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.

Antecedent infections in Fisher syndrome: sources of variation in clinical characteristics.

The clinical features of Guillain-Barré syndrome (GBS) are highly variable, according to the type of antecedent infection. Although a major GBS phenotype, Fisher syndrome (FS), has been shown to be preceded by infections similar to those preceding GBS, whether or not the clinical features in FS also vary according to antecedent infection remains unclarified. Frequent antecedent infections among this study of 70 FS patients included Haemophilus influenzae [n = 15 (21%)], Campylobacter jejuni [n = 10 (14%)], and cytomegalovirus (CMV) [n = 6 (8.6%)]. Compared with other FS patients, H. influenzae-seropositive FS patients more frequently had a history of prior upper respiratory tract infection; double vision as the initial symptom; and, except for oculomotor disturbance, more rarely showed cranial nerve involvement. C. jejuni-related FS occurred predominantly in younger male patients and characteristically presented with blurred vision. According to GBS disability scale, CMV-related FS tended to be more severe, although every patient received immunotherapy. Serum anti-GQ1b IgG antibodies were detected in most cases, regardless of antecedent infection type. At the nadir of illness, the most frequent diagnosis in H. influenzae-related cases was "pure FS" without limb weakness or central nervous system involvement (71%), in C. jejuni-related cases "incomplete FS" such as acute ophthalmoparesis with or without ataxia (60%), and in CMV-related cases (50%) advanced conditions such as GBS overlap and Bickerstaff brainstem encephalitis. These findings indicate that the type of preceding infection determined the neurological features of FS. CMV-related FS appeared to be similar to H. influenzae- and C. jejuni-related FS regarding anti-GQ1b antibody-mediated pathogenesis, as opposed to CMV-related GBS.

MIBG Myocardial Scintigraphy Identifies Premotor PD/DLB During a Negative DAT Scan Period: Second Report.

OBJECTIVES: Neuroimaging markers for Parkinson's disease (PD)/dementia with Lewy bodies (DLB) include dopamine transporter (DAT) scanning and metaiodobenzylguanidine (MIBG) myocardial scintigraphy. It is unknown which marker is useful to identify the premotor phase PD/DLB. We reported four patients who, during a negative DAT scan period, had a positive MIBG result that suggested premotor PD/DLB. Here we report 18 additional patients. METHODS: This study was a prospective cohort study. The recruiting period was five years; prospective follow-up period, 5.5 ± 3.0 years; and a once a year (minimum) follow-up visit. We recruited 745 referred subjects. The inclusion criteria were having at least one of the following known PD nonmotor features: (1) autonomic: postural hypotension (pure autonomic failure [PAF]), constipation, bladder dysfunction; (2) sleep: REM sleep behavior disorder (RBD); and (3) cognitive: mild cognitive impairment or psychiatric symptoms. Also, the patient had to have undergone both DAT and MIBG tests. RESULTS: Only 18 patients fulfilled these criteria. Their characteristics were: elderly (mean age 75.5 years), with long histories (onset 61.0 years; duration 14.5 years), and predominately male (14 men, four women). The patients' neurologic diagnoses were constipation/RBD in 10, constipation/RBD/PAF in six, and constipation/PAF in two. During the follow-up period, seven patients developed PD or DLB. An abnormal MIBG result was noted in 94%, and an abnormal DAT result was noted in 56%. CONCLUSIONS: MIBG has the potential to be a useful marker during the DAT scan negative period to identify premotor PD/DLB, but further studies are needed.

Gastrointestinal function in dementia with Lewy bodies: a comparison with Parkinson disease.

