Urogenital symptoms in mitochondrial disease: overlooked and undertreated.

BACKGROUND AND PURPOSE: Bowel symptoms are well documented in mitochondrial disease. However, data concerning other pelvic organs is limited. A large case-control study has therefore been undertaken to determine the presence of lower urinary tract symptoms (LUTS) and sexual dysfunction in adults with genetically confirmed mitochondrial disease. METHODS: Adults with genetically confirmed mitochondrial disease and control subjects were recruited from a specialist mitochondrial clinic. The presence and severity of LUTS and their impact on quality of life, in addition to sexual dysfunction and bowel symptoms, were captured using four validated questionnaires. Subgroup analysis was undertaken in patients harbouring the m.3243A>G MT-TL1 mitochondrial DNA mutation. A subset of patients underwent urodynamic studies to further characterize their LUTS. RESULTS: Data from 58 patients and 19 controls (gender and age matched) were collected. Adults with mitochondrial disease had significantly more overactive bladder (81.5% vs. 56.3%, P = 0.039) and low stream (34.5% vs. 5.3%, P = 0.013) urinary symptoms than controls. Urodynamic studies in 10 patients confirmed that bladder storage symptoms predominate. Despite high rates of LUTS, none of the patient group was receiving treatment. Female patients and those harbouring the m.3243A>G MT-TL1 mutation experienced significantly more sexual dysfunction than controls (53.1% vs. 11.1%, P = 0.026, and 66.7% vs. 26.3%, P = 0.011, respectively). CONCLUSIONS: Lower urinary tract symptoms are common but undertreated in adult mitochondrial disease, and female patients and those harbouring the m.3243A>G MT-TL1 mutation experience sexual dysfunction. Given their impact on quality of life, screening for and treating LUTS and sexual dysfunction in adults with mitochondrial disease are strongly recommended.

Factors Associated with Respiratory Health and Function in Duchenne Muscular Dystrophy: A Systematic Review and Evidence Grading.

BACKGROUND: Despite advances in the medical management of the disease, respiratory involvement remains a significant source of morbidity and mortality in children and adults with Duchenne muscular dystrophy (DMD). OBJECTIVE: The objective of this systematic literature review was to synthesize and grade published evidence of factors associated with respiratory health and function in DMD. METHODS: We searched MEDLINE, Embase, and the Cochrane Library for records of studies published from January 1, 2000 (to ensure relevance to current care practices), up until and including December 31, 2022, reporting evidence of prognostic indicators and predictors of disease progression in DMD. The quality of evidence (i.e., very low to high) was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. RESULTS: The bibliographic search strategy resulted in the inclusion of 29 articles. In total, evidence of 10 factors associated with respiratory health and function in patients with DMD was identified: glucocorticoid exposure (high- to very low-quality evidence), DMD mutations (low-quality evidence), DMD genetic modifiers (low-quality evidence), other pharmacological interventions (i.e., ataluren, eteplirsen, idebenone, and tamoxifen) (moderate- to very low-quality evidence), body mass index and weight (low-quality evidence), and functional ability (low-quality evidence). CONCLUSIONS: In conclusion, we identified a total of 10 factors associated with respiratory health in function in DMD, encompassing both pharmacological therapies, genetic mutations and modifiers, and patient clinical characteristics. Yet, more research is needed to further delineate sources of respiratory heterogeneity, in particular the genotype-phenotype association and the impact of novel DMD therapies in a real-world setting. Our synthesis and grading should be helpful to inform clinical practice and future research of this heavily burdened patient population.

Development of Continuum of Care for McArdle disease: A practical tool for clinicians and patients.

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.

Perioperative Care for Patients with Neuromuscular Disorders in the Netherlands - A Questionnaire Study Among Anaesthesiologists, Neurologists and Clinical Geneticists.

