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1.  Hypogonadism and erectile dysfunction in myotonic dystrophy type 1 
Acta Myologica  2013;32(2):106-109.
Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults. It affects many organs and systems besides muscle. Aim of this study was to assess frequency of erectile dysfunction (ED) and hypogonadism, the correlation between them and the impact of ED on quality of life (QoL) in patients with DM1. A series of 25 men (aged from 22 to 58 years) with a diagnosis of DM1 was analyzed. Muscular Impairment Rating Scale (MIRS) was used to assess severity of muscular involvement. Erectile function was assessed using the short form of the International Index of Erectile Function test (IIEF-5). Levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone were assessed. All patients completed the Serbian version of the SF-36 questionnaire as a measure of health-related QoL. ED was present in 18 (72%) of patients. Seven (28%) patients were euogonadic, 16 (64%) had compensated hypogonadism and 2 (8%) had primary hypogonadism. ED was somewhat more common in patients with hypogonadism (78% vs. 57%). Mental composite score of SF-36 was lower in patients with ED (p<0.05). Our results showed that 72% of men with DM1 had ED and hypogonadism. Studies with larger number of subjects are needed to resolve cascade of events that lays behind ED in DM1. Development of therapeutic strategies may have positive impact on QoL. Substitutive therapy with androgens may be benefitial.
PMCID: PMC3866901  PMID: 24399868
myotonic dystrophy type 1; erectile dysfunction; hypogonadis
2.  Long-term ventilation of patients with Duchenne muscular dystrophy: experiences at the Neuromuscular Centre Ulm 
Acta Myologica  2012;31(3):170-178.
The various measures used to treat the symptoms of Duchenne muscular dystrophy (DMD), i.e. medication with steroids, early operation on contractures and spine deformities as well as cardiac diagnostics and therapy, should always be accompanied by careful monitoring of the patient's respiratory status. Therapy for respiratory failure, in particular long-term ventilation, is now generally accepted as essential for DMD patients. The provision of assisted ventilation has made a decisive contribution to the quality of life for older patients and the stigma hitherto attached to it as being merely a means of keeping a patient comfortable towards the end of life has now been dispelled. Even outside the hospital, assisted ventilation has become routine. These days it is not uncommon for patients on assisted ventilation to have their life extended by 10 years or more.
Non-invasive ventilation is sufficient if used concomitantly with coughing aids. Before undergoing orthopaedic surgery the patient' s respiratory status has to be carefully assessed in order to minimize the risk of perioperative complications. Feeding and swallowing problems may develop if the patient has a scoliosis of the cervical spine region, even if he has had thoraco-lumbar spine surgery. There is still insufficient awareness of this potential problem in relation to respiratory care.
Interdisciplinary collaboration between hospitals, general practitioners, muscle and respiratory centres, as well as advocacies and self-help groups is vital. The administration of aids to support DMD patients is now facilitated by guidelines drawn up by several centres of excellence. Here we mainly describe the historic development of respiratory care at the Ulm Neuromuscular Centre.
PMCID: PMC3631799  PMID: 23620648
Duchenne muscular dystrophy; respiratory failure; non-invasive ventilation; increased survival
3.  The role of fibrosis in Duchenne muscular dystrophy 
Acta Myologica  2012;31(3):184-195.
Muscular dystrophies such as Duchenne muscular dystrophy (DMD) are usually approached as dysfunctions of the affected skeletal myofibres and their force transmission. Comparatively little attention has been given to the increase in connective tissue (fibrosis) which accompanies these muscular changes. Interestingly, an increase in endomysial tissue is apparent long before any muscular degeneration can be observed. Fibrosis is the result of a reactive or reparative process involving mechanical, humoral and cellular factors. Originating from vulnerable myofibres, muscle cell necrosis and inflammatory processes are present in DMD. Muscular recovery is limited due to the limited number and capacity of satellite cells. Hence, a proactive and multimodal approach is necessary in order to activate protective mechanisms and to hinder catabolic and tissue degrading pathways.
Several avenues are discussed in terms of potential antifibrotic therapy approaches. These include pharmaceutical, nutritional, exercise-based and other mechanostimulatory modalities (such as massage or yoga-like stretching) with the intention of exerting an anti-inflammatory and antifibrotic effect on the affected muscular tissues. A preventive intervention at an early age is crucial, based on the early and seemingly non-reversible nature of the fibrotic tissue changes. Since consistent assessment is essential, different measurement technologies are discussed.
