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Dysregulated microglia activation, leading to neuroinflammation, is crucial in neurodegenerative disease development and progression. We constructed an atlas of human brain immune cells by integrating nineteen single-nucleus RNA-seq and single-cell RNA-seq datasets from multiple neurodegenerative conditions, comprising 241 samples from patients with Alzheimer's disease, autism spectrum disorder, epilepsy, multiple sclerosis, Lewy body diseases, COVID-19, and healthy controls. The integrated Human Microglia Atlas (HuMicA) included 90,716 nuclei/cells and revealed nine populations distributed across all conditions. We identified four subtypes of disease-associated microglia and disease-inflammatory macrophages, recently described in mice, and shown here to be prevalent in human tissue. The high versatility of microglia is evident through changes in subset distribution across various pathologies, suggesting their contribution in shaping pathological phenotypes. A GPNMB-high subpopulation was expanded in AD and MS. In situ hybridization corroborated this increase in AD, opening the question on the relevance of this population in other pathologies., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Microglia play a crucial role in a range of neuropathologies through exacerbated activation. Microglial inflammatory responses can be influenced by prior exposures to noxious stimuli, like increased levels of extracellular adenosine and ATP. These are characteristic of brain insults like epileptic seizures and could potentially shape subsequent responses through epigenetic regulation. We investigated DNA methylation and expression changes in human microglia-like cells differentiated from monocytes following ATP-mediated preconditioning. We demonstrate that microglia-like cells display homeostatic microglial features, shown by surface markers, transcriptome, and DNA methylome. After exposure to ATP, TLR-mediated activation leads to an exacerbated pro-inflammatory response. These changes are accompanied by methylation and transcriptional reprogramming associated with enhanced immune-related functions. The reprogramming associated with ATP-mediated preconditioning leads to profiles found in microglial subsets linked to epilepsy. Purine-driven microglia immune preconditioning drives epigenetic and transcriptional changes that could contribute to altered functions of microglia during seizure development and progression., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Background: Apolipoprotein E (ApoE) is the main lipoprotein secreted in brain. It has a critical immunomodulatory function, influences neurotransmission and it is involved in repairing damaged neurons. ApoE e4 is an isoform of ApoE with altered function, and was previously associated with early onset epilepsy and refractoriness, both in animal models and in patients with focal epilepsies. There is a limited knowledge on ApoE's role in Genetic Generalized Epilepsies (GGE). Aim: To determine if ApoE isoforms are risk factors for GGE development. Methods: A group of 337 GGE patients (193 F, 144 M, 33.6 ± 14.2 years) was compared with a group of 342 healthy individuals in a case-control genetic association study. ApoE genotyping was performed using PCR-RFLP. Results: The genotypic frequency of ApoE e3/e2 was lower in GGE patients relative to controls (6.5% in GGE vs. 11.7% in controls, p  = 0.019, OR (95% CI) = 0.53 (0.305-0.905). No associations with other clinical data such as photosensitivity or age at disease onset were observed. Conclusion: Our results show that ApoE e3/e2 genotype may be a protective factor for GGE development. There is evidence that this genotype could be neuroprotective, preventing oxidative damage and promoting neuronal survival. Although replication studies are warranted, our data suggest that ApoE isoforms have a role in epileptogenic mechanisms regardless of the specific epileptic manifestations.

Familial amyloidotic polyneuropathy, ATTRV30M (p. TTRV50M) amyloidosis, is a neurodegenerative disease characterized by systemic extracellular amyloid deposition of a mutant transthyretin, TTR V30M. Anemia, with low erythropoietin (EPO) levels and spared kidney function, affects about 25% of symptomatic patients, suggesting a blockage of EPO-producing cells. Early non-fibrillar TTR aggregates are highly cytotoxic, inducing oxidative stress, the expression of apoptosis-related molecules and secretion of pro-inflammatory cytokines, factors capable of inhibiting EPO production. Low EPO levels in these patients are not related to renal amyloid deposition or the presence of circulating TTR V30M. However, the role of early non-fibrillar TTR aggregates remains unexplored. We used the EPO producing Hep3B human hepatoma cell line to study the effect of TTR oligomeric aggregates on EPO expression. Hep3B cells were incubated with soluble and oligomeric TTR V30M, and cell proliferation as well as caspase 3/7 activation was evaluated. Relative quantification of EPO mRNA transcripts was performed by real-time PCR. Significant reductions in cell viability (13 ± 7.3%) and activation of caspases 3/7 were seen after 24 h in the presence of oligomeric TTR V30M. Also, EPO expression was significantly reduced (50 ± 2.8%), in normoxic conditions. A reporter assay was constructed with a PCR fragment of the EPO promoter linked to the luciferase gene to evaluate the role of transcription factors targeting the promoter. A significant reduction of EPO promoter activity (53 ± 6.5%) was observed in transfected cells exposed to TTR oligomers. Our results show that oligomeric TTR V30M reduces EPO expression, at least in part through inhibition of promoter activity.

Introduction: Behçet's disease (BD) is a multisystem inflammatory disease of unknown etiology that may affect the CNS - Neuro-Behçet (NB). Our aim was to evaluate the frequency of neurological involvement and characterize a cohort of our NB patients., Methods: We retrospectively revised the clinical, laboratory and imaging data of a cohort of BD patients, followed in our hospital outpatient clinic., Results: We identified 138 BD patients. Twenty-five out of 138 had NB (15 female). Four patients presented with neurological symptoms. We identified a total of 37 attacks. Twenty-one attacks were classified as parenchymatous, four non-parenchymatous and 12 as other syndromes. Seventeen patients had CSF analysis performed (20 samples). Five samples were normal, 15 showed CSF pleocytosis. The most frequent finding on MRI performed in the acute phase was extensive lesions involving the brainstem. Two patients died due to the neurological involvement of BD., Conclusion: We found 18.1% prevalence of NB and a higher female-to-male ratio in our group than in other series. Gastrointestinal and vascular involvement was more frequent in the NB group. The fact that neurological involvement may be the first manifestation of BD with therapeutic implications and associated morbidity points out the relevance of an early diagnosis., (© 2015 S. Karger AG, Basel.)

