Genetic screening of Filipinos suspected with familial Parkinson's disease: A pilot study.

INTRODUCTION: Although genetic factors are known to play a role in the pathogenesis of Parkinson's disease (PD), true prevalence of familial PD is unknown. We conducted this pilot study to identify genes implicated in familial Parkinson's disease among Filipinos. METHODS: Eighteen Filipino patients belonging to 11 families with personal and family history of PD underwent thorough evaluation by movement disorders specialists. Samples were analyzed in Juntendo University, Tokyo, Japan. Sanger sequencing of polymerase chain reaction products was performed. Each sample was screened for 23 genes (SNCA, PARK 2, UCHL1, PINK 1, DJ-1, LRRK2, ATP13A2, GIGYF2, HTRA2, PLA266, FBX07, VPS35, EIF461, DNAJC13, CHCHD2, GCH1, MAPT, NR4A2, VPS13c, PSEN1, and GRN). RESULTS: Out of 18 patients, six harbored Parkinson-related gene mutations. Five individuals from three families were positive for PINK1 c.10140T > C(p.L347P) mutation while one had heterozygous variant PRKN c.136G>T(p.A465) gene mutation. Three families displayed autosomal recessive pattern while one family with PINK1 mutation showed autosomal dominant mode of inheritance. Bradykinesia and tremor were predominant symptoms. Mean age at onset of symptoms was 40.4 years among those with PINK1 mutations. CONCLUSION: In this study, we presented the clinical profiles and identified two genetic mutations among a small group of Filipino patients with familial PD. They were congruent with most studies showing these mutations as the most common causes of autosomal recessive early-onset PD. Preliminary data from this pilot study will guide planning for larger scale studies, such as collaborative projects including The Global Parkinson's Genetics Program (GP2).

Spectrum of Movement Disorders in two Movement Disorders Centers in the Philippines.

OBJECTIVE: Presently, there are no epidemiologic data on the prevalence of movement disorders in the Philippines. We aim to describe the most common phenomenologies and movement disorders in two specialty centers in Metro Manila dedicated to movement disorders. METHODS: We investigated the clinical spectrum and etiologies of movement disorders referred to our centers from January 2007-December 2019 using a standardized collection form. RESULTS: A total of 1438 patients presenting with complaints relating to movement disorders were evaluated between 2007 to 2019. There were 770 (53.5%) men. The mean age was 57.1 ± 17.9 years. The most common movement disorders were parkinsonism (n=677, 47.1%), myoclonus (n=212, 14.7%) and tremor (n=208, 14.5%). The least common was restless legs syndrome (n=4, 0.3%). There were 78 (37.7% of total dystonia cases) X-linked dystonia-parkinsonism patients referred to our clinic. Majority of the botulinum toxin injections were for hemifacial spasms (n=206). A small number of patients (n=41) were also seen at the center for deep brain stimulation programming. CONCLUSION: The most common movement disorders managed were parkinsonism, myoclonus and tremor. The most common diagnoses were Parkinson's disease, hemifacial spasm and essential tremor. This study highlights the spectrum of movement disorders encountered in two specialty clinics in two Philippine tertiary hospitals. Given these varied cases, there is also a need for more movement specialists and centers dedicated to movement disorders to manage these cases.

Novel Optineurin Frameshift Insertion in a Family With Frontotemporal Dementia and Parkinsonism Without Amyotrophic Lateral Sclerosis.