PMCID: PMC3631802  PMID: 23620650
Duchenne muscular dystrophy; fibrosis; endo- and perimysium; extracellular matrix; TGF-β1; myostatin; antifibrotic therapy
4.  Risk assessment and genetic counseling in families with Duchenne muscular dystrophy 
Acta Myologica  2012;31(3):179-183.
The Duchenne Muscular dystrophy (DMD) is the most frequent muscle disorder in childhood caused by mutations in the Xlinked dystrophin gene (about 65% deletions, about 7% duplications, about 26% point mutations and about 2% unknown mutations). The clinically milder Becker muscular dystrophy (BMD) is allelic to DMD. About 33% of all patients are due to de novo mutations and germ line mosaicism is frequently observed. While in earlier studies equal mutation rates in males and females had been reported, a breakdown by mutation types can better explain the sex ratio of mutations: Point mutations and duplications arise preferentially during spermatogenesis whereas deletions mostly arise in oogenesis.
With current analytical methods, the underlying mutation can be identified in the great majority of cases and be used for carrier detection. However, in families with no mutation carrier available, the genetic model to be used for counselling of relatives can be quite complex.
PMCID: PMC3631803  PMID: 23620649
Duchenne muscular dystrophy; Becker muscular dystrophy; dystrophin gene; molecular genetic diagnosis; genetic model; germ line mosaicism
5.  Next generation sequencing (NGS) strategies for the genetic testing of myopathies 
Acta Myologica  2012;31(3):196-200.
Next generation sequencing (NGS) technologies offer the possibility to map entire genomes at affordable costs. This brings the genetic testing procedure to a higher level of complexity. The positive aspect is the ease to cope with the complex diagnosis of genetically heterogeneous disorders and to identify novel disease genes. Worries arise from the management of too many DNA variations with unpredictable meaning and incidental findings that can cause ethical and clinical dilemmas. The technology of enrichment makes possible to focus the sequencing to the exome or to a more specific DNA target. This is being used to provide insights into the genetics underlying Mendelian traits involved in myopathies and to set up cost-effective diagnostic tests. This huge potential of the NGS applications makes likely that these will soon become the first approach in genetic diagnostic laboratories.
PMCID: PMC3631804  PMID: 23620651
Next generation sequencing; NGS; neuromuscular disorders
6.  Right atrial preference pacing algorithm in the prevention of paroxysmal atrial fibrillation in myotonic dystrophy type 1 patients: a long term follow-up study 
Acta Myologica  2012;31(2):139-143.
Atrial Preference Pacing (APP) is a pacemaker (PM) algorithm that works by increasing the atrial pacing rate to achieve continuous suppression of a spontaneous atrial rhythm and prevent supraventricular tachyarrhythmias. We have previously shown that atrial preference pacing may significantly reduce the number and the duration of AF episodes in myotonic dystrophy type 1 (DM1) patients who are paced for standard indications.
However, the role that APP therapies play in the prevention of AF in a long-term period remains still unclear. Aim of the present prospective study was to evaluate whether this beneficial effect is maintained for 24-months follow-up period.
To this aim, 50 patients with Myotonic Dystrophy type 1 who underwent dual-chamber PM implantation for first- and second- degree atrioventricular block, were consecutively enrolled and followed for 2 years. One month later the stabilization period, after the implantation, they were randomized to APP algorithm programmed OFF or ON for 6 months each, using a cross-over design, and remained in the same program for the second year. The results showed that while the number of AF episodes during active treatment (APP ON phases) was lower than that registered during no treatment (APP OFF phases), no statistically significant difference was found in AF episodes duration between the two phases. Furthermore, during the APP OFF and APP ON phases, the percentage of atrial pacing was 0 and 99%, respectively, while the percentage of ventricular pacing did not show differences statistically significant (11 vs. 9%, P = 0.2). Atrial premature beats were significantly higher during APP OFF phases than during APP ON phases. Lead parameters remained stable over time and there were no lead-related complications. Based on these 24-months follow-up data, we can conclude that, in DM1 patients who underwent dual-chamber PM implantation, APP is an efficacy algorithm for preventing paroxysmal AF even in long term periods.
