscular dystrophy (DMD) has highlighted the need to identify reliable outcome measures for young boys with DMD. The aim of this study was to develop a revised version of the North Star Ambulatory Assessment (NSAA) suitable for boys between the age of 3 and 5 years by identifying age appropriate items and revising the scoring system accordingly. Using the scale in 171 controls between the age of 2.9 and 4.8 years, we identified items that were appropriate at different age points. An item was defined as age appropriate if it was completed, achieving a full score, by at least 85% of the typically developing boys at that age. At 3 years (±3months) there were only 8 items that were age appropriate, at 3 years and 6 months there were 13 items while by the age of 4 years all 17 items were appropriate. A revised version of the scale was developed with items ordered according to the age when they could be reliably performed. The application of the revised version of the scale to data collected in young DMD boys showed that very few of the DMD boys were able to complete with a full score all the age appropriate items. In conclusion, our study suggests that a revised version of the NSAA can be used in boys from the age of 3 years to obtain information on how young DMD boys acquire new abilities and how this correlates with their peers.
doi:10.1371/journal.pone.0160195
PMCID: PMC4975396  PMID: 27494024
4.  TMEM5-associated dystroglycanopathy presenting with CMD and mild limb-girdle muscle involvement 
Neuromuscular Disorders  2016;26(7):459-461.
Highlights
•We studied a CMD patient with structural brain abnormalities.•Next-generation sequencing identified a reported variant in TMEM5.•We expanded the spectrum of TMEM5-associated disorders.
The dystroglycanopathies, which are caused by reduced glycosylation of alpha-dystroglycan, are a heterogeneous group of neurodegenerative disorders characterized by variable brain and skeletal muscle involvement. Recently, mutations in TMEM5 have been described in severe dystroglycanopathies. We present the clinical, molecular and neuroimaging features of an Italian boy who had delayed developmental milestones with mild limb-girdle muscle involvement, bilateral frontotemporal polymicrogyria, moderate intellectual disability, and no cerebellar involvement. He also presented a cochlear dysplasia and harbored a reported mutation (p.A47Rfs*42) in TMEM5, detected using targeted next-generation sequencing. The relatively milder muscular phenotype and associated structural brain abnormalities distinguish this case from previously reported patients with severe dystroglycanopathies and expand the spectrum of TMEM5-associated disorders.
doi:10.1016/j.nmd.2016.05.003
PMCID: PMC4925463  PMID: 27212206
Congenital muscular dystrophy; TMEM5; Polymicrogyria; Cochlear dysplasia; Limb-girdle muscle weakness
5.  Translational approach to address therapy in myotonia permanens due to a new SCN4A mutation 
Neurology  2016;86(22):2100-2108.
Objective:
We performed a clinical, functional, and pharmacologic characterization of the novel p.P1158L Nav1.4 mutation identified in a young girl presenting a severe myotonic phenotype.
Methods:
Wild-type hNav1.4 channel and P1158L mutant were expressed in tsA201 cells for functional and pharmacologic studies using patch-clamp.
Results:
The patient shows pronounced myotonia, slowness of movements, and generalized muscle hypertrophy. Because of general discomfort with mexiletine, she was given flecainide with satisfactory response. In vitro, mutant channels show a slower current decay and a rightward shift of the voltage dependence of fast inactivation. The voltage dependence of activation and slow inactivation were not altered. Mutant channels were less sensitive to mexiletine, whereas sensitivity to flecainide was not altered. The reduced inhibition of mutant channels by mexiletine was also observed using clinically relevant drug concentrations in a myotonic-like condition.
Conclusions:
Clinical phenotype and functional alterations of P1158L support the diagnosis of myotonia permanens. Impairment of fast inactivation is consistent with the possible role of the channel domain III S4-S5 loop in the inactivation gate docking site. The reduced sensitivity of P1158L to mexiletine may have contributed to the unsatisfactory response of the patient. The success of flecainide therapy underscores the usefulness of in vitro functional studies to help in the choice of the best drug for each individual.
doi:10.1212/WNL.0000000000002721
PMCID: PMC4891212  PMID: 27164696
6.  Histologic muscular history in steroid-treated and untreated patients with Duchenne dystrophy 
Neurology  2015;85(21):1886-1893.
