The Health History of First-Degree Relatives' Dyslipidemia Can Affect Preferences and Intentions following the Return of Genomic Results for Monogenic Familial Hypercholesterolemia.

Genetic testing is key in modern healthcare, particularly for monogenic disorders such as familial hypercholesterolemia. This Tohoku Medical Megabank Project study explored the impact of first-degree relatives' dyslipidemia history on individual responses to familial hypercholesterolemia genomic results. Involving 214 participants and using Japan's 3.5KJPN genome reference panel, the study assessed preferences and intentions regarding familial hypercholesterolemia genetic testing results. The data revealed a significant inclination among participants with a family history of dyslipidemia to share their genetic test results, with more than 80% of participants intending to share positive results with their partners and children and 98.1% acknowledging the usefulness of positive results for personal health management. The study underscores the importance of family health history in genetic-testing perceptions, highlighting the need for family-centered approaches in genetic counseling and healthcare. Notable study limitations include the regional scope and reliance on questionnaire data. The study results emphasize the association between family health history and genetic-testing attitudes and decisions.

Effects of motor cortical and peripheral axonal hyperexcitability on survival in amyotrophic lateral sclerosis.

BACKGROUND: Increased 'cortical' and 'peripheral' excitability are reportedly associated with shorter survival in amyotrophic lateral sclerosis (ALS) patients, suggesting that hyperexcitability contributes to motor neuron death. However, whether upper or lower motor function has a greater impact on survival is unclear. We aimed to investigate the component that strongly impacts the prognosis of ALS. METHODS: A total of 103 consecutive patients with ALS who underwent cortical (threshold tracking transcranial magnetic stimulation (TMS)) and motor nerve excitability tests were included. Motor cortical excitability was evaluated using short-interval intracortical inhibition (SICI) during TMS. Motor axonal excitability was assessed using the strength-duration time constant (SDTC). Survival time was defined as the time from examination to death or tracheostomy. RESULTS: Compared with healthy subjects, patients with ALS had lower SICI and longer SDTC (p<0.05), indicating increased excitability of cortical motor neurons and motor axons. According to the SICI and SDTC findings, patients were divided into the following four groups: 'cortical high and peripheral high (high-high)', 'high-low', 'low-high' and 'low-low' groups. In Kaplan-Meier curves, the 'high-high' and 'low-high' groups showed significantly shorter survival than the other groups. Multivariate analysis revealed that increased cortical (HR=5.3, p<0.05) and peripheral (HR=20.0, p<0.001) excitability were significantly associated with shorter survival. CONCLUSIONS: In patients with ALS, both motor cortical and peripheral hyperexcitability independently affected survival time, with peripheral hyperexcitability having a greater impact on shorter survival. The modulation of neuronal/axonal excitability is a potential therapeutic target for ALS.

Analysis of Genetic Polymorphism of Bitter Taste Receptor TAS2R38 and TAS2R46, and Its Relationship with Eating and Drinking Habits in Japanese ToMMo Subjects.

Human type 2 taste receptor (TAS2R) genes encode bitter-taste receptors that are activated by various bitter ligands. It has been said that TAS2R38 may detect bitter substances and then suppress their intake by controlling gustatory or digestive responses. The major haplotypes of TAS2R38 involve three non-synonymous, closely-linked single-nucleotide polymorphisms (SNPs), leading to three amino acid substitutions (A49P, V262A and I296V) and resulting in a PAV or AVI allele. The allele frequency of AVI/PAV was 0.42/0.58 in this study. The genotype frequency distributions of TAS2R38 were 18.32%, 46.95% and 33.95% for AVI/AVI, AVI/PAV and PAV/PAV, respectively, and were in Hardy-Weinberg equilibrium. Five haplotype combinations of minor alleles were identified: AVI/AAV, AVI/AVV, AAI/PAV, AVI/PVV, AVI/AAI, with corresponding frequencies of 0.49%, 0.10%, 0.10%, 0.05%, 0.05%, respectively, in 2,047 Japanese Tohoku Medical Megabank Organization (ToMMo) subjects (2KJPN). The 16 subjects with these minor alleles were excluded from the questionnaire analysis, which found no significant differences among the major TAS2R38 genotypes (AVI/AVI, AVI/PAV and PAV/PAV) in the intake frequency of cruciferous vegetables or in the frequency of drinking alcohol. This result differs from previous data using American and European subjects. This is the first study to analyze the relationship between TAS2R38 genotype and the eating and drinking habits of Japanese subjects. It was also shown that there were no relationships at all between the genetic polymorphism of TAS2R46 and the phenotypes such as clinical BMI, eating and drinking habits among the 3 genotypes of TAS2R46 (∗/∗, ∗/W, W/W) at position W250∗ (∗stop codon).

