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1.  Undiagnosed myopathy before surgery and safe anaesthesia table 
Acta Myologica  2013;32(2):100-105.
Patients with muscle pathology are a challenge for anaesthesiologists because of possible life-threatening general anaesthesia complications. A review of the current medical literature on the issue clearly indicates that increasing awareness by anaesthesiologists in recent years has led to a reduction in the occurrence of adverse events in patients with diagnostically well-defined muscle disease. On the other hand, the current emerging aspect is that the great majority of complications concern subjects with clinically non-overt (silent to mildly symptomatic) and thus undiagnosed myopathy. With a view to improving prevention of possible critical anaesthesia complications in such patients, we present a "Safe Anaesthesia Table", listing both the anaesthetic drugs to be avoided and those considered harmless for myopathic patients, irrespective of age and type of pathology. In addition, a brief outline about the clinical aspects suggestive of a possible muscle pathology is also provided. Using "safe drugs" during routine surgical procedures in subjects with suspected undiagnosed myopathy will enable the anaesthesiologist to avoid delaying surgery, while protecting them from anaesthesia complications. By following this approach the presumed myopathy can be properly investigated after surgery.
PMCID: PMC3866898  PMID: 24399867
anaesthesia complications; undiagnosed myopathy; safe anaesthesia; hyperCKemia
2.  A novel homozygous mutation at the GAA gene in Mexicans with early-onset Pompe disease 
Acta Myologica  2013;32(2):95-99.
Glycogen-storage disease type II, also named Pompe disease, is caused by the deficiency of the enzyme acid alpha-glucosidase, which originates lysosomal glycogen accumulation leading to progressive neuromuscular damage. Early-onset Pompe disease shows a debilitating and frequently fulminating course. To date, more than 300 mutations have been described; the majority of them are unique to each affected individual. Most early-onset phenotypes are associated with frameshift mutations leading to a truncated alpha-glucosidase protein with loss of function. Founder effects are responsible from many cases from few highprevalence world regions. Herein we described two apparently unrelated cases affected with classical early-onset Pompe disease, both pertaining to a small region from Central Mexico (the State of San Luis Potosí), the same novel homozygous frameshift mutation at gene GAA (c.1987delC) was demonstrated in both cases. This GAA gene deletion implies a change of glutamine to serine at codon 663, and a new reading frame that ends after 33 base pairs, which leads to the translation of a truncated protein. This report contributes to widen the knowledge on the effect of pathogenic mutations in Pompe disease. Here we postulate the existence of a founder effect.
PMCID: PMC3866899  PMID: 24399866
Early-onset Pompe disease; Acid maltase deficiency; Founder effect
3.  Clinical features of Pompe disease 
Acta Myologica  2013;32(2):82-84.
Glycogen storage disease type II - also called Pompe disease or acid maltase deficiency - is an autosomal recessive metabolic disorder, caused by an accumulation of glycogen in the lysosome due to deficiency of the lysosomal acid alpha-glucosidase enzyme. Pompe disease is transmitted as an autosomal recessive trait and is caused by mutations in the gene encoding the acid α-glucosidase (GAA), located on chromosome 17q25.2-q25.3. The different disease phenotypes are related to the levels of residual GAA activity in muscles. The clinical spectrum ranging from the classical form with early onset and severe phenotype to not-classical form with later onset and milder phenotype is described.
PMCID: PMC3866902  PMID: 24399863
Glycogen storage disease type II; Pompe disease; GAA activity
4.  Non-muscle involvement in late-onset Glycogenosis II 
Acta Myologica  2013;32(2):91-94.
Glycogenosis II (GSD II) is an autosomal recessive lysosomal storage disorder resulting from acid alpha-glucosidase deficiency, subsequent accumulation of glycogen in tissues, impairment of autophagic processes and progressive cardiac, motor and respiratory failure.