Objective:
Duchenne muscular dystrophy (DMD) is a lethal disease. The outcome measures used in numerous therapeutic trials include skeletal muscle biopsy. We studied the natural history of DMD from the standpoint of muscle histology with the aim of providing a reproducible tool for use in evaluating and comparing any histologic changes occurring in patients with DMD undergoing treatment and hence be able to determine how therapy modulates the histologic evolution of the disease.
Methods:
Three independent operators analyzed 56 muscle biopsies from 40 patients not treated with steroids, aged 1 to 10 years and 16 individuals treated with steroids, aged 7 to 10 years. We analyzed morphologic measures, normalized every measure for the average number of fibers observed for each year of age, and calculated intraclass correlation coefficients.
Results:
The average proportion of connective tissue in patients not treated with steroids was 16.98% from ages 1 to 6 years and 30% from ages 7 to 10 years (p < 0.0001). The average proportion in patients treated with steroids was 24.90%. Muscle fiber area mirrored that of connective tissue in both groups.
Conclusions:
Having provided a reproducible tool for evaluation and comparison of histologic changes occurring in patients undergoing clinical trials, it was observed that at ages 6 to 7 years, fibrotic tissue rapidly peaks to 29.85%; this is a crucial moment when muscle tissue loses its self-regeneration ability, veering toward fibrotic degeneration. These data should be considered when deciding the most suitable time to begin therapy.
doi:10.1212/WNL.0000000000002147
PMCID: PMC4662699  PMID: 26497992
7.  Novel findings associated with MTM1 suggest a higher number of female symptomatic carriers 
Neuromuscular Disorders  2016;26(4-5):292-299.
Highlights
•504 myopathic patients have been screened for MTM1 variants by NGS and CGH array approaches.•Seven novel XLMTM patients and the fifth case of a large Xq28 deletion have been identified.•The identification of two sporadic manifesting female carriers suggests that their number may be underestimated.•Large NGS panels, including the MTM1 gene, are useful tools to identify sporadic female XLMTM patients.•The identification of MTM1 variants, also as incidental findings, complicates genetic counseling.
Mutations in the MTM1 gene cause X-linked myotubular myopathy (XLMTM), characterized by neonatal hypotonia and respiratory failure, and are responsible for a premature mortality in affected males. Female carriers are usually asymptomatic but they may present with muscular weakness because of a hypothesized skewed pattern of X-chromosome inactivation.
By combining next generation sequencing (NGS) and CGH array approaches, we have investigated the role of MTM1 variants in a large cohort of undiagnosed patients with a wide spectrum of myopathies. Seven novel XLMTM patients have been identified, including two girls with an unremarkable family history for myotubular myopathy.
Moreover, we have detected and finely mapped a large deletion causing a myotubular myopathy with abnormal genital development.
Our data confirm that the severe neonatal onset of the disease in male infants is sufficient to address the direct molecular testing toward the MTM1 gene and, above all, suggest that the number of undiagnosed symptomatic female carriers is probably underestimated.
doi:10.1016/j.nmd.2016.02.004
PMCID: PMC4862961  PMID: 27017278
X-linked myotubular myopathy; MTM1 gene; Abnormal genital development; Next-generation sequencing; CGH array
8.  Timed Rise from Floor as a Predictor of Disease Progression in Duchenne Muscular Dystrophy: An Observational Study 
PLoS ONE  2016;11(3):e0151445.
Background
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.
Subjects and methods
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).
Results
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).
Conclusions
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.
doi:10.1371/journal.pone.0151445
PMCID: PMC4794120  PMID: 26982196
9.  Health-related quality of life and functional changes in DMD: A 12-month longitudinal cohort study 
Neuromuscular Disorders  2016;26(3):189-196.
Highlights
•At baseline, the PedsQLTM inventories correlated with almost all the functional measures.•There was a significant decrease between baseline and 12 months on PedsQLTM GCS.•This decrement paralleled with the decrement in the functional outcome measures.•PedsQLTM correlates with the level of impairment.•This correlations were not confirmed when 12 month changes are considered.
