Metabolic myopathies encompass muscle glycogenoses (GSD) and disorders of muscle fat oxidation (FAOD). FAODs and GSDs can be divided into two main clinical phenotypes; those with static symptoms ...related to fixed muscle weakness and atrophy, and those with dynamic, exercise-related symptoms that are brought about by a deficient supply of ATP. Together with mitochondrial myopathies, metabolic myopathies are unique among muscle diseases, as the limitation in exercise performance is not solely caused by structural damage of muscle, but also or exclusively related to energy deficiency. ATP consumption can increase 50–100-fold in contracting, healthy muscle from rest to exercise, and testing patients with exercise is therefore an appropriate approach to disclose limitations in work capacity and endurance in metabolic myopathies. Muscles rely almost exclusively on muscle glycogen in the initial stages of exercise and at high work intensities. Thus, patients with GSDs typically have symptoms early in exercise, have low peak work capacities and develop painful contractures in exercised muscles. Muscle relies on fat oxidation at rest and to a great extent during prolonged exercise, and therefore, patients with FAODs typically develop symptoms later in exercise than patients with GSDs. Due to the exercise-related symptoms in metabolic myopathies, patients generally have been advised to shun physical training. However, immobility is associated with multiple health issues, and may even cause unwanted metabolic adaptations, such as increased dependence on glycogen use and a reduced capacity for fatty acid oxidation, which is detrimental in GSDs. Training has not been studied systematically in any FAODs and in just a few GSDs. However, studies on single bouts of exercise in most metabolic myopathies show that particularly moderate intensity aerobic exercise is well tolerated in these conditions. Even low-intensity resistance training of short duration is tolerated in McArdle disease. Training in patients with FAOD potentially can also expand the metabolic bottleneck by increasing expression of the defective, but partially functional enzyme. Exercise performance in metabolic myopathies can be improved by different fuel supplementations and dietary interventions and should be considered as adjunct therapy to exercise training.
α‐methylacyl‐CoA racemase (AMACR) deficiency is a rare disorder, affecting peroxisomal metabolism of pristanic acid, with ten published adult cases. We describe an AMACR deficiency case with a ...clinical presentation dominated by episodic hyperCKaemia, suggesting that myopathic features of AMACR should be considered.
α‐methylacyl‐CoA racemase (AMACR) deficiency is a rare disorder, affecting peroxisomal metabolism of pristanic acid, with ten published adult cases. We describe an AMACR deficiency case with a clinical presentation dominated by episodic hyperCKaemia, suggesting that myopathic features of AMACR should be considered.
McArdle disease: a clinical review Quinlivan, R; Buckley, J; James, M ...
Journal of neurology, neurosurgery and psychiatry,
11/2010, Letnik:
81, Številka:
11
Journal Article
Recenzirano
Odprti dostop
The clinical phenotype of 45 genetically confirmed McArdle patients is described.
In the majority of patients (84%), the onset of symptoms was from early childhood but diagnosis was frequently ...delayed until after 30 years of age. Not all patients could recognise a second wind although it was always seen with exercise assessment. A history of myoglobinuria was not universal and episodes of acute renal failure had occurred in a minority (11%). The condition does not appear to adversely affect pregnancy and childbirth. Clinical examination was normal in most patients, muscle hypertrophy was present in 24% and mild muscle wasting and weakness were seen only in patients over 40 years of age and was limited to shoulder girdle and axial muscles. The serum creatine kinase was elevated in all but one pregnant patient. Screening for the mutations pArg50X (R50X) and pGly205Ser (G205S) showed at least one mutated allele in 96% of Caucasian British patients, with an allele frequency of 77% for pArg50X in this population. A 12 min walking test to evaluate patients is described.
The results demonstrated a wide spectrum of severity with the range of distance walked (195-1980 m); the mean distance walked was 512 m, suggesting significant functional impairment in most patients.
Muscle strength in myasthenia gravis Cejvanovic, S.; Vissing, J.
Acta neurologica Scandinavica,
June 2014, Letnik:
129, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Objective
Myasthenia gravis (MG) is characterized by fatigue and fluctuating muscle weakness as a result of impaired neuromuscular transmission (NMT). Although MG is a prototypic fatiguing disorder, ...little is known about how the condition affects fixed weakness, and if present, whether weakness is related to disease duration or gender. The aim of this study was to quantify the strength of patients with MG and investigate whether it is related to disease duration.
Methods
Eight muscle groups were tested by manual muscle testing and with a hand‐held dynamometer in 38 patients with generalized MG and 37 healthy age‐ and gender‐matched controls. The disease duration was recorded and compared with strength measures.
Results
On average, muscle strength was decreased by 28% compared with controls (P < 0.01). Repeated strength measures in individual patients did not differ, suggesting that the muscle force reported was not subject to fatigue, but reflected fixed weakness. The male patients showed a greater reduction in muscle force in all eight muscle groups than women with MG (60% vs 77% of normal, P < 0.05). In both men and women with MG, strength in shoulder abductors was most affected (51% vs 62% of normal). Muscle strength and disease duration were not related.