The late-onset form is characterized by wide variability in residual enzyme activity, age of onset, rate of disease progression and phenotypical spectrum. Although the pathological process mainly affects the skeletal muscle, several other tissues may be involved in the course of the disease; therefore GSD II should be regarded as a multisystem disorder in which glycogen accumulation is present in skeletal and smooth muscle, heart, brain, liver, spleen, salivary glands, kidney and blood vessels.
In this review, we briefly summarize the main non-muscle targets of the pathological process in late-onset GSD II.
Further studies aimed at evaluating the extra-muscle involvement in this group of patients will help to better define clinical features and prognostic factors and to delineate the natural history of the disease.
PMCID: PMC3866903  PMID: 24399865
Glycogenosis II; GSDII; Pompe disease
5.  Overlapping syndromes in laminopathies: a meta-analysis of the reported literature 
Acta Myologica  2013;32(1):7-17.
Mutations on the LMNA gene are responsible for an heterogeneous group of diseases. Overlapping syndromes related to LMNA gene alterations have been extensively reported. Study scope is to perform a systematic analysis of the overlapping syndromes so far described and to try to correlate the clinical features to the associated genetic alterations. We evaluated all the dominant overlapping syndromes reported by means of a PubMed search and by the analysis of the main databases containing the pathogenic LMNA gene variations and the associated diseases.
Metabolic alterations in association to skeletal and/or cardiac alterations proved to be the most frequent overlap syndrome. Overlapping syndromes are mostly associated to inframe mutations in exons 1, 2, 8 and 9. These data further improve the understanding of the pathogenesis of laminopathies.
PMCID: PMC3665370  PMID: 23853504
Lamin A/C; laminopathies; LMNA overlapping syndromes
6.  The heart and cardiac pacing in Steinert disease 
Acta Myologica  2012;31(2):110-116.
Myotonic dystrophy (Dystrophia Myotonica, DM) is the most frequently inherited neuromuscular disease of adult life. It is a multisystemic disease with major cardiac involvement. Core features of myotonic dystrophy are myotonia, muscle weakness, cataract, respiratory failure and cardiac conduction abnormalities. Classical DM, first described by Steinert and called Steinert's disease or DM1 (Dystrophia Myotonica type 1) has been identified as an autosomal dominant disorder associated with the presence of an abnormal expansion of a CTG trinucleotide repeat in the 3' untranslated region of DMPK gene on chromosome 19. This review will mainly focus on the various aspects of cardiac involvement in DM1 patients and the current role of cardiac pacing in their treatment.
PMCID: PMC3476856  PMID: 23097601
myotonic dystrophy type 1; arrhythmias; cardiac pacing
7.  Drug treatment of Duchenne muscular dystrophy: available evidence and perspectives 
Acta Myologica  2012;31(1):4-8.
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3,600-6,000 newborn males. It is manifested by the absence of the dystrophin protein in muscle fibres, which causes progressive damage leading to death in the third decade of life. The only medication so far shown to be effective in delaying the progression of this illness are corticosteroids, which have been shown to increase muscle strength in randomised controlled studies; long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction, dilated cardiomyopathy and scoliosis. Several potential drugs are now being investigated. Genetic therapy, involving the insertion of a dystrophin gene through a vector, has proven effective in animals but not humans. Currently under clinical study is Ataluren, a molecule that binds with ribosomes and may allow the insertion of an aminoacid in the premature termination codon, and exon-skipping, which binds with RNA and excludes specific sites of RNA splicing, producing a dystrophin that is smaller but functional. There are also studies attempting to modulate other muscular proteins, such as myostatin and utrophin, to reduce symptoms. This paper does not address cardiomyopathy treatment in DMD patients.
PMCID: PMC3440798  PMID: 22655510
Duchenne muscular dystrophy; drug treatment; clinical trials
8.  Treatment of dystrophinopathic cardiomyopathy: review of the literature and personal results 
Acta Myologica  2012;31(1):24-30.
