Clinical features of the myasthenic syndrome arising from mutations in GMPPB.

BACKGROUND: Congenital myasthenic syndrome (CMS) due to mutations in GMPPB has recently been reported confirming the importance of glycosylation for the integrity of neuromuscular transmission. METHODS: Review of case notes of patients with mutations in GMPPB to identify the associated clinical, neurophysiological, pathological and laboratory features. In addition, serum creatine kinase (CK) levels within the Oxford CMS cohort were retrospectively analysed to assess its usefulness in the differential diagnosis of this new entity. RESULTS: All patients had prominent limb-girdle weakness with minimal or absent craniobulbar manifestations. Presentation was delayed beyond infancy with proximal muscle weakness and most patients recall poor performance in sports during childhood. Neurophysiology showed abnormal neuromuscular transmission only in the affected muscles and myopathic changes. Muscle biopsy showed dystrophic features and reduced α-dystroglycan glycosylation. In addition, myopathic changes were present on muscle MRI. CK was significantly increased in serum compared to other CMS subtypes. Patients were responsive to pyridostigimine alone or combined with 3,4-diaminopyridine and/or salbutamol. CONCLUSIONS: Patients with GMPPB-CMS have phenotypic features aligned with CMS subtypes harbouring mutations within the early stages of the glycosylation pathway. Additional features shared with the dystroglycanopathies include myopathic features, raised CK levels and variable mild cognitive delay. This syndrome underlines that CMS can occur in the absence of classic myasthenic manifestations such as ptosis and ophthalmoplegia or facial weakness, and links myasthenic disorders with dystroglycanopathies. This report should facilitate the recognition of this disorder, which is likely to be underdiagnosed and can benefit from symptomatic treatment.

Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies.

Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of these, ALG2, ALG14, DPAGT1 and GFPT1, are involved in glycosylation. Here we identify a fifth glycosylation gene, GMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as congenital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electromyography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB-associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected individuals can respond to appropriate treatments.

Clinical features of the DOK7 neuromuscular junction synaptopathy.

Mutations in DOK7 have recently been shown to underlie a recessive congenital myasthenic syndrome (CMS) associated with small simplified neuromuscular junctions ('synaptopathy') but normal acetylcholine receptor and acetylcholinesterase function. We identified DOK7 mutations in 27 patients from 24 kinships. Mutation 1124_1127dupTGCC was common, present in 20 out of 24 kinships. All patients were found to have at least one allele with a frameshift mutation in DOK7 exon 7, suggesting that loss of function(s) associated with the C-terminal region of Dok-7 underlies this disorder. In 15 patients, we were able to study the clinical features in detail. Clinical onset was usually characterized by difficulty in walking developing after normal motor milestones. Proximal muscles were usually more affected than distal, leading to a 'limb-girdle' pattern of weakness; although ptosis was often present from an early age, eye movements were rarely involved. Patients did not show long-term benefit from anticholinesterase medication and sometimes worsened, and where tried responded to ephedrine. The phenotype can be distinguished from 'limb-girdle' myasthenia associated with tubular aggregates, where DOK7 mutations were not detected and patients respond to anticholinesterase treatments. CMS due to DOK7 mutations are common within our UK cohort and is likely to be under-diagnosed; recognition of the phenotype will help clinical diagnosis, targeted genetic screening and appropriate management.

Quantitative EMG of facial muscles in myasthenia patients with MuSK antibodies.

OBJECTIVE: Our aim was to study the pathophysiological process leading to facial muscle atrophy in 13 patients with MuSK antibody positive myasthenia gravis (MuSK-MG), and to compare with findings from 12 acetylcholine receptor antibody positive myasthenia patients (AChR-MG), selected because they suffered from the same degree of disease severity and required similar treatment. METHODS: Motor unit action potential (MUAP) and interference pattern analysis from orbicularis oculi (O oculi) and orbicularis oris (O oris) muscles were studied using a concentric needle electrode, and compared with findings in 20 normal subjects, 6 patients receiving botulinum toxin injections (representing a neurogenic model) and 6 patients with a muscle dystrophy (representing a myopathic model). The techniques and control data have been reported previously. RESULTS: The mean MUAP durations for O oculi and O oris were significantly reduced (p<0.001) in both MG cohorts when compared with healthy subjects, and were similar to those in the myopathic control group. They were significantly different from those obtained from the neurogenic control group (p<0.001 for both O oculi and O oris). The MUAP findings in O oculi occurred independently from neuromuscular blocking on single fibre EMG (SFEMG) in the same muscle. On turns amplitude analysis (TAA), 50% of MuSK-MG patients and 42% of AChR-MG patients had a pattern in O oculi which was similar to that in the myopathic control group, and 62% of MuSK-MG patients and 50% of AChR-MG patients had a pattern in O oris that was also similar to that in the myopathic control group. The TAA findings for O oculi and O oris in both MG cohorts were different from those obtained from the neurogenic control group. CONCLUSIONS: Facial muscle atrophy in MuSK-MG patients is not neurogenic and the pathophysiological changes are akin to a myopathic process. The selected AChR-MG patients also show evidence of a similar pathophysiological process in the facial muscles albeit to a lesser degree. SIGNIFICANCE: We propose that muscle atrophy in MuSK-MG is a myopathic process consisting of either muscle fibre shrinkage or loss of muscle fibres from motor units. The duration of disease and long-term steroid treatment may be further contributory factors.