BACKGROUND: Patients with neuromuscular disorders are at increased risk of suffering perioperative complications. Current knowledge concerning this topic is based on small retrospective studies and expert opinion. Therefore, an individualized multidisciplinary approach to perioperative anaesthesia planning is invaluable to anticipate difficulties and to optimize outcomes. OBJECTIVE: To evaluate current practice regarding preoperative counselling and perioperative care of neuromuscular patients, with the aim to facilitate standardization and improvement of perioperative care for neuromuscular patients. METHODS: A questionnaire-based cross-sectional, observational study was conducted between July, 1st 2020 and December, 31st, 2020 in Dutch anaesthesia, neurology and clinical genetics departments. Main outcome measures were 1.) frequency of consultation requests for neuromuscular patients prior to surgery, 2.) current practice, educational activities and departmental approach to this topic and 3.) preoperative counselling of neuromuscular patients. RESULTS: A total of 83 departments participated. Consultations for a neuromuscular patient scheduled for anaesthesia were requested from anaesthesia and neurology department only infrequently. Local guidelines concerning perioperative care of neuromuscular patients were available in 36.4% of the participating departments. Quality of specific training for residents and staff anaesthetists/neurologists covering perioperative care of neuromuscular patients was rated as 'very good' or 'good' by 42.9%. Neuromuscular patients scheduled for surgery were 'always' or 'often' discussed in multidisciplinary meetings involving anaesthesiologists and neurologists in 20.8% of the participating departments. CONCLUSION: Perioperative care for neuromuscular patients in the Netherlands is highly variable and might benefit from guidelines, education of health care professionals and multidisciplinary meetings between anaesthesiologists and neurologists on a regular basis.

RYR1 mutations are a common cause of congenital myopathies with central nuclei.

OBJECTIVE: Centronuclear myopathy (CNM) is a rare congenital myopathy characterized by prominence of central nuclei on muscle biopsy. CNM has been associated with mutations in MTM1, DNM2, and BIN1 but many cases remain genetically unresolved. RYR1 encodes the principal sarcoplasmic reticulum calcium release channel and has been implicated in various congenital myopathies. We investigated whether RYR1 mutations cause CNM. METHODS: We sequenced the entire RYR1 coding sequence in 24 patients with a diagnosis of CNM from South Africa (n = 14) and Europe (n = 10) and identified mutations in 17 patients. The most common genotypes featured compound heterozygosity for RYR1 missense mutations and mutations resulting in reduced protein expression, including intronic splice site and frameshift mutations. RESULTS: The high incidence in South African patients (n = 12/14) in conjunction with recurrent RYR1 mutations associated with common haplotypes suggested the presence of founder effects. In addition to central nuclei, prominent histopathological findings included (often multiple) internalized nuclei and type 1 fiber predominance and hypotrophy with relative type 2 hypertrophy. Although cores were not typically seen on oxidative stains, electron microscopy revealed subtle abnormalities in most cases. External ophthalmoplegia, proximal weakness, and bulbar involvement were prominent clinical findings. INTERPRETATION: Our findings expand the range of RYR1-related phenotypes and suggest RYR1 mutations as a common cause of congenital myopathies with central nuclei. Corresponding to recent observations in X-linked CNM, these findings indicate disturbed assembly and/or malfunction of the excitation-contraction machinery as a key mechanism in CNM and related myopathies.

Adult North Star Network (ANSN): Consensus Guideline For The Standard Of Care Of Adults With Duchenne Muscular Dystrophy.

There are growing numbers of adults with Duchenne Muscular Dystrophy living well into their fourth decade. These patients have complex medical needs that to date have not been addressed in the International standards of care. We sought to create a consensus based standard of care through a series of multi-disciplinary workshops with specialists from a wide range of clinical areas: Neurology, Cardiology, Respiratory Medicine, Gastroenterology, Endocrinology, Palliative Care Medicine, Rehabilitation, Renal, Anaesthetics and Clinical Psychology. Detailed reports of evidence reviewed and the consensus building process were produced following each workshop and condensed into this final document which was approved by all members of the Adult North Star Network including service users. The aim of this document is to provide a framework to improve clinical services and multi-disciplinary care for adults living with Duchenne Muscular Dystrophy.

McArdle disease: a clinical review.

