DAG1 haploinsufficiency is associated with sporadic and familial isolated or pauci-symptomatic hyperCKemia.

DAG1 encodes for dystroglycan, a key component of the dystrophin-glycoprotein complex (DGC) with a pivotal role in skeletal muscle function and maintenance. Biallelic loss-of-function DAG1 variants cause severe muscular dystrophy and muscle-eye-brain disease. A possible contribution of DAG1 deficiency to milder muscular phenotypes has been suggested. We investigated the genetic background of twelve subjects with persistent mild-to-severe hyperCKemia to dissect the role of DAG1 in this condition. Genetic testing was performed through exome sequencing (ES) or custom NGS panels including various genes involved in a spectrum of muscular disorders. Histopathological and Western blot analyses were performed on muscle biopsy samples obtained from three patients. We identified seven novel heterozygous truncating variants in DAG1 segregating with isolated or pauci-symptomatic hyperCKemia in all families. The variants were rare and predicted to lead to nonsense-mediated mRNA decay or the formation of a truncated transcript. In four cases, DAG1 variants were inherited from similarly affected parents. Histopathological analysis revealed a decreased expression of dystroglycan subunits and Western blot confirmed a significantly reduced expression of beta-dystroglycan in muscle samples. This study supports the pathogenic role of DAG1 haploinsufficiency in isolated or pauci-symptomatic hyperCKemia, with implications for clinical management and genetic counseling.

Refining the electroclinical spectrum of NPRL3-related epilepsy: A novel multiplex family and literature review.

OBJECTIVE: NPRL3-related epilepsy (NRE) is an emerging condition set within the wide GATOR-1 spectrum with a particularly heterogeneous and elusive phenotypic expression. Here, we delineated the genotype-phenotype spectrum of NRE, reporting an illustrative familial case and reviewing pertinent literature. METHODS: Through exome sequencing (ES), we investigated a 12-year-old girl with recurrent focal motor seizures during sleep, suggestive of sleep-related hypermotor epilepsy (SHE), and a family history of epilepsy in siblings. Variant segregation analysis was performed by Sanger sequencing. All previously published NRE patients were thoroughly reviewed and their electroclinical features were analyzed and compared with the reported subjects. RESULTS: In the proband, ES detected the novel NPRL3 frameshift variant (NM_001077350.3): c.151_152del (p.Thr51Glyfs*5). This variant is predicted to cause a loss of function and segregated in one affected brother. The review of 76 patients from 18 publications revealed the predominance of focal-onset seizures (67/74-90%), with mainly frontal and frontotemporal (32/67-47.7%), unspecified (19/67-28%), or temporal (9/67-13%) onset. Epileptic syndromes included familial focal epilepsy with variable foci (FFEVF) (29/74-39%) and SHE (11/74-14.9%). Fifteen patients out of 60 (25%) underwent epilepsy surgery, 11 of whom achieved complete seizure remission (11/15-73%). Focal cortical dysplasia (FCD) type 2A was the most frequent histopathological finding. SIGNIFICANCE: We reported an illustrative NPRL3-related epilepsy (NRE) family with incomplete penetrance. This condition consists of a heterogeneous spectrum of clinical and neuroradiological features. Focal-onset motor seizures are predominant, and almost half of the cases fulfill the criteria for SHE or FFEVF. MRI-negative cases are prevalent, but the association with malformations of cortical developments (MCDs) is significant, especially FCD type 2a. The beneficial impact of epilepsy surgery in patients with MCD-related epilepsy further supports the inclusion of brain MRI in the workup of NRE patients.

Moyamoya Vasculopathy in Neurofibromatosis Type 1 Pediatric Patients: The Role of Rare Variants of RNF213.

Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder caused by mutations in NF1 gene, coding for neurofibromin 1. NF1 can be associated with Moyamoya disease (MMD), and this association, typical of paediatric patients, is referred to as Moyamoya syndrome (MMS). MMD is a cerebral arteriopathy characterized by the occlusion of intracranial arteries and collateral vessel formation, which increase the risk of ischemic and hemorrhagic events. RNF213 gene mutations have been associated with MMD, so we investigated whether rare variants of RNF213 could act as genetic modifiers of MMS phenotype in a pediatric cohort of 20 MMS children, 25 children affected by isolated MMD and 47 affected only by isolated NF1. By next-generation re-sequencing (NGS) of patients' DNA and gene burden tests, we found that RNF213 seems to play a role only for MMD occurrence, while it does not appear to be involved in the increased risk of Moyamoya for MMS patients. We postulated that the loss of neurofibromin 1 can be enough for the excessive proliferation of vascular smooth muscle cells, causing Moyamoya arteriopathy associated with NF1. Further studies will be crucial to support these findings and to elucidate the possible role of other genes, enhancing our knowledge about pathogenesis and treatment of MMS.

Rescue by elexacaftor-tezacaftor-ivacaftor of the G1244E cystic fibrosis mutation's stability and gating defects are dependent on cell background.

BACKGROUND: Cystic fibrosis is caused by mutations impairing expression, trafficking, stability and/or activity of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The G1244E mutation causes a severe gating defect that it is not completely rescued by ivacaftor but requires the use of a second compound (a co-potentiator). Recently, it has been proposed that the corrector elexacaftor may act also as a co-potentiator. METHODS: By using molecular, biochemical and functional analyses we performed an in-depth characterization of the G1244E-CFTR mutant in heterologous and native cell models. RESULTS: Our studies demonstrate that processing and function of the mutant protein, as well as its pharmacological sensitivity, are markedly dependent on cell background. In heterologous expression systems, elexacaftor mainly acted on G1244E-CFTR as a co-potentiator, thus ameliorating the gating defect. On the contrary, in the native nasal epithelial cell model, elexacaftor did not act as a co-potentiator, but it increased mature CFTR expression possibly by improving mutant's defective stability at the plasma membrane. CONCLUSIONS: Our study highlights the importance of the cell background in the evaluation of CFTR modulator effects. Further, our results draw attention to the need for the development of novel potentiators having different mechanisms with respect to ivacaftor to improve channel activity for mutants with severe gating defect.

Training Specificity for Athletes: Emphasis on Strength-Power Training: A Narrative Review.

Specificity has two major components: A strength-endurance continuum (S-EC) and adherence to principles of Dynamic Correspondence. Available evidence indicates the existence of the S-EC continuum from two aspects. Indeed, the S-EC exists, particularly if work is equated as a high load low repetition scheme at one end (strength stimulus) and high volume (HIEE stimulus) at the other. Furthermore, some evidence also indicates that the continuum as a repetition paradigm with high-load, low repetition at one end (strength stimulus) and a high repetition, low load at the other end. The second paradigm is most apparent under three conditions: (1) ecological validity-in the real world, work is not equated, (2) use of absolute loads in testing and (3) a substantial difference in the repetitions used in training (for example 2-5 repetitions versus ≥10 repetitions). Additionally, adherence to the principles and criteria of dynamic correspondence allows for greater "transfer of training" to performance measures. Typically, and logically, in order to optimize transfer, training athletes requires a reasonable development of capacities (i.e., structure, metabolism, neural aspects, etc.) before more specific training takes place.

Corrigendum: Parental Somatic Mosaicism Uncovers Inheritance of an Apparently De Novo GFAP Mutation.

[This corrects the article DOI: 10.3389/fgene.2021.744068.].

Volleyball-Specific Skills and Cognitive Functions Can Discriminate Players of Different Competitive Levels.