MRI and clinical studies of facial and bulbar muscle involvement in MuSK antibody-associated myasthenia gravis.

A proportion of patients with myasthenia gravis (MG) without acetylcholine receptor (AChR) antibodies have antibodies to muscle-specific kinase (MuSK). MG with MuSK antibodies (MuSK-MG) is often associated with persistent bulbar involvement, including marked facial weakness and tongue muscle wasting. The extent of muscle wasting in MuSK-MG, and whether it is also found in the few acetylcholine receptor (AChR-MG) patients who have persistent bulbar involvement, is not clear. We studied 12 MuSK-MG patients and recruited 14 AChR-MG patients matched broadly for age, sex ratio, duration of disease and degree of ocular, bulbar and facial weakness. We used coronal and sagittal T1-weighted (T1W) and T2-weighted (T2W) magnetic resonance imaging (MRI) to assess muscle wasting in facial and tongue muscles. Hyperintense signal on T1W MRI and comparison of axial T1W sequences with cUTE sequences were used to assess fibrous/fatty tissue in the tongue. We compared the results with those of four patients with myotonic dystrophy and 12 healthy individuals. We correlated the changes with clinical and treatment histories, and established a new ocular-bulbar-facial-respiratory (OBFR) score. At the time of study, none of the clinical measures, including the OBFR score, differed between the two MG groups. MRI demonstrated thinning of the buccinator, orbicularis oris (O.oris) and orbicularis oculi (O.oculi) muscles in MuSK-MG patients compared with healthy controls, whereas thinning of these muscles was not significant in AChR-MG. Tongue areas with T1W high signal were increased in MuSK-MG patients and the intensity of the signal on axial T1W sequences was greater in MuSK-MG than in controls. To look for possible correlations between imaging and clinical findings, we pooled results from all MG patients. The duration of treatment with prednisolone at >40 mg on alternate days (AD) correlated positively with the percentage of tongue area with high signal (P = 0.006) and negatively with MRI measurements of individual muscles and with the mean muscle dimensions (P = 0.001). The new OBFR score correlated positively with current Myasthenia Gravis Foundation of America grades and with the percentage of high signal (P = 0.004) and negatively with the mean muscle dimensions (P < 0.001). The results show that bulbar and facial muscle weakness and wasting are associated with significant muscle atrophy and fatty replacement in MuSK-MG, which was not found in the AChR-MG patients. MuSK antibodies per se may predispose to muscle thinning, but the difficulties in obtaining clinical remission under steroid therapy in some patients, resulting in long duration of treatment with higher doses (>40 mg AD), may be an additional factor.

LGI1-antibody encephalitis is characterised by frequent, multifocal clinical and subclinical seizures.

PURPOSE: To describe clinical and electrographic characteristics of seizures LGI1-antibody encephalitis, and their correlations with two-year outcomes. METHODS: Video-electroencephalography recordings were performed on a cohort of 16 consecutive patients with LGI1-antibodies from two UK neuroscience-centers over five-years. RESULTS: From 14 of 16 patients (13 males; age-range 53-92years), 86 faciobrachial dystonic seizures were recorded at a median frequency of 0.4 per hour (range 0.1-9.8), and ictal EEG changes accompanied 5/86 events. In addition, 11/16 patients showed 53 other seizures - subclinical (n=18), motor (n=16), or sensory (n=19) - at a median of 0.1 per hour (range 0.1-2) associated with temporal and frontal discharges. The sensory events were most commonly thermal sensations or body-shuddering, and the motor events were frequently automatisms or vocalisations. Furthermore, multifocal interictal epileptiform discharges, from temporal, frontal and parietal regions, and interictal slow-wave activity were observed in 25% and 69% of patients, respectively. Higher observed seizure frequency correlated with poorer functional recovery at two-years (p=0.001). CONCLUSIONS: Multiple frequent seizure semiologies, in addition to numerous subclinical seizures and interictal epileptiform discharges, are hallmarks of LGI1-antibody encephalitis. High overall seizure frequency may predict more limited long-term recovery. These observations should encourage closer monitoring and proactive treatment of seizure activity in these patients.

