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The clinical manifestations of sporadic amyotrophic lateral sclerosis (ALS) vary widely. However, the current classification of ALS is mainly based on clinical presentations, while the roles of electrophysiological and biomedical biomarkers remain limited. Herein, we investigated a group of patients with sporadic ALS and an ALS mouse model with superoxide dismutase 1 (SOD1)/G93A transgenes using nerve excitability tests (NET) to investigate axonal membrane properties and chemical precipitation, followed by enzyme-linked immunosorbent assay analysis to measure plasma misfolded protein levels. Six of 19 patients (31.6%) with sporadic ALS had elevated plasma misfolded SOD1 protein levels. In sporadic ALS patients, only those with elevated misfolded SOD1 protein levels showed an increased inward rectification in the current-threshold (I/V) curve and an increased threshold reduction in the hyperpolarizing threshold electrotonus (TE) in the NET study. Two familial ALS patients with SOD1 mutations also exhibited similar electrophysiological patterns of NET. For patients with sporadic ALS showing significantly increased inward rectification in the I/V curve, we noted an elevation in plasma misfolded SOD1 level, but not in total SOD1, misfolded C9orf72, or misfolded phosphorylated TDP43 levels. Computer simulations demonstrated that the aforementioned axonal excitability changes are likely associated with an increase in hyperpolarization-activated cyclic nucleotide-gated (HCN) current. In SOD1/G93A mice, NET also showed an increased inward rectification in the I/V curve, which could be reversed by a single injection of the HCN channel blocker, ZD7288. Daily treatment of SOD1/G93A mice with ZD7288 partially prevented the early motor function decline and spinal motor neuron death. In summary, sporadic ALS patients with elevated plasma misfolded SOD1 exhibited similar patterns of motor axonal excitability changes as familial ALS patients and ALS mice with mutant SOD1 genes, suggesting the existence of SOD1-associated sporadic ALS. The observed NET pattern of increased inward rectification in the I/V curve was attributable to an elevation in the HCN current in SOD1-associated ALS.

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OBJECTIVES: Hereditary transthyretin (TTR) amyloidosis (ATTRv) is frequently complicated by polyneuropathy (ATTRv-PN) and cardiomyopathy (ATTRv-CM). The long-term efficacy of diflunisal on both polyneuropathy and cardiomyopathy in ATTRv patients, especially those with non-V30M genotypes, has not been fully investigated and compared with that of tafamidis. METHODS: We compared the structural and biochemical characteristics of A97S-TTR complexed with tafamidis with those of diflunisal, and prospectively followed up and compared the progression of polyneuropathy and cardiomyopathy between ATTRv-PN patients taking diflunisal and those taking tafamidis. RESULTS: Both diflunisal and tafamidis effectively bind to the two thyroxine-binding sites at the A97S-TTR dimer-dimer interface and equally and almost sufficiently reduce amyloid fibril formation. Thirty-five ATTRv-PN patients receiving diflunisal and 22 patients receiving tafamidis were enrolled. Compared with no treatment, diflunisal treatment significantly delayed the transition of FAP Stage 1 to 2 and Stage 2 to 3 and decreased the deterioration in parameters of the ulnar nerve conduction study (NCS). The progression of FAP stage or NCS parameters did not differ between patients treated with diflunisal and those treated with tafamidis. Both diflunisal and tafamidis treatments significantly decreased radiotracer uptake on 99mTc-PYP SPECT and stabilized cardiac wall thickness and blood pro-B-type natriuretic peptide levels. No significant adverse events occurred during diflunisal or tafamidis treatment. INTERPRETATIONS: The binding patterns of both tafamidis and diflunisal to A97S-TTR closely resembled those observed in the wild type. Diflunisal can effectively delay the progression of polyneuropathy and cardiomyopathy with similar efficacy to tafamidis and may become a cost-effective alternative treatment for late-onset ATTRv-PN.