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 PedsQLTM 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 PedsQLTM 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 PedsQLTM GCS and its first domain, in parallel with the decrement in the functional outcome measures. Correlation between the 12 month changes on the PedsQLTM inventories and functional measures were almost all negligible. Similar results were obtained on the Parent Proxy-Report.
In conclusion, PedsQLTM 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.
doi:10.1016/j.nmd.2016.01.003
PMCID: PMC4819956  PMID: 26916554
Duchenne muscular dystrophy; Quality of life; Outcome measures; PedsQLTM
10.  Patterns of disease progression in type 2 and 3 SMA: Implications for clinical trials 
Neuromuscular Disorders  2016;26(2):126-131.
Highlights
•The paper reports for the first time patterns of progression in type 2 and 3 SMA.•Different trajectories can be identified in ambulant and non-ambulant patients.•Age appears to be an important factor in determining trajectories of progression.
The aim of the study was to establish 12-month changes in the Hammersmith Functional motor scale in a large cohort of SMA patients, to identify patterns of disease progression and the effect of different variables. 268 patients were included in this multicentric study. Their age ranged between 2.5 and 55.5 years at baseline, 68 were ambulant and 200 non-ambulant. The baseline scores ranged between 0 and 66 (mean 23.91, SD 20.09). The 12-month change was between −14 and +9 (mean −0.56, SD 2.72). Of the 268 patients, 206 (76.86%) had changes between −2 and +2 points. Ambulant and non-ambulant subjects had a different relationship between baseline values and age (p for age X ambulation interaction = 0.007). There was no association with age in ambulant subjects, while there was a significant heterogeneity at different age for non-ambulant patients (p < 0.001). The 12-month change (adjusted for baseline) was not associated with age in ambulant patients (p = 0.34), but it was significantly different among various age groups in non-ambulant patients. Our results suggest that there are different profiles of progression in ambulant and non-ambulant patients, and that age may play an important role in the progression of non-ambulant patients.
doi:10.1016/j.nmd.2015.10.006
PMCID: PMC4762230  PMID: 26776503
Spinal muscular atrophy; Hammersmith Functional Motor Scale; Outcome measures
13.  Muscle imaging in patients with tubular aggregate myopathy caused by mutations in STIM1 
Neuromuscular Disorders  2015;25(11):898-903.
Highlights
•We characterized muscle imaging pattern in STIM1-related myopathy.•The subscapularis muscle was preferentially affected in the upper girdle.•Flexor hallucis longus was consistently affected in the lower limbs.•Muscle involvement is homogeneous and different from non-STIM1 patients.
Tubular aggregate myopathy is a genetically heterogeneous disease characterized by tubular aggregates as the hallmark on muscle biopsy. Mutations in STIM1 have recently been identified as one genetic cause in a number of tubular aggregate myopathy cases. To characterize the pattern of muscle involvement in this disease, upper and lower girdles and lower limbs were imaged in five patients with mutations in STIM1, and the scans were compared with two patients with tubular aggregate myopathy not caused by mutations in STIM1. A common pattern of involvement was found in STIM1-mutated patients, although with variable extent and severity of lesions. In the upper girdle, the subscapularis muscle was invariably affected. In the lower limbs, all the patients showed a consistent involvement of the flexor hallucis longus, which is very rarely affected in other muscle diseases, and a diffuse involvement of thigh and posterior leg with sparing of gracilis, tibialis anterior and, to a lesser extent, short head of biceps femoris. Mutations in STIM1 are associated with a homogeneous involvement on imaging despite variable clinical features. Muscle imaging can be useful in identifying STIM1-mutated patients especially among other forms of tubular aggregate myopathy.
doi:10.1016/j.nmd.2015.07.008
PMCID: PMC4768080  PMID: 26255678
Muscle MRI; STIM1; Tubular aggregate myopathy; Muscle imaging; MRI pattern; CT, computed tomography; TAM, tubular aggregate myopathy
14.  Benefits of glucocorticoids in non-ambulant boys/men with Duchenne muscular dystrophy: A multicentric longitudinal study using the Performance of Upper Limb test 
Neuromuscular Disorders  2015;25(10):749-753.