Returning individual genomic results to population-based cohort study participants with BRCA1/2 pathogenic variants.

BACKGROUND: Recent advances in human genome research have provided evidence for genotype-phenotype associations, pathogenicity, and clinical actionability of variants and genomic risk prediction of disease. However, the return of individual genomic results to healthy individuals is fraught with ethical and practical complexity. METHODS: Individual genomic results were returned to BRCA1/2 pathogenic variant (PV) carriers of the Tohoku Medical Megabank cohort study participants with an information on hereditary breast and ovarian cancer syndrome (HBOC). One hundred and eighty participants, including 9 BRCA1/2 PV carriers, were asked about their willingness to receive individual genomic results, without revealing the gene name and related disorders, prior to the study. Of the 142 participants who responded, 103 showed willingness to know their genomic information. Each of the six BRCA1/2 PV carriers who consented to participate in the study received information about HBOC in person and underwent validation testing with blood resampling. RESULTS: All participants were in their 60s or 70s; of the four females and two males, two had a history of breast cancer and five had a family history of HBOC-related cancers. All participants appreciated the information, without remarkable negative psychological impact of the return, and intended to undergo clinical risk surveillance. Five participants were accompanied by family members while receiving the results, and three first-degree female relatives wished to undergo genomic testing at the hospital. CONCLUSIONS: Our results suggest that returning actionable genomic information to participants in a population-based genome cohort study is beneficial for preventing or providing early-stage intervention for associated diseases.

Genome-wide Association Study of Axial Length in Population-based Cohorts in Japan: The Tohoku Medical Megabank Organization Eye Study.

Purpose: To elucidate the differences in ocular biometric parameters by generation and gender and to identify axial length (AL)-associated genetic variants in Japanese individuals, we analyzed Tohoku Medical Megabank Organization (ToMMo) Eye Study data. Design: We designed the ToMMo Eye Study, examined AL variations, and conducted genome-wide association studies (GWASs). Participants: In total, 33 483 participants aged > 18 years who were recruited into the community-based cohort (CommCohort) and the birth and three-generation cohort (BirThree Cohort) of the ToMMo Eye Study were examined. Methods: Each participant was screened with an interview, ophthalmic examinations, and a microarray analysis. The GWASs were performed in 22 379 participants in the CommCohort (discovery stage) and 11 104 participants in the BirThree Cohort (replication stage). We evaluated the associations of single nucleotide polymorphisms (SNPs) with AL using a genome-wide significance threshold (5 × 10-8) in each stage of the study and in the subsequent meta-analysis. Main Outcome Measures: We identified the association of SNPs with AL and distributions of AL in right and left eyes and individuals of different sexes and ages. Results: In the discovery stage, the mean AL of the right eye (23.99 mm) was significantly greater than that of the left eye (23.95 mm). This difference was reproducible across sexes and ages. The GWASs revealed 703 and 215 AL-associated SNPs with genome-wide significance in the discovery and validation stages, respectively, and many of the SNPs in the discovery stage were replicated in the validation stage. Validated SNPs and their associated loci were meta-analyzed for statistical significance (P < 5 × 10-8). This study identified 1478 SNPs spread over 31 loci. Of the 31 loci, 5 are known AL loci, 15 are known refractive-error loci, 4 are known corneal-curvature loci, and 7 loci are newly identified loci that are not known to be associated with AL. Of note, some of them shared functional relationships with previously identified loci. Conclusions: Our large-scale GWASs exploiting ToMMo Eye Study data identified 31 loci linked to variations in AL, 7 of which are newly reported in this article. The results revealed genetic heterogeneity and similarity in SNPs related to ethnic variations in AL.