PMCID: PMC3476853  PMID: 23097606
myotonic dystrophy; atrial preference pacing; atrial fibrillation
7.  Improvement of survival in Duchenne Muscular Dystrophy: retrospective analysis of 835 patients 
Acta Myologica  2012;31(2):121-125.
Duchenne Muscular Dystrophy (DMD) is the most common muscle disease in children. Historically, DMD results in loss of ambulation between ages 7 and 13 years and death in the teens or 20s. In order to determine whether survival has improved over the decades and whether the impact of nocturnal ventilation combined with a better management of cardiac involvement has been able to modify the pattern of survival, we reviewed the notes of 835 DMD patients followed at the Naples Centre of Cardiomyology and Medical Genetics from 1961 to 2006. Patients were divided, by decade of birth, into 3 groups: 1) DMD born between 1961 and 1970; 2) DMD born between 1971 and 1980; 3) DMD born between 1981 and 1990; each group was in turn subdivided into 15 two-year classes, from 14 to 40 years of age. Age and causes of death, type of cardiac treatment and use of a mechanical ventilator were carefully analyzed.
The percentage of survivors in the different decades was statistically compared by chi-square test and Kaplan-Meier survival curves analyses. A significant decade on decade improvement in survival rate was observed at both the age of 20, where it passed from 23.3% of patients in group 1 to 54% of patients in group 2 and to 59,8% in patients in group 3 (p < 0.001) and at the age of 25 where the survival rate passed from 13.5% of patients in group 1 to 31.6% of patients in group 2 and to 49.2% in patients in group 3 (p < 0.001).
The causes of death were both cardiac and respiratory, with a prevalence of the respiratory ones till 1980s. The overall mean age for cardiac deaths was 19.6 years (range 13.4-27.5), with an increasing age in the last 15 years. The overall mean age for respiratory deaths was 17.7 years (range 11.6-27.5) in patients without a ventilator support while increased to 27.9 years (range 23-38.6) in patients who could benefit of mechanical ventilation.
This report documents that DMD should be now considered an adulthood disease as well, and as a consequence more public health interventions are needed to support these patients and their families as they pass from childhood into adult age.
PMCID: PMC3476854  PMID: 23097603
Duchenne; survival; cardiomyopathy
8.  Survival in Duchenne muscular dystrophy 
Acta Myologica  2012;31(2):117-120.
To determine the survival in a population of German patients with Duchenne muscular dystrophy.
Patients and methods:
Information about 94 patients born between 1970 and 1980 was obtained by telephone interviews and questionnaires. In addition to age of death or actual age during the investigation, data concerning clinical course and medical interventions were collected.
67 patients with molecularly confirmed diagnoses had a median survival of 24.0 years. Patients without molecular confirmation (clinical diagnosis only) had a chance of 67 % to reach that age. Grouping of our patient cohort according to the year of death (before and after 2000), ventilation was recognized as main intervention affecting survival with ventilated reaching a median survival of 27.0 years. For those without ventilation it was 19.0 years.
Conclusion and clinical relevance:
our study provides survival data for a cohort of DMD patients in Germany stratified by year of death. Median survival was 24.0 years in patients confirmed by molecular testing. Ventilated patients had a median survival of 27 years. We consider this piece of information helpful in the medical care of DMD patients.
PMCID: PMC3476855  PMID: 23097602
duchenne muscular dystrophy; survival; ventilation
9.  TARDBP mutations are not a frequent cause of ALS in Finnish patients 
Acta Myologica  2012;31(2):134-138.
In previous studies 1-3 % of ALS patients have TARDBP mutations as the cause of the disease. TARDBP mutations have been reported in ALS patients in different populations but so far there are no studies on the frequency of TARDBP mutations in Finnish ALS patients. A cohort of 50 Finnish patients, 44 SALS and 6 FALS patients, were included in the study. Genomic DNA was extracted from venous blood or muscle tissue and a mutation analysis of TARDBP was performed. No definitely pathogenic mutations could be identified in TARDBP in our patient cohort. However, two previously unknown variations were found: one silent mutation in exon 2 and one relatively deep intronic single nucleotide insertion in intron 5. In addition, two previously known non-pathogenic polymorphisms in intron 5 were detected. The size of our cohort is obviously not large enough to conclusively exclude TARDBP mutations as a very rare cause of ALS in Finland. However, based on our results TARDBP mutations do not appear to be a frequent cause of familial or sporadic ALS in Finland.
