Proteolytic ectodomain shedding of muscle-specific tyrosine kinase in myasthenia gravis.

Autoantibodies to muscle-specific tyrosine kinase (MuSK) proteins at the neuromuscular junction (NMJ) cause refractory generalized myasthenia gravis (MG) with dyspnea more frequently than other MG subtypes. However, the mechanisms via which MuSK, a membrane protein locally expressed on the NMJ of skeletal muscle, is supplied to the immune system as an autoantigen remains unknown. Here, we identified MuSK in both mouse and human serum, with the amount of MuSK dramatically increasing in mice with motor nerve denervation and in MG model mice. Peptide analysis by liquid chromatography-tandem-mass spectrometry (LC-MS/MS) confirmed the presence of MuSK in both human and mouse serum. Furthermore, some patients with MG have significantly higher amounts of MuSK in serum than healthy controls. Our results indicated that the secretion of MuSK proteins from muscles into the bloodstream was induced by ectodomain shedding triggered by neuromuscular junction failure. The results may explain why MuSK-MG is refractory to treatments and causes rapid muscle atrophy in some patients due to the denervation associated with Ab-induced disruption of neuromuscular transmission at the NMJ. Such discoveries pave the way for new MG treatments, and MuSK may be used as a biomarker for other neuromuscular diseases in preclinical studies, clinical diagnostics, therapeutics, and drug discovery.

Brain PET Imaging of 11C-Methionine, 18F-FDG, and 18F-THK5351 in a Case of Lymphomatoid Granulomatosis.

ABSTRACT: A 52-year-old woman complained of upper respiratory symptoms and subsequently developed Wallenberg syndrome. Chest CT and brain MRI revealed multiple nodular lesions in the lungs and brain. She was pathologically diagnosed with low-grade lymphomatoid granulomatosis by lung biopsy. Brain PET examinations using 11C-methionine, 18F-FDG, and 18F-THK5351 were performed. Uptake of 11C-methionine and 18F-FDG was slightly increased in some lesions, likely reflecting the degree of inflammatory cell infiltration. 18F-THK5351 uptake was significantly increased in all lesions, likely reflecting the degree of reactive astrogliosis. This case illustrates the utility of PET studies for diagnosing lymphomatoid granulomatosis and provides insight into its pathophysiology.

Motor neuron disease with malignancy: Clinical and pathophysiological insights.

OBJECTIVE: While some regard an association between motor neuron disease (MND) and malignancy as co-incidental, others have argued that it could represent a distinct clinical entity. The present study undertook in depth phenotyping along with assessment of cortical function to further explore disease pathophysiology in MND with malignancy (MND-M) patients. METHODS: Clinical features along with assessment of peripheral and cortical function was undertaken in 13 MND-M and results were compared to sporadic and familial MND cohorts. RESULTS: From a cohort 13 patients (10 males; aged 65.2 ±â€¯2.0 years), 38.5% were diagnosed with a haematological malignancy. The lower motor neuron phenotype predominated in the in the MND-M patients (χ2 = 10.8, P < 0.01), with the upper motor neuron (UMN) score being significantly reduced in MND-M patients compared to sporadic and familial MND cohorts (χ2 = 6.84, P < 0.01). The neurological deficits did not respond to treatment of the underlying malignancy in the majority of MND-M (92%) patients, and as such there were no significant differences in survival between the cohorts. Despite a paucity of UMN signs, cortical hyperexcitability was evident in MND-M patients, as indicated by reduction in short interval intracortical inhibition (P < 0.01) and increase in motor evoked potential amplitude (P < 0.01), that were similar to findings in sporadic and familial MND cohorts. CONCLUSIONS: The present study suggests that MND-M falls within the spectrum of MND. SIGNIFICANCE: The concept of a co-incidental association between MND and malignancy is supported through the present study by the presence of cortical dysfunction, combined with clinical findings that can be explained within the spectrum of abnormality evident in classical MND phenotypes.

Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy.

Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.

Electromyographs of the flexor digitorum profundus muscle are useful for the diagnosis of inclusion body myositis.

INTRODUCTION: The frequent observation of high-amplitude and long-duration motor unit potentials (MUPs) in inclusion body myositis (IBM) is problematic, because it may lead to a misdiagnosis of amyotrophic lateral sclerosis (ALS). OBJECTIVE: To document the diagnostic utility of EMG from the flexor digitorum profundus (FDP) muscle for IBM. METHODS: Quantitative analyses of MUP parameters were performed in the FDP and biceps brachii (BB) muscles from 7 biopsy-confirmed IBM patients. RESULTS: In the FDP muscle, all MUP parameters were significantly decreased in IBM patients, which indicated the predominance of low-amplitude and short-duration MUPs in this muscle. In the BB muscle, most parameters were increased, suggesting the frequent contamination of high-amplitude and long-duration MUPs. CONCLUSIONS: Low-amplitude MUPs in the FDP muscle indicate the presence of an advanced myopathy in this muscle that was extremely weak for all subjects. Examining the FDP muscle would reduce the chance of misdiagnosing IBM as ALS.