Multiple sclerosis (MS) is a chronic neuroinflammatory autoimmune disease believed to arise from complex interactions of both environmental and genetic factors. As in other complex diseases with autoimmune features, a genetic association with the human leukocyte antigen (HLA) complex is well documented. Association and genome-wide studies were performed in Portuguese patients with MS over several years. Genes such as HLA-DRB1, HLA-A, HFE, TNFA, CTLA-4, PTPN22 and ApoE were investigated. ApoE, PTPN22 1858T, CTLA-4 -318C, TNFA-308A, HFE C282Y and TLR9 T-1237C polymorphisms were not shown to be associated with the development of MS. The HLA-DRB1*15 allele was confirmed as the major genetic marker for susceptibility to MS. The presence of HLA-A*02 and TNFA -238A alleles decreased the risk of developing MS. Patients carrying the HFE C282Y variant seem to have a worse prognosis. The HLA-DRB1*15 and PTPN22 1858T variants were associated with a better outcome in this population.

Background/aim: the kidney is the major site of erythropoietin production. Many efforts have been made to identify renal erythropoietin-producing cells. Previous studies showed conflicting results, but the predominant localization reported was the peritubular interstitial and tubular epithelial cells. This study was conducted to identify the erythropoietin-producing cells in renal biopsies from 10 cadaveric donors and 45 patients with familial amyloidosis ATTR V30M, thirteen of them with anemia. Familial amyloidosis Type I (FAP-I) is a genetic disorder caused by a transthyretin (TTR) protein variant presenting a single amino acid substitution of methionine for valine at position 30 of the polypeptide chain (TTR V30M). Anemia in FAP-I is associated with inappropriately low serum erythropoietin levels., Methods: erythropoietin expression was detected by in situ hybridization (ISH) and confirmed by laser capture microdissection followed by PCR. Renal segments were identified by immunohistochemistry., Results: erythropoietin was mainly expressed by epithelial distal tubular cells and collecting tubules and additionally, in a few biopsies, by glomerular cells. A similar expression pattern was observed in donors and FAP-I patients. No increased mRNA erythropoietin expression was found in anemic patients, all of them presenting only a slight expression in medulla and cortex., Conclusions: these results suggest the distal nephron as the major site of erythropoietin production, and support the notion that an inappropriate erythropoietin production is the cause of anemia in familial amyloidosis ATTR V30M.

Background/Objectives: Neuro-Behçet's disease (NBD) is one of the most severe complications of Behçet's disease (BD). The incidence of NBD varies widely worldwide. This study aimed to estimate its current incidence in Northern Spain. Methods: This was a retrospective population-based cohort study of 120 patients in Northern Spain diagnosed with BD according to the 2013 International Criteria for BD (ICBD) between 1 January 1999 and 31 December 2019. NBD diagnoses were made according to International Consensus Recommendation (ICR) criteria. Overall, 96 patients were included, and their demographic and clinical data were collected. The incidence of NBD was estimated by age, gender, and year of diagnosis between 1999–2019. Results: NBD was diagnosed in 23 of 96 (24%) patients (15 women/8 men) (mean age: 44 ± 13.9 years). HLA-B51 was positive in 5 of 13 (38.4%) cases tested. A total of 10 (43.5%) patients had parenchymatous NBD, 10 (43.5%) had non-parenchymatous NBD, and 3 (13%) had mixed NBD. Incidence during the study period was 0.13 (95% CI, 0.11–0.26) per 100,000 people-years. There were no significant differences in gender in the incidence rate stratified by age (p > 0.05). Furthermore, there was a linear relationship with a mild decrease in age at diagnosis over time. Conclusions: Epidemiological characteristics of NBD in Northern Spain are similar to those of neighboring countries, except female gender predominance. [ABSTRACT FROM AUTHOR]

Autoimmune diseases are generally characterized by a multifactorial etiology and are often associated with a genetic predisposition. Both iron metabolism and the inflammatory cytokine system have been shown to play a pivotal role in the dysregulation of the immune response in many different autoimmune conditions, rheumatologic diseases included. The purpose of this work was to analyze the frequency of mutations altering the expression of IL-6 or influencing iron metabolism in patients affected by autoimmune diseases such as Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). In this study, 144 patients were enrolled: 77 and 67 patients were affected by RA and SLE, respectively. In these cohorts, the frequency of the IL-6 polymorphism −174G>C located in the IL-6 gene promoter was tested. Moreover, the frequencies of the three HFE gene variations associated with iron overload were analyzed: p.His63Asp, p.Ser65Cys and p.Cys282Tyr. The two mutations p.His63Asp and p.Ser65Cys in the HFE gene did not reach statistical significance in any of the comparisons, regardless of the statistical model, cohorts of patients and control populations analyzed. The frequencies of the p.Cys282Tyr mutation and the IL-6 polymorphism −174G>C were found to be overall significantly decreased in RA and SLE patients when the Dominant model and Allele contrast were adopted with both the Odds Ratio and Chi-square. Although further investigation is needed, the examination of the frequencies of the −174G>C IL-6 promoter polymorphism and HFE mutations may add some valuable information on the interplay linking iron metabolism, inflammation and immunity in autoimmune diseases such as SLE and RA. [ABSTRACT FROM AUTHOR]