Frontotemporal Dementia (FTD) is a common cause of Young Onset Dementia and has diverse clinical manifestations involving behavior, executive function, language and motor function, including parkinsonism. Up to 50% of FTD patients report a positive family history, supporting a strong genetic basis, particularly in cases with both FTD and amyotrophic lateral sclerosis (FTD-ALS). Mutations in three genes are associated with the majority of familial FTD (fFTD) cases - microtubule associated protein tau gene (MAPT), granulin precursor (GRN), and hexanucleotide repeat expansions in chromosome 9 open reading frame 72- SMCR8complex subunit (C9orf72) while mutations in other genes such as optineurin (OPTN) have rarely been reported. Mutations in OPTN have been reported mostly in familial and sporadic cases of ALS, or in rare cases of FTD-ALS, but not in association with pure or predominant FTD and/or parkinsonian phenotype. Here, we report for the first time, a family from the Philippines with four members harboring a novel frameshift insertion at OPTN (Chr 10:13166090 G>GA) p.Lys328GluTer11, three of whom presented with FTD-related phenotypes. Additionally, one sibling heterozygous for the frameshift insertion had a predominantly parkinsonian phenotype resembling corticobasal syndrome, but it remains to be determined if this phenotype is related to the frameshift insertion. Notably, none of the affected members showed any evidence of motor neuron disease or ALS at the time of writing, both clinically and on electrophysiological testing, expanding the phenotypic spectrum of OPTN mutations. Close follow-up of mutation carriers for the development of new clinical features and wider investigation of additional family members with further genetic analyses will be conducted to investigate the possibility of other genetic modifiers in this family which could explain phenotypic heterogeneity.

X-linked dystonia Parkinsonism: crossing a new threshold.

X-linked dystonia parkinsonism (XDP) is a neurodegenerative disorder that has received significant interest on several fronts. Although much still remains to be elucidated regarding the disease cause, a robust amount of data has been produced in recent years compared to when it was first described in 1976. The debilitating nature of the overlapping dystonia and parkinsonism that characterizes this disorder has fueled much of the interest in unraveling its cause, clinical presentation, symptom progression, treatment and impact on the afflicted patients as well as their caregivers. Having made several significant advances in genetic studies, neuropathology, neurophysiology and clinical characterization, we are entering a new threshold in the study of this disorder, hopefully bringing us closer to potential treatments and possible cures. This review will focus on new information gathered regarding the motor and non-motor features of XDP, deep brain stimulation (DBS) as a potential treatment for XDP and the utility of the recently validated XDP-Movement Disorder Society of the Philippines (MDSP)-rating scale.

Autosomal Dominant Frontotemporal Lobar Degeneration in a Filipino Family with Progranulin Mutation.

BACKGROUND: Compared to Western populations, familial frontotemporal lobar degeneration (FTLD) is rare among Asians. Progranulin (GRN) gene mutation, which is a major cause of FTLD, is likewise rare. We present a family with FTLD from the Philippines with an autosomal dominant pattern of inheritance and GRN mutation and briefly review reports of GRN mutations in Asia. CASE PRESENTATION: The proband is 66 years old with progressive nonfluent aphasia (PNFA)-corticobasal syndrome . We assessed 3 generations of her pedigree and found 11 affected relatives with heterogenous phenotypes, usually behavioral variant frontotemporal dementia (FTD) and PNFA. Neuroimaging showed atrophy and hypometabolism consistent with FTD syndromes. White matter hyperintensities were seen in affected members even in the absence of vascular risk factors. A GRN mutation R110X was found in 6 members, 3 with symptoms and 3 were asymptomatic. Plasma GRN was low (<112 ng/mL) in all mutation carriers. No mutations were found in microtubule-associated protein tau, APP, PSEN1, and PSEN2 genes, and all were APOE3. CONCLUSION: This is the first Filipino family with autosomal dominant FTD documented with GRN mutation. Identifying families and cohorts would contribute to therapeutic developments in an area with FTD-GRN.

The Basal Ganglia Striosomes Affect the Modulation of Conflicts by Subliminal Information-Evidence from X-Linked Dystonia Parkinsonism.

Cognitive control is relevant when distracting information induces behavioral conflicts. Such conflicts can be produced consciously and by subliminally processed information. Interestingly, both sources of conflict interact suggesting that they share neural mechanisms. Here, we ask whether conjoint effects between different sources of conflict are modulated by microstructural basal ganglia dysfunction. To this end, we carried out an electroencephalography study and examined event-related potentials (ERPs) including source localization using a combined flanker-subliminal priming task in patients with X-linked dystonia Parkinsonism (XDP) and a group of healthy controls. XDP in its early stages is known to predominantly affect the basal ganglia striosomes. The results suggest that conjoint effects between subliminal and conscious sources of conflicts are modulated by the striosomes and were stronger in XDP patients. The neurophysiological data indicate that this effect is related to modulations in conflict monitoring and response selection (N2 ERP) mechanisms engaging the anterior cingulate cortex. Bottom-up perceptual gating, attentional selection, and motor response activation processes in response to the stimuli (P1, N1, and lateralized readiness potential ERPs) were unaffected. Taken together, these data indicate that striosomes modulate the processing of conscious and subliminal sources of conflict suggesting that microstructural basal ganglia properties are relevant for cognitive control.