The spectrum of clinicopathological features in pure autonomic neuropathy.

We assessed the clinicopathological features of nine patients with pure autonomic neuropathy, that is, neuropathy without sensory or motor deficits. The duration from symptom onset to diagnosis ranged from 1 month to 13 years. Of eight patients in whom serum antiganglionic acetylcholine receptor antibody was determined, four were positive. All patients who tested positive for this antibody manifested widespread autonomic dysfunction, with the exception of one patient who only experienced orthostatic hypotension. However, patients who were negative for the antiganglionic acetylcholine receptor antibody presented with partial autonomic failure. One of these patients had diffuse parasympathetic failure and generalized hypohidrosis but no orthostatic hypotension, which is clinically compatible with postganglionic cholinergic dysautonomia. Electron microscopic examination revealed a variable degree of reduction in unmyelinated fibers. Compared with normal controls, the patients had a significantly increased density of collagen pockets (p < 0.05). Additionally, the percentage of Schwann cell subunits with axons (out of the total number of Schwann cell subunits associated with unmyelinated fibers) was significantly decreased (p < 0.01). The density of unmyelinated fibers tended to decrease with increasing time between the onset of autonomic symptoms and biopsy (p < 0.05). In conclusion, the clinical and pathological features of pure autonomic neuropathy vary in terms of progression, autonomic involvement, presence of the antiganglionic acetylcholine receptor antibody, and loss of unmyelinated fibers.

Myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis with diffuse tubulointerstitial nephritis.

Renal involvement in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is characterized by focal segmental crescentic and/or necrotizing glomerulonephritis. Here, we report the case of a 66-year-old woman showing myeloperoxidase (MPO)-ANCA positivity and mononeuritis multiplex whose kidney biopsy revealed severe and diffuse tubulointerstitial nephritis despite the fact that crescentic necrotizing glomerulonephritis was focal. The mechanism of tubulointerstitial injury in ANCA-associated vasculitis remains unclear. Further studies are necessary to confirm the relationship between diffuse tubulointerstitial nephritis and ANCA-associated vasculitis.

[Electrodiagnosis of ALS].

Electrodiagnostic methods play important roles for the diagnosis and evaluation of ALS. They are useful for 1) the early establishment of the diagnosis, 2) the differential diagnosis, and 3) the quantitative evaluation of the progression. Needle electromyography reveals active neurogenic changes over the wide territories of the body. Fibrillation potentials and positive sharp waves indicate presence of denervated fibers. However, they are not specific for ALS or even neurogenic process, and widespread occurrence of fibrillations are also characteristic for myositis and inclusion body myositis (IBM). Fasciculation potentials are spontaneous firing of the lower motor neuron and most of them are supposed to arise from the nerve endings. Fasciculation potentials are seen solely in neurogenic process and sufficiently specific for ALS. Its diagnostic role, especially in the early diagnosis, has been stressed by several researchers, including the present authors (Sonoo 1996), and fasciculation potentials will be given the same significance as fibrillation potentials in the coming Awaji criteria for the diagnosis of ALS. Motor unit potentials (MUPs) in ALS often show polyphasia and instability reflecting the presence of immature sprouts. Unstable MUPs (increased jiggle) are counterparts of instability in SFEMG. Giant MUPs are frequent, but low amplitude MUPs may be also observed in rapidly progressing cases. Observation of the recruitment pattern is crucial for the differential diagnosis from myopathies. Nerve conduction studies are important for the exclusion of other diagnoses, especially multifocal motor neuropathy (MMN). Some degree of slowing and disappearance of F-waves can occur simply due to loss of motor units. The utility of Neurophsiological Index remains to be confirmed. Repetitive nerve stimulation often reveals decremental responses, whose presence supports the diagnosis of ALS. Decremental responses in ALS usually occur in wasted muscles with low CMAP amplitude, and may predict the speed of further deterioration of the CMAP.

Severe hypokinesis caused by paraneoplastic anti-Ma2 encephalitis associated with bilateral intratubular germ-cell neoplasm of the testes.

We report a 40-year-old man with severe hypokinesis as paraneoplastic manifestation of a microscopic "carcinoma in situ" of the testis. The young age of the patient, along with progressive neurologic deterioration, detection of anti-Ma2 antibodies, and ultrasound findings of bilateral microcalcifications, led to bilateral orchiectomy, revealing the tumor in both testes. After orchiectomy, neurological symptoms stabilized, but the patient eventually died of systemic complications caused by his severe neurological deficits. Anti-Ma2 paraneoplastic encephalitis should be considered in patients with severe hypokinesis, and intensive investigation and aggressive approach to treatment is encouraged to prevent progression of the neurological deficits.