Vutrisiran and tafamidis are approved therapies for treating hereditary transthyretin-mediated (ATTRv/hATTR) amyloidosis with polyneuropathy, a rapidly progressive and fatal disease. To assist healthcare decision-makers, an indirect treatment comparison (ITC) was undertaken to explore the comparative efficacy of vutrisiran and tafamidis. Individual patient data (vutrisiran vs. placebo) and published results (tafamidis vs. placebo) from phase 3 randomized controlled trials were used in a Bucher analysis to assess differences in treatment effects between vutrisiran and tafamidis on: Neuropathy Impairment Score-Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) score, NIS-LL Response, and modified Body Mass Index (mBMI). Greater treatment effects were observed at 18 months with vutrisiran vs. tafamidis for all endpoints, with statistically significant improvements in polyneuropathy (relative mean change in NIS-LL: −5.3 [95% confidence interval (CI): −9.4, −1.2; p = 0.011]), health-related quality of life (HRQOL, relative mean change in Norfolk QOL-DN: −18.3 [95% CI: −28.6, −8.0; p < 0.001]), and nutritional status (relative mean change in mBMI: 63.9 [95% CI: 10.1, 117.7; p = 0.020]). This analysis suggests vutrisiran has greater efficacy on multiple measures of polyneuropathy impairment and HRQOL compared to tafamidis in patients with ATTRv amyloidosis with polyneuropathy. Hereditary transthyretin-mediated (ATTRv/hATTR) amyloidosis is a rare genetic disease that runs in families, affecting about 50,000 people worldwide. This condition results in abnormal protein deposits building up, causing damage to multiple nerves (polyneuropathy) and other organs, which can shorten lifespan and have other harmful effects. Polyneuropathy symptoms include weakness, numbness, pain, dizziness, and diarrhea. Over time, everyday activities become more difficult as patients become increasingly disabled and dependent on others. Several treatments have been approved for the polyneuropathy of ATTRv amyloidosis. Many of these work in different ways to impact the disease process. An indirect treatment comparison is a well-established statistical method used by healthcare decision-makers to compare treatments when head-to-head trials are unavailable. Indirect treatment comparisons using a common approach, the Bucher method, yield similar conclusions to head-to-head studies over 90% of the time. This method was used to compare clinical trial data for tafamidis and vutrisiran, two approved treatments for ATTRv amyloidosis with polyneuropathy. The findings show that vutrisiran is more effective than tafamidis at addressing the polyneuropathy of ATTRv amyloidosis as measured by changes to sensory or motor nervous system functioning and nutritional status. Also, vutrisiran showed greater maintenance of health-related quality of life compared to tafamidis. The expected benefits of vutrisiran over tafamidis are large enough to be noticeable and clinically meaningful to a patient or clinician. This highlights the potential advantages of vutrisiran compared to tafamidis with regard to preservation of physical function and quality of life when treating ATTRv amyloidosis with polyneuropathy. [ABSTRACT FROM AUTHOR]

Background: Hereditary transthyretin amyloidosis (ATTRv) is an ultra-rare, life-shortening disease with a high unmet need. This study examined ATTRv caregiver health-related quality of life (HRQoL) and productivity. Methods: A cross-sectional online survey, including EQ-5D-3L, Hospital anxiety and depression scale (HADS), and caregiver and patient characteristics questions, was developed to assess ATTRv caregiver burden. A companion general population survey collected EQ-5D-3L, HADS and chronic health conditions data. Caregiver-control group differences in HRQoL were assessed using t-tests and chi-square tests. Ordinary Least Squares regression was used to estimate the disutility of being a caregiver compared to controls stratified by patient ambulatory status. Results: Thirty-six caregivers and matched controls completed the survey (n = 72). The disease severity of patients they cared for was varied: 33% required no assistance walking, 58% required assistance with walking and 9% required a wheelchair/were bedridden. On average, caregivers spent 6 h daily on practical care and 4 h daily on emotional support. Fifty-six percent indicated that they had changed their employment due to providing ATTRv care. Caregivers reported lower HRQoL, as indicated by lower EQ-5D 3L utility scores (M = 0.772, SD = 0.178 vs. M = 0.849, SD = 0.218) and higher HADS anxiety (9.3 vs. 6.1, p < 0.01) and depression (7.6 vs. 4.4, p < 0.01) scores, compared with matched controls. Caregivers were also more likely to report sleep problems (33% vs. 8%, p < 0.01) and stress (42% vs. 0%, p < 0.001) as chronic conditions than controls. Conclusions: The study results indicate that caring for a person with ATTRv can have a considerable negative impact on caregivers' HRQoL and productivity. The study findings provide important information for economic evaluations of ATTRv treatments. [ABSTRACT FROM AUTHOR]

Hereditary transthyretin amyloidosis (ATTRv) is endemic in northern Sweden (Västerbotten). The awareness of ATTRv amyloidosis is lower in Stockholm, a non-endemic region in Sweden. The aim of this study was to compare the possible differences in diagnostic delay, disease phenotypes, treatment and survival between a non-endemic and an endemic region in Sweden. The in- and outpatient diagnosis registry at the Department of Neurology at Karolinska University Hospital and the Amyloidosis Centre at University Hospital of Umeå were used to identify patients between January 2006 and November 2017. In total, 21 patients in Stockholm and 134 patients in Västerbotten were included. The time between symptom onset to time-point of diagnosis was significantly longer in Stockholm vs Västerbotten. This corresponded to a longer median time between first visit at amyloidosis centre to time-point of diagnosis in Stockholm vs in Västerbotten. The most common reason for a diagnostic delay was negative tissue biopsies. There was a diagnostic-, but no patient-delay in non-endemic Stockholm vs endemic Västerbotten. Despite a more severe neuropathic phenotype in Stockholm at the onset, the systemic affection over the course of disease and of survival seems not to be influenced by the diagnosis delay in Stockholm. [ABSTRACT FROM AUTHOR]

Hereditary Amyloidosis associated with variant Transthyretin (ATTRv Amyloidosis) is a progressive and highly disabling neurological disorder that affects gait. Quantitative motion analysis is useful for assessing motor function, including gait, in diseases affecting movement. A single markerless RGB-D camera enables 3D full-body motion capture in a less expensive and intrusive, and more portable way than multi-camera marker-based systems. In this study, we examine whether a gait analysis system based on an RGB-D camera can be used to detect significant changes in the gait of ATTRv amyloidosis patients over time, when compared with a 12-camera system. We acquired 3D data provided by both systems from six ATTRv amyloidosis patients, while performing a simple gait task, once (T0) and 18 months later (T1). A direct comparison of systems has already been conducted. In this work, however, for each patient, we investigated if the RGB-D camera system detects statistically significant differences between the two different acquisitions in a similar way to the reference system, and whether it is reliable to use during patients' follow-up. The obtained results show that the differences detected between T0 and T1 for both systems follow the same tendency for 65% of the spatiotemporal gait parameters, and for 38% of the kinematic parameters (38%). The most reliable parameters were: stride duration/length, gait speed (and its variability), and arm/foot swing velocity, all with an almost perfect strength of agreement. [ABSTRACT FROM AUTHOR]