Turns amplitude analysis of the orbicularis oculi and oris muscles.

OBJECTIVE: The aim of the study was to determine whether 'clouds' from turns amplitude analysis obtained from the orbicularis oculi and oris muscles without force monitoring can be used to differentiate pathological processes affecting the face. METHODS: The interference pattern from orbicularis oculi and orbicularis oris was studied using a concentric needle electrode. Data-points from 20 normal subjects were plotted on a logarithmic scale of mean amplitude between turns versus turns/second, from which linear regression analysis defined the 95% confidence intervals. This enabled us to draw the boundaries of the normal cloud on a linear plot. Data-points from the interference pattern in two pathological cohorts, of 6 patients receiving botulinum toxin injections (representing a neurogenic model), and 6 patients with a muscle dystrophy (representing a myopathic model) were plotted against the normal cloud. These findings were compared and correlated with the mean durations obtained on motor unit action potential analysis from these same two facial muscles. RESULTS: The majority of patients receiving botulinum toxin injections into their facial muscles showed a pattern of high amplitude with low turns/s, or low amplitude with a low-to-normal range of turns/s in both facial muscles. These findings were associated with high-duration motor unit action potentials in most cases. In the myopathic group of patients 66% showed a pattern of low amplitude with low-to-normal range of turns/s in O oculi and O oris. This correlated with short-duration motor unit action potentials in both facial muscles. CONCLUSIONS: We have demonstrated that turns amplitude analysis without force monitoring can be used to study the interference pattern from facial muscles and can be applied to differentiate primary neurogenic from myopathic pathological processes. SIGNIFICANCE: Turns amplitude analysis without force monitoring in the facial muscles can be used as an effective and practical method of interference pattern analysis to complement findings from conventional motor unit action potential analysis.

Isolated paediatric neurosarcoidosis presenting as epilepsia partialis continua: a case report and review of literature.

Isolated paediatric neurosarcoidosis (IPN) is exceptionally rare and only seven cases have been reported so far in the literature. We report the clinical and radiological profile of a 7 year-old boy with epilepsia partialis continua (EPC) who was initially thought to have Acute Disseminated Encephalomyelitis (ADEM), but was subsequently found to have isolated neurosarcoidosis. Additionally, we performed a literature search on Medline and Embase and secondary sources of data such as reference list of articles reviewed. Whilst cranial neuropathy is the commonest presenting feature in adults with neurosarcoidosis, paediatric patients are more likely to present with seizures. Diagnosis presents a clinical challenge as a result of its protean manifestations. Due to its rarity, there remains a lack of evidence base to inform the best choice of treatment for these children. Our patient was successfully treated with a combination of various immunomodulants.

Modern electroencephalography.

Electroencephalography (EEG) has been in continuous development over at least 70 years and is firmly established as a tool in the management of epilepsy. For a while, the technique fell into disregard because of difficulties with interpretation, specificity and sensitivity. Whilst clinicians have to be aware of these problems, they have been largely addressed by recent computer digitization of signals, which permits longer standard recordings and monitoring linked to a simultaneous video. These techniques are not only an essential component of a specialist epilepsy service, where inpatient video-EEG telemetry is vital both for diagnosis and assessment before neurosurgical treatment, but also in general and acute medical settings, particularly for the management of status epilepticus. Further developments in computing will extend the use of EEG in all of these roles and long-term monitoring for diagnosis and management of coma will become more widely available.

Presence and pathogenic relevance of antibodies to clustered acetylcholine receptor in ocular and generalized myasthenia gravis.