ABSTRACT: Formenti, D, Trecroci, A, Duca, M, Vanoni, M, Ciovati, M, Rossi, A, and Alberti, G. Volleyball-specific skills and cognitive functions can discriminate players of different competitive levels. J Strength Cond Res 36(3): 813-819, 2022-The aim of this study was to investigate whether volleyball-specific skills, physical performance, and general cognitive functions differ between players of different competitive levels. Twenty-six female volleyball players competing at 2 different levels (n = 13, regional; n = 13, provincial) were tested on volleyball-specific skills (accuracy and technique of setting, passing, spiking, and serving), change of direction speed (COD) by the modified T-test, countermovement jump (CMJ) and general cognitive functions (executive control by Flanker task and perceptual speed by visual search task). Four machine learning models were tested to detect the best one to predict players' level. Regional players presented higher passing, spiking, serving accuracy (p < 0.05) and setting, passing, spiking, and serving technique (p < 0.05) than provincial players. Regional players had also better performance in COD and CMJ than provincial players (p < 0.05). Regional players presented lower response time than provincial players in both congruent and incongruent conditions of the Flanker task, and in both 10 items and 15 items conditions of the visual search task (p < 0.05). Decision tree classifier was the machine learning model with the highest performance to discriminate regional and provincial players (93% precision and 73% recall) by considering passing technique, congruent and incongruent condition of the Flanker task, 15 items and 10 items condition of the visual search task, and spiking technique. These findings demonstrated the importance of assessing volleyball-specific skills and cognitive functions as playing a role to discriminate players of different competitive levels.

Parental Somatic Mosaicism Uncovers Inheritance of an Apparently De Novo GFAP Mutation.

Alexander disease is a leukodystrophy caused by heterozygous mutations of GFAP gene. Recurrence in siblings from healthy parents provides a confirmation to the transmission of variants through germinal mosaicism. With the use of DNA isolated from peripheral blood, next-generation sequencing (NGS) of GFAP locus was performed with deep coverage (≥500×) in 11 probands and their parents (trios) with probands heterozygous for apparently de novo GFAP mutations. Indeed, one parent had somatic mosaicism, estimated in the range of 8.9%-16%, for the mutant allele transmitted to the affected sibling. Parental germline mosaicism deserves attention, as it is critical in assessing the risk of recurrence in families with Alexander disease.

The first case of mosaic MNX1 mutation in an adult female with features of Currarino syndrome.

BACKGROUND: Currarino syndrome (CS) is a rare genetic condition characterized by the association of three major clinical signs: anorectal malformation (ARM), sacro-coccygeal bone defects, and presacral mass. Different kinds of ARM can be present such as anteriorly placed anus, imperforate anus, anorectal stenosis, rectal duplication, and fistulae. The presacral mass can be a benign teratoma, a dermoid or neurenteric cyst, anterior meningocele or hamartoma. Females are more frequently affected and usually present with associated gynecologic and urinary tract problems. CS is considered an autosomal dominant trait, with reduced penetrance and variable expressivity. CS is associated with mutations in the MNX1 gene (motor neuron and pancreas homeobox-1, previously known as HLXB9) mapped to chromosome 7q36. Heterozygous loss-of-function mutations in the coding sequence of MNX1 gene have been reported in nearly all familial CS cases and in approximately 30% of CS sporadic patients. CASE: Here, we present the case of a woman with features of CS carrying a mosaic mutation in the coding region of MNX1 gene. This is the only reported case of a CS diagnosis in which the mutation is present in less than 50% of cells. CONCLUSION: The lower detection rate of MNX1 mutations in sporadic cases could similarly be explained by somatic mosaicism, mutations occurring outside the coding regions, or genetic heterogeneity.

Genotype-Phenotype Correlations in Neurofibromatosis Type 1: A Single-Center Cohort Study.

Neurofibromatosis type 1 (NF1) is a proteiform genetic condition caused by pathogenic variants in NF1 and characterized by a heterogeneous phenotypic presentation. Relevant genotype-phenotype correlations have recently emerged, but only few pertinent studies are available. We retrospectively reviewed clinical, instrumental, and genetic data from a cohort of 583 individuals meeting at least 1 diagnostic National Institutes of Health (NIH) criterion for NF1. Of these, 365 subjects fulfilled ≥2 NIH criteria, including 235 pediatric patients. Genetic testing was performed through cDNA-based sequencing, Next Generation Sequencing (NGS), and Multiplex Ligation-dependent Probe Amplification (MLPA). Uni- and multivariate statistical analysis was used to investigate genotype-phenotype correlations. Among patients fulfilling ≥ 2 NIH criteria, causative single nucleotide variants (SNVs) and copy number variations (CNVs) were detected in 267/365 (73.2%) and 20/365 (5.5%) cases. Missense variants negatively correlated with neurofibromas (p = 0.005). Skeletal abnormalities were associated with whole gene deletions (p = 0.05) and frameshift variants (p = 0.006). The c.3721C>T; p.(R1241*) variant positively correlated with structural brain alterations (p = 0.031), whereas Lisch nodules (p = 0.05) and endocrinological disorders (p = 0.043) were associated with the c.6855C>A; p.(Y2285*) variant. We identified novel NF1 genotype-phenotype correlations and provided an overview of known associations, supporting their potential relevance in the implementation of patient management.