Hereditary amyloidosis associated with transthyretin (ATTRv), is a rare autosomal dominant disease characterized by length-dependent symmetric polyneuropathy that has gait impairment as one of its consequences. The gait pattern of V30M ATTRv amyloidosis patients has been described as similar to that of diabetic neuropathy, associated with steppage, but has never been quantitatively characterized. In this study we aim to characterize the gait pattern of patients with V30M ATTRv amyloidosis, thus providing information for a better understanding and potential for supporting diagnosis and disease progression evaluation. We present a case series in which we conducted two gait analyses, 18 months apart, of five V30M ATTRv amyloidosis patients using a 12-camera, marker based, optical system as well as six force platforms. Linear kinematics, ground reaction forces, and angular kinematics results are analyzed for all patients. All patients, except one, showed a delayed toe-off in the second assessment, as well as excessive pelvic rotation, hip extension and external transverse rotation and knee flexion (in stance and swing phases), along with reduced vertical and mediolateral ground reaction forces. The described gait anomalies are not clinically quantified; thus, gait analysis may contribute to the assessment of possible disease progression along with the clinical evaluation. [ABSTRACT FROM AUTHOR]

Background and purpose: This study was undertaken to assess skin biopsy as a marker of disease onset and severity in hereditary transthyretin amyloidosis with polyneuropathy (ATTRv‐PN), a treatable disease. Methods: In this single center retrospective study, skin Congo red staining and intraepidermal nerve fiber density (IENFD) were evaluated in symptomatic ATTRv‐PN patients and asymptomatic TTR gene mutation carriers between 2012 and 2019. Non‐ATTRv subjects with suspected small fiber neuropathy who underwent skin biopsy during the same timespan were used as controls. Results: One hundred eighty‐three symptomatic ATTRv‐PN patients, 36 asymptomatic carriers, and 537 non‐ATTRv patients were included. Skin biopsy demonstrated amyloid depositions in 80% of the 183 symptomatic cases. Skin amyloid deposits were found in 75% of early stage ATTRv‐PN patients, and in 14% of asymptomatic carriers. All 183 symptomatic and 34 of 36 asymptomatic patients displayed decreased ankle IENFD with a proximal–distal gradient distribution, and reduced IEFND correlated with disease severity and duration. Conclusions: Our study demonstrates skin amyloid deposits are a marker of ATTRv‐PN disease onset, and decreased IENFD a marker of disease progression. These results are of major importance for the early identification of ATTRv‐PN patients in need of disease‐modifying treatments. [ABSTRACT FROM AUTHOR]

Aim: Study of intraepidermal nerve fiber density (IENFD) by skin biopsy represents a promising tool in the evaluation of patients with ATTRv polyneuropathy (ATTRv-PN). Herein, we retrospectively analyze intraepidermal innervation and quantitative sensory test (QST) data from an Italian cohort of Italian ATTRv-PN patients and asymptomatic carriers aimed to provide insights into early nerve pathological and functional changes in this disease.Methods: IENFD and QST data of 14 ATTRv-PN patients and 14 asymptomatic carriers were retrospectively analyzed together with clinical and paraclinical data such as disease stage and severity, neuropathic pain scales, and sural SNAP amplitude.Results: Given an estimated time to the predicted age of onset of symptomatic disease of 20.27 + / - 7.9 years, small nerve fiber loss seems to be unexpectedly early in carriers. Moreover, carriers showed skin denervation at the proximal (thigh) site, suggesting a non-length-dependent neuropathic process. IENFD at ankle correlated with disease severity and other paraclinical variables such as sural nerve potential amplitude and QST parameters. Patients at earlier stages of the disease did not show significant differences in ankle IENFD compared with asymptomatic carriers, but significant differences in terms of QST parameters, small fiber neuropathy symptoms, and neuropathic pain.Conclusions: Skin biopsy can disclose an early non-length-dependent small fiber loss in ATTRv-PN and, together with QST, could provide a useful insight disease onset and progression. [ABSTRACT FROM AUTHOR]

B P453 b Chognot, C. P724 Choi, J. P350 Chomyk, A. B 175 b , P391 Chou, S. B P133 b Chouteau, R. P968 Chretien, N. P391 Christie, E. 175, P391 Christodoulou, C. P353, P985 Chu, L. B P078 b Chu, R. P441, P539 Chua, S. P148 Chun, J. B P712 b , P716 Chung, K.K. P456 Chung, Y.H. 064 Bjørnerud, A. P437 Bjornevik, K. 056, B P378 b Bjørnevik, K. P138 Black, L. P149 Blackburn, K. P987 Blagitko-Dorfs, N. P791 Blagotinsek Osep, A. P698 Blanchard, O. P057 Blanche, J. P541 Blanchette, F. P281 Blanck, R. P640 Blanco, Y. P463, P549, P647, P653, P800 Blandford, S.N. [Extracted from the article]

Transthyretin-associated familial amyloid polyneuropathy (TTR-FAP) is an unusual but life-threatening disease that is autosomal dominant inherited and involves the mutation of the transthyretin (TTR) gene. A total of 26 patients with TTR-FAP and different mutations, including the p.Glu 109Gln mutation (previously annotated p. Glu89Gln), were previously reported in Turkey. Herein, we reported two patients from the same family who had the same p.Glu 109Gln mutation but had different clinical phenotypes. The clinical picture mainly involved polyneuropathy in one patient and cardiac involvement in the other patient. This case report mentions that TTR-FAP can cause different clinical phenotypes, even due to the same mutation and even in the same family. [ABSTRACT FROM AUTHOR]

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a rare form of treatable severe progressive sensory-motor and autonomic polyneuropathy. Albeit usually axonal, late-onset ATTRv-PN can show clear demyelinating features at electrodiagnostic studies, sometimes fulfilling CIDP diagnostic criteria. High-resolution nerve ultrasonography (HRUS) is an emerging useful supportive tool in the diagnosis of CIDP. Herein, we present a late-onset ATTRv-PN patient in which both clinical-neurophysiological and HRUS features could have led to a CIDP misdiagnosis. Nerve alterations at HRUS and MRI have already been reported in ATTRv-PN, albeit not in ATTRv-PN patients with clinical and electrodiagnostic features of CIDP. Our case shows that ATTRv-PN could present the same morphological nerve alterations pattern of CIDP at ultrasonography, adding HRUS findings as a further source of misdiagnosis late-onset ATTRv-PN. [ABSTRACT FROM AUTHOR]