Validation of the XDP-MDSP rating scale for the evaluation of patients with X-linked dystonia-parkinsonism.

X-linked dystonia-parkinsonism(XDP) is a neurodegenerative disorder endemic to the Philippines. A rating scale was developed by the authors under the guidance of the Movement Disorder Society of the Philippines (MDSP) to assess XDP severity and progression, functional impact, and response to treatment in future clinical trials. Our main objective was to validate our new scale, the XDP-MDSP scale. The initial validation process included pragmatic testing to XDP patients followed by a modified Delphi procedure with an international advisory panel of dystonia, parkinsonism and scale development experts. Pearson correlation was used to assess construct validity of our new scale versus the assess construct validity of our new scale versus standard dystonia, parkinsonism, non-motor and functional scales; and also to assess divergent validity against behavioral and cognitive scales. The 37-item XDP-MDSP scale has five parts: I-dystonia, II-parkinsonism, III-non-motor features, IV-ADL, and V-global impression. After initial validation, the scale was administered to 204 XDP patients. Inter-domain correlation for the first four parts was acceptable. The correlation between these domains and the global rating was slightly lower. Correlations between Parts I, II, III, and IV versus standard dystonia, parkinsonism, non-motor and functional scales were acceptable with values ranging from 0.323 to 0.428. For divergent validity, a significant correlation was seen with behavioral scales. No significant correlation was noted with the cognitive scale. The proposed XDP-MDSP scale is internally valid but the global rating subscale may need to be modified or eliminated. While there is convergent validity, divergent validation was successful only on cognitive and not behavioral scales. The frequent co-occurrence of anxiety and depression, and its effect on the motor and functional state, may explain this finding.

Dysfunctions in striatal microstructure can enhance perceptual decision making through deficits in predictive coding.

An important brain function is to predict upcoming events on the basis of extracted regularities of previous inputs. These predictive coding processes can disturb performance in concurrent perceptual decision-making and are known to depend on fronto-striatal circuits. However, it is unknown whether, and if so, to what extent striatal microstructural properties modulate these processes. We addressed this question in a human disease model of striosomal dysfunction, i.e. X-linked dystonia-parkinsonism (XDP), using high-density EEG recordings and source localization. The results show faster and more accurate perceptual decision-making performance during distraction in XDP patients compared to healthy controls. The electrophysiological data show that sensory memory and predictive coding processes reflected by the mismatch negativity related to lateral prefrontal brain regions were weakened in XDP patients and thus induced less cognitive conflict than in controls as reflected by the N2 event-related potential (ERP). Consequently, attentional shifting (P3a ERP) and reorientation processes (RON ERP) were less pronounced in the XDP group. Taken together, these results suggests that striosomal dysfunction is related to predictive coding deficits leading to a better performance in concomitant perceptual decision-making, probably because predictive coding does not interfere with perceptual decision-making processes. These effects may reflect striatal imbalances between the striosomes and the matrix compartment.

Striosomal dysfunction affects behavioral adaptation but not impulsivity-Evidence from X-linked dystonia-parkinsonism.