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BACKGROUND: The phase 3 NEURO-TTRansform trial showed eplontersen treatment for 65 weeks reduced transthyretin (TTR), halted progression of neuropathy impairment, and improved quality of life (QoL) in adult patients with hereditary TTR-mediated amyloidosis with polyneuropathy (ATTRv-PN), vs. historical placebo. METHODS: NEURO-TTRansform enrolled patients with ATTRv-PN. A subset of patients were randomized to receive subcutaneous inotersen 300 mg weekly (Weeks 1-34) and subsequently switched to subcutaneous eplontersen 45 mg every 4 weeks (Weeks 37-81). Change in serum TTR and treatment-emergent adverse events (TEAEs) were evaluated through Week 85. Effects on neuropathy impairment, QoL, and nutritional status were also evaluated. RESULTS: Of 24 patients randomized to inotersen, 20 (83%) switched to eplontersen at Week 37 and four discontinued due to AEs/investigator decision. Absolute change in serum TTR was greater after switching from inotersen (-74.3%; Week 35) to eplontersen (-80.6%; Week 85). From the end of inotersen treatment, neuropathy impairment and QoL were stable (i.e., did not progress) while on eplontersen, and there was no deterioration in nutritional status. TEAEs were fewer with eplontersen (Weeks 37-85; 19/20 [95%] patients) compared with inotersen (up to Week 35; 24/24 [100%] patients). Mean platelet counts decreased during inotersen treatment (mean nadir reduction ‒40.7%) and returned to baseline during eplontersen treatment (mean nadir reduction, ‒3.2%). CONCLUSIONS: Switching from inotersen to eplontersen further reduced serum TTR, halted disease progression, stabilized QoL, restored platelet count, and improved tolerability, without deterioration in nutritional status. This supports a positive benefit-risk profile for patients with ATTRv-PN who switch from inotersen to eplontersen.

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BACKGROUND: Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a progressive fatal disorder caused by deposition of mutant transthyretin (TTR) amyloids mainly in the nerves and heart. Autonomic dysfunction is a major disabling manifestation, affecting 90% of patients with late-onset ATTRv-PN. The current study aimed to investigate brain functional alterations associated with dysautonomia due to peripheral autonomic nerve degeneration in ATTRv-PN. METHODS: Resting-state functional MRI data were acquired from 43 ATTRv-PN patients predominantly of A97S (p.A117S) genotype, and the functional connectivity of central autonomic regions was assessed. RESULTS: Compared with age-matched healthy controls, the ATTRv-PN patients exhibited (1) reduced functional connectivity of the central autonomic regions such as hypothalamus, amygdala, anterior insula, and middle cingulate cortex with brain areas of the limbic, frontal, and somatosensory systems, and (2) correlations of reduced functional autonomic connectivity with the severity of autonomic dysfunction especially orthostatic intolerance, decreased heart rate variability, and greater clinical disability. CONCLUSIONS: Our findings provide evidence linking peripheral autonomic dysfunction with altered connectivity in the central autonomic network in ATTRv-PN.

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BACKGROUND AND PURPOSE: Various electrodiagnostic criteria have been developed in Guillain-Barré syndrome (GBS). Their performance in a broad representation of GBS patients has not been evaluated. Motor conduction data from the International GBS Outcome Study (IGOS) cohort were used to compare two widely used criterion sets and relate these to diagnostic amyotrophic lateral sclerosis criteria. METHODS: From the first 1500 patients in IGOS, nerve conduction studies from 1137 (75.8%) were available for the current study. These patients were classified according to nerve conduction studies criteria proposed by Hadden and Rajabally. RESULTS: Of the 1137 studies, 68.3% (N = 777) were classified identically according to criteria by Hadden and Rajabally: 111 (9.8%) axonal, 366 (32.2%) demyelinating, 195 (17.2%) equivocal, 35 (3.1%) inexcitable and 70 (6.2%) normal. Thus, 360 studies (31.7%) were classified differently. The areas of differences were as follows: 155 studies (13.6%) classified as demyelinating by Hadden and axonal by Rajabally; 122 studies (10.7%) classified as demyelinating by Hadden and equivocal by Rajabally; and 75 studies (6.6%) classified as equivocal by Hadden and axonal by Rajabally. Due to more strictly defined cutoffs fewer patients fulfilled demyelinating criteria by Rajabally than by Hadden, making more patients eligible for axonal or equivocal classification by Rajabally. In 234 (68.6%) axonal studies by Rajabally the revised El Escorial (amyotrophic lateral sclerosis) criteria were fulfilled; in axonal cases by Hadden this was 1.8%. CONCLUSIONS AND DISCUSSION: This study shows that electrodiagnosis in GBS is dependent on the criterion set utilized, both of which are based on expert opinion. Reappraisal of electrodiagnostic subtyping in GBS is warranted.