Highlights
•The paper reports the effect of steroids on upper limb function in non ambulant DMD boys.•Boys continuing steroids after loss of ambulation perform better than those who stopped at the time of loss of ambulation.•The Performance of Upper Limb test can reliably capture change over time and the effect of intervention.
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.
doi:10.1016/j.nmd.2015.07.009
PMCID: PMC4597096  PMID: 26248957
Upper limb; Glucocorticoids; Duchenne muscular dystrophy; Non ambulant; PUL
15.  Prevalence of congenital muscular dystrophy in Italy 
Neurology  2015;84(9):904-911.
Objective:
We provide a nationwide population study of patients with congenital muscular dystrophy in Italy.
Methods:
Cases were ascertained from the databases in all the tertiary referral centers for pediatric neuromuscular disorders and from all the genetic diagnostic centers in which diagnostic tests for these forms are performed.
Results:
The study includes 336 patients with a point prevalence of 0.563 per 100,000. Mutations were identified in 220 of the 336 (65.5%). The cohort was subdivided into diagnostic categories based on the most recent classifications on congenital muscular dystrophies. The most common forms were those with α-dystroglycan glycosylation deficiency (40.18%) followed by those with laminin α2 deficiency (24.11%) and collagen VI deficiency (20.24%). The forms of congenital muscular dystrophy related to mutations in SEPN1 and LMNA were less frequent (6.25% and 5.95%, respectively).
Conclusions:
Our study provides for the first time comprehensive epidemiologic information and point prevalence figures for each of the major diagnostic categories on a large cohort of congenital muscular dystrophies. The study also reflects the diagnostic progress in this field with an accurate classification of the cases according to the most recent gene discoveries.
doi:10.1212/WNL.0000000000001303
PMCID: PMC4351663  PMID: 25653289
16.  Early Neurodevelopmental Findings Predict School Age Cognitive Abilities in Duchenne Muscular Dystrophy: A Longitudinal Study 
PLoS ONE  2015;10(8):e0133214.
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.
doi:10.1371/journal.pone.0133214
PMCID: PMC4537199  PMID: 26275215
17.  Long term follow-up to evaluate the efficacy of miglustat treatment in Italian patients with Niemann-Pick disease type C 
Background
Twenty-five patients with Niemann Pick disease type C (age range: 7 months to 44 years) were enrolled in an Italian independent multicenter trial and treated with miglustat for periods from 48 to 96 months.
Methods
Based on the age at onset of neurological manifestations patients’ phenotypes were classified as: adult (n = 6), juvenile (n = 9), late infantile (n = 6), early infantile (n = 2). Two patients had an exclusively visceral phenotype. We clinically evaluated patients’ neurological involvement, giving a score of severity ranging from 0 (best) to 3 (worst) for gait abnormalities, dystonia, dysmetria, dysarthria, and developmental delay/cognitive impairment, and from 0 to 4 for dysphagia. We calculated a mean composite severity score transforming the original scores proportionally to range from 0 to 1 to summarize the clinical picture of patients and monitor their clinical course.
Results
We compared the results after 24 months of treatment in 23 patients showing neurological manifestations. Stabilization or improvement of all parameters was observed in the majority of patients. With the exception of developmental delay/cognitive impairment, these results persisted after 48–96 months in 41 – 55% of the patients (dystonia: 55%, dysarthria: 50%, gait abnormalities: 43%, dysmetria: 41%, respectively). After 24 months of therapy the majority of the evaluable patients (n = 20), demonstrated a stabilization or improvement in the ability to swallow four substances of different consistency (water: 65%, purée: 58%, little pasta: 60%, biscuit: 55%). These results persisted after 48–96 months in 40-50% of patients, with the exception of water swallowing. Stabilization or improvement of the composite severity score was detected in the majority (57%) of 7 patients who were treated early (within 3.5 years from onset) and rarely in patients who received treatment later.