Conclusions
These findings show that patients with generalized MG have (i) a significant generalized, fixed muscle weakness, (ii) that male patients with MG have a more severe muscle weakness than women, (iii) that proximal upper limb muscles are most affected, and (iv) that disease duration alone is not a predictor of loss of muscle strength.
Objective
Dysphagia can be troublesome in sporadic inclusion body myositis (sIBM) and oculopharyngeal muscular dystrophy (OPMD), but no established treatment exists. Cricopharyngeal muscle botulinum ...toxin injection has at case level been reported to be effective. We evaluated safety and efficacy of botulinum toxin injections in the cricopharyngeal muscle in patients with dysphagia due to sIBM or OPMD.
Methods
Participants were included from our outpatient clinic. Cricopharyngeal constriction was confirmed by laryngoscopy. After EMG confirmation of needle placement in the cricopharyngeal muscle, botulinum toxin A was injected in awake patients. An individualized dose of 5–10 units of botulinum toxin A was applied initially and titrated up a maximum of 3 times. Outcome measures were change in dysphagia questionnaire, timed cold-water swallow test and subjective dysphagia status (worse, unchanged, improved). Due to the need for individualized dosing and a limited number of available patients, an uncontrolled, un-blinded design was used.
Results
Thirteen patients, 3 with OPMD, received at least 1 injection. In the dysphagia questionnaire, all but 2 subjects, none with subjective worsening, improved (
p
< 0.001). Subjectively, seven felt an improvement, 4 no change and 2 a worsening. No overall change was seen the timed cold-water swallow test. No serious adverse events were observed.
Conclusion
Botulinum toxin injection of the cricopharyngeal muscle in patients with OPMD and sIBM had a beneficial effect on dysphagia in most of the treated patients. Two of 13 patients experienced a temporary worsening not reflected in dysphagia score. Limitations are the un-blinded and un-randomized design and subjective assessments methods.
Prospective trial registration
EudraCT-number: 2014-002210-23.
McArdle disease (glycogen storage disease type V; GSDV) is a rare genetic disease caused by the inability to break down glycogen in skeletal muscle due to a deficiency in myophosphorylase. Glycolysis ...is only partially blocked in GSDV, as muscle fibres can take up circulating glucose and convert it to glucose-6-phosphate downstream of the metabolic block. Because skeletal muscle predominantly relies on anaerobic energy during the first few minutes of transition from rest to activity, and throughout more intense activities, individuals with GSDV experience muscle fatigue/pain, tachypnea, and tachycardia during these activities. If warning signs are not heeded, a muscle contracture may rapidly occur, and if significant, may lead to acute rhabdomyolysis. Without a cure or treatment, individuals with GSDV must be consistent in employing proper management techniques; however, this can be challenging due to the nuances inherent in this metabolic myopathy. The International Association for Muscle Glycogen Storage Disease collaborated with an international team of five expert clinicians to identify areas of learning to achieve an optimal state. A Continuum of Care model was developed that outlines five pivotal steps (diagnosis; understanding; acceptance; learning and exercise) to streamline assessments and more succinctly assist clinicians in determining patient-specific learning needs. This model serves as a translational tool to help optimize care for this patient population.
Objectives
Rhabdomyolysis and myalgia are common conditions, and mutation in the ryanodine receptor 1 gene (RYR1) is suggested to be a common cause. Due to the large size of RYR1, however, sequencing ...has not been widely accessible before the recent advent of next‐generation sequencing technology and limited phenotypic descriptions are therefore available.
Material & Methods
We present the medical history, clinical and ancillary findings of patients with RYR1 mutations and rhabdomyolysis and myalgia identified in Denmark, France and The Netherlands.
Results
Twenty‐two patients with recurrent rhabdomyolysis (CK > 10 000) or myalgia with hyperCKemia (>1.5 × ULN) and a RYR1 mutation were identified. One had mild wasting of the quadriceps muscle, but none had fixed weakness. Symptoms varied from being restricted to intense exercise to limiting ADL function. One patient developed transient kidney failure during rhabdomyolysis. Two received immunosuppressants on suspicion of myositis. None had episodes of malignant hyperthermia. Muscle biopsies were normal, but CT/MRI showed muscle hypertrophy in most. Delay from first symptom to diagnosis was 12 years on average. Fifteen different dominantly inherited mutations were identified. Ten were previously described as pathogenic and 5 were novel, but rare/absent from the background population, and predicted to be pathogenic by in silico analyses. Ten of the mutations were reported to give malignant hyperthermia susceptibility.
Conclusion
Mutations in RYR1 should be considered as a significant cause of rhabdomyolysis and myalgia syndrome in patients with the characteristic combination of rhabdomyolysis, myalgia and cramps, creatine kinase elevation, no weakness and often muscle hypertrophy.
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.
MSTO1
encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype–phenotype spectrum remains to be explored, pathogenic variants in
MSTO1
have recently been ...reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of
MSTO1
-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in
MSTO1
on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic
MSTO1
pathogenic variants, and we provide functional characterization from seven
MSTO1
-related disease patient fibroblasts. Bi-allelic loss-of-function variants in
MSTO1
manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with
MSTO1
mutations and further define the clinical spectrum and the natural history of
MSTO1
-related disease.
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