Gea Drost

Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are a common cause of neuromuscular disease, ranging from various congenital myopathies to the malignant hyperthermia (MH) susceptibility trait without associated weakness. We sequenced RYR1 in 39 unrelated families with rhabdomyolysis and/or exertional myalgia, frequent presentations in the neuromuscular clinic that often remain unexplained despite extensive investigations. We identified 9 heterozygous RYR1 mutations/variants in 14 families, 5 of them (p.Lys1393Arg; p.Gly2434Arg; p.Thr4288_Ala4290dup; p.Ala4295Val; and p.Arg4737Gln) previously associated with MH. Index cases presented from 3 to 45 years with rhabdomyolysis, with or without exertional myalgia (n=12), or isolated exertional myalgia (n=2). Rhabdomyolysis was commonly triggered by exercise and heat and, less frequently, viral infections, alcohol and drugs. Most cases were normally strong and had no personal MH history. Inconsistent additional features included heat intolerance, and cold-induced muscle stiffness. Muscle biopsies showed mainly subtle changes. Familial RYR1 mutations were confirmed in relatives with similar or no symptoms. These findings suggest that RYR1 mutations may account for a substantial proportion of patients presenting with unexplained rhabdomyolysis and/or exertional myalgia. Associated clinico-pathological features may be subtle and require a high degree of suspicion. Additional family studies are paramount in order to identify potentially MH susceptible relatives.

Redefining the clinical phenotypes of non-dystrophic myotonic syndromes

Objective: To redefine phenotypical characteristics for both chloride (ClCh) and sodium channelopathies (NaCh) in non-dystrophic myotonic syndromes (NDM). Methods: In a cross-sectional, nationwide study, standardised interviews and clinical bedside tests were performed in 62 genetically confirmed NDM patients, 32 ClCh and 30 NaCh. Results: Standardised interviews revealed that ClCh reported a higher frequency of muscle weakness (75 vs 36.7%; p<0.01), the warm-up phenomenon (100 vs 46.7%; p<0.001), and difficulties in standing up quickly (90.6 vs 50.0%; p<0.001), running (90.6% vs 66.7; p<0.05) and climbing stairs (90.6 vs 63.3%; p = 0.01). Patients with NaCh reported an earlier onset (4.4 vs 9.6 years; p<0.001), and higher frequencies of paradoxical (50.0 vs 0%; p<0.001) and painful myotonia (56.7 vs 28.1%; p<0.05). Standardised clinical bedside tests showed a higher incidence and longer relaxation times of myotonia in the leg muscles for ClCh (100 vs 60%; mean duration of chair tests 12.5 vs 6.3 s; p<0.001), and in eyelid muscles for NaCh (96.7 vs 46.9%; mean relaxation time of 19.2 vs 4.3 s; p<0.001). Transient paresis was only observed in ClCh (62.5%) and paradoxical myotonia only in NaCh (30.0%). Multivariate logistic regression analyses allowed clinical guidelines to be proposed for genetic testing. Conclusion: This study redefined the phenotypical characteristics of NDM in both ClCh and NaCh. The clinical guidelines proposed may help clinicians working in outpatient clinics to perform a focused genetic analysis of either CLCN1 or SCN4A.

In tandem analysis of CLCN1 and SCN4A greatly enhances mutation detection in families with non-dystrophic myotonia