BACKGROUND: Executive functions including behavioral adaptation and impulse control are commonly impaired in movement disorders caused by striatal pathology. However, as yet it is unclear what aspects of behavioral abnormalities are related to pathology in which striatal subcomponent, that is, the matrix and the striosomes. We therefore studied cognitive control in X-linked dystonia-parkinsonism, a model disease of striosomal degeneration, using behavioral paradigms and EEG. METHODS: We studied genetically confirmed X-linked dystonia-parkinsonism patients (N = 21) in their early disease stages and healthy matched controls. Error-related behavioral adaptation was tested in a flanker task and response inhibition in a Go/Nogo paradigm during EEG. We focused on error-related negativity during error processing and the Nogo-N2 and Nogo-P3 in the response inhibition task. Source localization analyses were calculated. In addition, total wavelet power and phase-locking factor reflecting neural synchronization processes in time and frequency across trials were calculated. RESULTS: Error processing and behavioral adaptation predominantly engaging the anterior cingulate cortex was markedly impaired in X-linked dystonia-parkinsonism. This was reflected in abnormal reaction times correlating with error-related negativity amplitudes, error related theta band activity, and the phase-locking factor. Also, abnormal error processing correlated with dystonia severity but not with parkinsonism. Response inhibition and corresponding EEG activity were normal. CONCLUSIONS: This dissociable pattern of cognitive deficits most likely reflects predominant dysfunction of the striosomal compartment and its connections to the anterior cingulate cortex in X-linked dystonia-parkinsonism. The results underscore the importance of striosomes for cognitive function in humans and suggest that striosomes are relays of error-related behavioral adaptation but not inhibitory control. © 2017 International Parkinson and Movement Disorder Society.

Botulinum toxin as early intervention for spasticity after stroke or non-progressive brain lesion: A meta-analysis.

Spasticity is a functionally limiting disorder that commonly occurs following stroke or severe brain injury, and may lead to disability and pain. In tandem with neurorehabilitation, botulinum toxin type A (BoNT-A) is the recommended first-line treatment for spasticity and, to date, the majority of trials have reported BoNT-A use in patients >6months after ictus. The present meta-analysis aimed to evaluate the effects of early BoNT-A injection for post-stroke spasticity on improvements in hypertonicity, disability, function and associated pain. A literature search yielded six studies reporting the effects of BoNT-A treatment within 3months post-stroke; three in the upper limb and three in the lower limb. All six studies permitted concomitant rehabilitation. Reduction in hypertonicity was compared in all six studies and revealed a significant treatment effect (P=0.0002) on the most affected joints between weeks 4 and 12 following injection. However, no significant effects of treatment were observed for improvement in disability at week 4 or improvement in function at weeks 4 and 20-24. A trend towards reduction in spasticity-related pain at week 4 following BoNT-A treatment (P=0.13) was also observed. These results demonstrate the beneficial effects of BoNT-A treatment on improving hypertonicity within 3months post-stroke and emphasise the importance of concomitant neurorehabilitation therapy.

X-linked Dystonia-Parkinsonism manifesting in a female patient due to atypical turner syndrome.

BACKGROUND: Recessive X-linked dystonia-parkinsonism almost exclusively affects men. We investigated the genetic mechanisms causing this disorder in a female patient. METHODS: We confirmed the presence of an X-linked dystonia-parkinsonism-specific change in our patient by sequencing. In addition, we employed quantitative real-time PCR and array comparative genomic hybridization to determine the patient's X-chromosome copy number. RESULTS: The patient's sequence electropherogram suggested a higher amount of the mutated allele compared with the wild-type allele. Subsequently, extensive gene dosage analyses revealed a copy number of the X chromosomes between 1 and 2, indicating loss of 1 X chromosome in a subset of cells. Phenotypic reevaluation of the patient showed several clinical features of Turner syndrome. CONCLUSIONS: Our female X-linked dystonia-parkinsonism patient suffered from an undiagnosed X-chromosome monosomy in a subset of cells (45,X/46,XX), suggesting an atypical Turner syndrome and contributing the first molecular explanation for the manifestation of an X-linked dystonia-parkinsonism phenotype in women. © 2013 Movement Disorder Society.

