Danon disease is a severe multisystem disorder clinically characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation in male patients, and by a milder phenotype ...(predominantly involving cardiac muscle) in female patients. The disease is inherited as an X‐linked dominant trait. The primary deficiency of lysosome‐associated membrane protein‐2 (LAMP‐2) causes disruption of autophagy, leading to an impaired fusion of lysosomes to autophagosomes and biogenesis of lysosomes. We surveyed over 500 Danon disease patients reported in the literature from the first description to the present, in order to summarize the clinical, pathological and molecular data and treatment perspectives. An early molecular diagnosis is of crucial importance for genetic counselling and for therapeutic interventions: in male patients, the prognosis is poor due to rapid progression towards heart failure, and only heart transplantation modifies the disease course.
Regulated removal of proteins and organelles by autophagy-lysosome system is critical for muscle homeostasis. Excessive activation of autophagy-dependent degradation contributes to muscle atrophy and ...cachexia. Conversely, inhibition of autophagy causes accumulation of protein aggregates and abnormal organelles, leading to myofiber degeneration and myopathy. Defects in lysosomal function result in severe muscle disorders such as Pompe (glycogen storage disease type II (GSDII)) disease, characterized by an accumulation of autophagosomes. However, whether autophagy is detrimental or not in muscle function of Pompe patients is unclear. We studied infantile and late-onset GSDII patients and correlated impairment of autophagy with muscle wasting. We also monitored autophagy in patients who received recombinant α-glucosidase. Our data show that infantile and late-onset patients have different levels of autophagic flux, accumulation of p62-positive protein aggregates and expression of atrophy-related genes. Although the infantile patients show impaired autophagic function, the late-onset patients display an interesting correlation among autophagy impairment, atrophy and disease progression. Moreover, reactivation of autophagy in vitro contributes to acid α-glucosidase maturation in both healthy and diseased myotubes. Together, our data suggest that autophagy protects myofibers from disease progression and atrophy in late-onset patients.
Duchenne muscular dystrophy (DMD) is the most common single-gene lethal disorder. Substantial patient-patient variability in disease onset and progression and response to glucocorticoids is seen, ...suggesting genetic or environmental modifiers.
Two DMD cohorts were used as test and validation groups to define genetic modifiers: a Padova longitudinal cohort (n = 106) and the Cooperative International Neuromuscular Research Group (CINRG) cross-sectional natural history cohort (n = 156). Single nucleotide polymorphisms to be genotyped were selected from mRNA profiling in patients with severe vs mild DMD, and genome-wide association studies in metabolism and polymorphisms influencing muscle phenotypes in normal volunteers were studied.
Effects on both disease progression and response to glucocorticoids were observed with polymorphism rs28357094 in the gene promoter of SPP1 (osteopontin). The G allele (dominant model; 35% of subjects) was associated with more rapid progression (Padova cohort log rank p = 0.003), and 12%-19% less grip strength (CINRG cohort p = 0.0003).
Osteopontin genotype is a genetic modifier of disease severity in Duchenne dystrophy. Inclusion of genotype data as a covariate or in inclusion criteria in DMD clinical trials would reduce intersubject variance, and increase sensitivity of the trials, particularly in older subjects.
Update on polyglucosan storage diseases Cenacchi, Giovanna; Papa, V.; Costa, R. ...
Virchows Archiv : an international journal of pathology,
12/2019, Letnik:
475, Številka:
6
Journal Article
Recenzirano
An abnormal structural form of glycogen (with less branching points or amylopectin-like polysaccharide) called polyglucosan (PG) may accumulate in various tissues such as striated and smooth muscles, ...brain, nerve, liver and skin, and cause a group of nine different genetic disorders manifesting with a variety of clinical phenotypes that affect mainly the nervous system (Lafora disease, adult PG body disease), the heart (glycogen storage disease type XV, hypertrophic cardiomyopathy type 6, PG body myopathy type 1) and the skeletal muscle (glycogen storage disease type IV, glycogen storage disease type VII, PG body myopathy type 2), depending on the organs which are mostly affected by the PG aggregates. The pathological feature of PG storage in tissues is a hallmark of these disorders. Whole-genome sequencing has allowed to obtain a diagnosis in a large number of patients with a previously unrecognized disorder. We describe the clinical, pathological and molecular features of these genetic disorders, for many of which the pathological mechanisms underlying the corresponding mutant gene have been investigated and, at least in part, understood.
Objective: To provide evidence‐based guidelines to general neurologists for the assessment of patients with pauci‐ or asymptomatic hyperCKemia.
Background: Recent epidemiologic studies show that up ...to 20% of ‘normal’ individuals have an elevated creatine kinase activity in the serum (sCK). The possibility of a subclinical myopathy is often raised, and patients may be unnecessarily denied treatment with statins.
Search strategy: Electronic databases including Medline, the Cochrane Library and the American Academy of Neurology were searched for existing guidelines. Articles dealing with series of patients investigated for asymptomatic/pauci‐symptomatic hyperCKemia and articles dealing with myopathies that can present with asymptomatic hyperCKemia were identified and reviewed.
Results: The only guidelines found were those approved by the Italian Association of Myology Committee, and the only relevant articles identified describe class IV studies.