Non-dystrophic myotonias (NDMs) are caused by mutations in CLCN1 or SCN4A. The purpose of the present study was to optimize the genetic characterization of NDM in The Netherlands by analysing CLCN1 and SCN4A in tandem. All Dutch consultant neurologists and the Dutch Patient Association for Neuromuscular Diseases (Vereniging Spierziekten Nederland) were requested to refer patients with an initial diagnosis of NDM for clinical assessment and subsequent genetic analysis over a full year. Based on clinical criteria, sequencing of either CLCN1 or SCN4A was performed. When previously described mutations or novel mutations were identified in the first gene under study, the second gene was not sequenced. If no mutations were detected in the first gene, the second gene was subsequently also analysed. Underlying NDM mutations were explored in 54 families. In total, 20% (8 of 40) of our probands with suspected chloride channel myotonia showed no CLCN1 mutations but subsequent SCN4A screening revealed mutations in all of them. All 14 probands in whom SCN4A was primarily sequenced showed a mutation. In total, CLCN1 mutations were identified in 32 families (59%) and SCN4A in 22 (41%), resulting in a diagnostic yield of 100%. The yield of mutation detection was 93% with three recessive and three sporadic cases not yielding a second mutation. Among these mutations, 13 in CLCN1 and 3 in SCN4A were novel. In conclusion, the current results show that in tandem analysis of CLCN1 and SCN4A affords high-level mutation ascertainment in families with NDM.

Pyridostigmine in postpolio syndrome: no decline in fatigue and limited functional improvement.

Objectives: To investigate the effect of pyridostigmine on fatigue, physical performance, and muscle function in subjects with postpoliomyelitis syndrome. Methods: 67 subjects with increased fatigue and new weakness in one quadriceps muscle showing neuromuscular transmission defects, were included in a randomised, double blind, placebo controlled trial of 60 mg pyridostigmine four times a day for 14 weeks. Primary outcome was fatigue (on the “energy” category of the Nottingham health profile). Secondary outcomes included two minute walking distance and quadriceps strength and jitter. Motor unit size of the quadriceps was studied as a potential effect modifier. The primary data analysis compared the changes from baseline in the outcomes in the last week of treatment between groups. Results: 31 subjects treated with pyridostigmine and 31 subjects treated with placebo completed the trial. No significant effect of pyridostigmine was found on fatigue. The walking distance improved more in the pyridostigmine group than in the placebo group (by 7.2 m (6.0%); p<0.01). Subgroup analysis showed that a significant improvement in walking performance was only found in subjects with normal sized motor units. Quadriceps strength improved more in the pyridostigmine group than in the placebo group (by 6.7 Nm (7.2%); p = 0.15). No effect of pyridostigmine was found on jitter. Conclusions: Pyridostigmine in the prescribed dose did not reduce fatigue in subjects with postpoliomyelitis syndrome. However, it may have a limited beneficial effect on physical performance, especially in subjects with neuromuscular transmission defects in normal sized motor units.

Fasciculation potentials in high-density surface EMG.

Summary: Fasciculation potentials (FPs) are observed in healthy individuals, but also in patients with neurogenic disorders. The exact site of origin and the clinical relevance in distinguishing, for example, amyotrophic lateral sclerosis (ALS) from other neurogenic diseases based on specific characteristics of the FPs is still a matter of debate and needs further exploration. This report describes the use of high-density surface EMG (HD-sEMG), with multiple electrodes in a compact grid to noninvasively record FPs. The technique provides both temporal and spatial information of fasciculations. Examples of the FPs of a patient diagnosed with definite ALS are presented. FPs are shown in different electrode montages and the unique spatial characteristics of different FPs are presented. During 30-second recordings, 137 FPs were detected that via a decomposition algorithm could be assigned to 11 different underlying sources. It is concluded that HD-sEMG, both because of its noninvasive character and the unique spatiotemporal information, is very suitable to examine fasciculations. It allows long stable recording times and provides quantitative information. This electrophysiologic tool is expected to expand the existing knowledge of FP properties.

Eosinophilic fasciitis in a child mimicking a myopathy.