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BACKGROUND: To examine the efficacy and safety of patisiran, an RNA interference therapeutic, in patients from Taiwan with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy. METHODS: The APOLLO phase 3 trial included patients from Taiwan who received patisiran 0.3 mg/kg intravenously or placebo once every 3 weeks (q3w) for 18 months (18 M), followed by patisiran 0.3 mg/kg q3w in an ongoing global open-label extension (OLE) study. The primary endpoint was change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 18 M. RESULTS: Eighteen Taiwanese patients were enrolled in APOLLO (patisiran, n = 8; placebo, n = 10; all A97S gene variant) and 14 continued in the global OLE. In this Taiwanese sub-population, beneficial treatment effects at 18 M were observed in mNIS+7 (least squares mean difference in change from baseline [patisiran-placebo], -26.5 points; 95% confidence interval: -45.5, -7.5). Patients who switched from placebo to patisiran demonstrated slowing of polyneuropathy progression at month 12 in the global OLE, while those who received patisiran in APOLLO maintained the beneficial treatment effects. Patisiran had an acceptable safety profile in the Taiwanese sub-population. CONCLUSION: This analysis suggests that patisiran is well tolerated and may provide a substantial clinical benefit for Taiwanese patients with hATTR amyloidosis with polyneuropathy. TRIAL REGISTRATION INFORMATION: The studies were registered on the ClinicalTrials.gov. The APOLLO study ClinicalTrials.gov identifier is NCT01960348 (https://clinicaltrials.gov/ct2/show/NCT01960348), with the registration date of October 10, 2013, and the first patient was enrolled on December 13, 2013. For the global OLE, the ClinicalTrials.gov identifier is NCT02510261 (https://clinicaltrials.gov/ct2/show/NCT02510261) with the registration date of July 29, 2015, and the first patient was enrolled on July 13, 2015. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that treatment with patisiran is safe and efficacious in Taiwanese patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy.

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Increasing evidence suggests that gut microbiota alterations are related to development and phenotypes of many neuropsychiatric diseases. Here, we evaluated the fecal microbiota and its clinical correlates in patients with hereditary transthyretin amyloidosis (ATTRv) and polyneuropathy. Fecal microbiota from 38 ATTRv patients and 39 age-matched controls was analyzed by sequencing 16S V3-V4 ribosomal RNA, and its relationships with clinical characteristics of polyneuropathy and cardiomyopathy were explored. The familial amyloidotic polyneuropathy stage was stage I, II, and III in 13, 18, and 7 patients. 99mTc-PYP SPECT showed a visual score of 2 in 15 and 3 in 21 patients. The gut microbiota of ATTRv patients showed higher alpha diversity (ASV richness and Shannon effective numbers) and dissimilar beta diversity compared to controls. Relative abundance of microbiota was dominated by Firmicutes and decreased in Bacteroidetes in ATTRv patients than in controls. Patients with more myocardial amyloid deposition were associated with increased alpha diversity, and the abundance of Clostridia was significantly correlated with pathophysiology of polyneuropathy in ATTRv patients. These findings demonstrated alterations in the gut microbiota, especially Firmicutes, in ATTRv. The association between altered microbiota and phenotypes of cardiomyopathy and polyneuropathy might suggest potential contributions of gut microbiota to ATTRv pathogenesis.