Cardiomyopathy is an almost universal finding in boys affected by Duchenne muscular dystrophy (DMD). Myocardial changes, as a result of the lack of dystrophin, consist of cell membrane degradation, interstitial inflammation, fatty replacement and fibrosis.
Dystrophinopathic cardiomyopathy generally starts as a preclinical or intermediate stage, with evolution toward advanced stages characterized by ventricle enlargement but also by symptoms and signs of heart failure (dyspnoea, peripheral edema and liver enlargement). However in few patients the dilation could be the first manifestation of the heart involvement.
The ability to detect overt cardiomyopathy increases with age, such that more than 80% of boys older than 18 years will have abnormal systolic function.
Several drugs have been employed with the aim to contrast the evolution of cardiomyopathy toward stages of severe congestive heart failure. A review of cardiac treatment in DMD and personal experience are reported and discussed.
PMCID: PMC3440799  PMID: 22655514
Dystrophinopathic cardiomyopathy; deflazacort; ACE-inhibitors
9.  Surgical treatment of Duchenne muscular dystrophy patients in Germany: the present situation 
Acta Myologica  2012;31(1):21-23.
In 1988, we familiarised ourselves at Poitiers with the concept of operative treatment of the lower limbs and the spine in Duchenne muscular dystrophy (DMD) patients which Yves Rideau and his collaborators (1, 2) had developed there in the early 1980s. Thereupon, we immediately established the techniques at our home universities, first at the Technische Universität Aachen and, from 1999 on, at the Universitätsklinikum Erlangen, Germany. Since then, we have applied the technique to more than 500 DMD patients in total by performing more than 800 operations on the lower limbs and/or spine. In support of findings reported by Professor Rideau in this issue (3) we observed that, where patients are still ambulatory at the time of operation, the operation delays the point at which patients become wheelchair-bound by about two years. Likewise, patients receiving this treatment were/are also able to perform the Gowers' manoeuvre for around two years longer (4-6).
PMCID: PMC3440800  PMID: 22655513
Duchenne muscular dystrophy; prophylactic surgery; prevention of scoliosis
10.  Rationale for treating oedema in Duchenne muscular dystrophy with eplerenone 
Acta Myologica  2012;31(1):31-39.
Recently we reported a cytoplasmic sodium overload to cause a severe osmotic oedema in Duchenne muscular dystrophy (DMD). Our results suggested that this dual overload of sodium ions and water precedes the dystrophic process and persists until fatty muscle degeneration is complete. The present paper addresses the questions as to whether these overloads are important for the pathogenesis of the disease, and if so, whether they can be treated. As a first step, we investigated the effects of various diuretic drugs on a cell model of DMD, i.e. rat diaphragm strips previously exposed to amphotericin B. We found that both carbonic anhydrase inhibitors and aldosterone antagonists were able to repolarise depolarised muscle fibres. Since carbonic anhydrase inhibitors are known to have acidifying effects and this might be detrimental to the ventilation of DMD patients, we mainly concentrated on the modern spironolactone derivative, eplerenone. This drug had a very high repolarizing power, the parameter considered by us as being most relevant for a beneficial effect. In a pilot study we administered this drug to a 22-yr-old female DMD patient who was bound to an electric wheelchair and has had no corticosteroid therapy before. Eplerenone decreased both cytoplasmic sodium and water overload and increased muscle strength and mobility. We conclude that eplerenone has beneficial effects on DMD muscle. In our opinion the cytoplasmic oedema is cytotoxic and should be treated before fatty degeneration takes place.
PMCID: PMC3440802  PMID: 22655515
Duchenne muscular dystrophy; eplerenone; cytotoxic oedema
11.  Pre-clinical drug tests in the mdx mouse as a model of dystrophinopathies: an overview 
Acta Myologica  2012;31(1):40-47.