Background: Hereditary Transthyretin Amyloidosis Polyneuropathy is a rare life-threatening neurologic disease that imposes considerable mortality and it is associated with progressive related disabilities. In this study, we aimed to assess the effect of the disease across health-related quality of life dimensions, in both carriers of the mutation and patients, to compare health-related quality of life with general population, as well as to explore health-related quality of life prognostic factors among patients, including disease progression and treatment.Methods: This study was a multi-institutional, longitudinal, prospective, observational study of hereditary Transthyretin Amyloidosis Polyneuropathy Portuguese adult subjects (621 asymptomatic carriers and 733 symptomatic patients) enrolled in the Transthyretin Amyloidosis Outcomes Survey. Health-related quality of life was captured with the preference-based instrument EQ-5D-3 L. For general population the dataset included all subjects enrolled in a representative national study (n = 1500). Different econometric models were specified; multivariate probit, generalized linear model and generalized estimating equations model; including demographic and clinical covariates.Results: Hereditary Transthyretin Amyloidosis Polyneuropathy patients have their health status severely impaired in all quality of life dimensions and more anxiety/depression problems were found among asymptomatic carriers. No differences on utility were found between carriers and general population (p = 0.209). Among patients, the utility value is estimated to be 0.51 (0.021), a decrement of 0.27 as compared with general population utility. Higher disease duration, advanced disease stage and not receiving treatment are associated with impaired health-related quality of life. No differences were found between genders (p = 0.910) or between late (≥50 years) and early-onset patients (p = 0.254). The utility estimate ranged from 0.63 (0.009) in stage I to 0.01 (0.005) in stage IV.Conclusions: Hereditary Transthyretin Amyloidosis Polyneuropathy symptoms and progressive associated disabilities substantially decrease patient's health-related quality of life. Clinical strategies focused on health-related quality of life preservation such as close follow-up of asymptomatic carriers, prompt diagnosis and adequate, early treatment would benefit patient's long-term outcomes, slowing the progressive decline in health-related quality of life. [ABSTRACT FROM AUTHOR]

Hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (formerly known as Familial Amyloid Polyneuropathy) is a rare disease due to mutations in the gene encoding transthyretin (TTR) and characterized by multisystem extracellular deposition of amyloid, leading to dysfunction of different organs and tissues. hATTR amyloidosis represents a diagnostic challenge for neurologists considering the great variability in clinical presentation and multiorgan involvement. Generally, patients present with polyneuropathy, but clinicians should consider the frequent cardiac, ocular and renal impairment. Especially a hypertrophic cardiomyopathy, even if usually latent, is identifiable in at least 50% of the patients. Therapeutically, current available options act at different stages of TTR production, including synthesis inhibition (liver transplantation and/or gene-silencing drugs) or tetramer TTR stabilization (TTR stabilizers), increasing survival at different disease stages. [ABSTRACT FROM AUTHOR]

Monogenic autoinflammatory diseases (mAIDs) are inherited errors of innate immunity characterized by systemic inflammation recurring with variable frequency and involving the skin, serosal membranes, synovial membranes, joints, the gastrointestinal tube, and/or the central nervous system, with reactive amyloidosis as a potential severe long-term consequence. Although individually uncommon, all mAIDs set up an emerging chapter of internal medicine: recent findings have modified our knowledge regarding mAID pathophysiology and clarified that protean inflammatory symptoms can be variably associated with periodic fevers, depicting multiple specific conditions which usually start in childhood, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndrome, and mevalonate kinase deficiency. There are no evidence-based studies to establish which potential genotype analysis is the most appropriate in adult patients with clinical phenotypes suggestive of mAIDs. This review discusses genetic and clinical hints for an ideal diagnostic approach to mAIDs in adult patients, as their early identification is essential to prompt effective treatment and improve quality of life, and also highlights the most recent developments in the diagnostic work-up for the most frequent hereditary periodic febrile syndromes worldwide. [ABSTRACT FROM AUTHOR]

Background: Permanent primary congenital hypothyroidism (CH) can be caused by thyroid dysgenesis or dyshormonogenesis. A molecular genetic study is recommended in dyshormonogenesis, in syndromic hypothyroidism and when there is a family history of CH. The aim of this study was to identify a monogenic etiology for CH in selected individuals from a cohort of primary permanent CH. Methods: From an initial cohort of 79 patients with permanent CH (3–19 years), 11 patients were selected for molecular analyses. Nine patients with dyshormonogenesis (normal in-situ gland or goiter) were screened for causative variants, by next-generation sequencing (NGS), in 28 genes known to be responsible for CH. One patient with a family history of CH was screened for the paired-box gene 8 (PAX8) gene and another patient with a syndromic CH was screened for the NKX2-1 gene. Results: We found a monogenic basis of disease in eight patients, involving the thyroid peroxidase (TPO) gene (four patients), the thyroglobulin (TG) gene (two patients), and the PAX8 and NKX2-1 genes (one patient each). Two patients were heterozygotes, one harboring a variant in the TG gene and the other in the SLC5A5 gene. In one patient, we found no potential causative variants in any of the 28 genes screened. We described five novel variants: three in the TG gene, one in the NKX2-1 and one in the SLC5A5 gene, all of them classified as pathogenic. Conclusions: In eight of the 11 screened patients, a monogenic disease was found. These results highlight the advantage of using an NGS panel and provide further data regarding the molecular basis of CH. [ABSTRACT FROM AUTHOR]