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INTRODUCTION: Hereditary transthyretin (ATTRv, v for variant) amyloidosis is a rare, progressive, fatal disease with multisystem manifestations, caused by pathogenic variants in the transthyretin (TTR) gene. Vutrisiran, an RNA interference therapeutic that results in rapid TTR knockdown, improved neuropathy and quality of life (QOL) versus external placebo in patients with ATTRv amyloidosis with polyneuropathy in the phase 3 HELIOS-A study (NCT03759379). This post hoc analysis evaluates the impact of baseline neuropathy severity on response to vutrisiran treatment. METHODS: Patients were randomized (3:1) to vutrisiran (n = 122; 25 mg subcutaneous injection once every 3 months) or patisiran (n = 42; 0.3 mg/kg intravenous infusion once every 3 weeks), which served as a reference group. In this post hoc analysis, patients were grouped into quartiles of increasing baseline Neuropathy Impairment Score (NIS): Quartile (Q)1 ≥ 5.0 to ≤ 20.5; Q2 > 20.5 to ≤ 44.1; Q3 > 44.1 to ≤ 73.1; Q4 > 73.1 to ≤ 127.0. Mean change from baseline to Month 18 was summarized by quartile for a range of efficacy endpoints. RESULTS: Across all baseline NIS quartiles, vutrisiran demonstrated benefit versus external placebo in measures of neuropathy severity (modified NIS + 7), QOL (Norfolk Quality of Life-Diabetic Neuropathy), disability (Rasch-built Overall Disability Scale), gait speed (10-m walk test), and nutritional status (modified body mass index). Overall, patients in lower versus higher NIS quartiles (less severe neuropathy) at baseline maintained better scores at Month 18. The external placebo group progressively worsened in all measures at Month 18. CONCLUSIONS: Vutrisiran demonstrated benefit in neurologic function and other key efficacy measures versus external placebo across all four baseline neuropathy severity quartiles. Patients initiating vutrisiran earlier in their disease course retained the highest neurologic function level after 18 months, highlighting the importance of early diagnosis and treatment. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT03759379.

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Label-free imaging methodologies for nerve fibers rely on spatial signal continuity to identify fibers and fail to image free intraepidermal nerve endings (FINEs). Here, we present an imaging methodology-called discontinuity third harmonic generation (THG) microscopy (dTHGM)-that detects three-dimensional discontinuities in THG signals as the contrast. We describe the mechanism and design of dTHGM and apply it to reveal the bead-string characteristics of unmyelinated FINEs. We confirmed the label-free capability of dTHGM through a comparison study with the PGP9.5 immunohistochemical staining slides and a longitudinal spared nerve injury study. An intraepidermal nerve fiber (IENF) index based on a discontinuous-dot-connecting algorithm was developed to facilitate clinical applications of dTHGM. A preliminary clinical study confirmed that the IENF index was highly correlated with skin-biopsy-based IENF density (Pearson's correlation coefficient R = 0.98) and could achieve differential identification of small-fiber neuropathy (p = 0.0102) in patients with diabetic peripheral neuropathy.

