Primary Neuromuscular Disorders Research Articles

Estimation of kidney function in patients with primary neuromuscular diseases: is serum cystatin C a better marker of kidney function than creatinine?

BackgroundUsing serum creatinine leads to an overestimation of kidney function in patients with primary neuromuscular disorders, and reduced kidney function may remain undetected. Cystatin C (CysC) could provide a better estimation.AimTo evaluate the precision, accuracy, and bias of two creatinine-, one cystatin C-based and one combined equation to estimate glomerular filtration rate (eGFR) in patients with primary neuromuscular disease.Patients and methodsOf the 418 patients initially identified at the out-patient clinic, data on kidney function was obtained for 145 adult patients (age 46 ± 14 years, BMI 26 ± 6 kg/m2) with primary neuromuscular disease. Kidney function was measured by iohexol clearance, and blood samples for serum creatinine and CysC were drawn simultaneously. Bias was defined as the mean difference between eGFR and measured iohexol clearance, and accuracy as the proportion of eGFRs within ± 10% (P10) of measured clearance.ResultsKidney function (iohexol clearance) was 81 ± 19 (38–134) ml/min/1.73m2. All equations overestimated kidney function by 22–60 ml/min/1.73m2. eGFR CysC had the lowest bias overall 22 (95% CI 20–26) ml/min/1.73m2 also at all levels of kidney function we evaluated (at 30–59 ml/min/1.73m2 bias was 27 (95% CI 21–35), at 60–89 it was 25 (95% CI 20–28) and at ≥ 90 it was 12 (95% CI 7–22)). eGFR CysC also had the best accuracy in patients with reduced kidney function (P10 was 5.9% at 30–59 ml/min/1.73m2).ConclusionsCystatin C-based estimations of kidney function performed better than creatinine-based ones in patients with primary neuromuscular disease, but most importantly, all evaluated equations overestimated kidney function, especially in patients with reduced kidney function. Therefore, kidney function should be measured by gold-standard methods when precision and accuracy are needed.Graphic abstract

Megarectum: systematic histopathological evaluation of 35 patients and new common pathways in chronic rectal dilatation

AimsMegarectum is well described in the surgical literature but few contemporary pathological studies have been undertaken. There is uncertainty whether ‘idiopathic’ megarectum is a primary neuromuscular disorder or whether chronic...

P.99A multiplex in situ hybridisation and immunohistochemical (ISH-IHC) assay to study developmental changes in relation to fibre type and sodium channels in human skeletal muscle and their contribution to disease severity

SCN4A codes for a skeletal muscle sodium channel (SCN) that is essential for muscle excitability and contraction. SCN4A mutations cause a number of neuromuscular phenotypes including myotonia and periodic paralysis. Infants with SCN4A mutations have common and/or severe respiratory compromise include life-threatening apnoeas, whilst adults do not. Recently we described SCN4A-linked sudden infant death. Surviving infants show a spontaneous reduction in respiratory episodes with age, even if untreated, suggesting a developmental contribution to the clinical phenotype. Lack of isoform-specific SCN monoclonal antibodies are a major bottleneck in functional and pathological studies of SCN gene mutations. To study the expression of SCNs in relation to the fibre type and developmental stage we have developed two multiplex assays for testing on whole transverse frozen sections from control human skeletal muscle biopsies (0-16 years) in whom a primary neuromuscular disorder is excluded. Samples are recruited from the MRC CNMD biobank in London. Assay 1 (ISH-IHC) includes fluorescent multiplex labelling of isoform-specific mRNA probes to SCN4A, SCN5A (ACDBio), and antibodies to pan-fast/slow myosin heavy chain and laminin alpha-2, latter used as mask for myofibre identification. Assay 2 is a fully automated multi-coloured chromogenic IHC protocol (Roche Diagnostics) allowing detection of myosin heavy chain isoforms I, IIA and IIX in a single skeletal muscle section. Further assay optimisation including creating an Assay-1-2 hybrid and developing a digital script for mRNA quantification are in progress. Age-stratified data on fibre-type composition and fibre-specific SCN4A/5A-mRNA expression will be presented. Knowledge of developmental changes in fibre-type proportions may help in understanding differences in phenotype of infants and adults with SCN4A mutations. mRNA expression data will be valuable in validating future isoform-specific SCN antibodies.