Purpose: Autonomic dysfunction is a very common, early and distressing aspect of hereditary transthyretin (ATTR) amyloidosis leading to significant loss of quality of life and morbidity for patients. Although the clinical variability of ATTR has been well characterized as neuropathic, cardiac or mixed phenotype, the extent of autonomic involvement remains poorly understood. Despite the fact that the autonomic nervous system has not been specifically evaluated in any of the clinical trials of tafamidis, and that, for some primary and secondary endpoints used in these trials, the behavior cannot be separated from non-autonomic items, an attempt was made to use published material to indirectly access the efficacy of tafamidis in treating dysautonomia. Methods: Literature review summarizing the results of primary and secondary endpoints related to the autonomic features used in the original tafamidis trials, the post hoc publications, and real-world data, on the effect of tafamidis on autonomic dysfunction in patients with ATTR amyloidosis. Results: There is some evidence that indirectly demonstrates that tafamidis is safe and could slow or arrest the progression of autonomic neuropathy in patients with ATTR amyloidosis, in addition to its well-described effects to ameliorate sensory-motor peripheral neuropathy. Conclusion: Although the current evidence is scarce, tafamidis might be effective in arresting the progression of autonomic neuropathy in patients with ATTR amyloidosis. Tafamidis might be more effective at the early stage of the disease; however, individual responses must be monitored. [ABSTRACT FROM AUTHOR]

Background: Familial amyloid polyneuropathy (FAP) or ATTRv (amyloid TTR variant) amyloidosis is a fatal hereditary disease characterized by the deposition of amyloid fibrils composed of transthyretin (TTR). The current diagnosis of ATTRv relies on genetic identification of TTR mutations and on Congo Red-positive amyloid deposits, which are absent in most ATTRv patients that are asymptomatic or early symptomatic, supporting the need for novel biomarkers to identify patients in earlier disease phases allowing disease control.Methods: In an effort to search for new markers for ATTRv, our group searched for nine inflammation markers in ATTRv serum from a cohort of 28 Brazilian ATTRv patients.Results: We found that the levels of six markers were increased (TNF-α, IL-1β, IL-8, IL-33, IFN-β and IL-10), one had decreased levels (IL-12) and two of them were unchanged (IL-6 and cortisol). Interestingly, asymptomatic patients already presented high levels of IL-33, IL-1β and IL-10, suggesting that inflammation may take place before fibril deposition.Conclusions: Our findings shed light on a new, previously unidentified aspect of ATTRv, which might help define new criteria for disease management, as well as provide additional understanding of ATTRv aggressiveness. [ABSTRACT FROM AUTHOR]

Background: Phenylketonuria (PKU) management practices differ between and within countries. In 2007, the Portuguese Society for Metabolic Disorders (SPDM) approved the Portuguese Consensus (PC) for the nutritional treatment of PKU. The recently published European PKU Guidelines (EPG, 2017) systematically reviewed recent evidence and aimed to harmonise treatment protocols in Europe. The objective of this study was to appraise the EPG acceptance and implementation in Portuguese treatment centres. Methods: An electronic questionnaire was prepared and the link was sent to 135 SPDM members. It outlined the 10 EPG key recommendations and compared each statement with the consensus recommendations published by SPDM. Responses were recorded and descriptive analyses were performed. Results: Twenty-five professionals completed the questionnaire, and over half (56%) were nutritionists/dieticians. At least one questionnaire from each of the 10 national treatment centres was returned. In general, responders accepted most of the recommendations. However, only the recommendation about target phenylalanine (Phe) concentrations between 120 and 360 μmol/L for patients <12 years received 100% consensus with a further seven recommendations gaining over 70% consensus. Almost half of the professionals (48%, n = 12) required further discussion about the EPG-safe upper target blood Phe concentration (600 μmol/L) suggested for patients aged ≥12 years. Almost one third (32%, n = 8) failed to agree with the recommendation in the EPG-proposed classification of Phe hydroxylase (PAH) deficiency. Conclusions: The EPG received overall good acceptance, but there was divided opinion about some recommendations which require further discussion before implementation by the Portuguese treatment centres. [ABSTRACT FROM AUTHOR]

Aims: Cardiac amyloidosis remains a great challenge for the cardiologist. One of the three main aetiological forms, transthyretin-related hereditary amyloidosis (ATTRm), can present with several phenotypes, depending mainly on the specific mutation. We aimed to characterize the phenotype of patients with ATTRm due to Ile68Leu mutation, comparing them to patients with wild-type transthyretin amyloidosis (ATTRwt).Methods and Results: Data of 67 Ile68Leu ATTRm patients from two Italian referral centres (Bologna and Florence) were retrospectively analysed and compared to those of 82 ATTRwt patients. Fifty-five unaffected mutation carriers were also analysed. Cumulative disease onset was 50% at age 71. A total of 56/67 (84%) patients had a predominantly cardiac phenotype at presentation with concentric increase in left ventricular wall thickness [median 17 mm], and normal or near normal left ventricular ejection fraction (79% of patients). Low QRS voltages were present only in 29% of patients but voltage/mass ratio was low (0.5). Carpal tunnel syndrome was noted in 43%. The overall phenotypic profile was similar to ATTRwt but Ile68Leu ATTRm patients typically presented younger (median 71 vs. 78 years) and were more likely to have (mild) symptomatic neurological involvement (19% vs. 2%). Male prevalence was 44% in unaffected mutation carriers and 78% in affected patients. Age-adjusted survival was comparable between groups.Conclusions: Ile68Leu ATTRm is a cause of familial amyloidotic cardiomyopathy endemic in central-northern Italy and presents as hypertrophic/restrictive cardiomyopathy quite similar to ATTRwt. Male preponderance is present in affected patients but not in unaffected mutation carriers. Age-adjusted survival is similar to ATTRwt. [ABSTRACT FROM AUTHOR]