Increase in eosinophil-derived neurotoxin level in school children with allergic disease.

Background: Eosinophils are major effector cells of allergic disease and excellent markers of eosinophilic inflammation. Accurate and reliable biomarkers are helpful in the diagnosis, treatment, and control of allergic disease. Objective: This study aimed to investigate an alternate marker of eosinophilic inflammation, eosinophil-derived neurotoxin (EDN), in a number of allergic diseases. Methods: Three hundred ninety-six elementary school-age children with various allergic conditions were recruited for this study. Subgroups included food allergies (FAs), atopic dermatitis (AD), bronchial asthma (BA), and allergic rhinitis (AR). EDN levels in these groups were compared to those in 93 healthy controls (HC). Results: All subjects with allergic disease had elevated levels of serum EDN (median [interquartile range]: FA, 124.2 ng/mL [59.13-160.5 ng/mL]; AD, 110.8 ng/mL [57.52-167.9 ng/mL]; BA, 131.5 ng/mL [60.60-171.0 ng/mL]; AR, 91.32 ng/mL [46.16-145.0 ng/mL]) compared to HC (38.38 ng/mL [32.40-55.62 ng/mL]) (p < 0.0001). These elevated levels were consistent throughout the age range (6-12 years) of the healthy study subjects (p = 0.0679). EDN levels also correlated well with total immunoglobulin E (Rs = 0.5599, p < 0.0001). Looking at all individuals with an allergic disease, the area under the curve was 0.790. Conclusions: Direct measures of eosinophilic inflammation are needed for accurate diagnosis, treatment, and monitoring of allergic diseases. EDN may be a worthy biomarker of eosinophil activity and a useful screening tool for allergic diseases including FA, AD, BA, and AR.

Relationship between motor cortical and peripheral axonal hyperexcitability in amyotrophic lateral sclerosis.

BACKGROUND: Previous studies have shown that patients with amyotrophic lateral sclerosis (ALS) have hyperexcitability in both the motor cortex and peripheral motor axons, but the relationship between central and peripheral excitability has not been fully disclosed. METHODS: Threshold tracking transcranial magnetic stimulation (TMS) and motor nerve excitability testing were prospectively performed in 53 patients with ALS and 50 healthy subjects, and their relations to compound muscle action potential (CMAP) amplitude and revised ALS Functional Rating Scale were cross-sectionally analysed. RESULTS: Compared with controls, patients with ALS showed both cortical and peripheral hyperexcitability; TMS showed reduced short-interval intracortical inhibition (interstimulus interval 1-7 ms) (p<0.001) and shortened silent period (p<0.05), and median nerve excitability testing revealed greater changes in depolarising threshold electrotonus (TEd) and greater superexcitability (p<0.0001, both), suggesting reduced axonal potassium currents. Significant correlations between cortical and peripheral excitability indices were not found. Greater changes in TEd (90-100 ms) (R=-0.33, p=0.03) and superexcitability (R=0.36, p=0.01) were associated with smaller amplitude of CMAP, whereas cortical excitability indices had no correlation with CMAP amplitude. More rapid motor functional decline was associated with only greater TEd (90-100 ms) (ß=0.46, p=0.001). CONCLUSIONS: Our results suggest that in ALS, cortical excitability is continuously high regardless of the extent of the peripheral burden, but peripheral hyperexcitability is associated with the extent of the peripheral burden and disease evolution speed. Alterations of ion channel function may play an important role in ALS pathophysiology.