Duchenne muscular dystrophy is a lethal X-linked muscle disease affecting 1/3500 live male birth. It results from defects in the subsarcolemmal protein dystrophin, a component of the dystrophinglycoprotein complex (DGC) which links the intracellular cytoskeleton to the extracellular matrix. The absence of dystrophin leads to muscle membrane fragility, muscle necrosis and gradual replacement of skeletal muscle by fat and connective tissue, through a complex and still unclear cascade of interconnecting events. No cure is currently available, with glucocorticoids being the sole drugs in clinical use in spite of their remarkable side effects. A great effort is devoted at performing pre-clinical tests on the mdx mouse, the mostly used homologous animal model for DMD, with the final aim to identify drugs safer than steroids and able to target the pathogenic mechanisms so to delay pathology progression. This review updates the efforts on this topic, focusing on the open issues about the animal model and highlighting the classes of pharmaceuticals that are more promising as diseasemodifiers, while awaiting for more corrective therapies. Although caution is necessary in data transfer from mdx model to DMD patients, the implementation of standard operating procedures and the growing understanding of the pathology may allow a more accurate evaluation of therapeutics, alone or in combination, in pre-clinical settings. A continuous cross-talk with clinicians and patients associations are also crucial points for proper translation of data from mouse to bedside.
PMCID: PMC3440805  PMID: 22655516
Duchenne muscular dystrophy; mdx mouse model; pharmaceuticals; pre-clinical studies; translational research
12.  Old and new therapeutic developments in steroid treatment in Duchenne muscular dystrophy 
Acta Myologica  2012;31(1):9-15.
Steroids have been used since two decades and several trials were conducted to establish their efficacy in DMD patients with various regimens. The clinical outcomes showed increased function in the treated boys, and in a single trial with deflazacort, prolongation of ambulation but with different side effects. Steroids clinical efficacy is now established. The main concern is to increase steroid efficacy and decrease side effect and toxicity. A trial comparing daily prednisone, deflazacort and intermittent glucocorticoids (prednisone 10 days on/10 days off) (FOR-DMD) is starting under NIH grant. The primary outcomes will be muscle strength, forced vital capacity and patient/parents satisfaction.
PMCID: PMC3440806  PMID: 22655511
Steroids; Duchenne; DMD; side effect; quality of life
13.  The Canadian experience with long term deflazacort treatment in Duchenne muscular dystrophy 
Acta Myologica  2012;31(1):16-20.
Deflazacort is the most commonly prescribed corticosteroid for the treatment of Duchenne muscular dystrophy in Canada. We review the long term experience with deflazacort treatment at two centers in Canada; Montreal and Toronto. Deflazacort has benefitted both cohorts by prolonged ambulation, preserved cardiac and respiratory function, less scoliosis and improved survival. Common side effects in both cohorts include weight gain, decreased height and cataract formation. The Canadian experience supports the use of deflazacort in treating boys with Duchenne muscular dystrophy.
PMCID: PMC3440807  PMID: 22655512
Deflazacort; Duchenne Muscular Dystrophy; Canada
14.  Genetic counseling in Pompe disease 
Acta Myologica  2011;30(3):179-181.
Pompe disease is caused by glycogen accumulation due to a deficiency of the lysosomal acid alpha-glucosidase enzyme by which it is degraded. It is a rare disease, accounting for 1:40.000 births. It is inherited as an autosomal recessive trait so that a couple presents a recurrent risk of 25% to have a child affected, at each pregnancy. The diagnosis could be achieved by biochemical and/ or molecular testing. Carrier detection and prenatal diagnosis are available when the molecular defect is known.
PMCID: PMC3298105  PMID: 22616199
Pompe disease; genetic counselling; prenatal diagnosis
15.  Cardiac involvement in patients with Spinal Muscular Atrophies 
Acta Myologica  2011;30(3):175-178.