A 14-year-old boy was suspected of having a myopathy with joint contractures. He presented with progressive painless joint contractures of his right wrist and fingers, and reduced muscle strength of his right arm, without obvious skin changes. Laboratory investigation showed a normal CK, hypergammaglobulinemia and eosinophilia. Ultrasonography revealed thickened fasciae in the forearm. A full thickness biopsy confirmed the diagnosis of eosinophilic fasciitis. The contractures diminished quickly with prednisolone and methotrexate. The ultrasound scans 2 years after diagnosis showed improvement, although some thickening of the fasciae was still present, indicating residual changes. In conclusion, eosinophilic fasciitis has to be regarded as a differential diagnosis of painless joint contractures in children. Ultrasonography can be helpful to suspect the diagnosis.

Recurrent neuropathy associated with Ehlers–Danlos syndrome

Sirs: The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders characterized by articular hypermobility, skin hyperextensibility and tissue fragility resulting in recurrent joint dislocations, vascular lesions, easy bruising, and excessive scarring [1]. The hypermobility type of EDS is restricted to mild skin involvement and generalized joint hypermobility [2]. EDS is associated with deficiency of extracellular-matrix proteins such as collagen I, III and V and tenascinX, but in the hypermobility type the protein deficiency is in most cases unknown [2, 8, 10]. Although initially described by Beighton in 1970 [1], peripheral nervous system involvement in EDS has only been reported sporadically [4, 6, 7, 9]. We report a patient with the hypermobility type of EDS who subsequently experienced an axillary neuropathy, brachial plexopathy and sciatic neuropathy. A 30-year-old female with the hypermobility type of EDS (type III) presented with acute onset of paresis and sensory disturbances of her left leg. The previous evening, she had fallen asleep while sitting cross-legged. Sedation caused by analgesics probably enabled her to fall asleep in this seemingly awkward position. When she woke up after approximately four hours, she experienced weakness and numbness of her lower left leg. This had not recovered the next day. EDS was diagnosed at the age of 20 years. She had suffered from recurrent dislocation of her right shoulder, which was initially complicated by an axillary neuropathy. Gradually, the dislocation became irreversible and was accompanied by increasing numbness and paresthesias in her whole arm probably due to stretching of the brachial plexus. Both the axillary neuropathy and brachial plexopathy were confirmed by nerve conduction studies and electromyography. She underwent a series of fixation operations on her right shoulder. Nevertheless, because of recurrent dislocations, post-operative infections, and a continued brachial plexopathy her right arm was amputated at the age of 27. Neuropathological studies of the ulnar and radial nerve revealed neither signs of infection nor signs of myxoid degeneration. The perineurium and endoneurium appeared normal. There was no more ultrastructural material available so that a still more refined investigation could not be performed. Her family history was negative for EDS or hereditary neuropathy with liability to pressure palsies. DNA analysis for 17p11.2 deletion was negative. Physical examination upon arrival at the emergency room revealed joint hypermobility and a smooth and velvety skin without striae or hyperextensibility. Knee flexion (MRC-grade 4) and foot extension (MRC-grade 2) were weak. Foot flexion and toe movements were absent. Sensory loss was present over the lateral lower leg and foot. Knee jerks were symmetrical; the left ankle jerk was absent. Two sequential EMG examinations, performed on day 2 and 3 weeks later showed signs of a previous left peroneal neuropathy, probably due to her long-standing habit of sitting cross-legged, and several findings that indicated a recent sciatic neuropathy in the same limb. These were: first absent and later delayed H-reflex latencies over the tibial nerve, normal findings in the gluteus medius muscle and spontaneous activity in the tibialis anterior muscle after two weeks. She was discharged to a rehabilitation clinic for physical therapy and was given a foot-ankleorthesis. Muscle strength improved gradually. The pathophysiological mechanism of peripheral neuropathy in the hypermobility type of EDS appears evident; i. e. hypermobility of joints causes abnormal stretching of or pressure on peripheral nerves, resulting in neuropathy or plexopathy [1, 4]. In addition, increased vulnerability of peripheral nerves to stretching or pressure due to the genetic connective tissue defect in EDS might be involved. Extracellular matrix proteins which are known to be involved in EDS, such as collagen I, III, V and tenascin-X, are distributed throughout the connective tissue of peripheral nerves [3, 5]. Tenascin-X or collagen I, III or V deficient perineurium and endoneurium might fail to resist excessive mechanical stress, resulting in impaired peripheral nerve function. Clinicians and patients need to be aware of this possible risk of neuropathies in EDS in order to prevent recurrent nerve injuries.