Background:The objective of the present study was to evaluate the long-term safety and efficacy of tafamidis in treating hereditary transthyretin amyloid polyneuropathy. Methods:A prospectively planned interim analysis was conducted on an on-going, phase III, open-label extension study following an 18-month, randomized, controlled study and 12-month, open-label extension study in ATTRV30M patients and a single-arm, open-label study in non-ATTRV30M patients. Thirty-seven ATTRV30M patients received placebo for 18 months, then switched to tafamidis and 38 ATTRV30M patients and 18 non-ATTRV30M patients continuously received tafamidis from day 1, up to 6 years. Results:Long-term tafamidis was associated with a favourable safety/tolerability profile, without any unexpected adverse events. Patients initiating tafamidis at the start of the randomized study had less polyneuropathy progression versus those switching to tafamidis following 18 months of placebo and were less likely to progress to the next ambulatory stage after up to 6 years follow-up. In the patients who switched from placebo to tafamidis, polyneuropathy progression and deterioration in quality of life slowed significantly during long-term tafamidis treatment as compared with the previous placebo treatment. In non-ATTRV30M patients, some polyneuropathy progression was observed across all efficacy measures. Conclusions:These data provide evidence for the long-term (up to 6 years) safety and efficacy of tafamidis.ClinicalTrials.gov:NCT00925002 [ABSTRACT FROM AUTHOR]

Hereditary (familial) amyloid polyneuropathy (FAP) is a systemic disease that includes a sensorimotor polyneuropathy related to transthyretin (TTR) mutations. So far, a scale designed to classify the severity of this disease has not yet been validated. This work proposes the implementation of an artificial neural network (ANN) in order to develop a severity scale for monitoring the disease progression in FAP patients. In order to achieve this goal, relevant symptoms and laboratory findings were collected from 98 Brazilian patients included in THAOS – the Transthyretin Amyloidosis Outcomes Survey. Ninety-three percent of them boreVal30Met, the most prevalent variant of TTR worldwide; 63 were symptomatic and 35 were asymptomatic. These data were numerically codified for the purpose of constructing a Self-Organizing Map (SOM), which maps data onto a grid of artificial neurons. Mapped data could be clustered by similarity into five groups, based on increasing FAP severity (from Groups 1 to 5). Most symptoms were virtually absent from patients who mapped to Group 1, which also includes the asymptomatic patients. Group 2 encompasses the patients bearing symptoms considered to be initial markers of FAP, such as first signs of walking disabilities and lack of sensitivity to temperature and pain. Interestingly, the patients with cardiac symptoms, which also carry cardiac-associated mutations of the TTR gene (such asVal112IleandAla19Asp), were concentrated in Group 3. Symptoms such as urinary and fecal incontinence and diarrhea characterized particularly Groups 4 and 5. Renal impairment was found almost exclusively in Group 5. Model validation was accomplished by considering the symptoms from a sample with 48 additional Brazilian patients. The severity scores proposed here not only identify the current stage of a patient’s disease but also offer to the physician an easy-to-read, 2D map that makes it possible to track disease progression. [ABSTRACT FROM AUTHOR]

Introduction: This observational, cross-sectional, single-center study aimed to identify instruments capable of measuring disease progression in transthyretin familial amyloid polyneuropathy (TTR-FAP).Methods: The relationship between disease stage and Neuropathy Impairment Score-Lower Limbs (NIS-LL) and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score was assessed in 61 (stages 1-3) patients with TTR-FAP (V30M variant) and 16 healthy controls. Composite measures of large- and small-nerve fiber function, and modified body mass index (mBMI) were also assessed.Results: Ordinal-based NIS-LL and Norfolk QOL-DN scores discriminated between disease stages (P < 0.0001 for NIS-LL and Norfolk QOL-DN). Longer disease duration correlated with worse NIS-LL and Norfolk QOL-DN. Karnofsky performance score declined progressively by disease stage. Composite measures of nerve fiber function differentiated stage 1 from stage 2 disease. The mBMI declined with advancing disease.Conclusions: NIS-LL, Norfolk QOL-DN score, composite endpoints of nerve fiber function, and mBMI are valid, reliable measures of TTR-FAP severity. Muscle Nerve 55: 323-332, 2017. [ABSTRACT FROM AUTHOR]

Background: Peptidylarginine deiminase (PAD) catalyzes the conversion of arginine residues to citrulline residues, termed citrullination. Recent studies have suggested that PAD isoform 2 (PADI2) plays an important role in tumors, although its tumorigenic effect and mechanism are largely unknown. Materials and methods: Immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) were used to investigate the expression level of PADI2 in various tumor tissues and patient blood samples, respectively. MNK-45 and Bel-7402 tumor cell lines originating from gastric and liver tumors, respectively, were treated with anti-PADI2 siRNA, and the subsequent cell proliferation, apoptosis and migration were observed. Polymerase chain reaction (PCR) arrays, including Cancer PathwayFinder, Oncogenes and Tumor Suppressor Genes, p53 Signaling Pathway, Signal Transduction Pathway and Tumor Metastasis PCR arrays, were used to investigate the tumorigenic pathway of PADI2 in the siRNA-treated tumor cells. This analysis was verified by real-time PCR. Results: Immunohistochemistry detected significantly increased expression of PADI2 in invasive breast ductal carcinoma, cervical squamous cell carcinoma, colon adenocarcinoma, liver hepatocellular carcinoma, lung cancer, ovarian serous papillary adenocarcinoma and papillary thyroid carcinoma samples. ELISA detected a twofold increase in PADI2 expression in the blood of 48.3% of patients with liver cancer, 38% of patients with cervical carcinoma and 32% of patients with gastric carcinoma. Increased apoptosis and decreased cell proliferation and migration were observed in the anti-PADI2 siRNA-treated MNK-45 cells, and increased cell proliferation and migration and decreased apoptosis were observed in the treated Bel-7402 cells with suppressed PADI2 expression. PCR arrays and real-time PCR detected significantly decreased CXCR2 and EPO expression in the MNK-45 cells and Bel-7402 cells, respectively, with the anti-PADI2 siRNA treatments. Conclusion: PADI2 expression is increased in many types of tumor tissues and patient blood samples. PADI2 may advance abnormal cell behavior in gastric cancers by mediating CXCR2, a well-known gene that stimulates cell proliferation and invasion. However, PADI2 might have deleterious effects on tumor growth and metastasis in liver tumor cells by regulating the expression of EPO, a gene with controversial functions in tumor growth. The results suggest that the effect of PADI2 on tumorigenesis is multifactorial, depending on the tumor type. [ABSTRACT FROM AUTHOR]