The spinal muscular atrophies (SMAs) include a group of disorders characterized by progressive weakness of the lower motor neurons. Several types of SMAs have been described based on age onset of clinical features: Acute infantile (SMA type I), chronic infantile (SMA type II), chronic juvenile (SMA type III), and adult onset (SMA type IV) forms. The incidence is about 1:6,000 live births with a carrier frequency of 1:40 for the severe form and 1:80 for the juvenile form. The mortality and/or morbidity rates of SMAs are inversely correlated with the age at onset. SMAs are believed to only affect skeletal muscles; however, new data on SMA mice models suggest they may also impact the heart.
Aim of the study was to retrospectively examine the cardiological records of 37 type molecularly confirmed II/III SMA patients, aged 6 to 65 years, in order to evaluate the onset and evolution of the cardiac involvement in these disorders. All patients had a standard ECG and a routine echocardiography. The parameters analysed were the following: Heart rate (HR), PQ interval, PQ segment, Cardiomyopathic Index (ratio QT/PQs), ventricular and supraventricular ectopic beats, pauses ≥ 2,5msec, ventricle diameters, wall and septum thickness, ejection fraction, fiber shortening.
The results showed that HR and the other ECG parameters were within the normal limits except for the Cardiomyopathic Index that was higher than the normal values (2,6-4,2) in 2 patients. Left ventricular systolic function was within the normal limits in all patients. A dilation of the left ventricle without systolic dysfunction was observed in only 2 patients, aged respectively 65 and 63 years; however they were hypertensive and/or affected by coronary artery disease. Data here reported contribute to reassure patients and their clinicians that type II/III SMAs do not present heart dysfunction.
PMCID: PMC3298107  PMID: 22616198
Spinal Muscular Atrophies; heart involvement; cardiomyopathy
16.  Familial amyotrophic lateral sclerosis, a historical perspective 
Acta Myologica  2011;30(2):117-120.
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease of the upper and lower motor neuron of unknown etiology. Although a familial cause for this disease has been suspected early one, it is only in the past two decades that advances in modern genetics led to the identification of more than 10 genes linked to familial ALS and helped us understand some of the complex genetic and environmental interactions that may contribute to sporadic ALS. In this article, we chronologically summarize the genetic breakthroughs in familial and sporadic ALS and depict how it shaped our understanding of disease pathogenesis and our quest for rational therapies.
PMCID: PMC3235825  PMID: 22106714
17.  Diagnostic value of markers of muscle degeneration in sporadic inclusion body myositis 
Acta Myologica  2011;30(2):103-108.
Sporadic inclusion body myositis (s-IBM) is characterized histologically by the association of concomitant inflammatory and degenerative processes. We evaluated the sensitivity and specificity of different markers of the degenerative process in order to refine the histological diagnosis. We performed an immunohistochemical study with antibodies directed against ubiquitin, amyloid-β precursor protein (AβPP), amyloid-β (Aβ), SMI-31, SMI-310, Tar-DNA binding protein-43 (TDP-43) and p62 on s-IBM and control muscle biopsies. Based on conventional stains 36 patients with characteristic clinical features of s-IBM were subclassified as presumed definite s-IBM (d s-IBM, n = 17) or possible s-IBM (p s-IBM, n = 19) according to the presence or absence of vacuolated muscle fibers. Immunohistochemically, TDP-43 and p62 were the most sensitive markers, accumulating in all d s-IBM and in 31% and 37%, respectively, of the p s-IBM cases and thus enabling reclassification of these cases as d s-IBM. We recommend using TDP-43 and p62 antibodies in the histological diagnosis workup of s-IBM. The specificity of these markers has to be further validated in prospective series.
PMCID: PMC3235833  PMID: 22106712
inclusion body myositis; inflammatory myopathy; protein aggregate myopathy; immunohistochemistry; Tar-DNA binding protein-43; p62
18.  Hereditary inclusion-body myopathy with sparing of the quadriceps: the many tiles of an incomplete puzzle 
Acta Myologica  2011;30(2):91-95.