Botulinum toxin therapy in established post-stroke upper limb spasticity

Amongst stroke patients, more than a third will develop spasticity, especially those that involve the paretic upper limbs. Despite establish intensive rehabilitaion programs in place, spasticity still affect a post-stroke patient's quality of life and create significant economic and caregiver burdens. The rationale for botulinum toxin type A (BoNT-A) use in spasticity is hinged on the toxin's ability to reduce muscle overactivity via a dual cholinergic blockede of extrafusal and intrafusal muscle. Efficacy and safety of BoNT-A in established post-stroke spasticity have been widely published, effectively establishing robustness of data and first line recommendation. Consensus guidelines and algorithms on the clinical use of BoNT-A for symptomatic upper limb spasticity are now also available. While BoNT-A has been universally shown to reduce muscle tone in spasticity, optimizing therapy requires judicious use of the toxin, while raising one's consciousness of adverse event, including muscle weakness, unwanted or desired in therapy. BoNT-A should not be administered alone in post-stroke spasticity, and its effects are best optimized in concert with a comprehensive neurorehabilitation program.

Anxiety symptoms among cognitively-intact, community dwelling Filipino patients with Parkinson disease

OBJECTIVE: To determine the prevalence of anxiety and its correlation with the quality of life among cognitively-intact, community dwelling Filipino patients with idiopathic Parkinson disease (PD) seen at the Movement Disorders Clinic of a tertiary hospital.STUDY DESIGN: Prospective, cross-sectional study. METHODS: Seventy six (76) Filipino outpatients fulfilling the United Kingdom Parkinson Disease Society Brain Bank Clinical Diagnostic Criteria for PD were included in the study. Demographic data were obtained including: age, sex, onset of disease, disease duration and medication intake. The Mini Mental State Examination (MMSE) was done to exclude significant cognitive impairment. The Hamilton Anxiety scale (HAM-A) was administered to quantify anxiety. The degree of anxiety was correlated with the quality of life instrument, Short form health survey (SF 36); and the functional and motor severity using the Unified Parkinson Disease Rating Scales (UPDRS).FINDINGS: Our cohort of patients had a mean: age of 61 years (range: 42 - 81 years), and disease duration of 1.3 years (33 months). Out of the 76 patients, 37( 48.6%) probably had significant anxiety symptoms based on the the HAM A. Anxiety greatly impacts scores on SF 36.CONCLUSION: The prevalence of anxiety among this Filipino cohort of patients is 48.6% which is higher than commonly reported worldwide. The presence of anxiety significantly correlated with poorer quality of life.

Botulinum toxin-A targeted for focal/ multifocal dystonias- An open- label application in X-linked Dystonia-Parkinsonism

Targeted for relief of spasms, posturing, pain, impaired function and disfigurement, botulinum toxin type-A (BoNT-A) was injected in dystonias of X-linked dystonia-parkinsonism (XDP). From 1992-2012, focal/ multifocal dystonia combinations were injected in XDP at the following regions: Peri-ocular (21 cases), oromandibular (50 cases), ligual (35 cases), laryngeal (5 cases), cervical (56 cases), truncalaxil (24 cases) upper limbs (13 cases) and lower limbs (18 cases). Pain was frequently reported in 40/50 cases with oromandibular dystonia, 28/56 cases with cervical dystonia, 18/24 cases with truncal-axil dystonia and 16/31 cases with limb dystonia. Outcomes were assessment through the global dystonia rating scale (DRS) at week 4, VAS pain reduction at week 4, duration of BoNT-A effects and safety. Cranial, laryngeal and cervical dystonia showed substantial improvement (DRS median score of 3-4), whereas truncal-axil and limb dystonias showed moderate improvement (DRS median score of 2), following BoNT-A. Pain reduction ranged from 30-100% (VAS), for those dystonias that reported co-morbid pain. BoNT-A effects had a duration ranging from 8-20 weeks. Procedures were generally well tolerated, and the adverse events were most significant in laryngeal injections (voice breathiness, but was eventually followed by a strong voice). The other events were mouth dryness, dysphagia and weekness in oromandibular, cervical and limb dystonias, respectively. Therefore, BoNT-A is a safe and valuable therapeutic option for the dystonias of XDP, especially the disabling and painful dystonias. BoNT-A injection working protocols could be adopted in dystonia that adheres to cost minimization (e.g. lower dose end per selected muscles), yet achieving a substantial benefit, and a reduced adverse event profile. Futhermore, this present study allowed us to recommend a "high potency, low dillution" of BoNT-A in oromandibular, linual, laryngeal, cervical and distal limb dystonias. In dystonias of the abdominal, paraspinal and proximal limb muscles, the "low potency, high dilution" BoNT-A injection protocol could be adopted.