Conclusions
The results of this study suggest that miglustat treatment can improve or stabilize neurological manifestations, at least for a period of time; the severity of clinical conditions at the beginning of treatment can influence the rate of disease progression. This conclusion applies particularly to patients with juvenile or adult onset of the disease.
Trial registration
EudraCT number 2006-005842-35
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-015-0240-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13023-015-0240-y
PMCID: PMC4359492  PMID: 25888393
Niemann-Pick disease type C; NPC; Miglustat; NB-DNJ; Substrate reduction therapy; Treatment; Therapy
18.  Functional and Morphological Improvement of Dystrophic Muscle by Interleukin 6 Receptor Blockade 
EBioMedicine  2015;2(4):285-293.
The anti-inflammatory agents glucocorticoids (GC) are the only available treatment for Duchenne muscular dystrophy (DMD). However, long-term GC treatment causes muscle atrophy and wasting. Thus, targeting specific mediator of inflammatory response may be more specific, more efficacious, and with fewer side effects. The pro-inflammatory cytokine interleukin (IL) 6 is overproduced in patients with DMD and in the muscle of mdx, the animal model for human DMD. We tested the ability of inhibition of IL6 activity, using an interleukin-6 receptor (Il6r) neutralizing antibody, to ameliorate the dystrophic phenotype. Blockade of endogenous Il6r conferred on dystrophic muscle resistance to degeneration and alleviated both morphological and functional consequences of the primary genetic defect. Pharmacological inhibition of IL6 activity leaded to changes in the dystrophic muscle environment, favoring anti-inflammatory responses and improvement in muscle repair. This resulted in a functional homeostatic maintenance of dystrophic muscle.
These data provide an alternative pharmacological strategy for treatment of DMD and circumvent the major problems associated with conventional therapy.
Graphical abstract
Highlights
•Inhibition of IL6 activity leads to changes in the dystrophic muscle environment.•IL6R neutralizing antibody ameliorates the dystrophic phenotype.•IL6 blockade counters muscle decline in mdx mice.
doi:10.1016/j.ebiom.2015.02.014
PMCID: PMC4485902  PMID: 26137572
IL6; Muscular dystrophy; Inflammation; Necrosis; Therapy
19.  Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy 
The Journal of Clinical Investigation  2014;124(11):4693-4708.
Nemaline myopathy (NM) is a genetic muscle disorder characterized by muscle dysfunction and electron-dense protein accumulations (nemaline bodies) in myofibers. Pathogenic mutations have been described in 9 genes to date, but the genetic basis remains unknown in many cases. Here, using an approach that combined whole-exome sequencing (WES) and Sanger sequencing, we identified homozygous or compound heterozygous variants in LMOD3 in 21 patients from 14 families with severe, usually lethal, NM. LMOD3 encodes leiomodin-3 (LMOD3), a 65-kDa protein expressed in skeletal and cardiac muscle. LMOD3 was expressed from early stages of muscle differentiation; localized to actin thin filaments, with enrichment near the pointed ends; and had strong actin filament-nucleating activity. Loss of LMOD3 in patient muscle resulted in shortening and disorganization of thin filaments. Knockdown of lmod3 in zebrafish replicated NM-associated functional and pathological phenotypes. Together, these findings indicate that mutations in the gene encoding LMOD3 underlie congenital myopathy and demonstrate that LMOD3 is essential for the organization of sarcomeric thin filaments in skeletal muscle.
doi:10.1172/JCI75199
PMCID: PMC4347224  PMID: 25250574
21.  Natural history of pulmonary function in collagen VI-related myopathies 
Brain  2013;136(12):3625-3633.