The hereditary inclusion-body myopathies encompass several syndromes with autosomal recessive or dominant inheritance. Despite a different clinical presentation they all have a progressive course leading to severe disability and share similar pathologic findings at the muscle biopsy. Quadriceps-sparing autosomal recessive hereditary inclusion-body myopathy (h-IBM) is the commonest form and is tied to mutations of the UDP-Nacetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) that codes for a rate-limiting enzyme in the sialic acid biosynthetic pathway. Despite the identification of the causative gene defect, it has not been clarified how mutations of the GNE gene impair muscle homeostasis. Although several lines of evidence argue in favor of an abnormal sialylation of muscle glycoproteins playing a key role in h-IBM pathogenesis, others studies have demonstrated new functions of the GNE gene, outside the sialic acid biosynthetic pathway, that may also be relevant. This review illustrates the clinical and pathologic characteristics of h- IBM and the main clues available to date concerning the possible pathogenic mechanisms of this disorder. Understanding the molecular mechanism underlying h-IBM pathology is a fundamental requisite to plan a future attempt to therapy.
PMCID: PMC3235839  PMID: 22106710
h-IBM; quadriceps sparing myopathy; GNE mutations
19.  Strategy for genetic testing in Charcot-Marie-Disease 
Acta Myologica  2011;30(2):109-116.
Charcot Marie Tooth disease (CMT) affects one in 2500 people. Genetic testing is often pursued for family planning purposes, natural history studies and for entry into clinical trials. However, identifying the genetic cause of CMT can be expensive and confusing to patients and physicians due to locus heterogeneity.
We analyzed data from more than 1000 of our patients to identify distinguishing features in various subtypes of CMT. Data from clinical phenotypes, neurophysiology, family history, and prevalence was combined to create algorithms that can be used to direct genetic testing for patients with CMT.
The largest group of patients in our clinic have slow motor nerve conduction velocities (MNCV) in the upper extremities. Approximately 88% of patients in this group have CMT1A. Those who had intermediate MNCV had primarily CMT1X (52.8%) or CMT1B (27.8%). Patients with very slow MNCV and delayed walking were very likely to have CMT1A (68%) or CMT1B (32%). No patients with CMT1B and very slow MNCV walked before 15 months of age. Patients with CMT2A form our largest group of patients with axonal forms of CMT.
Combining features of the phenotypic and physiology groups allowed us to identify patients who were highly likely to have specific subtypes of CMT. Based on these results, we created a series of algorithms to guide testing. A more detailed review of this data is published in Annals of Neurology (1).
PMCID: PMC3235845  PMID: 22106713
CMT; Charcot Marie Tooth disease; genetic testing
20.  Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy 
Acta Myologica  2011;30(2):121-126.
The term myofibrillar myopathies (MFM) refers to uncommon neuromuscular disorders that pathologically are characterized by myofibrillar degeneration and ectopic expression of several proteins. MFM are partly caused by mutations in genes that encode mainly Z-disk-related proteins (desmin, αB-crystallin, myotilin, ZASP, filamin C and BAG3). We reviewed clinical, light and electron microscopy, immunohistochemistry, immunoblotting and genetic findings of 21 patients with MFM (15 unrelated patients and three pairs of brothers) investigated at our neuromuscular center. MFM patients begin to show symptoms at any age, from juvenile to late adult life and present a different distribution of muscle weakness. Cardiac involvement and peripheral neuropathy are common. Typical histological features include focal areas with reduction/ loss of ATPase and oxidative enzyme activity, and amorphous material (eosinophilic on hematoxylin and eosin and dark blue on Engel-Gomori trichrome) in these abnormal fiber areas. Electron microscopy shows disintegration of myofibrils starting from the Z-disk and accumulation of granular and filamentous material among the myofilaments. Immunohistochemical studies demonstrate focal accumulation of desmin, αB-crystallin and myotilin in abnormal muscle fibers while immunoblot analysis does not highlight differences in the expression of these proteins also including ZASP protein. Therefore, unlike immunoblot, immunohistochemistry together with light and electron microscopy is a useful diagnostic tool in MFM. Finally three of our 21 patients have missense mutations in the desmin gene, two brothers carry missense mutations in the gene encoding myotilin, one has a missense mutation in αB-crystallin, and none harbour pathogenic variations in the genes encoding ZASP and BAG3.