A Pilot Study for Return of Individual Pharmacogenomic Results to Population-Based Cohort Study Participants.

Introduction: Pharmacogenomic (PGx) testing results provide valuable information on drug selection and appropriate dosing, maximization of efficacy, and minimization of adverse effects. Although the number of large-scale, next-generation-sequencing-based PGx studies has recently increased, little is known about the risks and benefits of returning PGx results to ostensibly healthy individuals in research settings. Methods: Single-nucleotide variants of three actionable PGx genes, namely, MT-RNR1, CYP2C19, and NUDT15, were returned to 161 participants in a population-based Tohoku Medical Megabank project. Informed consent was obtained from the participants after a seminar on the outline of this study. The results were sent by mail alongside sealed information letter intended for clinicians. As an exception, genetic counseling was performed for the MT-RNR1 m.1555A > G variant carriers by a medical geneticist, and consultation with an otolaryngologist was encouraged. Questionnaire surveys (QSs) were conducted five times to evaluate the participants' understanding of the topic, psychological impact, and attitude toward the study. Results: Whereas the majority of participants were unfamiliar with the term PGx, and none had undergone PGx testing before the study, more than 80% of the participants felt that they could acquire basic PGx knowledge sufficient to understand their genomic results and were satisfied with their potential benefit and use in future prescriptions. On the other hand, some felt that the PGx concepts or terminology was difficult to fully understand and suggested that in-person return of the results was desirable. Conclusions: These results collectively suggest possible benefits of returning preemptive PGx information to ostensibly healthy cohort participants in a research setting.

Neuronal Hyperexcitability and Free Radical Toxicity in Amyotrophic Lateral Sclerosis: Established and Future Targets.

Amyotrophic lateral sclerosis (ALS) is a devastating disease with evidence of degeneration involving upper and lower motor neuron compartments of the nervous system. Presently, two drugs, riluzole and edaravone, have been established as being useful in slowing disease progression in ALS. Riluzole possesses anti-glutamatergic properties, while edaravone eliminates free radicals (FRs). Glutamate is the excitatory neurotransmitter in the brain and spinal cord and binds to several inotropic receptors. Excessive activation of these receptors generates FRs, inducing neurodegeneration via damage to intracellular organelles and upregulation of proinflammatory mediators. FRs bind to intracellular structures, leading to cellular impairment that contributes to neurodegeneration. As such, excitotoxicity and FR toxicities have been considered as key pathophysiological mechanisms that contribute to the cascade of degeneration that envelopes neurons in ALS. Recent advanced technologies, including neurophysiological, imaging, pathological and biochemical techniques, have concurrently identified evidence of increased excitability in ALS. This review focuses on the relationship between FRs and excitotoxicity in motor neuronal degeneration in ALS and introduces concepts linked to increased excitability across both compartments of the human nervous system. Within this cellular framework, future strategies to promote therapeutic development in ALS, from the perspective of neuronal excitability and function, will be critically appraised.

Different patterns of sensory nerve involvement in chronic inflammatory demyelinating polyneuropathy subtypes.

INTRODUCTION/AIMS: Among subtypes of chronic inflammatory demyelinating polyneuropathy (CIDP), different immune pathophysiologies have been proposed. In this study, sensory nerve conduction studies were compared among clinical subtypes to attempt to better understand the underlying pathophysiology. METHODS: A total of 138 patients with CIDP was classified into clinical subtypes: typical CIDP (N = 68), multifocal CIDP (N = 27), or other (N = 2). Patients with immunoglobulin M (IgM) neuropathy anti-myelin-associated glycoprotein neuropathy (MAG; N = 19) were also included as disease controls. Sensory nerve action potentials (SNAPs) were recorded in the median, ulnar, and superficial radial and sural nerves. RESULTS: SNAP amplitudes (P < .05) and conduction velocities (P < .01) in the median nerve and conduction velocities (P < .05) in the ulnar nerve were lower in typical CIDP than in multifocal CIDP, whereas those in the radial and sural nerves were comparable in each group. Low median and normal sural SNAP amplitudes were more common in typical CIDP (P < .005) than in multifocal CIDP, suggesting predominant involvement at terminal portions of the nerves. DISCUSSION: Terminal portions of sensory nerves are preferentially affected in typical CIDP compared with multifocal CIDP. These findings might be partially explained by the hypothesis of antibody-mediated demyelination in typical CIDP at the regions where the blood-nerve barrier is anatomically deficient, whereas multifocal CIDP predominantly affects the nerve trunks, largely due to cell-mediated demyelination, with disruption of the blood-nerve barrier.