PURPOSE: To investigate gastrointestinal function in dementia with Lewy bodies and Parkinson disease. METHODS: We examined gastric emptying and colonic transit time in 19 dementia with Lewy bodies and 46 Parkinson disease patients. RESULTS: Gastric emptying was longer in dementia with Lewy bodies than in Parkinson disease (p = 0.014). Colonic transit time tended to be longer in dementia with Lewy bodies than in Parkinson disease. There was no relationship between gastric emptying and colonic transit time, nor between gastric emptying, colonic transit time and age. CONCLUSION: Gastric emptying was prolonged in dementia with Lewy bodies compared to Parkinson disease.

Bladder dysfunction as the initial presentation of multiple system atrophy: a prospective cohort study.

OBJECTIVES: Multiple system atrophy (MSA) is a disease that combines autonomic (orthostatic or bladder) with motor [parkinsonian (MSA-P) or cerebellar (MSA-C)] dysfunction. While bladder dysfunction may occur earlier than motor disorders, thus far no prospective study has been available to determine how often and how early bladder autonomic dysfunction predates motor dysfunction in MSA. Therefore, we present data from detailed history-taking in patients with MSA. METHODS: This is a prospective cohort study. Detailed history-taking was performed and a questionnaire administered in 121 MSA patients (73 MSA-C, 48 MSA-P; 74 men, 47 women; age, 58 ± 8.0 years; initial recruitment period, 5 years; follow-up, 6.5 ± 4.0 years). RESULTS: Among the patients with MSA-C, 40 patients (55%) suffered motor dysfunction first, 22 (30%) suffered autonomic dysfunction first, and 11 (15%) initially suffered both simultaneously. Among the patients with MSA-P, 22 patients (46%) suffered motor dysfunction first, 22 (46%) suffered autonomic dysfunction first, and two (8%) initially suffered both simultaneously. Among the 'autonomic-first' subgroup of MSA-C patients, five suffered orthostatic dysfunction first, 13 suffered urinary dysfunction first, and four initially suffered both simultaneously. Among the 'autonomic-first' subgroup of MSA-P patients, six suffered orthostatic dysfunction first, nine suffered urinary dysfunction first, and seven initially suffered both simultaneously. Urinary symptoms were further preceded by erectile dysfunction in men. Overall, 18.2% of patients suffered only urinary symptoms initially, and the mean interval from the onset of urinary to the onset of motor symptoms was 2.8 years (range 1-7 years). CONCLUSION: In MSA patients, 18.2% presented with bladder dysfunction as the sole initial manifestation, and the mean interval from the onset of urinary to the onset of motor symptoms was 2.8 years. It is clinically important to avoid unnecessary prostatic surgery when MSA patients see urologists before neurologists.

Lower Urinary Tract Function in Familial Spastic Paraplegia.

In order to investigate lower urinary tract function in hereditary spastic paraplegia (HSP), we recruited 12 HSP patients: 8 men, 4 women; mean age, 64.6 years; mean disease duration, 18.9 years; walk without cane, 2, walk with cane, 6, wheelchair bound, 3. We performed urinary symptom questionnaires and a urodynamic testing in all patients. As a result, urinary symptoms were observed in all but 3, including urinary urgency/frequency (also called overactive bladder) in 9 and hesitancy/poor stream in 6. Urodynamic abnormalities included detrusor overactivity during bladder filling in 10, underactive detrusor on voiding in 8 (detrusor hyperactivity with impaired contraction [DHIC] in 5), detrusor-sphincter dyssynergia (DSD) on voiding in 3, and post-void residual in 5. Sphincter electromyography showed neurogenic motor unit potential in 4. In conclusion, we observed high frequency of urinary symptoms in HSP. Urodynamics indicated that the main mechanism is DHIC with/without DSD for their urinary symptom, and sacral cord involvement in some cases. These findings facilitate patients' care including clean, intermittent catheterization.

Distal limb weakness phenotype of Guillain-Barré syndrome.