PMCID: PMC3235861  PMID: 22106715
Myofibrillar myopathies, desmin; αB-crystallin; myotilin; Z-band alternatively spliced PDZ motif containing protein (ZASP); filamin C; Z-disk
21.  Progress and problems in muscle glycogenoses 
Acta Myologica  2011;30(2):96-102.
In this selective review, we consider a number of unsolved questions regarding the glycogen storage diseases (GSD). Thus, the pathogenesis of Pompe disease (GSD II) is not simply explained by excessive intralysosomal glycogen storage and may relate to a more general dysfunction of autophagy. It is not clear why debrancher deficiency (GSD III) causes fixed myopathy rather than exercise intolerance, unless this is due to the frequent accompanying neuropathy. The infantile neuromuscular presentation of branching enzyme deficiency (GSD IV) is underdiagnosed and is finally getting the attention it deserves. On the other hand, the late-onset variant of GSD IV (adult polyglucosan body disease APBD) is one of several polyglucosan disorders (including Lafora disease) due to different etiologies. We still do not understand the clinical heterogeneity of McArdle disease (GSD V) or the molecular basis of the rare fatal infantile form. Similarly, the multisystemic infantile presentation of phosphofructokinase deficiency (GSD VII) is a conundrum. We observed an interesting association between phosphoglycerate kinase deficiency (GSD IX) and juvenile Parkinsonism, which is probably causal rather than casual. Also unexplained is the frequent and apparently specific association of phosphoglycerate mutase deficiency (GSD X) and tubular aggregates. By paying more attention to problems than to progress, we aimed to look to the future rather than to the past.
PMCID: PMC3235878  PMID: 22106711
glycogen storage diseases; GSD; polyglucosan disorders
22.  Stromal cell-derived factors in Duchenne muscular dystrophy  
Acta Myologica  2010;29(3):398-403.
Duchenne muscular dystrophy (DMD) is characterized by increased muscle damage and an abnormal blood flow after muscle contraction leading to a state of functional ischemia. Abundant evidence suggests that endothelial circulating progenitor cells (EPCs) play an important role in mediating vascular and muscle repair mechanisms and that the stromal cell-derived factor (SDF)-1 α chemokine is responsible for both progenitor cell mobilization from the bone marrow to peripheral blood and homing to the sites of vascular and tissue injury. Since normal neovascularization is disrupted in DMD pathogenesis and may contribute ultimately to heart failure and sudden death, the aim of the present study is to investigate whether the (SDF)-1 α, and EPCs surface receptors in terms of CD34, CD133 and kinase domain receptor (KDR) are involved in DMD pathophysiology. In the present study, peripheral blood concentrations of circulating CD34, CD133, and CD34/ CD 133 progenitor cells were measured by flow cytometry, together with serum levels of (SDF)-1α and hypoxia inducible factor (HIF-1α.), in 28 DMD patients vs. 20 healthy age and socioeconomic matching controls. Results showed a significant increase in the number of mononuclear cells bearing EPC markers, HIF-1α mRNA expression and serum (SDF)-1 α, indicating that regeneration is an ongoing process in these patients. However, this regeneration cannot counterbalance the damage induced by dystrophine mutation.
PMCID: PMC3146336  PMID: 21574524
Duchenne dystrophy; stromal cell-derived factors; EPCs surface receptors
23.  Range of motion exercise of temporo-mandibular joint with hot pack increases occlusal force in patients with Duchenne muscular dystrophy  
Acta Myologica  2010;29(3):392-397.