Fatigue and activity-dependent conduction block in neuromuscular disorders.

Objective: Fatigue is a major disabling problem in patients with neuromuscular disorders. Both nerve demyelination and increased axonal branching associated with collateral sprouting reduce the safety factor for impulse transmission and could cause activity-dependent hyperpolarization and conduction block during voluntary contraction, and thus fatigue. This study aimed to investigate whether activity-dependent conduction block is associated with fatigue in demyelinating neuropathies and lower motor neuron disorders. Methods: This study included 31 patients (17 with chronic inflammatory demyelinating polyneuropathy [CIDP] and 14 with spinal and bulbar muscular atrophy [SBMA]). Sixteen healthy subjects served as normal controls. Fatigue was assessed using the Fatigue Scale for Motor and Cognitive Functions (FSMC). Compound muscle action potential (CMAP) recording and nerve excitability testing after median nerve stimulation in the wrist were performed before and after maximal voluntary contraction of the abductor pollicis brevis for 1 min. Results: Patients with CIDP/SBMA had prominent fatigue with higher FSMC motor scores (P < 0.0001) than normal controls. After voluntary contractions, CMAP amplitudes decreased significantly in four of the 17 patients with CIDP and one of the 14 patients with SBMA. The reduction in CMAP amplitude was associated with the fatigue score in the motor but not in the cognitive domain. After voluntary contraction, excitability testing showed axonal hyperpolarization in the normal and CIDP/SBMA groups. Conclusions: In CIDP or SBMA, fatigue is caused by voluntary contraction-induced membrane hyperpolarization and conduction block, presumably due to the critically lowered safety factor due to demyelination or increased axonal branching. Significance: Peripheral fatigue can be objectively assessed using CMAP amplitudes and nerve excitability testing.

Fasciculation intensity and limb dominance in amyotrophic lateral sclerosis: a muscle ultrasonographic study.

BACKGROUND AND PURPOSE: Muscle ultrasonography has been increasingly recognized as a useful tool for detection of fasciculations. Separately, concordance between dominant hand and onset side has been reported in amyotrophic lateral sclerosis (ALS). The aim of this study was to reveal the distribution of fasciculations in the whole body, focusing on handedness. METHODS: In 106 consecutive patients with ALS, muscle ultrasonography was systematically performed in 11 muscles (the tongue, and bilateral biceps brachii, 1st dorsal interosseous [FDI], T10-paraspinalis, vastus lateralis and tibialis anterior muscles). The fasciculation intensity was scored from 0 to 3 for each muscle. RESULTS: Fasciculations were more frequently found in the limb muscles than the tongue and paraspinalis. Side and handedness analyses revealed that fasciculation intensity in FDI was significantly more prominent on the right (median [inter-quartile range] 2 [0 - 3]) than left (1.5 [0 - 3]; p = 0.016), and in the dominant hand (2 [1 - 3]) than non-dominant side (1.5 [0 - 3]; p = 0.025). The differences were greater in patients with upper limb onset. There were no side differences in the lower limb muscles. Multivariate analyses showed that male patients had more frequent fasciculations in the dominant FDI (ß = 0.22, p < 0.05). CONCLUSION: More intensive fasciculations are present in the FDI in the dominant hand and gender might be associated with fasciculation intensities. This distribution pattern of fasciculations might be associated with pathogenesis of ALS.