OBJECTIVE: Several regional variants of Guillain-Barré syndrome (GBS) have been proposed in western countries, but other variants remain unclear, especially among mildly disabled cases. The aim of this study was to identify unvalidated GBS phenotypes among Japanese patients with mild GBS. METHODS: Retrospective study of a cohort of patients at a University Hospital in Japan. RESULTS: Among 107 GBS patients, 25 (23%) were classified as having mild GBS (GBS disability scale ≤ 2 at nadir). A review of mild cases identified 8 patients (7.5% of all GBS and 32% of mild GBS) with an unusual phenotype, namely a distal limb weakness form of GBS (DL-GBS), which showed limited distribution of limb weakness within hands and feet with preserved strength in proximal limb muscles. The patients with DL-GBS were characterized by mild-to-moderate weakness in distal parts of limbs especially fingers, lacking or mild sensory disturbance at distal limbs, sometimes hyperreflexia at legs, and having prior Campylobacter jejuni enteritis. Among the patients with GBS after C. jejuni enteritis, DL-GBS patients were characterized by frequent detection of anti-GM1 antibodies without anti-GD1a antibodies, whereas the others were often positive for the two antibodies. CONCLUSIONS: DL-GBS is a distinct regional phenotype of GBS, which should be differentiated from cervical myelopathy. It can be generally categorized as a mild type of GBS after C. jejuni enteritis, which has characteristic pattern of anti-ganglioside autoantibodies.

The Relationship between Bladder, Periarterial and Somatic Neuropathy in Diabetes.

Objective Diabetes commonly affects the bladder nerves. However, the relationship among bladder, periarterial and somatic neuropathy in diabetes is not well known. In the present study we investigated these relationships. Methods A total of 110 diabetic subjects were enrolled in the study. All were referred for screening for diabetic neuropathy, irrespective of their symptoms. The patients included 61 men and 49 women; the mean age was 59.3 years (31-85 years); the mean disease duration was 14.0 years (5-30 years); and the mean HbA1c value was 10.1% (5.1-16.3%). We performed a nerve conduction study (NCS, A-alpha/beta and B fiber), ultrasound-based measurement of the post-void residual (PVR) volume (abnormal, >50 mL, mainly A-delta/C fiber) and postural blood pressure measurement (abnormal, >-20 mmHg, A-delta/C fiber). Fisher's exact probability test and Student's t-test were used to analyze the significance of differences. Results NCS abnormality, an abnormal PVR volume, and postural hypotension were noted in 74, 19, and 36 of the subjects, respectively. There were clear relationships between NCS and an abnormal PVR volume (p<0.05), postural hypotension and an abnormal PVR volume (p<0.05), or NCS and postural hypotension (p<0.01). There were also subjects who had NCS abnormality alone, a high PVR volume alone or postural hypotension alone. An abnormal PVR volume was not associated with the HbA1c value, but was clearly related to the duration of diabetes (p<0.05). Conclusion Bladder dysfunction was correlated with somatic and periarterial neuropathy. On the other hand, 16% of the cases of bladder dysfunction occurred in patients without somatic or periarterial neuropathy; thus, the regular measurement of the PVR volume is necessary.

Immunization of mice with LRP4 induces myasthenia similar to MuSK-associated myasthenia gravis.

Since the first report of experimental animal models of myasthenia gravis (MG) with autoantibodies against low-density lipoprotein receptor-related protein 4 (LRP4), there have not been any major reports replicating the pathogenicity of anti-LRP4 antibodies (Abs). Recent clinical studies have cast doubt on the specificity and pathogenicity of anti-LRP4 antibodies for MG, highlighting the need for further research. In this study, we purified antigens corresponding to the extracellular region of human LRP4 stably expressed with chaperones in 293 cells and used these antigens to immunize female A/J mice. Immunization with LRP4 protein caused mice to develop myasthenia having similar electrophysiological and histological features as are observed in MG patients with circulating Abs against muscle-specific kinase (MuSK). Our results clearly demonstrate that active immunization of mice with LRP4 proteins causes myasthenia similar to the MG induced by anti-MuSK Abs. Further experimental and clinical studies are required to prove the pathogenicity of anti-LRP4 Abs in MG patients.