The OSMR Gene Is Involved in Hirschsprung Associated Enterocolitis Susceptibility through an Altered Downstream Signaling.

Hirschsprung (HSCR) Associated Enterocolitis (HAEC) is a common life-threatening complication in HSCR. HAEC is suggested to be due to a loss of gut homeostasis caused by impairment of immune system, barrier defense, and microbiome, likely related to genetic causes. No gene has been claimed to contribute to HAEC occurrence, yet. Genetic investigation of HAEC by Whole-Exome Sequencing (WES) on 24 HSCR patients affected (HAEC) or not affected (HSCR-only) by enterocolitis and replication of results on a larger panel of patients allowed the identification of the HAEC susceptibility variant p.H187Q in the Oncostatin-M receptor (OSMR) gene (14.6% in HAEC and 5.1% in HSCR-only, p = 0.0024). Proteomic analysis on the lymphoblastoid cell lines from one HAEC patient homozygote for this variant and one HAEC patient not carrying the variant revealed two well distinct clusters of proteins significantly up or downregulated upon OSM stimulation. A marked enrichment in immune response pathways (q < 0.0001) was shown in the HAEC H187 cell line, while proteins upregulated in the HAEC Q187 lymphoblasts sustained pathways likely involved in pathogen infection and inflammation. In conclusion, OSMR p.H187Q is an HAEC susceptibility variant and perturbates the downstream signaling cascade necessary for the gut immune response and homeostasis maintenance.

Relationship between Cognitive Functions and Sport-Specific Physical Performance in Youth Volleyball Players.

The aim of this study was to investigate the relationship between basic cognitive functions and sport-specific physical performance in young volleyball players. Forty-three female volleyball players (age 11.2 ± 0.8 years) were tested for cognitive performance by measuring simple reaction time (clinical reaction time), executive control (Flanker task), and perceptual speed (visual search task). Moreover, a set of tests was used to assess physical abilities as volleyball-specific skills (accuracy of setting, passing, and serving) and motor skills (change of direction, vertical jump, and balance). A cumulated value for both cognitive and sport-specific physical performance tests was computed by adding up each test's domain outcomes. Pearson's r correlation analysis showed a large positive correlation (r = 0.45, d-value = 1.01) of the cumulated score summarizing cognitive functions with the cumulated score summarizing sport-specific physical performance. Moreover, small-to-medium correlations (d-value from 0.63 to 0.73) were found between cognitive and motor skills. Given the cumulative scores, these results suggest that volleyball athletes with superior basic cognitive functions present better sport-specific physical performance. Our findings encourage to extend the knowledge of the associations between cognitive and motor skills within a sports performance context.

Differences in inhibitory control and motor fitness in children practicing open and closed skill sports.

The aim of the present study was to investigate the differences between types of sport (i.e., closed vs. open skills sport) on inhibitory control and motor fitness in children. Forty-nine children were allocated into three groups based on their sports participation, which comprised an open skill sport group, a closed skill sport group, and a sedentary group. Participants were tested on cognitive performance (inhibitory control by the Flanker task) and motor fitness (reaction time, speed, agility, power, balance). Open skill sport group appeared to display higher inhibitory control (response time and accuracy of incongruent condition of the Flanker task) and motor fitness performance (reaction time, speed, agility, power) than sedentary group, whereas its superiority over closed skill sport group was found only in speed and agility. Moreover, closed skill sport group had only a better reaction time than sedentary group. Our data supports the framework according to which cognitive demands in complex motor actions may contribute to explain the beneficial effects of exercise on inhibitory control. This might suggest that the complexity of the environment (typical in open skill sports) in which sport training is performed plays a key role for both cognitive and motor development in children.