Maternal Baseline Characteristics and Perinatal Outcomes: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

BACKGROUND: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study was launched in 2013 to evaluate the complex interactions of genetic and environmental factors in multifactorial diseases. The present study describes the maternal baseline profile and perinatal data of participating mothers and infants. METHODS: Expectant mothers living in Miyagi Prefecture were recruited from obstetric facilities or affiliated centers between 2013 and 2017. Three sets of self-administered questionnaires were collected, and the medical records were reviewed to obtain precise information about each antenatal visit and each delivery. Biospecimens, including blood, urine, umbilical cord blood, and breast milk, were collected for the study biobank. The baseline maternal sociodemographic characteristics, results of screening tests, and obstetric outcomes were analyzed according to the maternal age group. RESULTS: A total of 23,406 pregnancies involving 23,730 fetuses resulted in 23,143 live births. Younger maternal participants had a tendency toward a higher incidence of threatened abortion and threatened premature labor, while older age groups exhibited a significantly higher rate of low lying placenta, placenta previa, gestational diabetes, and hypertensive disorders of pregnancy. CONCLUSIONS: The present study clearly shows the distribution of maternal baseline characteristics and the range of perinatal outcomes according to maternal age group. This cohort study can provide strategic information for creating breakthroughs in the pathophysiology of perinatal, developmental, and noncommunicable diseases by collaborative data visiting or sharing.

The return of individual genomic results to research participants: design and pilot study of Tohoku Medical Megabank Project.

Certain large genome cohort studies attempt to return the individual genomic results to the participants; however, the implementation process and psychosocial impacts remain largely unknown. The Tohoku Medical Megabank Project has conducted large genome cohort studies of general residents. To implement the disclosure of individual genomic results, we extracted the potential challenges and obstacles. Major challenges include the determination of genes/disorders based on the current medical system in Japan, the storage of results, prevention of misunderstanding, and collaboration of medical professionals. To overcome these challenges, we plan to conduct multilayer pilot studies, which deal with different disorders/genes. We finally chose familial hypercholesterolemia (FH) as a target disease for the first pilot study. Of the 665 eligible candidates, 33.5% were interested in the pilot study and provided consent after an educational "genetics workshop" on the basic genetics and medical facts of FH. The genetics professionals disclosed the results to the participants. All positive participants were referred to medical care, and a serial questionnaire revealed no significant psychosocial distress after the disclosure. Return of genomic results to research participants was implemented using a well-prepared protocol. To further elucidate the impact of different disorders, we will perform multilayer pilot studies with different disorders, including actionable pharmacogenomics and hereditary tumor syndromes.

Association between Serum Biotin Levels and Cedar Pollinosis in Japanese Schoolchildren.

Biotin is a water-soluble B complex vitamin and coenzyme of five types of carboxylase and plays crucial roles in fatty acid, glucose, and amino acid metabolism. Nutritional biotin deficiency and defective enzymes essential for biotin metabolism cause inflammatory diseases such as eczema-like dermatitis and Crohn's disease; however, little is known about the pathophysiological roles of biotin. This study investigated the relationship between biotin metabolism and human allergic sensitization and diseases by measuring serum levels of biotin, total immunoglobulin E (IgE) and allergen-specific IgEs in more than 400 Japanese schoolchildren aged 6 to 12. The prevalence of allergic diseases, and environmental and life-style factors were also examined by a questionnaire. Like total IgE, serum biotin levels of children showed a log-normal distribution. Meanwhile, Spearman's rank correlation analysis showed weak but significant positive associations between serum biotin levels and total IgE (rho=0.147, p=0.0029) as well as allergen-specific IgEs against egg whites (rho=0.215, p=0.00013), cedar pollen (rho=0.176, p=0.00036), and cat dander (rho=0.130, p=0.0085). Furthermore, mean serum biotin levels in children with cedar pollinosis, but not with other allergic diseases such as asthma and allergic rhinitis, were significantly higher than in those without (p=0.0015). These results suggest a correlation between serum biotin levels and the development of cedar pollinosis. Further prospective studies are needed to evaluate the causal relationship between biotin metabolism and cedar pollen sensitization and pollinosis development.