The spectrum of clinical phenotypes associated with a deficiency or dysfunction of collagen VI in the extracellular matrix of muscle are collectively termed ‘collagen VI-related myopathies’ and include Ullrich congenital muscular dystrophy, Bethlem myopathy and intermediate phenotypes. To further define the clinical course of these variants, we studied the natural history of pulmonary function in correlation to motor abilities in the collagen VI-related myopathies by analysing longitudinal forced vital capacity data in a large international cohort. Retrospective chart reviews of genetically and/or pathologically confirmed collagen VI-related myopathy patients were performed at 10 neuromuscular centres: USA (n = 2), UK (n = 2), Australia (n = 2), Italy (n = 2), France (n = 1) and Belgium (n = 1). A total of 486 forced vital capacity measurements obtained in 145 patients were available for analysis. Patients at the severe end of the clinical spectrum, conforming to the original description of Ullrich congenital muscular dystrophy were easily identified by severe muscle weakness either preventing ambulation or resulting in an early loss of ambulation, and demonstrated a cumulative decline in forced vital capacity of 2.6% per year (P < 0.0001). Patients with better functional abilities, in whom walking with/without assistance was achieved, were initially combined, containing both intermediate and Bethlem myopathy phenotypes in one group. However, one subset of patients demonstrated a continuous decline in pulmonary function whereas the other had stable pulmonary function. None of the patients with declining pulmonary function attained the ability to hop or run; these patients were categorized as intermediate collagen VI-related myopathy and the remaining patients as Bethlem myopathy. Intermediate patients had a cumulative decline in forced vital capacity of 2.3% per year (P < 0.0001) whereas the relationship between age and forced vital capacity in patients with Bethlem myopathy was not significant (P = 0.1432). Nocturnal non-invasive ventilation was initiated in patients with Ullrich congenital muscular dystrophy by 11.3 years (±4.0) and in patients with intermediate collagen VI-related myopathy by 20.7 years (±1.5). The relationship between maximal motor ability and forced vital capacity was highly significant (P < 0.0001). This study demonstrates that pulmonary function profiles can be used in combination with motor function profiles to stratify collagen VI-related myopathy patients phenotypically. These findings improve our knowledge of the natural history of the collagen VI-related myopathies, enabling proactive optimization of care and preparing this patient population for clinical trials.
doi:10.1093/brain/awt284
PMCID: PMC3859224  PMID: 24271325
collagen VI-related myopathies; natural history; forced vital capacity; optimization of care; outcome measure
22.  Psychological and practical difficulties among parents and healthy siblings of children with Duchenne vs. Becker muscular dystrophy: an Italian comparative study 
Acta Myologica  2014;33(3):136-143.
This study explored the burden in parents and healthy siblings of 4-17 year-old patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies, and whether the burden varied according to clinical aspects and social resources.
Data on socio-demographic characteristics, patient's clinical history, parent and healthy children burden, and on parent's social resources were collected using self-reported questionnaires administered to 336 parents of patients with DMD (246) and BMD (90).
Parents of patients with DMD reported higher burden than those of patients with BMD, especially concerning feeling of loss (84.3% DMD vs. 57.4% BMD), stigma (44.2% DMD vs. 5.5% BMD) and neglect of hobbies (69.0% DMD vs. 32.5% BMD). Despite the burden, 66% DMD and 62.4% BMD parents stated the caregiving experience had a positive impact on their lives. A minority of parents believed MD has a negative influence on the psychological well-being (31.0% DMD vs. 12.8% BMD), and social life of unaffected children (25.7% vs. 18.4%).
In the DMD group, burden correlated with duration of illness and parent age, and burden was higher among parents with lower social contacts and support in emergencies. In DMD, difficulties among healthy children were reported as higher by parents who were older, had higher burden and lower social contacts. In both groups, burden increased in relation to patient disability.
These findings underline that the psychological support to be provided to parents of patients with MD, should take into account clinical features of the disease.
PMCID: PMC4369844  PMID: 25873782
Duchenne muscular dystrophy; Becker muscular dystrophy; parents, healthy siblings; burden; social network
23.  The 6 Minute Walk Test and Performance of Upper Limb in Ambulant Duchenne Muscular Dystrophy Boys 
PLoS Currents  2014;6:ecurrents.md.a93d9904d57dcb08936f2ea89bca6fe6.