PMCID: PMC3476858  PMID: 23097605
Amyotrophic lateral sclerosis; mutation screening; TARDBP
10.  ClC1 chloride channel in myotonic dystrophy type 2 and ClC1 splicing in vitro 
Acta Myologica  2012;31(2):144-153.
Myotonic dystrophy type 2 (DM2) is caused by CCTG-repeat expansions. Occurrence of splicing and mutations in the muscle chloride channel gene CLCN1 have been reported to contribute to the phenotype. To examine the effect of CLCN1 in DM2 in Germany, we determined the frequency of a representative ClC1 mutation, R894X, and its effect on DM2 clinical features. Then, we examined CLCN1 mRNA splice variants in patient muscle functionally expressed the most abundant variant, and determined its subcellular localization. Finally, we established a cellular system for studying mouse clcn1 pre-mRNA splicing and tested effects of expression of (CCUG)18, (CUG)24 and (AAG)24 RNAs. The R894X mutation was present in 7.7% of DM2 families. DM2 R894X-carriers had more myotonia and myalgia than non-carriers. The most abundant CLCN1 splice variant in DM2 (80% of all transcripts) excluded exons 6-7 and lead to a truncated ClC1236X protein. Heterologous ClC1236X expression did not yield functional channels. Co-expression with ClC1 did not show a dominant negative effect, but a slightly suppressive effect. In C2C12 cells, the clc1 splice variants generated by (CCUG)18-RNA resembled those in DM2 muscle and differed from those generated by (CUG)24 and (AAG)24. We conclude that ClC1 mutations exert gene dose effects and enhance myotonia and pain in DM2 in Germany. Additionally, the ClC1236X splice variant may contribute to myotonia in DM2. Since splice variants depend on the types of repeats expressed in the cellular C2C12 model, similar cell models of other tissues may be useful for studying repeatdependent pathogenetic mechanisms more easily than in transgenic animals.
PMCID: PMC3476861  PMID: 23097607
PROMM; myotonic dystrophy; chloride channel
11.  The impact of permanent muscle weakness on quality of life in periodic paralysis: a survey of 66 patients 
Acta Myologica  2012;31(2):126-133.
The periodic paralyses are hereditary muscle diseases which cause both episodic and permanent weakness. Permanent weakness may include both reversible and fixed components, the latter caused by fibrosis and fatty replacement. To determine the degree of handicap and impact of permanent weakness on daily life, we conducted a 68-question online survey of 66 patients over 41 years (mean age, 60 ± 14 years). Permanent weakness occurred in 68%, muscle pain in 82% and muscle fatigue in 89%. Eighty-three percent of patients reported themselves as moderately to very active between ages 18-35. At the time of the survey only 14% reported themselves as moderately to very active. Contrary to the literature, only 21% of patients reported decreased frequency of episodic weakness with increased age. Sixty-seven percent had incurred injuries due to falls. Mobility aids were required by 49%. Strength increased in 49% of patients receiving professional physiotherapy and in 62% performing self-managed exercise routines. A decline of strength was observed by 40% with professional and by 16% with self-managed exercise routine, suggesting that overworking muscles may not be beneficial. There is an average of 26 years between age at onset and age at diagnosis indicating that diagnostic schemes can be improved. In summary our data suggests that permanent muscle weakness has a greater impact on the quality of life of patients than previously anticipated.
PMCID: PMC3476862  PMID: 23097604
periodic paralysis; myopathy; paramyotonia congenita
12.  A novel N440K sodium channel mutation causes myotonia with exercise-induced weakness - exclusion of CLCN1 exon deletion/duplication by MLPA 
Acta Myologica  2011;30(2):133-137.
We report a 4-generation Turkish family with 10 affected members presenting with myotonia and potassium- and exerciseinduced paralytic attacks. The clinical presentation was neither typical for the chloride channel myotonias Thomsen and Becker nor for the separate sodium channel myotonia entities potassiumaggravated myotonia, paramyotonia congenita, and hyperkalemic periodic paralysis. It is best described by a combination of potassium-aggravated myotonia and hyperkalemic periodic paralysis. We excluded exonic chloride channel mutations including CLCN1 exon deletion/duplication by MLPA. Instead we identified a novel p.N440K sodium channel mutation that is located at the inner end of segment S6 of repeat I. We discuss the genotype phenotype relation.