Recommendations: HyperCKemia needs to be redefined as values beyond 1.5 times the upper limit of normal (which itself needs to be appropriately defined). Pauci‐ or asymptomatic hyperCKemia with no apparent medical explanation may be investigated with a muscle biopsy if one or more of the following are present; the sCK is ≥3× normal, the electromyogram is myopathic or the patient is <25 years of age. In addition, women with sCK<3 times normal may be offered DNA testing because of the possibility of carrying a dystrophin mutation.
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This updated and expanded new edition of a successful book describes genetic diagnostic entities of neuromuscular disorders. Neuromuscular syndromes are presented clinically either as a case study or ...as an overview from the literature, accompanied by text presenting molecular defects, and differential diagnosis. This collection of neuromuscular disorders features the differential clinical phenotypes related to each genotype and are representative of the whole spectrum of a genetic muscle disorder, helping the clinician and neuromuscular physician to make a diagnosis.
In this work, the presence of calcium-dependent calcium channels and their receptors (RyR) has been investigated in Paracentrotus lividus eggs and early embryos, from unfertilized egg to ...four-blastomere stages. Electrophysiological recordings of RyR single-channel current fluctuations showed that RyRs are functional during the first developmental events with a maximum at zygote stage, c. 40 min after fertilization, corresponding to the first cleavage. The nature of vertebrate-like RyRs active at this stage was established by specific activation/blockade experiments.
Muscular dystrophy is a heterogeneous group of disorders characterized by decreased muscle mass, atrophy and connective tissue proliferation. nNOS (nitric oxide synthase) is an important regulator of ...vascular blood flow. Metabolic myopathies mare disorders of utilization of carbohydrates and fatty acids in muscle. The acute nature of energy failure is manifested either by a metabolic crisis (CPT-II deficiency), muscle weakness sometimes associated with respiratory failure (GSDII). The discovery of a new syndrome, NLSD-M (neutral lipid storage disorder), introduces the need of the response to therapy, either dietary or medical, to prevent for each disorder the chronic fatigue, the respiratory insufficiency and cardiomyopathy. Fatigue is a complex phenomenon related to exercise performance and muscle metabolism chosen as a primary endpoint in the overall glycogenosis cases. In other cases, critical events, such as myoglobinuria with increased serum creatine kinase is found. The impact of several polymorphisms reveals variants in the same genetic disorders. MicroRNAs regulate muscle mass and atrophy but their role in these disorders is under investigation. Current therapy consists in steroids for muscular dystrophies, carnitine, riboflavin, medium chain triglycerides, and enzyme replacement therapy for glycogenosis type II. The availability of new therapy can be life-saving for some of these disorders.
Muscular dystrophy is a heterogeneous group of disorders characterized by decreased muscle mass, atrophy and connective tissue proliferation. nNOS (nitric oxide synthase) is an important regulator of ...vascular blood flow. Metabolic myopathies mare disorders of utilization of carbohydrates and fatty acids in muscle. The acute nature of energy failure is manifested either by a metabolic crisis (CPT-II deficiency), muscle weakness sometimes associated with respiratroy failure (GSDII). The discovery of a new syndrome, NLSD-M (neutral lipid storage disorder), introduces the need of the response to therapy, either dietary or medical, to prevent for each disorder the chronic fatigue, the respiratory insufficiency and cardiomyopathy. Fatigue is a complex phenomenon related to exercise performance and muscle metabolism chosen as a primary endpoint in the overall glycogenosis cases. In other cases, critical events, such as myoglobinuria with increased serum creatine kinase is found. The impact of several polymorphisms reveals variants in the same genetic disorders. MicroRNAs regulate muscle mass and atrophy but their role in these disorders is under investigation. Current therapy consists in steroids for muscular dystrophies, carnitine, riboflavin, medium chain triglycerides, and enzyme replacement therapy for glycogenosis type II. The availability of new therapy can be life-saving for some of these disorders.
Background and purpose
Pompe disease is a rare inheritable muscle disorder for which enzyme replacement therapy (ERT) has been available since 2006. Uniform criteria for starting and stopping ERT in ...adult patients were developed and reported here.
Methods
Three consensus meetings were organized through the European Pompe Consortium, a network of experts from 11 European countries in the field of Pompe disease. A systematic review of the literature was undertaken to determine the effectiveness of ERT in adult patients on a range of clinical outcome measures and quality of life. A narrative synthesis is presented.
Results
Consensus was reached on how the diagnosis of Pompe disease should be confirmed, when treatment should be started, reasons for stopping treatment and the use of ERT during pregnancy. This was based on expert opinion and supported by the literature. One clinical trial and 43 observational studies, covering a total of 586 individual adult patients, provided evidence of a beneficial effect of ERT at group level. At individual patient level, the response to treatment varied, but factors associated with a patient's response to ERT were not described in many studies. Eleven observational studies focused on more severely affected patients, suggesting that ERT can also be beneficial in these patients. There are no studies on the effects of ERT in pre‐symptomatic patients.
Conclusions
This is the first European consensus recommendation for starting and stopping ERT in adult patients with Pompe disease, based on the extensive experience of experts from different countries.
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