The broadening application of chemodenervation in X-linked dystonia-parkinsonism (Part II): an open-label experience with botulinum toxin-A (Dysport®) injections for oromandibular, lingual, and truncal-axial dystonias.

While the majority of chemodenervation clinics worldwide typically use botulinum toxins for the treatment of common conditions such as blepharopsams, cervical dystonia, limb dystonia, and spasticity, the unusually high concentration of X-linked dystonia-parkinsonism (XDP) has allowed us to collect and describe our experience in the use of botulinum toxin type A (BoNT-A) on rarer dystonic patterns. BoNT-A (Dysport®) was injected in a total 109 dystonias of XDP. Our cohort included: 50 cases in the oromandibular area (jaw opening: 32 cases, jaw closing: 12 cases, and jaw deviation: 6 cases); 35 cases in the lingual area (tongue protrusion: 27 cases and tongue curling: 8 cases); and, 24 cases in the truncal-axial area (flexor: 12 cases, extensor: 7 cases, and lateral-extensor: 5 cases). Interestingly, pain, often a nonprominent symptom of dystonias, was frequently reported in 40/50 XDP cases with oromandibular dystonia and 18/24 XDP cases with truncal-axial dystonia. All BoNT-A procedures were performed under electromyography guidance. A "high potency, low dilution" BoNT-A protocol was applied for oromandibular, lingual, cranial, cervical, and distal limb dystonias; whereas for dystonias of the abdominal, paraspinal, and proximal limb muscles, a "low potency, high dilution" BoNT-A injection protocol was applied. Outcomes measures included: the global dystonia rating scale (DRS) and pain visual analog scale (VAS) reduction at week 4; duration of BoNT-A effects; and, side effect profile. The median DRS score after 4 weeks was 3 ("substantial improvement") for oromandibular and lingual dystonias and 2 ("moderate improvement") for truncal-axial dystonias. Pain reduction was significantly reduced (75%-80% in oromandibular; 30%-80% in truncal-axial dystonias). The median duration of BoNT-A effect was 16 weeks for oromandibular, 12 weeks for lingual, and 11 weeks for truncal-axial dystonias. Compared to a generally safe and well-tolerated BoNT-A injections for truncal-axial dystonias, the oromandibular-lingual dystonias had the following frequency of adverse events: oromandibular--19% in jaw opening and 17% in jaw closing dystonias; lingual--19% in tongue protrusion and 13% in tongue curling dystonias. The most frequent adverse events were mouth dryness and dysphagia. Thus, BoNT-A injection working protocols may be adopted in XDP dystonia that adheres to cost minimization (e.g., lower dose end per selected muscle), while achieving some benefit, and potentially reduce the adverse event profile.

The broadening application of chemodenervation in X-linked dystonia-parkinsonism (Part I): muscle afferent block versus botulinum toxin-A in cervical and limb dystonias.

Botulinum toxin (BoNT) is an established mainstay treatment for dystonia. However, its use, especially in developing countries, is significantly limited by its cost. Chemodenervation with muscle afferent block (MAB) using lidocaine-ethanol may provide a more cost-effective alternative to traditional BoNT injections. A study comparing MAB with BoNT type-A in cases of X-linked dystonia-Parkinsonism (XDP) having cervical dystonia indicated a modest and short-lived efficacy with MAB, while a more robust efficacy in dystonia and pain parameters, lasting up to 11 weeks, was observed in the two BoNT type-A preparations (Dysport® and Botox®). In another study comparing BoNT type-A formulations for limb dystonia of XDP, a prior MAB was used to select target muscles for toxin injection. During toxin injections in the limb muscles, Dysport® and Botox® did not show significant differences with regard to global severity and disability scales, duration of effect, and adverse event (AE) profile. Dysphagia was the most common AE following BoNT type-A injections in cervical dystonia, while weakness was the most frequent AE noted with injections for limb dystonia. MAB injections carried a high incidence of dizziness and pain during injections. However, because MAB is a more cost-effective alternative that can be given repeatedly, it has been used in the XDP population while awaiting funds for BoNT type-A and/or for selecting muscles for injection as a test drug.