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BACKGROUND/PURPOSE: Double-filtration plasmapheresis (DFPP) can be used to remove circulating pathogenic molecules. By reclaiming filtered albumin, DFPP reduces the need for albumin and plasma replacement. Large proteins, such as fibrinogen, are removed. Our institution adopts a DFPP treatment protocol consisting of active surveillance of coagulation profiles and prophylactic supplementation of blood products containing fibrinogen. This study aims to investigate the effects of consecutive DFPP treatments on serial coagulation profiles and the risk of bleeding under this protocol. METHODS: Serial laboratory data and bleeding events at a single tertiary medical center were prospectively collected. Prophylactic transfusion of cryoprecipitate or fresh frozen plasma (FFP) was instituted if significant coagulopathy or a clinically evident bleeding event was observed. RESULTS: After the first treatment session, plasma fibrinogen levels decreased from 332 ± 106 mg/dL to 96 ± 44 mg/dL in the 37 study patients. In the following sessions, plasma fibrinogen levels were maintained at around 100 mg/dL under prophylactic transfusion. No major bleeding events were recorded, but five (14%) patients experienced minor bleeding. CONCLUSION: DFPP treatment might be performed safely along with active monitoring of coagulation profiles and prophylactic transfusion of cryoprecipitate or FFP.

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Background: Transthyretin cardiomyopathy (ATTR-CM) is a debilitating disease that has received much attention since the emergence of novel treatments. The Transthyretin Cardiomyopathy Clinical Trial showed that tafamidis, a transthyretin tetramer stabilizer, effectively reduced the declines in functional capacity and quality of life. However, Ala97Ser (A97S) hereditary ATTR-CM is underrepresented in major ATTR-CM tafamidis trials. Objectives: We aim to investigate the change in global longitudinal strain (GLS) of A97S ATTR-CM patients after 12 months of tafamidis treatment. Methods: We retrospectively analysed a prospective cohort of patients with A97S ATTR-CM who received tafamidis meglumine (61 mg/day) at the National Taiwan University Hospital. Echocardiography with speckle tracking strain analysis was performed at baseline and 12 months after treatment. Results: In all, 20 patients were included in the cohort. The baseline left ventricular ejection fraction (LVEF) and interventricular septum (IVS) thickness were 59.20 ± 13.23% and 15.10 ± 3.43 mm, respectively. After 12 months of tafamidis treatment, the LVEF and IVS were 61.83 ± 15.60% (p = 0.244) and 14.59 ± 3.03 mm (p = 0.623), respectively. GLS significantly improved from -12.70 ± 3.31% to -13.72 ± 3.17% (p = 0.048), and longitudinal strain (LS) in apical and middle segments significantly improved from -16.05 ± 4.82% to -17.95 ± 3.48% (p = 0.039) and -11.89 ± 4.38% to -13.58 ± 3.12% (p = 0.039), respectively. Subgroup analysis showed that patients with LVEF < 50% had a better treatment response and improvement in GLS. The patients with an IVS ⩾ 13 mm had an improvement in two-chamber LS from -10.92 ± 4.25% to -13.15 ± 3.87% (p = 0.042) and an improvement in apical left ventricular LS from -15.30 ± 5.35% to -17.82 ± 3.99% (p = 0.031). Conclusion: Tafamidis significantly improved GLS, and particularly apical and middle LS in A97S ATTR-CM patients.

Tafamidis improves myocardial longitudinal strain in A97S transthyretin cardiac amyloidosis Transthyretin cardiomyopathy (ATTR-CM) is a severe heart condition that has gained attention due to recent advancements in treatments. One of these treatments, called tafamidis, has been shown to be effective in maintaining heart function and quality of life. However, there has been limited research on a specific genetic variation of ATTR-CM: A97S. Our aim was to determine whether A97S ATTR-CM patients experienced improved heart function after one year of tafamidis treatment. We conducted this study at the National Taiwan University Hospital, where we enrolled 20 A97S ATTR-CM patients. We used echocardiography to evaluate their heart function, focusing on a parameter called global longitudinal strain. The results showed that after one year of tafamidis treatment, these patients experienced a significant improvement in their global longitudinal strain, particularly in the apical and middle regions of the heart. In conclusion, tafamidis appears to be beneficial for A97S ATTR-CM patients by enhancing their heart's global longitudinal strain, which is a positive sign for their cardiac health.