METHODS: The clinical phenotype of 45 genetically confirmed McArdle patients is described. RESULTS: 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. CONCLUSION: 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.

The role of lactate in the exercise-induced human growth hormone response: evidence from McArdle disease.

PURPOSE: Increased blood lactate concentration has been suggested as a primary stimulus for the exercise-induced growth hormone response (EIGR). Patients with McArdle disease are unable to produce lactate in response to exercise and thus offer a unique model to assess the role of lactate in the EIGR. Accordingly, McArdle's patients were exercised to test the hypothesis that lactate is a major stimulus of the EIGR. METHODS: 11 patients with McArdle disease (3 male, 8 female; age: 35.5 (SD 13.9) years, height: 166 (8) cm, body mass: 75.2 (13.1) kg) were recruited for the study. The patients walked initially at 0.42 m/s, increasing by 0.14 m/s per 3 min stage. Exercise was terminated when participants completed 3 minutes at 1.80 m/s or when a Borg CR10 pain scale rating of "4" was reached. Stages were separated by 60 s for capillary blood sampling for analysis of hGH and blood lactate concentration. RESULTS: McArdle's patients' blood lactate levels remained at resting levels (0.3-1.2 mmol/l) as exercise intensity increased. Nine out of 11 participants failed to demonstrate an EIGR obtaining hGH values below the clinical definition of a response (>3 microg/l). CONCLUSION: The absence of an EIGR in nine out of 11 participants suggests that lactate could play a major role in the EIGR in humans.

The histopathological spectrum of malignant hyperthermia and rhabdomyolysis due to RYR1 mutations.

OBJECTIVE: The histopathological features of malignant hyperthermia (MH) and non-anaesthetic (mostly exertional) rhabdomyolysis (RM) due to RYR1 mutations have only been reported in a few cases. METHODS: We performed a retrospective multi-centre cohort study focussing on the histopathological features of patients with MH or RM due to RYR1 mutations (1987-2017). All muscle biopsies were reviewed by a neuromuscular pathologist. Additional morphometric and electron microscopic analysis were performed where possible. RESULTS: Through the six participating centres we identified 50 patients from 46 families, including patients with MH (n = 31) and RM (n = 19). Overall, the biopsy of 90% of patients showed one or more myopathic features including: increased fibre size variability (n = 44), increase in the number of fibres with internal nuclei (n = 30), and type I fibre predominance (n = 13). Abnormalities on oxidative staining, generally considered to be more specifically associated with RYR1-related congenital myopathies, were observed in 52%, and included unevenness (n = 24), central cores (n = 7) and multi-minicores (n = 3). Apart from oxidative staining abnormalities more frequently observed in MH patients, the histopathological spectrum was similar between the two groups. There was no correlation between the presence of cores and the occurrence of clinically detectable weakness or presence of (likely) pathogenic variants. CONCLUSIONS: Patients with RYR1-related MH and RM exhibit a similar histopathological spectrum, ranging from mild myopathic changes to cores and other features typical of RYR1-related congenital myopathies. Suggestive histopathological features may support RYR1 involvement, also in cases where the in vitro contracture test is not informative.

Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V).