Electromyography and muscle biopsy in paediatric neuromuscular disorders – Evaluation of current practice and literature review

The conduct and interpretation of electromyography in children is considered difficult and therefore often avoided. We assessed the diagnostic accuracy of the paediatric electromyography protocol used in our tertiary reference centre and compared it to muscle biopsy results and clinical diagnosis. Electromyography was performed in unsedated children with suspected neuromuscular diseases between January 2010 and September 2017 and was analysed quantitatively. Muscle pathology was classified into seven groups based on existing histopathology reports. The clinical diagnosis, including myopathic, neurogenic and non-neuromuscular categories was used as the gold standard. 171 children between the age of 12 days to 17.4 years were included in the analysis. 41 children (24%) were under the age of 2 years at the time of electromyography. 98 (57%) children were diagnosed with a myopathic disorder, 18 (11%) with a neurogenic disease and 55 (32%) as not having a primary neuromuscular disorder. In detecting myopathic disease, electromyography performed as well as muscle biopsy (sensitivity 87.8% for electromyography vs. 84.5% for muscle biopsy; specificity 75.7% vs. 86.4%). This also applied to children under the age of 2 years (sensitivity 81.8% vs. 86.4%). Quantitative analysis of a limited electromyography protocol performed in unsedated children is a very valuable diagnostic tool.

Vici syndrome: a review.

Vici syndrome [OMIM242840] is a severe, recessively inherited congenital disorder characterized by the principal features of callosal agenesis, cataracts, oculocutaneous hypopigmentation, cardiomyopathy, and a combined immunodeficiency. Profound developmental delay, progressive failure to thrive and acquired microcephaly are almost universal, suggesting an evolving (neuro) degenerative component. In most patients there is additional variable multisystem involvement that may affect virtually any organ system, including lungs, thyroid, liver and kidneys. A skeletal myopathy is consistently associated, and characterized by marked fibre type disproportion, increase in internal nuclei, numerous vacuoles, abnormal mitochondria and glycogen storage. Life expectancy is markedly reduced.Vici syndrome is due to recessive mutations in EPG5 on chromosome 18q12.3, encoding ectopic P granules protein 5 (EPG5), a key autophagy regulator in higher organisms. Autophagy is a fundamental cellular degradative pathway conserved throughout evolution with important roles in the removal of defective proteins and organelles, defence against infections and adaptation to changing metabolic demands. Almost 40 EPG mutations have been identified to date, most of them truncating and private to individual families.The differential diagnosis of Vici syndrome includes a number of syndromes with overlapping clinical features, neurological and metabolic disorders with shared CNS abnormalities (in particular callosal agenesis), and primary neuromuscular disorders with a similar muscle biopsy appearance. Vici syndrome is also the most typical example of a novel group of inherited neurometabolic conditions, congenital disorders of autophagy.Management is currently largely supportive and symptomatic but better understanding of the underlying autophagy defect will hopefully inform the development of targeted therapies in future.

The Malignant Hyperthermia RYR1Y522S Mutation affects Calcium Homeostasis in Arterial Smooth Muscle Cells

Type 1 ryanodine receptor (RyR1) is a key protein involved in the regulation of the intracellular Ca2+ concentration in skeletal muscle cells, playing a crucial role in muscle contraction by releasing Ca2+ from the sarcoplasmic reticulum after plasma membrane depolarization. Dysregulation of calcium signals due to defects in RyR1 have been associated with a wide range of primary neuromuscular disorders, including Malignant Hyperthermia Susceptibility and a number of congenital myopathies including Core Myopathies, some forms of Centronuclear myopathy and Congenital Fiber Type Disproportion. Thus mutations in RYR1 (the gene encoding RyR1) may lead to alterations of Ca2+ homeostasis not only in skeletal muscle, but also in other tissues expressing this intracellular calcium release channel. In the present report we performed the biochemical characterization and immunofluorescence analysis of RyR1 in arterial smooth muscle cells. We found that smooth muscle cells isolated from the RYR1Y522S knock in mouse exhibited increased frequency of localized calcium release events (sparks) and smaller intracellular Ca2+ stores compared to WT littermates, although the resting calcium was not affected. In conclusion we show that a RYR1 mutation associated with Malignant Hyperthermia alters vascular smooth muscle cell function by affecting calcium homeostasis.