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Transthyretin hereditary amyloid polyneuropathy, also traditionally known as transthyretin familial amyloid polyneuropathy (ATTR-FAP), is a rare, relentless, fatal hereditary disorder. Tafamidis, an oral, non-NSAID, highly specific transthyretin stabilizer, demonstrated safety and efficacy in slowing neuropathy progression in early-stage ATTRV30M-FAP in a 1.5-year, randomized, double-blind, placebo-controlled trial, and 1-year open-label extension study, with a second long-term open-label extension study ongoing. Subgroup analysis of the effectiveness of tafamidis in the pivotal study and its open-label extensions revealed a relatively cohesive cohort of patients with mild neuropathy (i.e. Neuropathy Impairment Score for Lower Limbs [NIS-LL] ≤ 10) at the start of active treatment. Early treatment with tafamidis for up to 5.5 years (≥1 dose of tafamidis meglumine 20 mg once daily during the original trial or after switching from placebo in its extension) resulted in sustained delay in neurologic progression and long-term preservation of nutritional status in this cohort. Mean (95% CI) changes from baseline in NIS-LL and mBMI were 5.3 (1.6, 9.1) points and −7.8 (−44.3, 28.8) kg/m2× g/L at 5.5 years, respectively. No new safety issues or side effects were identified. These data represent the longest prospective evaluation of tafamidis to date, confirm a favorable safety profile, and underscore the long-term benefits of early intervention with tafamidis. Trial Registration:ClincalTrials.gov Identifier: NCT00409175, NCT00791492, and NCT00925002. [ABSTRACT FROM AUTHOR]

Background: Hereditary transthyretin amyloidosis (ATTR) is usually characterised by a progressive peripheral and autonomic neuropathy often with associated cardiac failure and is due to dominantly inherited transthyretin mutations causing accelerated amyloid deposition. The UK population is unique in that the majority of patients have the T60A missense mutation in ATTR where tyrosine is replaced by adenine at position 60. This has been traced to a single founder mutation from north-west Ireland. The neuropathy phenotype is less well described than the cardiac manifestations in this group.Methods: We present the findings from an observational cohort study of patients with ATTR attending the National Hospital Inherited Neuropathy Clinic between 2009 and 2013. Detailed clinical neurological and electrophysiological data were collected on all patients alongside correlating autonomic and cardiac assessments. Follow-up data were available on a subset.Results: Forty-four patients with genetically confirmed ATTR were assessed; 37 were symptomatic; mean age at onset=62 years, range=38-75 years; 75.7% male. T60A was the most common mutation (17/37), followed by V30M (5/37). A severe, rapidly progressive, predominantly length dependent axonal sensorimotor neuropathy was the predominant phenotype. T60A patients were distinguished by earlier and more frequent association with carpal tunnel syndrome; a predominance of negative sensory symptoms at onset; significant vibration deficits; and a non-length dependent progression of motor deficit. Progression of the neuropathy was observed over a relatively short follow-up period (2 years) in 20 patients with evidence of clinically measurable annual change in Medical Research Council (MRC) sum score (-1.5 points per year) and Charcot Marie Tooth Neuropathy Score (CMTNS:2.7 points per year), and a congruent trend in the electrophysiological measures used.Conclusion: The description of the ATTR neuropathy phenotype, especially in the T60A patients, should aid early diagnosis as well as contribute to the understanding of its natural history. [ABSTRACT FROM AUTHOR]

Tafamidis is a transthyretin (TTR) stabilizer able to prevent TTR tetramer dissociation. There have been a few encouraging studies on Tafamidis efficacy in early-onset inherited transthyretin amyloidosis (ATTR) due to Val30Met mutation. However, less is known about its efficacy in later disease stages and in non-Val30Met mutations. We performed a multi-center observational study on symptomatic ATTR patients prescribed to receive Tafamidis. We followed up patients according to a standardized protocol including general medical, cardiological and neurological assessments at baseline and every 6 months up to 3 years. Sixty-one (42 males) patients were recruited. Only 28 % of enrolled subjects had the common Val30Met mutation, mean age of onset was remarkably late (59 years) and 18 % was in advanced disease stage at study entry. Tafamidis proved safe and well-tolerated. One-third of patients did not show significant progression along 36 months, independently from mutation type and disease stage. Neurological function worsened particularly in the first 6 months but progression slowed significantly thereafter. Autonomic function remained stable in 33 %, worsened in 56 % and improved in 10 %. Fifteen percent of patients showed cardiac disease progression and 30 % new onset of cardiomyopathy. Overall, Tafamidis was not able to prevent functional progression of the disease in 23 (43 %) subjects, including 16 patients who worsened in their walking ability and 12 patients who reached a higher NYHA score during the follow-up period. A higher mBMI at baseline was associated with better preservation of neurological function. In conclusion, neuropathy and cardiomyopathy progressed in a significant proportion of patients despite treatment. However, worsening of neurological function slowed after the first 6 months and also subjects with more advanced neuropathy, as well as patients with non-Val30Met mutation, benefited from treatment. Body weight preservation is an important favorable prognostic factor. [ABSTRACT FROM AUTHOR]

Amyloid formation of the human plasma protein transthyretin (TTR) is associated with several human disorders, including familial amyloidotic polyneuropathy (FAP) and senile systemic amyloidosis. Dissociation of TTR’s native tetrameric assembly is the rate-limiting step in the conversion into amyloid, and this feature presents an avenue for intervention because binding of an appropriate ligand to the thyroxin hormone binding sites of TTR stabilizes the native tetrameric assembly and impairs conversion into amyloid. The desired features for an effective TTR stabilizer include high affinity for TTR, high selectivity in the presence of other proteins, no adverse side effects at the effective concentrations, and a long half-life in the body. In this study we show that the commonly used flame retardant tetrabromobisphenol A (TBBPA) efficiently stabilizes the tetrameric structure of TTR. The X-ray crystal structure shows TBBPA binding in the thyroxine binding pocket with bromines occupying two of the three halogen binding sites. Interestingly, TBBPA binds TTR with an extremely high selectivity in human plasma, and the effect is equal to the recently approved drug tafamidis and better than diflunisal, both of which have shown therapeutic effects against FAP. TBBPA consequently present an interesting scaffold for drug design. Its absorption, metabolism, and potential side-effects are discussed. [ABSTRACT FROM AUTHOR]