PMCID: PMC3235863  PMID: 22106717
chloride channel myotonia Thomsen and Becker; sodium channel myotonia; hyperkalemic periodic paralysis; potassiumaggravated myotonia; paramyotonia congenita; CLCN1; MLPA
13.  Dysferlinopathy course and sportive activity: clues for possible treatment 
Acta Myologica  2011;30(2):127-132.
LGMD2B is a frequent proximo-distal myopathy with rapid evolution after age 20. Exacerbating factors may be physical exercise and inflammation. There is very little information about the effect of sportive activity in LGMD2B, since eccentric exercise frequently results in muscle damage. LGMD2B has often an onset with myalgia and MRI imaging (STIR-sequences) shows myoedema. In a prolonged observational study of a series of 18 MM/LGMD2B patients we have studied the pattern of clinical and radiological evolution. The disease has an abrupt onset in the second decade and most patients perform sports before definite disease onset. On the basis of Gardner-Medwin and Walton scale, grade 4 is reached two years faster in patients who performed sports (over 1000 hours). Other considerations regarding pathogenetic mechanism and response to treatment show a poor response to immunosuppressive treatment of muscle inflammation. Preventing a strenuous physical activity should be recommended in patients with high CK and diagnosed or suspected to have dysferlin deficiency.
PMCID: PMC3235880  PMID: 22106716
dysferlin; pathogenesis; physical exercise; sport activity
14.  The Microglial-Motoneuron dialogue in ALS 
Acta Myologica  2011;30(1):4-8.
Neuroinflammation is a pathological hallmark of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), and is characterized by activated microglia at sites of neuronal injury. In ALS. neurons do not die alone; neuronal injury is noncell- autonomous and depends upon a well-orchestrated dialogue between motor neurons and microglia. Evidence from transgenic models expressing mutant superoxide dismutase 1 (SOD) suggests that the dialogue between motor neurons and microglia initially protects motor neurons. However, with increasing stress and injury within motor neurons, induced by the presence of misfolded proteins such as mSOD1, mitochondrial function and axoplasmic flow are impaired and endoplasmic reticulum stress is induced; misfolded proteins themselves or alternate signals are released from motor neurons and activate microglia. Activated microglia, in turn, switch from anti-inflammatory and neuroprotective to proinflammatory and neurotoxic. Neurotoxic signaling from motor neurons promotes microglial release of reactive oxygen species and pro-inflammatory cytokines further enhancing motor neuron stress and cell injury and initiating a self-propagating cycle of motor neuron injury and cell death. A greater understanding of how to restore the imbalance between neuroprotection and cytotoxicity will depend upon a greater understanding of the motor neuron-microglial dialogue.
PMCID: PMC3185827  PMID: 21842586
Microglia; Motoneurons; ALS
15.  Sporadic-inclusion body myositis (s-IBM) is not so prevalent in Istanbul/Turkey: a muscle biopsy based survey 
Acta Myologica  2011;30(1):34-36.
In a muscle biopsy based study, only 9 out of 5450 biopsy samples, received from all parts of greater Istanbul area, had typical clinical and most suggestive light microscopic sporadic-inclusion body myositis (s-IBM) findings. Two other patients with and ten further patients without characteristic light microscopic findings had referring diagnosis of s-IBM. As the general and the ageadjusted populations of Istanbul in 2010 were 13.255.685 and 2.347.300 respectively, the calculated corresponding ‘estimated prevalences' of most suggestive s-IBM in the Istanbul area were 0.679 X 10-6 and 3.834 X 10-6. Since Istanbul receives heavy migration from all regions of Turkey and ours is the only muscle pathology laboratory in Istanbul, projection of these figures to the Turkish population was considered to be reasonable and an estimate of the prevalence of s-IBM in Turkey was obtained.
The calculated ‘estimated prevalence' of s-IBM in Turkey is lower than the previously reported rates from other countries. The wide variation in the prevalence rates of s-IBM may reflect different genetic, immunogenetic or environmental factors in different populations.
PMCID: PMC3185828  PMID: 21842592
Sporadic inclusion body myositis; s-IBM; prevalence; myopathy
16.  HIV-related neuromuscular diseases: nemaline myopathy, amyotrophic lateral sclerosis and bibrachial amyotrophic diplegia 
Acta Myologica  2011;30(1):29-31.