The Performance of Upper Limb (PUL) test was specifically developed for the assessment of upper limbs in Duchenne muscular dystrophy (DMD). The first published data have shown that early signs of involvement can also be found in ambulant DMD boys. The aim of this longitudinal Italian multicentric study was to evaluate the correlation between the 6 Minute Walk Test (6MWT) and the PUL in ambulant DMD boys. Both 6MWT and PUL were administered to 164 ambulant DMD boys of age between 5.0 and 16.17 years (mean 8.82). The 6 minute walk distance (6MWD) ranged between 118 and 557 (mean: 376.38, SD: 90.59). The PUL total scores ranged between 52 and 74 (mean: 70.74, SD: 4.66). The correlation between the two measures was 0.499. The scores on the PUL largely reflect the overall impairment observed on the 6MWT but the correlation was not linear. The use of the PUL appeared to be less relevant in the very strong patients with 6MWD above 400 meters, who, with few exceptions had near full scores. In patients with lower 6MWD the severity of upper limb involvement was more variable and could not always be predicted by the 6MWD value or by the use of steroids. Our results confirm that upper limb involvement can already be found in DMD boys even in the ambulant phase.
doi:10.1371/currents.md.a93d9904d57dcb08936f2ea89bca6fe6
PMCID: PMC4208936  PMID: 25642376
24.  Long Term Natural History Data in Ambulant Boys with Duchenne Muscular Dystrophy: 36-Month Changes 
PLoS ONE  2014;9(10):e108205.
The 6 minute walk test has been recently chosen as the primary outcome measure in international multicenter clinical trials in Duchenne muscular dystrophy ambulant patients. The aim of the study was to assess the spectrum of changes at 3 years in the individual measures, their correlation with steroid treatment, age and 6 minute walk test values at baseline. Ninety-six patients from 11 centers were assessed at baseline and 12, 24 and 36 months after baseline using the 6 minute walk test and the North Star Ambulatory Assessment. Three boys (3%) lost the ability to perform the 6 minute walk test within 12 months, another 13 between 12 and 24 months (14%) and 11 between 24 and 36 months (12%). The 6 minute walk test showed an average overall decline of −15.8 (SD 77.3) m at 12 months, of −58.9 (SD 125.7) m at 24 months and −104.22 (SD 146.2) m at 36 months. The changes were significantly different in the two baseline age groups and according to the baseline 6 minute walk test values (below and above 350 m) (p<0.001). The changes were also significantly different according to steroid treatment (p = 0.01). Similar findings were found for the North Star Ambulatory Assessment. These are the first 36 month longitudinal data using the 6 minute walk test and North Star Ambulatory Assessment in Duchenne muscular dystrophy. Our findings will help not only to have a better idea of the progression of the disorder but also provide reference data that can be used to compare with the results of the long term extension studies that are becoming available.
doi:10.1371/journal.pone.0108205
PMCID: PMC4182715  PMID: 25271887
25.  6 Minute Walk Test in Duchenne MD Patients with Different Mutations: 12 Month Changes 
PLoS ONE  2014;9(1):e83400.
Objective
In the last few years some of the therapeutical approaches for Duchenne muscular dystrophy (DMD) are specifically targeting distinct groups of mutations, such as deletions eligible for skipping of individual exons. The aim of this observational study was to establish whether patients with distinct groups of mutations have different profiles of changes on the 6 minute walk test (6MWT) over a 12 month period.
Methods
The 6MWT was performed in 191 ambulant DMD boys at baseline and 12 months later. The results were analysed using a test for heterogeneity in order to establish possible differences among different types of mutations (deletions, duplications, point mutations) and among subgroups of deletions eligible to skip individual exons.
Results
At baseline the 6MWD ranged between 180 and 560,80 metres (mean 378,06, SD 74,13). The 12 month changes ranged between −325 and 175 (mean −10.8 meters, SD 69.2). Although boys with duplications had better results than those with the other types of mutations, the difference was not significant.
Similarly, boys eligible for skipping of the exon 44 had better baseline results and less drastic changes than those eligible for skipping exon 45 or 53, but the difference was not significant.
Conclusions
even if there are some differences among subgroups, the mean 12 month changes in each subgroup were all within a narrow Range: from the mean of the whole DMD cohort. This information will be of help at the time of designing clinical trials with small numbers of eligible patients.
doi:10.1371/journal.pone.0083400
PMCID: PMC3885414  PMID: 24421885

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