Skeletal muscle involvement in cardiomyopathies

The link between heart and skeletal muscle disorders is based on similar molecular, anatomical and clinical features, which are shared by the 'primary' cardiomyopathies and 'primary' neuromuscular disorders. There are, however, some peculiarities that are typical of cardiac and skeletal muscle disorders. Skeletal muscle weakness presenting at any age may indicate a primary neuromuscular disorder (associated with creatine kinase elevation as in dystrophinopathies), a mitochondrial disease (particularly if encephalopathy, ocular myopathy, retinitis, neurosensorineural deafness, lactic acidosis are present), a storage disorder (progressive exercise intolerance, cognitive impairment and retinitis pigmentosa, as in Danon disease), or metabolic disorders (hypoglycaemia, metabolic acidosis, hyperammonaemia or other specific biochemical abnormalities). In such patients, skeletal muscle weakness usually precedes the cardiomyopathy and dominates the clinical picture. Nevertheless, skeletal involvement may be subtle, and the first clinical manifestation of a neuromuscular disorder may be the occurrence of heart failure, conduction disorders or ventricular arrhythmias due to cardiomyopathy. ECG and echocardiogram, and eventually, a more detailed cardiovascular evaluation may be required to identify early cardiac involvement. Paediatric and adult cardiologists should be proactive in screening for neuromuscular and related disorders to enable diagnosis in probands and evaluation of families with a focus on the identification of those at risk of cardiac arrhythmia and emboli who may require specific prophylactic treatments, for example, pacemaker, implantable cardioverter-defibrillator and anticoagulation.

Physiological Role(S) of RyR1 in Smooth Muscle Cells

Type 1 ryanodine receptor (RyR1) is a key protein involved in the regulation of the intracellular Ca2+ concentration in skeletal muscle cells, playing a crucial role in muscle contraction by releasing Ca2+ from the sarcoplasmic reticulum after plasma membrane depolarization. Dysregulation of calcium signals due to defects in RyR1 have been associated with a wide range of primary neuromuscular disorders, including Malignant Hyperthermia Susceptibility and a number of congenital myopathies including Core Myopathies, some forms of Centronuclear myopathy and congenital fiber type disproportion. Though RyR1 is preferentially expressed in skeletal muscles recent data has shown that it is also expressed in some areas of the central nervous system, in some cells of the immune system (B-lymphocytes and dendritic cells) and in smooth muscle cells. Thus mutations in RYR1 (the gene encoding RyR1) may lead to alterations of Ca2+ homeostasis not only in skeletal muscle, but also in other tissues expressing this intracellular calcium release channel.Using an animal model knocked in for the RYR1Y522S mutation we observed that bleeding times were increased by more than two fold in heterozygous mice compared to their wild type littermates, with no differences in platelet numbers nor aggregation characteristics between heterozygous RYR1Y522S carriers and control littermates. Bleeding abnormalities have also been seen in some patients with dominant RYR1 mutations; as part of a comprehensive study we investigated in detail RyR1 expression in smooth muscle cells isolated from different tissues and if there is a causal link between RYR1 mutations and prolonged bleeding times.

Laparoscopic diaphragmatic plication for diaphragmatic paralysis and eventration: An objective evaluation of short-term and midterm results

We sought to objectively assess our outcomes after laparoscopic diaphragmatic plication for symptomatic hemidiaphragmatic paralysis or eventration using a respiratory quality-of-life questionnaire and pulmonary function tests. We performed a retrospective review of all symptomatic patients with hemidiaphragmatic paralysis or eventration who underwent laparoscopic diaphragmatic plication from March 1, 2005, through August 31, 2008. Patients with primary neuromuscular disorders were excluded from our analysis. We collected St George's Respiratory Questionnaire scores (a respiratory quality-of-life questionnaire) and pulmonary function test results preoperatively and at 1 month and 1 year postoperatively. A 2-sided significance level of .05 was used for all statistical testing. During the study period, 25 patients underwent laparoscopic diaphragmatic plication (9 right-sided and 16 left-sided plications); 1 patient required conversion to a thoracotomy. St George's Respiratory Questionnaire total scores (59.3 +/- 26.8) improved by more than 20 points on average (a reduction of > or = 4 points after an intervention is considered a clinically significant improvement). This improvement was statistically significant at 1 month (36.6 +/- 15.9, P = .001) and maintained significance at 1 year (30.8 +/- 18.8, P = .009). Similarly, percent predicted maximum forced inspiratory flow (93.2% +/- 34.1%) was significantly improved 1 month after plication (113.9% +/- 31.8%, P = .01) and maintained significance at 1 year (111.5% +/- 30.9%, P = .02). Our objective evaluation of laparoscopic diaphragmatic plication for hemidiaphragmatic paralysis or eventration demonstrated significant short-term and midterm improvements in respiratory quality of life and pulmonary function test results. This approach represents a potential paradigm shift in the surgical management of hemidiaphragmatic paralysis or eventration.