The human immunodeficiency virus (HIV) causes diverse disorders of the brain, spinal cord and peripheral nerves. Rarely, polymyositis and myoglobinuria are seen. Two other neuromuscular syndromes in people with HIV antibodies are nemaline myopathy and bibrachial amyotrophic diplegia, a form of motor neuron disease. The associations between these diseases and the possibility that HIV infection could be a risk factor for either amyotrophic lateral sclerosis (ALS) itself or other motor neuron diseases are investigated.
PMCID: PMC3185829  PMID: 21842590
HIV-Related Neuromuscular Diseases; nemaline myopathy; amyotrophic lateral sclerosis; bibrachial amyotrophic diplegia
17.  Continuous muscle activity, Morvan's syndrome and limbic encephalitis: ionic or non ionic disorders? 
Acta Myologica  2011;30(1):32-33.
The early pathophysiologic study showed increasing evidence that autoimmunity is implicated in the pathogenesis of neuromyotonia. Antibodies to voltage gated potassium channel were detected in the serum of patients who had peripheral nerves hyperexcitability and also Morvan's disease or limbic encephalitis. These discoveries offered new approaches to treatments.
Recently, antibodies previously attributed to VGKC recognise 2 surface antigens LGI1 and CASPR2 into the VGKC complex. Finally, VGKC antibodies are directed to 2 proteins the first one is a key hippocampic protein containing pre and post synaptic proteins. The second one CASPR2 is an hippocampic and paranodal protein.
There clinical significance is different: hyperexcitability, limbic encephalitis without thymoma for LGI1, hyperexcitability, Morvan limbic encephalitis and frequent thymoma for CASPR2.
In conclusion, the term NMT - LE - VGKC should be changed to NMT- LE with LGI1 and CASPR2 antibodies and classified as auto immune synaptic disorders. Mutations in genes encoding both these proteins are found in hereditary epilepsy and other syndromes. Various potassium channelopathies are closely linked to Morvan's syndromes. A new classification of antibodies will be necessary.
PMCID: PMC3185830  PMID: 21842591
Neuromyotonia; autoimmunity; Isaac's Syndrome
18.  Desmin A213V substitution represents a rare polymorphism but not a mutation and is more prevalent in patients with heart dilation of various origins 
Acta Myologica  2011;30(1):42-45.
Several desmin mutations have been described in patients with cardiomyopathies and distal myopathies. Among them, A213V substitution has been associated with three completely different clinical phenotypes: restrictive cardiomyopathy, dilated cardiomyopathy and isolated distal myopathy. However, the identification of this substitution also in control subjects has highlighted the question if the A213V shift represents a conditional mutation, giving rise to cardiomyopathy only in the presence of other predisposing factors. The aim of the present work was to study the potential role of this substitution in predisposing to heart dilation.
Methods and results. We screened 108 patients with heart dilation due to ischemic heart disease, alcoholic cardiomyopathy or viral myocarditis, and 300 healthy controls for the presence of A213V substitution by direct sequencing and confirmed the results by site-specific restriction. In the control group A213V substitution was identified in 3 out of 300 patients, representing a rare polymorphism with a frequency of approximately 1%, which corresponds to the earlier reported frequency. In the study group A213V substitution was found in 5 out of 108 cases, corresponding to approximately 4.6% (p < 0.035). Therefore we conclude that A213V desmin substitution represents a conditional mutation, i.e. a rare polymorphism that plays a role as a predisposing factor resulting in maladaptive heart remodelling in the presence of other pathological factors.
PMCID: PMC3185831  PMID: 21842594
Desmin; polymorphisms; heart dilation
19.  Activation of NF-kB pathway in Duchenne muscular dystrophy: relation to age 
Acta Myologica  2011;30(1):16-23.
Muscle degeneration in Duchenne muscular dystrophy (DMD) is exacerbated by increased oxidative stress and the endogenous inflammatory response, with a key role played by nuclear factor kappa-B (NF-κB) and other related factors such as tumor necrosis factor (TNF)-α and interleukin (IL)-6. However the time course of expression of these molecules and the relation with the amount of necrosis and regeneration have never been investigated.
The expression of NF-κB, the cytokines TNF-α and IL-6 and the antioxidant enzyme glutathione peroxidase (GPx) was studied in muscle samples from 14 patients with DMD aged between 2 and 9 years. Moreover a quantitative morphological evaluation was performed to evaluate necrotic and regenerative areas.