The purpose of this study is to evaluate whether the range of motion exercise of the temporo-mandibular joint (jaw ROM exercise) with a hot pack and massage of the masseter muscle improve biting disorder in Duchenne muscular dystrophy (DMD). The subjects were 18 DMD patients (21.3 ± 4.1 years old). The jaw ROM exercise consisted of therapist-assisted training (2 times a week) and self-training (before each meal every day). The therapist-assisted training consisted of the application of a hot pack on the cheek of the masseter muscle region (15 minutes), the massage of the masseter (10 minutes), and jaw ROM exercise (5 minutes). The self-training involved jaw ROM exercise by opening the mouth to the maximum degree, ten times. These trainings continued for six months. Outcomes were evaluated by measuring the greatest occlusal force and the distance at the maximum degree of mouth opening between an incisor of the top and that of the bottom. Six months later, the greatest occlusal force had increased significantly compared with that at the start of jaw ROM exercise (intermediate values: from 73.8N to 97.3N) (p = 0.005) as determined by the Friedman test and Scheffé's nonparametric test. The patients' satisfaction with meals increased. However, the maximum degree of mouth opening did not change after six months of jaw ROM exercise. Jaw ROM exercise in DMD is effective for increasing the greatest occlusal force.
PMCID: PMC3146337  PMID: 21574523
Duchenne muscular dystrophy; exercise; occlusal force
24.  Pathogenesis and treatment of mitochondrial myopathies: recent advances  
Acta Myologica  2010;29(2):333-338.
In this brief review, I have highlighted recent advances in several areas of mitochondrial medicine, including mtDNA-related diseases, mendelian mitochondrial encephalomyopathies, and therapy. The pathogenic mechanisms of mtDNA mutations, especially those affecting mitochondrial protein synthesis, are still largely unknown. The pathogenicity of homoplasmic mtDNA mutations has become evident but has also called attention to modifying nuclear genes, yet another example of impaired intergenomic signaling. The functional significance of the homoplasmic changes associated with mitochondrial haplogroups has been confirmed. Among the mendelian disorders, a new form of “indirect hit” has been described, in which the ultimate pathogenesis is toxic damage to the respiratory chain. Three therapeutic strategies look promising: (i) allogeneic hematopoietic stem cell transplantation in MNGIE (mitochondrial neurogastrointestinal encephalomyopathy); (ii) bezafibrate, an activator of PGC-1α, has proven effective in animal models of mitochondrial myopathy; and (iii) pronucleus transfer into a normal oocyte is effective in eliminating maternal transmission of mtDNA, thus preventing the appearance of mtDNA-related disorders.
PMCID: PMC3040593  PMID: 21314015
mtDNA-related disorders; mendelian mitochondrial disorders; homoplasmy; pathogenesis; therapy
Acta Myologica  2008;27(3):114-122.
Sudden cardiac death, or cardiac arrest, is a major health problem, causing about 166,200 deaths each year among adults in the United States. It may be caused by almost all known heart diseases. Most cardiac arrests occur when the diseased heart begins to exhibit rapid and/or chaotic activity, such as ventricular tachycardia or fibrillation. Some are due to extreme slowing of the heart. All these events are called life-threatening arrhythmias. Arrhythmogenic cardiomyopathy is a frequent feature in several muscular dystrophies with a potential risk of cardiac sudden death. Among the measures able to predict the propensity to develop life-threatening arrhythmias, heart rate variability is an accepted non invasive measurement of cardiac autonomic modulation. The use of heart rate variability to measure the extent of changes in autonomic nervous system is an established risk stratification procedure in different diseases. In fact numerous studies have demonstrated the positive prognostic power of altered heart rate variability values to predict all-cause mortality, cardiac events, sudden cardiac death and heart transplantation. Usefulness of heart rate variability as a predictor of sudden cardiac death in muscular dystrophies has been reviewed.
PMCID: PMC2858940  PMID: 19472920
Heart rate variability; sudden cardiac death; muscular dystrophies

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