Novel ACTG2 variants disclose allelic heterogeneity and bi-allelic inheritance in pediatric chronic intestinal pseudo-obstruction.

Variants in the ACTG2 gene, encoding a protein crucial for correct enteric muscle contraction, have been found in patients affected with chronic intestinal pseudo-obstruction, either congenital or late-onset visceral myopathy, and megacystis-microcolon-intestinal hypoperistalsis syndrome. Here we report about ten pediatric and one adult patients, from nine families, carrying ACTG2 variants: four show novel still unpublished missense variants, including one that is apparently transmitted according to a recessive mode of inheritance. Four of the remaining five probands carry variants affecting arginine residues, that have already been associated with a severe phenotype. A de novo occurrence of the variants could be confirmed in six of these families. Since a genotype-phenotype correlation is affected by extrinsic factors, such as, diagnosis delay, quality of clinical management, and intra-familial variability, we have undertaken 3D molecular modeling to get further insights into the effects of the variants here described. The present findings and further ACTG2 testing of patients presenting with intestinal pseudo-obstruction, will improve our understanding of visceral myopathies, including implications in the prognosis and genetic counseling of this set of severe disorders.

Kinematics and Kinetics of Bulgarian-Bag-Overloaded Sprints in Young Athletes.

BACKGROUND: Effective sprinting requires large acceleration capabilities. To accelerate, large amount of force must be produced and applied effectively. The use of different implements such as sleds and vests can increase the amount of force produced and alter sprinting effectiveness. We propose the use of increasing overload via the Bulgarian Bag (BB) as a means to modify athletes' sprint and acutely increase force and power production. METHODS: 24 young athletes performed three sprints over 20 m in three different conditions: unloaded (BW) and loaded with BB weighing 2.5% (BB2.5) and 5% (BB5) of the athlete's body mass. Sprint times at 2.5, 5, 10, 15, and 20 m were acquired and used to compute the force-velocity relationship for the sprints. Maximal velocity (V0), peak force (F0), peak power (PP), and decrease in ratio of force (DRF) were computed. RESULTS: the additional load caused a decrease in sprint times (p < 0.05) and V0 (p = 0.028), conversely no differences were found for F0 (p = 0.21), PP (p = 0.50), and DRF (p = 0.83). CONCLUSIONS: Based on those findings, BB can be an alternative method to effectively overload sprint training toward improving sprinting performance.

Effects of an Initial Muscle Strength Level on Sports Performance Changes in Collegiate Soccer Players.

The purposes of this study were to investigate effects of partial block periodized strength training on physical performance and to examine relationships between initial muscle strength measured with isometric mid-thigh pull (IMTP) and performance changes after 7 weeks of strength training. Seventeen collegiate male soccer players participated. Initial muscle strength was determined using IMTP while physical performance included 10 m and 20 m sprints and static vertical jump with a polyvinyl chloride pipe (SJ0), 20 kg barbell (SJ20), and barbell loaded to 40 kg bar (SJ40). Performance testing was performed at three points: before first week (baseline), fourth week (T1), and seventh week (T2). Statistically small to moderate changes were found from baseline to T2 in peak power (PP; p < 0.001, ES = 0.49), net impulse (NI; p < 0.001, ES = 0.49), peak velocity (PV; p < 0.001, ES = 0.62), allometrically scaled PP (PPa; p < 0.001, ES = 0.62) in SJ20 and jump height (JH) in SJ40 (p < 0.001, ES = 0.36). Moderate to large correlations were found between isometric peak force and the changes from baseline to T2 in SJ20 PP (p = 0.04, r = -0.49), SJ20 PF (p = 0.03, r = -0.52), PPa (p = 0.04, r = -0.50), and SJ20 allometrically scaled peak force (p = 0.04, r = -0.49). Properly structured strength training maximizes task-specific physical performance. Initial muscle strength negatively affects the magnitudes of adaptations to physical performance.

Mental fatigue impairs physical activity, technical and decision-making performance during small-sided games.