BACKGROUND: McArdle disease (Glycogen Storage Disease type V) is caused by the absence of the glycolytic enzyme, muscle phosphorylase. People present with exercise-induced pain, cramps, fatigue, and myoglobinuria, which can result in acute renal failure if it is severe. OBJECTIVES: To systematically review the evidence from randomised controlled trials of pharmacological or nutritional treatments in improving exercise performance and quality of life in McArdle disease. SEARCH STRATEGY: We updated the review by searching the Cochrane Neuromuscular Disease Group Trials Register (November 2007), MEDLINE (January 1966 to November 2007) and EMBASE (January 1980 to November 2007) using the search terms 'McArdle disease' and its synonym 'Glycogen Storage Disease type V'. SELECTION CRITERIA: We included randomised controlled trials (including crossover studies) and quasi-randomised trials. Open trials and individual patient studies with no participant or observer blinding were included in the discussion. Types of interventions included any pharmacological agent or micronutrient or macronutrient supplementation. Primary outcome measures included any objective assessment of exercise endurance (for example aerobic capacity (VO(2)) max, walking speed, muscle force or power and improvement in fatiguability). Secondary outcome measures included metabolic changes (such as reduced plasma creatine kinase activity and a reduction in the frequency of myoglobinuria), subjective measures (including quality of life scores and indices of disability) and serious adverse events. DATA COLLECTION AND ANALYSIS: Three review authors checked the titles and abstracts identified by the search and reviewed the manuscripts. Two review authors (RQ and RB) independently assessed methodological quality of the full text of potentially relevant studies and extracted data onto a specially designed form. MAIN RESULTS: We reviewed 24 studies. Twelve trials fulfilled the criteria for inclusion, with two being first identified in this update. The 12 excluded trials are included in the discussion. The largest treatment trial included 19 cases. The other trials included fewer than 12 cases. As there were only single trials for a given intervention we were unable to undertake a meta-analysis. AUTHORS' CONCLUSIONS: There is no evidence of significant benefit from any specific nutritional or pharmacological treatment in McArdle disease. In one small trial low dose creatine produced slight benefit but high dose creatine caused myalgia. Ingestion of oral sucrose immediately before exercise reduced perceived ratings of exertion and heart rate and improved exercise tolerance. This treatment will not influence sustained or unexpected exercise and may cause significant weight gain. A carbohydrate rich diet did benefit patients. Because of the rarity of McArdle disease, there is a need to develop international multicentre collaboration and standardised assessment protocols for future treatment trials.

Mastication and Oral Motor Function in McArdle Disease: Patient Reported Complaints.

BACKGROUND: Exertional myalgia and cramps of the limb and trunk muscles are typical in McArdle disease, but mastication and oral motor limitations have not been systematically investigated before. OBJECTIVE: Determine the reported prevalence and characteristics of limitations on oral motor activities, mastication, swallowing, and other oral motor activities in patients with McArdle disease. METHODS: An observational study was carried out in 28 patients using a standardised questionnaire on mastication and oral motor function. RESULTS: 57% of the participants reported difficulties with mastication. Muscle cramps during mastication occurred in 57% of the patients. A feeling that food remains in the throat occurred in 32%. Adaptations during mastication were needed in 42% of the patients. Mastication difficulties, muscle cramps during mastication and mastication adjustments were inversely correlated with age (r2 = - 0.445, p < 0.05; r2 = - 0.509, p < 0.01; r2 = - 0.456, p < 0.05). Feeling of food remaining in throat, cramps during mastication and during other oral motor muscle activities, were correlated with disease severity (r2 = 0.476, p < 0.01; r2 = 0.463, p < 0.01; r2 = 0.461, p < 0.01; r2 = 0.432, p < 0.05). CONCLUSIONS: In short, reported mastication difficulties are prevalent in people with McArdle disease, most frequently in younger people. Therefore, awareness of mastication and oral motor problems is required.

Pharmacological and nutritional treatment trials in McArdle disease.

A systematic review of evidence for randomised controlled trials using pharmacologic and nutritional therapies in McArdle disease was undertaken. Primary outcome measures included any objective assessment of exercise endurance. Secondary outcome measures included changes in metabolic parameters, subjective measures such as quality of life scores and adverse outcomes. Ten randomised controlled trials were identified. Two trials low dose creatine (60 mg/kg/day) and oral sucrose 75 g prior to exercise demonstrated a positive effect.

The use of stock orthoses to assist gait in neuromuscular disorders: a pilot study.