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BACKGROUND: Hereditary transthyretin amyloid cardiomyopathy (hATTR-CM) is a progressive and fatal disease. Recent evidence indicates that bone scintigraphy may serve as a tool to monitor the effectiveness of hATTR-CM treatment. The objective of this study was to examine how eplontersen therapy influences the semiquantitative uptake of technetium-99m-pyrophosphate in individuals diagnosed with hATTR-CM. METHODS AND RESULTS: We retrospectively analyzed a prospective cohort from the NEURO-TTRansform trial, including patients with hATTR-CM receiving eplontersen (45 mg/4 weeks). A control group comprised patients with hATTR-CM who had not received eplontersen, inotersen, tafamidis, or patisiran. Technetium-99m-pyrophosphate single-photon emission computed tomography/computed tomography was conducted at baseline and during follow-up. Thirteen patients with hATTR-CM were enrolled, with 6 receiving eplontersen and 7 serving as the control group. The median follow-up time was 544 days. The eplontersen group exhibited a significant decrease in volumetric heart and lung ratio (3.774 to 2.979, P=0.028), whereas the control group showed no significant change (4.079 to 3.915, P=0.237). Patients receiving eplontersen demonstrated a significantly greater reduction in volumetric heart and lung ratio compared with the control group (-20.7% versus -3.4%, P=0.007). CONCLUSIONS: The volumetric heart and lung ratio used to quantify technetium-99m-pyrophosphate uptake showed a significant reduction subsequent to eplontersen treatment in individuals diagnosed with hATTR-CM. These findings suggest the potential efficacy of eplontersen in treating hATTR-CM and highlight the value of technetium-99m-pyrophosphate single-photon emission computed tomography/computed tomography as a tool for monitoring therapeutic effectiveness.

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OBJECTIVE: Despite amyloid deposition as a hallmark of hereditary transthyretin amyloidosis (ATTRv) with polyneuropathy, this pathology could not completely account for nerve degeneration. ATTRv patients frequently have vasomotor symptoms, but microangiopathy hypothesis in ATTRv was not systemically clarified. METHODS: This study examined the vascular pathology of sural nerves in ATTRv patients with transthyretin (TTR) mutation of p.Ala117Ser (TTR-A97S), focusing on morphometry and patterns of molecular expression in relation to nerve degeneration. We further applied human microvascular endothelial cell (HMEC-1) culture to examine the direct effect of TTR-A97S protein on endothelial cells. RESULTS: In ATTRv nerves, there was characteristic microangiopathy compared to controls: increased vessel wall thickness and decreased luminal area; both were correlated with the reduction of myelinated fiber density. Among the components of vascular wall, the area of collagen IV in ATTRv nerves was larger than that of controls. This finding was validated in a cell model of HMEC-1 culture in which the expression of collagen IV was upregulated after exposure to TTR-A97S. Apoptosis contributed to the endothelial cell degeneration of microvasculatures in ATTRv endoneurium. ATTRv showed prothrombotic status with intravascular fibrin deposition, which was correlated with (1) increased tissue factor and coagulation factor XIIIA and (2) reduced tissue plasminogen activator. This cascade led to intravascular thrombin deposition, which was colocalized with upregulated p-selectin and thrombomodulin, accompanied by complement deposition and macrophages infiltration, indicating thromboinflammation in ATTRv. INTERPRETATION: Microangiopathy with thromboinflammation is characteristic of advanced-stage ATTRv nerves, which provides an add-on mechanism and therapeutic target for nerve degeneration.

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Importance: Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis. Objective: To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy. Design, Setting, and Participants: NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR (NCT01737398; March 2013-November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo ("placebo") group. Interventions: Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60). Main Outcomes and Measures: Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, -22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, -4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights. Results: Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was -81.7% with eplontersen and -11.2% with placebo (difference, -70.4% [95% CI, -75.2% to -65.7%]; P < .001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, -24.8 [95% CI, -31.0 to -18.6; P < .001) and for Norfolk QoL-DN (-5.5 vs 14.2; difference, -19.7 [95% CI, -25.6 to -13.8]; P < .001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group. Conclusions and Relevance: In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10.