BACKGROUND: Clustered acetylcholine receptor antibodies (clustered AChR-Abs) have been detected in a proportion of patients with previously "seronegative" (SN) generalized myasthenia gravis (GMG), but their presence in patients with ocular MG (OMG) and their pathogenicity in vivo are unknown. OBJECTIVE: To test the presence of clustered AChR-Abs and their pathophysiologic properties in patients with SNMG. DESIGN: Screening and diagnostic tests. SETTING: Regional specialist myasthenia center and clinical laboratory. PATIENTS: Serum samples from 16 patients with SN and OMG were tested for binding to clustered AChRs. Results from 28 further SN patients (14 OMG) were correlated with their single fiber electromyography values. MAIN OUTCOME MEASURES: Presence, complement-fixation capacity, correlation with neurophysiologic changes, and in vivo pathogenicity of clustered AChR-Abs. RESULTS: Up to 50% of patients with previous SN-OMG had complement-fixing IgG1 clustered AChR-Abs. IgG binding (n = 28) and complement deposition (n = 21) each correlated with the mean consecutive difference (jitter) on single-fiber electromyography. Injection of purified IgG from 2 patients with clustered AChR-Abs into wild-type or complement regulator-deficient mice reduced miniature end plate potential amplitudes to an extent similar to that found with AChR-Abs, and complement was deposited at the end plates. A trend was noted toward an increase in the number of packets of acetylcholine released (quantal content). CONCLUSIONS: A proportion of patients with SN-GMG or OMG have clustered AChR-Abs that correlate with their electrophysiologic features. Clustered AChR-Abs can passively transfer disease to mice, demonstrating their pathogenicity, and the mechanisms seem similar to those of patients with typical AChR-Abs.

Correlating extent of neuromuscular instability with acetylcholine receptor antibodies.

In a retrospective study of 86 patients with myasthenia gravis (MG), we correlated the acetylcholine receptor (AChR) antibody titers with single-fiber EMG studies to explore whether a relationship exists between these parameters. We found that the AChR antibody titers correlated significantly with the mean of the mean consecutive difference of orbicularis oculi (OO, P<0.0001) and extensor digitorum communis (EDC, P<0.0001). The correlation was found to be stronger in OO. The antibody titers also correlated with the percentage of potential pairs with increased jitter in both muscles and, again, the correlation was more significant in OO (P<0.0001) than in EDC (P=0.001). We speculate that this relationship is stronger in OO than in the limb muscles, because the architectural and immunological differences in the motor unit render OO more vulnerable and sensitive to disturbances in neuromuscular transmission.

Single-fiber electromyography in limb and facial muscles in muscle-specific kinase antibody and acetylcholine receptor antibody myasthenia gravis.

We examined the findings from single-fiber electromyography in extensor digitorum communis (EDC) and orbicularis oculi (OOc) in 13 myasthenia gravis (MG) patients with muscle-specific kinase antibodies (MuSK-MG) and 12 MG patients with acetylcholine receptor antibodies (AChR-MG) with similar clinical scores. More than 70% of AChR-MG patients had abnormal jitter in both EDC and OOc, but the majority of MuSK-MG patients had normal jitter in EDC despite abnormal jitter in OOc. These findings demonstrate clear differences between the neurophysiology of MuSK-MG and AChR-MG.

Single-fiber EMG with a concentric needle electrode: validation in myasthenia gravis.

We performed a retrospective study to validate whether a disposable concentric needle electrode (CNE) can be used in place of a single-fiber (SF) electrode for jitter measurements in myasthenia gravis (MG). Normal values for voluntary contraction of orbicularis oculi (OO) and extensor digitorum communis (EDC) were collected from 20 healthy subjects. The method was validated by a retrospective analysis of 56 consecutive MG patients, the "gold standard" being a positive acetylcholine receptor (AChR) antibody titer at the time of the electrophysiological (electromyography) study and the clinical diagnosis. Receiver operating characteristic (ROC) curves were constructed to define maximal sensitivity and specificity of the technique. The sensitivity was 96.4% (95% confidence interval 87.5%-99.6%), with no false-positive results, similar to traditional SF EMG and confirming that the disposable CNE is a justifiable alternative.

Reversible optic neuropathy associated with low-dose methotrexate therapy.

A 66-year-old woman had progressive bilateral optic neuropathy with dense central scotomas and dyschromatopsia. She had been taking oral methotrexate 2.5 mg three times per week for rheumatoid arthritis for the previous 10 months (total intake 322.5 mg) without folic acid supplementation. She had never smoked or abused alcohol and her diet was healthy. Serum folate was reduced at 1.6 ng/mL (normal >4 ng/mL) and vitamin B12 levels were normal. After stopping methotrexate and after administration of oral folic acid, she experienced complete recovery of vision. Serum folate levels returned to normal during folic acid treatment but decreased to below normal once folic treatment was stopped. The persistently low folate level remains unexplained and may reflect a genetic defect in folate metabolism. Methotrexate can cause toxic side effects resulting from folate inhibition but has not been shown definitively to cause a reversible optic neuropathy associated with low serum folate.