Brody syndrome: A clinically heterogeneous entity distinct from Brody disease: A review of literature and a cross-sectional clinical study in 17 patients

Brody disease is a rare inherited myopathy due to reduced sarcoplasmic reticulum Ca(2+) ATPase (SERCA)1 activity caused by mutations in ATP2A1, which causes delayed muscle relaxation and silent cramps. So far the disease has mostly been diagnosed by measurement of SERCA1 activity. Since mutation analysis became more widely available, it has appeared that not all patients with reduced SERCA1 activity indeed have ATP2A1 mutations, and a distinction between Brody disease (with ATP2A1 mutations) and Brody syndrome (without ATP2A1 mutations) was proposed. We aim to compare the clinical features of patients with Brody disease and those with Brody syndrome and detect clinical features which help to distinguish between the two. In addition, we describe the Brody syndrome phenotype in more detail. We therefore performed a literature review on clinical features of both Brody disease and Brody syndrome and a cross-sectional clinical study consisting of questionnaires, physical examination, and a review of medical files in 17 Brody syndrome patients in our centre. The results showed that Brody disease presents with an onset in the 1st decade, a generalized pattern of muscle stiffness, delayed muscle relaxation after repetitive contraction on physical examination, and autosomal recessive inheritance. Patients with Brody syndrome more often report myalgia and experience a considerable impact on daily life. Future research should focus on the possible mechanisms of reduction of SERCA activity in Brody syndrome and other genetic causes, and on evaluation of treatment options.

Na+‐K+‐ATPase is not involved in the warming‐up phenomenon in generalized myotonia

The initial temporary weakness that occurs in autosomal‐recessive generalized myotonia diminishes with repetitive contractions. Physiological understanding of this phenomenon is incomplete. The underlying hypothesis of our study was that the “warming‐up” phenomenon relates to the exercise‐related activation of Na+‐K+‐ATPase. Three patients performed isometric exercise of the brachioradialis muscle on two separate days. Randomly, on one of these days the contraction was preceded by a 30‐min infusion of the Na+‐K+‐ATPase inhibitor ouabain into the brachial artery of the exercising arm (0.4 μg.min–1.dl–1). Force was measured simultaneously with electrical muscle activity using high‐density surface electromyography (HD‐sEMG). A transient rapid decline in force occurred after initiation of exercise, accompanied by electrophysiological changes indicating sarcolemmal conduction block. Ouabain infusion did not affect the recovery from transient paresis or the accompanying electromyographic changes, indicating that the warming‐up phenomenon in generalized myotonia is not mediated by Na+‐K+‐ATPase. Muscle Nerve, 2005

Isolated eyelid closure myotonia in two families with sodium channel myotonia

Sodium channelopathies (NaCh), as part of the non-dystrophic myotonic syndromes (NDMs), reflect a heterogeneous group of clinical phenotypes accompanied by a generalized myotonia. Because of recent availability of diagnostic genetic testing in NDM, there is a need for identification of clear clinical genotype–phenotype correlations. This will enable clinicians to distinguish NDMs from myotonic dystrophy, thus allowing them to inform patients promptly about the disease, perform genetic counseling, and orient therapy (Vicart et al. Neurol Sci 26:194–202, 2005). We describe the first distinctive clinical genotype–phenotype correlation within NaCh: a strictly isolated eyelid closure myotonia associated with the L250P mutation in SCN4A. Using clinical assessment and needle EMG, we identified this genotype–phenotype correlation in six L250P patients from one NaCh family and confirmed this finding in another, unrelated NaCh family with three L250P patients.