This pilot study compares the effect on walking speed, in eight subjects with neuromuscular conditions, of wearing Ligaflex ankle-foot orthoses (AFO), Leafspring orthoses and shoes or with shoes alone. Range of motion, muscle strength and sensation were tested in the lower leg. Subjects underwent a standardized timed 10-m walking test five times in each of the orthoses and shoes as a measure of gait efficiency. A self-administered questionnaire was used to seek the subjects' perceptions of their functional difficulties and their opinions about the relative comfort and stability of these orthoses. Subjects had reduced ranges and strength of dorsiflexion and eversion. Some had proprioceptive deficiencies. Mean walking speed was 0.99 m/s (Leafspring) and 1.1 m/s (Ligaflex or shoes) compared to about 1.3 m/s for a normal population. Repeated measures ANOVA revealed that subjects were significantly slower in Leafspring compared to Ligaflex or to shoes. Questionnaire results rated the Leafspring as least comfortable and the Ligaflex most stable. Providing stability may be more important than assisting foot clearance when weakness is restricted to distal muscles. Further research is required to evaluate the comfort and effectiveness of orthoses to compensate for ankle instability in people with neuromuscular conditions.

Investigating sodium valproate as a treatment for McArdle disease in sheep.

McArdle disease is due to an absence of the enzyme muscle glycogen phosphorylase and results in significant physical impairment in humans. We hypothesised that sodium valproate, an HDAC inhibitor, might have the ability to up-regulate the enzyme. We treated McArdle sheep with sodium valproate given enterically at 20-60 mg/kg body wt. Compared with untreated control animals, there was increased expression of phosphorylase in muscle fibres. The response was dose dependent and reached a maximum 2 hours after the application and increased with repeated applications. Improvement in mobility could not be demonstrated. These findings suggest that sodium valproate is a potential therapeutic treatment for McArdle disease.

Cardiac transplantation in Becker muscular dystrophy.

Becker muscular dystrophy is associated with abnormal cardiac features in about 75% of cases; up to one-third will develop ventricular dilatation leading to congestive cardiac failure. As this form of muscular dystrophy is relatively benign, failure to respond to medical treatment warrants assessment for cardiac transplantation.

Cardiac function, metabolism and perfusion in Duchenne and Becker muscular dystrophy.

We studied 23 DMD and eight BMD patients using cardiac echo, 24 h ECG and positron emission tomography (PET) with the radiotracers N-13 ammonia and F-18 fluorine deoxyglucose. The ECG was abnormal in 23 cases with alterations in the PR and/or QT intervals, abnormal Q waves in the lateral leads and ST segment depression. Twenty-four hour ECG showed that patients were more likely to produce premature ventricular ectopic beats with advancing age and 17 patients had paroxysmal ST segment depression. LV function was normal or mildly reduced in 24 cardiac echoes. PET studies were visibly abnormal in 15 patients. Regional perfusion defects involving the apex, lateral or anterior left ventricular walls were present, nine cases demonstrated a corresponding increase in glucose metabolism. Three out of 15 demonstrated matched perfusion/metabolism defects. One BMD had severe LV dilation with globally poor perfusion and metabolism. The abnormalities seen with PET were confirmed with both quantitative and semi-quantitative analysis of radioactive counts. Similar results were obtained for both DMD and BMD, where both groups demonstrated significant regional perfusion/metabolism mismatches. We have shown a reduced uptake of N-13 ammonia which is indicative of a reduction in myocardial perfusion. The use of N-13 ammonia to measure perfusion has been validated in animal studies. PET with either N-13 ammonia- or oxygen labelled water can be used to measure myocardial perfusion. We chose N-13 ammonia as this was most readily available to us.

Congenital sensory neuropathy in association with ichthyosis and anterior chamber cleavage syndrome.

Two patients with a congenital neuropathy are described. Both had atypical features including: ichthyosis and a mild anterior chamber cleavage syndrome. Both had severely reduced, or absent, sensation for light touch, vibration, position and temperature. Pain sensation was mildly reduced. There was some evidence of motor involvement but this was relatively minor compared with the sensory involvement. Nerve action potentials were small or absent and sural nerve biopsies showed almost complete absence of myelinated nerve fibres with multiple bundles of abnormally arranged axons and Schwann cell processes. These patients appear to have an undescribed syndrome in which the large sensory neurons and the anterior chamber of the eye did not develop properly. This may reflect a failure of migration, differentiation or proliferation of neural crest cells.