Ai Miyashiro

Sera from patients with multifocal motor neuropathy disrupt the blood-nerve barrier

Objective In multifocal motor neuropathy (MMN), the destruction of the blood-nerve barrier (BNB) has been considered to be the key step in the disease process. The purpose of the present study was to ascertain whether sera from patients with MMN can open the BNB, and which component of patient sera is the most important for this disruption. Methods We evaluated the effects of sera from patients with MMN, patients with amyotrophic lateral sclerosis, and control subjects on the expression of tight junction proteins and vascular cell adhesion molecule-1 (VCAM-1), and on the transendothelial electrical resistance (TEER) in human peripheral nerve microvascular endothelial cells (PnMECs). Results The sera from patients with MMN decreased the claudin-5 protein expression and the TEER in PnMECs. However, this effect was reversed after application of an anti-vascular endothelial growth factor (anti-VEGF) neutralising antibody. The VEGF secreted by PnMECs was significantly increased after exposure to the sera from patients with MMN. The sera from patients with MMN also increased the VCAM-1 protein expression by upregulating the nuclear factor kappa-B (NF-κB) signalling. The immunoglobulin G purified from MMN sera decreased the expression of claudin-5 and increased the VCAM-1 expression in PnMECs. Conclusions The sera from MMN patients may disrupt the BNB function via the autocrine secretion of VEGF in PnMECs, or the exposure to autoantibodies against PnMECs that are contained in the MMN sera. Autoantibodies against PnMECs in MMN sera may activate the BNB by upregulating the VCAM-1 expression, thereby allowing for the entry of a large number of circulating inflammatory cells into the peripheral nervous system.

Oromandibular dystonia associated with SCA36

examination showed homovanillic acid 73 nmol/L (reference values (r.v.) 148–434), 5-hydroxyindoleacetic acid 29 nmol/ L (r.v. 68–115), 3-oxy-methyl-dopa 5016 nmol/L (r.v. < 50), 3-metoxy-4-hydroxyphenilglicole 29 nmol/L (r.v. 28– 60), and 5-hydroxythryptophan 74 nmol/L (r.v. < 10). With parental written informed consent, pergolide was replaced with rotigotine (6 mg/day; 0.25 mg/kg per day), which rapidly resulted in a relevant reduction of hypo/bradykinesia, vanishing of on–off phenomena, and improvement of gross motor functions (faster and unsupported gait, increased resistance to motor efforts, and improved postural tone, head control, and muscular strength). As with pergolide, no oculogyric crises were reported. No effects on fine-motor abilities, facial hypomimia, drooling, orthostatic hypotension, and sleep disturbances were observed. These results were stable after 1 year of treatment (Video and Table 1). No adverse effects of rotigotine occurred. The medication (8 mg/24 hours; 0.17 mg/kg per day) was not efficacious in his elder brother. The more advanced clinical stage and the more severe motor impairment of the brother could explain the apparent inefficacy of rotigotine in this second case. Present experiences suggest transdermal rotigotine as a promising specific treatment for gross motor symptoms in the early stages of AADC deficiency.

Are multifocal motor neuropathy patients underdiagnosed? An epidemiological survey in Japan.

Introduction: Our objective was to do an epidemiologic survey of patients with multifocal motor neuropathy (MMN) in comparison with those with amyotrophic lateral sclerosis (ALS) in Japan. Methods: In this retrospective study, we examined 46 patients with MMN and 1,051 patients with ALS from major neuromuscular centers in Japan from 2005 to 2009. Diagnosis was based on the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) and the revised El Escorial criteria. The efficacy of intravenous immunoglobulin (IVIg) was also taken into consideration in the diagnosis of MMN. Results: The ratio of MMN to ALS patients (0–0.10) varied among the centers, but mostly converged to 0.05. The prevalence was estimated to be 0.29 MMN patients and 6.63 ALS patients per 100,000 population. Conclusions: The frequency of MMN patients was around 1 out of 20 ALS patients, and MMN was possibly underdiagnosed in some centers. Muscle Nerve 49:357–361, 2014