The highest percentage of necrosis was revealed within 4 years of age, with a significant negative correlation with age (p < 0.003), which paralleled to a significant decrement of regenerating area (p < 0.0004). We reported the novel observation that the number of NF-κB positive fibers and the NF-κB DNA-binding activity, revealed by EMSA, are high at two years of life and significantly decline with age (p < 0.0005 and p < 0.0001). The expression of TNF-α, IL-6 and GPx was upregulated in DMD muscles compared to controls and significantly increased with age on realtime PCR analysis (p < 0.0002; p < 0.0005; p < 0.03 respectively) and ELISA (p < 0.002; p < 0.02; p < 0.0001 respectively).
Since anti-inflammatory and anti-oxidant drugs are nowadays being translated to clinical studies in DMD, the reported insights on these therapeutic targets appear relevant. Further studies on the interactions among these pathways in different DMD phases and on the response of these cascades to treatments currently under investigation are needed to better elucidate their relevance as therapeutic targets.
PMCID: PMC3185832  PMID: 21842588
20.  Cardiological manifestations of mitochondrial respiratory chain disorders 
Acta Myologica  2011;30(1):9-15.
Mitochondrial Respiratory Chain Disorders (MRCD) are a heterogeneous group of disorders that share the involvement of the cellular bioenergetic machinery due to molecular defects affecting the mitochondrial oxidative phosphorylation system (OXPHOS).
Clinically, they usually involve multiple tissues although they tend to mainly affect nervous system and skeletal muscle. Cardiological manifestations are frequent and include hypertrophic or dilated cardiomyopathies and heart conduction defects, being part of adult or infantile multisystemic mitochondrial disorders or, less frequently, presenting as isolated clinical condition.
The aim of this review is to update the cardiological manifestations in both adult and infantile mitochondrial disorders going briefly over mitochondrial genetics.
Cardiac involvement is a common feature associated with early and late onset forms of MRCD. In particular cases, these conditions should be considered into the diagnostic algorithm of idiopathic cardiomyopathies. Physicians strictly related with this disorders need to be aware of heart complications and therefore periodical cardiological examinations should be performed in such patients. Finally, therapeutic strategies are suggested to treat cardiac disorders in MRCD
PMCID: PMC3185833  PMID: 21842587
Mitochondrial cardiomyopathies; molecular diagnosis; therapy
21.  Mesoangioblasts of inclusion-body myositis: a twofold tool to study pathogenic mechanisms and enhance defective muscle regeneration 
Acta Myologica  2011;30(1):24-28.
Mesoangioblasts are a class of adult stem cells of mesoderm origin, potentially useful for the treatment of primitive myopathies of different etiology. Extensive in vitro and in vivo studies in animal models of muscular dystrophy have demonstrated the ability of mesoangioblast to repair skeletal muscle when injected intra-arterially. In a previous work we demonstrated that mesoangioblasts obtained from diagnostic muscle biopsies of IBM patients display a defective differentiation down skeletal muscle and this block can be corrected in vitro by transient MyoD transfection. We are currently investigating different pathways involved in mesoangioblasts skeletal muscle differentiation and exploring alternative stimulatory approaches not requiring extensive cell manipulation. This will allow to obtain safe, easy and efficient molecular or pharmacological modulation of pro-myogenic pathways in IBM mesoangioblasts. It is of crucial importance to identify factors (ie. cytokines, growth factors) produced by muscle or inflammatory cells and released in the surrounding milieu that are able to regulate the differentiation ability of IBM mesoangioblasts. To promote myogenic differentiation of endogenous mesoangioblasts in IBM muscle, the modulation of such target molecules selectively dysregulated would be a more handy approach to enhance muscle regeneration compared to transplantation techniques.
Studies on the biological characteristics of IBM mesoangioblasts with their aberrant differentiation behavior, the signaling pathways possibly involved in their differentiation block and the possible strategies to overcome it in vivo, might provide new insights to better understand the etiopathogenesis of this crippling disorder and to identify molecular targets susceptible of therapeutic modulation.
PMCID: PMC3185835  PMID: 21842589
mesoangioblasts; myogenic stem cells; inclusion-body myositis; muscle regeneration
22.  A correlative study of Quantitative EMG and biopsy findings in 31 patients with myopathies 
Acta Myologica  2011;30(1):37-41.