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BACKGROUND: Transthyretin cardiac cardiomyopathy (ATTR-CM) is a rare but life-threatening disease. Tafamidis is an effective treatment for patients with ATTR-CM, however its long-term effects on cardiac remodeling and cardiac amyloid deposition are unknown. This study aimed to used cardiac magnetic resonance (CMR) to investigate the effects of tafamidis on patients with hereditary A97S ATTR-CM. METHODS: We retrospectively analyzed a prospective cohort of ATTR-CM patients, including 14 with hereditary A97S ATTR-CM and 17 healthy controls with baseline CMR data. All ATTR-CM patients received tafamidis treatment and received CMR with extracellular volume (ECV) at baseline and after 1 year of follow-up. RESULTS: Baseline N-terminal pro-B-type natriuretic peptide, left ventricular (LV) mass, LV ejection fraction, global radial, circumferential and longitudinal strain, T1 mapping and ECV were significantly worse in the patients with ATTR-CM compared with the healthy controls. After 1 year of tafamidis treatment, ECV decreased from 51.5 ± 8.9% to 49.0 ± 9.4% (P = 0.041), however there were no significant changes in LV mass, LV ejection fraction, global radial strain, global circumferential strain, global longitudinal strain and T1 mapping. CONCLUSIONS: After a one-year treatment period, tafamidis exhibited subtle but statistically significant reductions in ECV, potentially indicating a decrease in amyloid deposition among patients diagnosed with hereditary A97S ATTR-CM.

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Background: Hereditary transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal disease. A97S (p.Ala117Ser) is the most common transthyretin genetic mutation in Taiwan. Tafamidis is a transthyretin stabilizer, and it has been shown to improve outcomes. However, its effect on A97S ATTR-CM subtypes remains unknown. Objectives: This study aimed to investigate the efficacy of tafamidis in patients with hereditary A97S ATTR-CM after 6 months of treatment. Methods: We retrospectively analyzed ATTR-CM patients who received tafamidis (61 mg/day) treatment at National Taiwan University Hospital. Functional status, biochemistry and echocardiography were measured at baseline and after 6 months of tafamidis treatment. The outcome measure was to compare the N-terminal pro-brain natriuretic peptide (NT-proBNP) level at baseline and after 6 months of tafamidis treatment. Results: Twenty patients were enrolled in this study. Their mean age was 63.0 ± 5.8 years and 75% were men. The baseline left ventricular (LV) mass index was 200.9 ± 63.9 g/m2, and the baseline LV ejection fraction was 58.9 ± 13.5%. After 6 months of treatment, the log NT-proBNP level significantly improved from 2.9 ± 0.6 to 2.7 ± 0.5 (p = 0.036). Subgroup analysis showed that the LV posterior wall thickness and left atrial diameter were significantly higher in the patients with improved NT-proBNP, suggesting the benefits of tafamidis for ATTR-CM patients with severe cardiac involvement. Conclusions: The patients with hereditary A97S ATTR-CM in this study had decreased levels of NT-proBNP after 6 months of tafamidis treatment, and this reduction was especially pronounced in those with more severe cardiac involvement.