Increased proinflammatory cytokines in sera of patients with multifocal motor neuropathy

BACKGROUND Multifocal motor neuropathy (MMN) is characterized by clinical improvement with intravenous immunoglobulin and the frequent detection of anti-ganglioside antibodies. However, the immunological background of the neuronal damage in MMN is still unclear. OBJECTIVE The aim of this study is to investigate abnormalities in the cytokine and chemokine profiles of MMN patients. METHODS Sera from 16 patients with MMN, 16 patients with sporadic amyotrophic lateral sclerosis (ALS), and 15 patients with other non-inflammatory neurological diseases (ONDs) were analyzed for 27 cytokines and chemokines using a multiplex bead array. We also checked whether the altered cytokine/chemokine profile in the MMN group differed significantly in the presence or absence of abnormal electrophysiological findings. RESULTS Serum IL-1Ra, IL-2, G-CSF, TNF-α, and TNFR1 levels were significantly higher in the MMN group than in the ONDs group. Of these, G-CSF and TNF-α also showed significant increases compared to the ALS group. Serum G-CSF and TNF-α levels were significantly higher in MMN patients presenting with focal demyelination including conduction block than in patients without any focal demyelination. CONCLUSIONS Proinflammatory cytokines may contribute to peripheral nerve demyelination in MMN.

Generalized dystonia in a patient with a novel mutation in the GLUD1 gene

Hyperinsulinism-hyperammonemia syndrome (HHS; MIM 606762) is a form of congenital hyperinsulinism caused by mutations in the glutamate dehydrogenase 1 gene (GLUD1). This gene encodes glutamate dehydrogenase (GDH), which catalyzes the oxidation of glutamate to ammonia. Mutations in GLUD1 cause GDH hyperactivity by lowering the enzyme’s sensitivity to guanosine-50-triphosphate (GTP), an allosteric inhibitor of GDH, resulting in persistent hyperammonemia and hyperinsulinism. Although GLUD1-related HHS is frequently associated with epilepsy and mental retardation, generalized dystonia has only been reported in 1 case. Here, we confirm this association and describe a fulminant clinical progression of dystonia to dystonic storm, as well as significant improvement with bilateral globus pallidus internus deep brain stimulation (GPi-DBS). The female patient grew normally until 6 months of age, when she had an episode of generalized tonic–clonic seizures that responded poorly to antiepileptic drugs. Laboratory tests at age 33 months revealed hypoglycemia and hyperinsulinemia followed by persistent hyperammonemia. She also had moderate mental retardation, although her EEG and brain MRI appeared normal. A diagnosis of HHS was made, and we began treatment with diazoxide, which controlled her blood glucose levels and stopped the seizures. At age 11, she developed stereotyped repetitive neck rotation and upper arm contraction. The dystonic movements spread to whole areas of the body within a few months and were refractory to pharmacotherapy that included trihexyphenidyl, risperidone, clonazepam, baclofen, and L-3,4-dihydroxyphenylalanine. The patient eventually developed a life-threatening dystonic storm at age 16, and bilateral GPi-DBS was performed. GPi-DBS had a striking impact on her symptoms; her preoperative Burke-Fahn-Marsden Dystonia Rating Scale score of 112 decreased to 11.5 after GPi-DBS (Video). This improvement was essentially stable on examination 1 year after surgery. The genetic study was approved by the ethics committee, and participants provided written informed consent. We analyzed GLUD1 gene exons by PCR sequencing and confirmed the presence of a heterozygous sequence variation in exon 7: c.943C>T (Fig. 1A). Basal GDH activity was 35 nmol/min/mg of protein (control, 29), and allosteric inhibition by GTP (IC50) was 1819 nM (control, 135). These results are consistent with HHS caused by GLUD1 gene mutations. The patient underwent magnetic resonance spectroscopy (H-MRS) at age 14 (Fig. 1B–D), according to a previously reported method. Coding exons of the TOR1A and THAP1 genes did not contain mutations. Bahi-Buisson et al previously described generalized dystonia with prominent cranial-cervical features in a patient affected with the major GTP-binding site mutation. The mutation in the presented case lies in the same region. Further parallels include the age of dystonia onset, repeated hypoglycemic seizures, and moderate learning disability. Although epilepsy is reported frequently with the major mutation in the GTP-binding site, clonazepam may have masked the patient’s EEG aberrations. This case further supports that mutations in the GLUD1 gene could be a potential cause of dystonia and also suggests that GLUD1-related dystonia occurs through unique GLUD1 gene mutation– induced disruption of metabolic pathways. GLUD1 mutations can induce GDH overactivity that chronically depletes glutamate, which serves as the precursor of GABA. Loss of GABAergic inhibition is critical in dystonia development. Indeed, an MRS study showed that this patient had reduced levels of GABA and glutamate in the basal ganglia. Moreover, our patient showed decreased GABA levels in CSF and plasma (96 pmol/mL [normal controls, 239 6 76] and 74 pmol/mL [normal controls, 120–210], respectively). These data suggest that HHS-associated dystonia may be caused by altered GABAergic neurotransmission from GDH overactivity following direct mutation of the major GTP-binding site.