Effect of racial background on motor cortical function as measured by threshold tracking transcranial magnetic stimulation.

A previous study using traditional paired-pulse TMS methods (amplitude-tracking) has reported differences in resting motor threshold (RMT) and short-interval intracortical inhibition (SICI) between healthy subjects of Caucasian and Han Chinese backgrounds, probably due to differences in the skull shape. The amplitude-tracking method delivers stimuli with constant intensity and causes substantial variabilities in motor-evoked potential amplitudes. To overcome this variability, threshold tracking transcranial magnetic stimulation (TT-TMS) has been developed. The present study aimed to investigate whether racial differences in motor cortical function exist, using TT-TMS. A total of 83 healthy volunteers (30 Caucasians, 25 Han Chinese, and 28 Japanese) were included in the present series. In TT-TMS and nerve conduction studies, electrodes were placed on the dominant limb, with measures recorded from the abductor pollicis brevis muscle. Stimulations were delivered with a circular coil, directly above the primary motor cortex. There were no significant differences at all the SICI intervals between races. Similarly, there were no significant differences in other measures of excitability including mean RMT, intracortical facilitation, and cortical silent period. Contrary to traditional amplitude-tracking TMS, motor cortical excitability and thereby motor cortical function is minimally influenced by racial differences when measured by TT-TMS. Recent studies have disclosed that SICI measured by TT-TMS differentiates amyotrophic lateral sclerosis (ALS) from ALS mimic disorders, with high sensitivity and specificity, in Caucasians. This study suggested that TT-TMS can be applied for the ALS diagnosis in Asian patients, as well as Caucasians.NEW & NOTEWORTHY Threshold tracking transcranial magnetic stimulation (TT-TMS) was applied for Caucasians, Han Chinese, and Japanese. No significant differences were found in TMS excitability indexes among races. Recent studies have disclosed that TT-TMS indexes differentiate amyotrophic lateral sclerosis (ALS) from ALS mimic disorders, with high sensitivity and specificity, in Caucasians. This study suggested that TT-TMS can be applied for the ALS diagnosis in Asian patients, as well as Caucasians.

Dispersion of mean consecutive differences in single-fiber electromyography increases diagnostic sensitivity for myasthenia gravis.

INTRODUCTION: In this study we aimed to investigate the dispersion of mean consecutive difference (MCD) of concentric needle jitter studies of patients with myasthenia gravis (MG) and its effect on diagnostic sensitivity for MG. METHODS: One hundred fifty-three patients, including 76 patients with MG and 77 controls with possible MG who later received another diagnosis, underwent stimulated concentric needle jitter studies of the frontalis muscle. MCD mean, standard deviation (SD), and coefficient of variation (CV) were calculated. Diagnostic sensitivity and specificity were determined using receiver operating characteristic (ROC) analyses. RESULTS: MG patients showed a significantly greater MCD mean (MG: control, 26.3 µs; 13.5 µs [median]; P < .0001), MCD SD (MG: control, 12.8 µs; 5.1 µs [median]; P < .0001), and MCD CV (MG: control, 46.1; 37.5 [median]; P < .001) than those without MG. An ROC curve of SD showed a large area under the curve (0.88), and a cut-off value of 7.2 µs, which was calculated by maximum Youden index, exhibited high diagnostic sensitivity (86%) for MG. Combined MCD mean, outliers, and SD criteria showed higher sensitivity (88%) than conventional criteria alone (82%), at the expense of lower specificity. Five MG patients with normal MCD mean and abnormal MCD SD had only ocular symptoms. DISCUSSION: The dispersion of MCD as measured by MCD SD greater than 7.2 µs is significantly increased in patients with MG and may be a useful measure of abnormal jitter in the diagnosis of MG, especially for identifying patients with mild disease.