Genetic Screening for Spinocerebellar Ataxia Genes in a Japanese Single-Hospital Cohort.

OBJECTIVE: Diagnosis of sporadic cerebellar ataxia is a challenge for neurologists. A wide range of potential causes exist, including chronic alcohol use, multiple system atrophy of cerebellar type (MSA-C), and sporadic late cortical cerebellar atrophy. Recently, an autosomal-dominant spinocerebellar ataxia (SCA) mutation was identified in a cohort of patients with non-MSA-C sporadic cerebellar ataxia. The aim of this study is to genetically screen genes involved in SCA in a Japanese single-hospital cohort. METHODS: Over an 8-year period, 140 patients with cerebellar ataxia were observed. There were 109 patients with sporadic cerebellar ataxia (no family history for at least four generations, 73 patients with MSA-C, and 36 patients with non-MSA-C sporadic cerebellar ataxia) and 31 patients with familial cerebellar ataxia. We performed gene analysis comprising SCA1, 2, 3, 6, 7, 8, 12, 17, 31, and dentatorubro-pallidoluysian atrophy (DRPLA) in 28 of 31 non-MSA-C sporadic patients who requested the test. Familial patients served as a control. RESULTS: Gene abnormalities were found in 57% of non-MSA-C sporadic cerebellar ataxia cases. Among patients with sporadic cerebellar ataxia, abnormalities in SCA6 were the most common (36%), followed by abnormalities in SCA1 (7.1%), SCA2 (3.6%), SCA3 (3.6%), SCA8 (3.6%), and DRPLA (3.6%). In contrast, gene abnormalities were found in 75% of familial cerebellar ataxia cases, with abnormalities in SCA6 being the most common (29%). For sporadic versus familial cases for those with SCA6 abnormalities, the age of onset was older (69 years vs. 59 years, respectively), and CAG repeat length was shorter (23 vs. 25, respectively) in the former than in the latter (not statistically significant). CONCLUSION: Autosomal-dominant mutations in SCA genes, particularly in SCA6, are not rare in sporadic cerebellar ataxia. The reason for the frequency of mutations in SCA6 remains unclear; however, the reason may reflect a higher age at onset and variable penetrance of SCA6 mutations.

Bladder recovery relates with increased mid-cingulate perfusion after shunt surgery in idiopathic normal-pressure hydrocephalus: a single-photon emission tomography study.

AIMS OF STUDY: It is reported that severe bladder disorder in idiopathic normal-pressure hydrocephalus (iNPH) is predicted by right frontal hypoperfusion. However, it is not known whether bladder recovery is predicted by brain perfusion change after shunt surgery. To address this issue, we compared bladder and brain function before and after shunt surgery in iNPH. METHODS: We enrolled 75 patients in the study. Before and 12 months after shunt surgery, we analyzed brain perfusion by SPECT and bladder disorder by a specialized grading scale. The scale consisted of grade 0, none; grade 1, urinary urgency and frequency; grade 2, urinary incontinence 1-3 times a week; grade 3, urinary incontinence >daily; and grade 4, loss of bladder control. More than one grade improvement is defined as improvement, and more than one grade decrement as worsening; otherwise no changes. RESULTS: Comparing before and after surgery, in the bladder-no-change group (32 cases) there was an increase in blood flow which is regarded as reversal of enlargement in the Sylvian fissure and lateral ventricles (served as control). In contrast, in the bladder-improved group (32 cases) there was an increase in bilateral mid-cingulate, parietal, and left frontal blood flow (p < 0.05). In the bladder-worsened group (11 cases) no significant blood flow change was observed. CONCLUSION: The present study showed that after shunt surgery, bladder recovery is related with mid-cingulate perfusion increase in patients with iNPH. The underlying mechanism might be functional restoration of the mid-cingulate that normally inhibits the micturition reflex.