DYT6 in Japan-genetic screening and clinical characteristics of the patients

dissynergic, propulsive pattern emerged, resulting in a festinating gait with lateral displacement of the body (see Video Segment 1). Skilled movements of the upper limbs were preserved. The boy’s score on the Leiter-R IQ test was 78, and his performance on the Tower of London test was within normal range (z 5 20.50). A trial with levodopa (L-dopa)/ carbidopa was ineffective. Starting from age 9 years, brain magnetic resonance imaging revealed progressive cerebral and cerebellar atrophy. Proton magnetic resonance spectroscopy detected a decline in N-acetylaspartate levels and increased lipid signals in both the cerebral white matter and the basal ganglia. Generalized myoclonic and tonic seizures, which were triggered by photic stimulation, were observed first at age 11 years. Somatosensory stimulation of the limbs evoked giant cortical potentials, suggesting cortical myoclonus. At age 12 years, the boy lost the ability to read and write, although social interaction and verbal comprehension were relatively preserved (Vineland Adaptive Behavior Scale: socialization domain, 6 years and 2 months; receptive subdomain, 7 years and 9 months). Between ages 12 and 15 years, he experienced a further clinical decline, with severe hypokinesia and bradykinesia, impairment of postural reactions, ataxia, continuous rest and action myoclonic jerks, hypomimia, anarthric mutism, and upper limb-kinetic apraxia (see Video Segment 2). Visual functions remained unaffected. CLN6 gene sequencing revealed a homozygous c.700T!C transition (p.Phe234Leu), which involved a transmembrane domain (TM6) of the protein. The alteration was confirmed in the parents’ DNA, thus suggesting possible consanguinity.

Hyperexcitability as a potential cause for diffuse lower motor neuron loss in Isaacs’ syndrome

We present a patient who initially developed diffuse painful muscle cramps who had elevated antibodies against voltage‐gated potassium channel (VGKC) complex. Despite the initial improvement after immunomodulatory therapy, she later developed progressive atrophy and weakness of the limb muscles whose electrophysiological finding mimicked that in lower motor neuron disease. A potential causal relationship between anti‐VGKC complex antibody‐associated hyperexcitability and lower motor axon loss is discussed.

Diagnostic spectrum of multifocal motor neuropathy

We carried out a retrospective study to define clinical features in a large series of patients with multifocal motor neuropathy (MMN) and to assess the diagnostic spectrum of MMN.