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Background and Objectives: Charcot-Marie-Tooth disease (CMT) is a syndrome of a hereditary neurodegenerative condition affecting the peripheral nervous system and is a single gene disorder. Deep phenotyping coupled with advanced genetic techniques is critical in discovering new genetic defects of rare genetic disorders such as CMT. Methods: We applied multidisciplinary investigations to examine the neurophysiology and nerve pathology in a family that fulfilled the diagnosis of CMT2. When phenotype-guided first-tier genetic tests and whole-exome sequencing did not yield a molecular diagnosis, we conducted full genome analysis by examining phased whole-genome sequencing and whole-genome optical mapping data to search for the causal variation. We then performed a systematic review to compare the reported patients with interstitial microdeletion in the short arm of chromosome 4. Results: In this family with CMT2, we reported the discovery of a heterozygous 85-kb microdeletion in the short arm of chromosome 4 (4p16.3)[NC_000004.12:g.1733926_1819031del] spanning 3 genes [TACC3 (intron 6-exon 16), FGFR3 (total deletion), and LETM1 (intron 10-exon14)] that cosegregated with disease phenotypes in family members. The clinical features of peripheral nerve degeneration in our family are distinct from the well-known 4p microdeletion syndrome of Wolf-Hirschhorn syndrome, in which brain involvement is the major phenotype. Discussion: In summary, we used the full genome analysis approach to discover a new microdeletion in a family with CMT2. The deleted segment contains 3 genes (TACC3, FGFR3, and LETM1) that likely play a role in the pathogenesis of nerve degeneration.

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OBJECTIVE: This study aimed to explore the clinical significance of brain imaging signatures in the context of clinical neurological deficits in association with upper and lower motor neuron degeneration in amyotrophic lateral sclerosis (ALS). METHODS: We performed brain MRI examinations to quantitatively evaluate (1) gray matter volume and (2) white matter tract fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD). Image-derived indices were correlated with (1) global neurological deficits of MRC muscle strength sum score, revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R), and forced vital capacity (FVC), and (2) focal scores of University of Pennsylvania Upper motor neuron score (Penn score) and the summation of compound muscle action potential Z scores (CMAP Z sum score). RESULTS: There were 39 ALS patients and 32 control subjects matched for age and gender. Compared to controls, ALS patients had a lower gray matter volume in the precentral gyrus of the primary motor cortex, which was correlated with FA of corticofugal tracts. The gray matter volume of the precentral gyrus was correlated with FVC, MRC sum score, and CMAP Z sum score, while the FA of the corticospinal tract was linearly associated with CMAP Z sum score and Penn score on multivariate linear regression model. INTERPRETATION: This study indicated that clinical assessment of muscle strength and routine measurements on nerve conduction studies provided surrogate markers of brain structural changes for ALS. Furthermore, these findings suggested parallel involvement of both upper and lower motor neurons in ALS.

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BACKGROUND: Whole-exome sequencing (WES) facilitates the diagnosis of hereditary neuromuscular disorders. To achieve an accurate diagnosis, physicians should interpret the genetic report carefully along with clinical information and examinations. We described our experience with (1) clinical validation in patients with variants found using WES and (2) a diagnostic approach for those with negative findings from WES. METHODS: WES was performed on patients with the clinical impression of hereditary neuromuscular disorders. Information on clinical manifestations, neurological examination, electrodiagnostic studies, histopathology of muscle and nerve, and laboratory tests were collected. RESULTS: Forty-one patients (Male/Female: 18/23, age of onset: 34.5±15.9) accepted WES and were categorized into four scenarios: (1) patients with a positive WES result, (2) patients with an inconclusive WES result but supporting clinical data, (3) negative findings from WES, but a final diagnosis after further work-up, and (4) undetermined etiology from WES and in further work-ups. The yield rate of the initial WES was 63.4% (26/41). Among these, seventeen patients had positive WES result, while the other nine patients had inconclusive WES result but supporting clinical data. Notably, in the fifteen patients with negative findings from WES, four patients (26.7%) achieved a diagnosis after further workup: tumor-induced osteomalacia, metabolic myopathy with pathogenic variants in mitochondrial DNA, microsatellite expansion disease, and vasculitis-related neuropathy. The etiologies remained undetermined in eleven patients (myopathy: 7, neuropathy: 4) after WES and further workup. CONCLUSIONS: It is essential to design genotype-guided molecular studies to correlate the identified variants with their clinical features. For patients who had negative findings from WES, acquired diseases, mitochondrial DNA disorders and microsatellite expansion diseases should be considered.

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