Muscle membrane excitability after exercise in thyrotoxic periodic paralysis and thyrotoxicosis without periodic paralysis.

We evaluated whether the paralytic attacks in thyrotoxic periodic paralysis (TPP) are primarily due to the abnormal excitability of the muscle membrane caused by a preexisting latent abnormality or to the effects of thyroid hormone. The prolonged exercise (PE) test was used to evaluate muscle membrane excitability in 21 patients with TPP and 11 patients with thyrotoxicosis without paralytic attacks (Tw/oPP) in the hyperthyroid state. The PE tests were compared between the hyperthyroid and euthyroid states in five of the TPP and three of the Tw/oPP patients. Compared to 20 healthy subjects, a significant increase in compound muscle action potential (CMAP) amplitudes immediately after exercise and a significant time-dependent gradual decline in CMAP amplitudes starting from 20 min after exercise were observed in the TPP patients. A significant decline in CMAP amplitudes was also observed in the Tw/oPP patients but only at 50 min after exercise. All of the TPP and Tw/oPP patients had a tendency to improve in the euthyroid state; the PE tests remained abnormal only in the TPP patients. Paralytic attacks in TPP patients are due primarily to a preexisting latent abnormal excitability of the muscle membrane, possibly genetic in origin.

Molecular mechanism of rigid spine with muscular dystrophy type 1 caused by novel mutations of selenoprotein N gene.

Mutations of selenoprotein N, 1 gene (SEPN1) cause rigid spine with muscular dystrophy type 1 (RSMD1), multiminicore disease, and desmin-related myopathy. We found two novel SEPN1 mutations in two Japanese patients with RSMD1. To clarify the pathomechanism of RSMD1, we performed immunohistochemical studies using a newly developed antibody for selenoprotein N. Selenoprotein N was diffusely distributed in the cytoplasm of the control muscle, but was reduced and irregularly expressed in the cytoplasm of a patient with RSMD1. The expression pattern was very similar to that of calnexin, a transmembrane protein of the endoplasmic reticulum. Selenoprotein N seems to be an endoplasmic reticulum glycoprotein, and loss of this protein leads to disturbance of muscular function. One of the families had the SEPN1 homozygous mutation in the initiation codon 1_2 ins T in exon 1 and showed truncated protein expression. The other had a homozygous 20-base duplication mutation at 80 (80_99dup, frameshift at R27) which, in theory, should generate many nonsense mutations including TGA. These nonsense mutations are premature translation termination codons and they degrade immediately by the process of nonsense-mediated decay (NMD). However, truncated selenoprotein N was also expressed. A possible mechanism behind this observation is that SEPN1 mRNAs may be resistant to NMD. We report on the possible molecular mechanism behind these mutations in SEPN1. Our study clarifies molecular mechanisms of this muscular disorder.

The origin of spontaneous discharges in acquired neuromyotonia. A Macro EMG study.

OBJECTIVE: To study the generator sites of spontaneous discharges in patients with immune-mediated neuromyotonia. METHODS: Macro EMGs triggered by both spontaneously and voluntarily activated single action potentials were recorded and the mean peak-to-peak amplitude and area of the macro motor unit potentials were compared in two patients with typical acquired neuromyotonia having positive antibodies against voltage-gated potassium channels. RESULTS: Mean peak-to-peak amplitude and area of Macro EMG motor unit potentials (macro MUPs) triggered by spontaneous discharges were significantly smaller than those triggered by voluntary activation in both patients. However, a few macro MUPs triggered by spontaneous discharges resembled those triggered by voluntary activation. CONCLUSIONS: Spontaneous discharges in two patients with immune-mediated neuromyotonia seem to be mostly generated at sites distal to the terminal axon branching points. SIGNIFICANCE: This finding may provide a new insight in the understanding of spontaneous discharges in immune-mediated neuromyotonia.