A direct correlation of QEMG with muscle biopsy findings might help delineate the sensitivity of QEMG in identifying muscle pathology as well as provide information on electrophysiological- histological correlations. In a study of 31 patients with a variety of myopathies we found that the sensitivity of QEMG was between 24 to 69% depending of the specific method of signal analysis. The positive predictive value of abnormal QEMG was more than 90% while its negative predictive value was only about 20%. Amplitude outlier analysis was superior especially in minimally weak muscles (MRC > 4) and was particularly sensitive at detecting increased variability in fiber size and more subtle myopathic changes.
PMCID: PMC3185837  PMID: 21842593
Quantitative electromyography; muscle biopsy; sensitivity
23.  State of the art in muscle glycogenoses  
Acta Myologica  2010;29(2):339-342.
The recognition of a series of metabolic/enzymatic dysfunctions in glycogenoses has allowed new therapeutic advances for their treatment due to the development of recombinant enzyme. A recent advance appears enzymatic replacement therapy (ERT) in glycogenosis type II in both infantile, juvenile and adult form. Targeted manipulation of diet has been tried both in glycogenosis type II (Pompe disease) and type V (Mc Ardle disease).
PMCID: PMC3040590  PMID: 21314016
Glycogenosis; Pompe disease; McArdle disease; enzyme replacement therapy
24.  State of the art in muscle lipid diseases 
Acta Myologica  2010;29(2):351-356.
Fatty acid oxidation in mitochondrial matrix is a major source of energy in muscle, especially when physiological energy demand is increased and exceeds what can be provided through glycolysis. Not surprisingly, a group of muscle disorders due to defects in this system usually leads to the development of acute rhabdomyolysis in conditions such as infection, fasting and prolonged exercise. This group includes β-oxidation cycle defects and deficiencies of carnitine palmitoyltransferase II (CPTII) and very-long-chain acyl-CoA dehydrogenase (VLCAD). Muscle pathology is usually not very helpful for the diagnosis but immunohistochemistry may be useful for screening VLCAD deficiency. Another group of lipid dysmetablolism is lipid storage myopathy (LSM) that is pathologically characterized by increased lipid droplets both in number and size in muscle fibers. So far, causative genes have been identified in four different LSMs, comprising primary carnitine deficiency, multiple acyl-CoA dehydrogenase deficiency or glutaric aciduria type II, neutral lipid storage disease with ichthyosis, and neutral lipid storage disease with myopathy. Clinically, the LSM patients show slowly progressive muscle weakness unlike the former group. Final diagnosis is usually made by specific biochemical assays with mutation analyses. As some effective drugs have been widely used and some promising therapies are under certified, comprehensive understanding of these diseases from clinical, pathological and molecular aspects would be of much help for the patients.
PMCID: PMC3040591  PMID: 21314018
Lipid storage myopathy; primary carnitine deficiency; multiple acyl-coenzyme A dehydrogenase deficiency; neutrolipid storage disease; carnitine palmitoyltransferase II; very long-chain acyl-CoA dehydrogenase
25.  State of the art in hereditary muscle channelopathies  
Acta Myologica  2010;29(2):343-350.
A combination of electrophysiological and genetic studies has resulted in the identification of several skeletal muscle disorders to be caused by pathologically functioning ion channels and has led to the term channelopathies. Typical hereditary muscle channelopa thies are congenital myasthenic syndromes, non-dystrophic myotonias, periodic paralyses, malignant hyperthermia, and central core disease. Most muscle channelopathies are commonly considered to be benign diseases. However, lifethreatening weakness episodes or progressive permanent weakness may make these diseases severe, particularly the periodic paralyses (PP). Even in the typical PP forms characterized by episodic occurrence of weakness, up to 60% of the patients suffer from permanent weakness and myopathy with age. In addition, some PP patients present with a predominant progressive muscle weakness phenotype. The weakness can be explained by strongly depolarized fibers that take up sodium and water and that are electrically inexcitable. Drugs that repolarize the fiber membrane can restore muscle strength and may prevent progression.
PMCID: PMC3040592  PMID: 21314017
Congenital myasthenic syndromes; non-dystrophic myotonias; periodic paralyses; susceptibility to malignant hyperthermia; central core disease

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