Patología neuromuscular en cuidados intensivos

The spectrum of neuromuscular disease encountered in today's intensive care units (ICU) has evolved over the last few decades. However, in spite of many studies on neuromuscular disorders complicating critical illness as well as its epidemiology, etiology, treatment and prognosis, several key areas remain unclear. Two main groups are found among these neuromuscular abnormalities. The first group includes primary neuromuscular disorders present on admission to the ICU in which a possible etiology can be identified. Guillain-Barré syndrome and myasthenia gravis are two of the most common diseases admitted to ours units. In the second group, weakness is acquired in the ICU in the absence of preexisting neuromuscular disease. It is believed to reflect illnesses or treatments occurring in the ICU. Critical illness polyneuropathy (CIP) is the most clearly defined neuromuscular complication in this group. However, although we have better knowledge of its clinical, diagnosis, and prognosis features, its pathophysiological substrate has not been fully elucidated. Neuromuscular junction defects and specially myopathies, that frequently coexist with CIP, are the others main causes of acquired weakness in critically ill patients. Advances in understanding of these neuromuscular disorders could have an important impact in terms of developing effective preventive and therapeutic interventions that could help to improve the poor prognosis of these patients.

Abnormal urethral motor function is common in female stress, mixed, and urge incontinence

To investigate the urethral motor function in incontinent women. The intraurethral pressure was measured continuously in the high-pressure zone of the urethra at rest and during repeated short squeezes around the microtip transducer catheter in a group of 205 women with clinically manifest urinary incontinence (severe), and compared with the findings of investigations in 87 middle-aged women (53-63 years) with treatment naïve incontinence (mild-to-moderate) and healthy controls. Women with established incontinence significantly (P < 0.001) more often (66%) had a pressure fall during or immediately following squeeze than women with treatment naïve incontinence (35%) or asymptomatic women (25%). The acceleration of urinary flow and the maximal flow rate were significantly (P < 0.01) increased in patients with incontinence: acceleration was 13 +/- 2.2 (17.8), 20 +/- 2.8 (18.9), and 32 +/- 4.9 (24.9) degrees (mean +/- SEM; SD) for incontinence, naïve incontinence and no incontinence, respectively; maximum urinary flow rate was 23, 22, and 16 ml/sec. No statistical differences in any of these measures were seen when stress and urge incontinence were compared. Women with stress, urge, and mixed urinary incontinence seem to have a primary neuromuscular disorder in the urethra, which presents itself as an overactive opening mechanism with a urethral pressure fall instead of a pressure increase on provocation during the filling phase of the bladder, and during bladder emptying a more efficient opening of the bladder outlet than in normal women. We suggest that one and the same pathophysiological mechanism participates in female stress, urge, and mixed incontinence.

Clinical problems in the management of ileus of the large intestine.

Summary Large-intestinal ileus remains a major challenge in diagnosis and management. A small personal series of 14 cases seen in recent years has been used to illustrate some of the problems. It is noted that primary neuromuscular disorders can be indistinguishable from organic obstruction. The secondary paralytic forms of ileus may have a complex origin, and often more than one etiologic factor is involved. Ischemic disease may cause ileus of the large bowel in subtle forms. Microscopic examination of the stool in these cases may reveal useful information. Iatrogenic factors will probably continue to plague us. The clinician should always remember to question the patient about the drugs he is taking. If operation is indicated, cecostomy seems safest and may control an otherwisedangerous state of distention. The success of cecostomy depends upon well-informed nursing management.