The aim of this study was to investigate the effects of mental fatigue on physical activity, technical and decision-making performance during small-sided games. Nine sub-elite soccer players were enrolled in the study. The players performed two small-sided games on two occasions within a crossover experimental design. Before each game, they underwent a mental fatiguing task (Stroop task) and a control task (documentary watching) in a randomized, counterbalanced order. Players' physical activity, technical, and decision-making performance were obtained during small-sided games by GPS and video scouting. Results showed that distance in acceleration covered per min, negative passes, passing accuracy, and shot accuracy were likely impaired than control task after a mental fatiguing protocol. Decision-making performance of negative passes, passes accuracy, and dribbling accuracy resulted also likely decreased compared with control task. These findings demonstrated that mental fatigue impacted on technical, GPS-derived, and soccer-specific decision-making performance during SSG. In conclusion, avoiding cognitively demanding tasks before playing soccer-specific activities may be advisable to preserve players' physical activity, technical, and decision-making skills.

Short-Term Compound Training on Physical Performance in Young Soccer Players.

This study aimed to investigate the effects of a five-week compound training (with strength and plyometric exercises performed on separate days) on sprint, change of direction, and vertical jump in young soccer players. Eighteen novices in strength and plyometric training were assigned to either a compound training (CMPT) or a control condition (CNT). Both groups trained three times per week. One session was dedicated to soccer-specific drills. The other two weekly sessions were dedicated to circuit-based training routines employing on one-day strength exercises and on the other day plyometric exercises in the CMPT group. At the same time, the CNT group performed two weekly soccer-specific training sessions. All players were tested by 15-m sprint, change-of-direction and acceleration test (CODAT), squat jump, and countermovement jump with arms swing tests. CMPT group improved CODAT, squat jump and countermovement jump to a higher extent compared to CNT group (large vs small or trivial effects, p < 0.05), while both groups had similar 15-m sprint performance (p > 0.05). These results support the use of compound training to improve change of direction and vertical jump performances in young novice soccer players, which are unfamiliar with structured and advanced strength and plyometric training.

Acute Effect of Exercise on Cognitive Performance in Middle-Aged Adults: Aerobic Versus Balance.

BACKGROUND: Recent evidence has suggested that chronic physical activities including balance exercises have positive effects on cognition, but their acute effects are still unknown. In the present study, the authors tested the hypothesis that an acute bout of balance exercise would enhance cognitive performance compared with aerobic activity. METHODS: A total of 20 healthy middle-aged adults completed 2 acute 30-minute balance and moderate-intensity aerobic exercise sessions on 2 counterbalanced separate occasions. To assess cognitive functions, performance tasks in executive control, perceptual speed, and simple reaction time were tested before and immediately after each exercise session. RESULTS: Although there were no significant interactions (time × exercise condition, P > .05), the main effects of time were significant in executive control (P < .05), perceptual speed (P < .05), and simple reaction time (P < .001), showing improvements after both exercises. CONCLUSIONS: These findings highlight that both types of exercise (aerobic, more metabolic and less cognitively demanding; balance, more cognitively and less metabolically demanding) were able to positively affect simple reaction time performance, perceptual speed, and executive control independently of physiological adjustments occurring during aerobic or balance exercise.

A novel knock-in mouse model of cryopyrin-associated periodic syndromes with development of amyloidosis: Therapeutic efficacy of proton pump inhibitors.

BACKGROUND: Cryopyrin-associated periodic syndromes (CAPS) are a group of autoinflammatory diseases linked to gain-of-function mutations in the NOD-like receptor family, pyrin domain containing 3 (NLRP3) gene, which cause uncontrolled IL-1ß secretion. Proton pump inhibitors (PPIs), which are commonly used as inhibitors of gastric acid production, also have anti-inflammatory properties, protect mice from sepsis, and prevent IL-1ß secretion by monocytes from patients with CAPS. OBJECTIVE: We sought to develop a novel Nlrp3 knock-in (KI) mouse model of CAPS to study amyloidosis, a severe CAPS complication, and test novel therapeutic approaches. METHODS: We generated KI mice by engineering the N475K mutation, which is associated with the CAPS phenotype, into the mouse Nlrp3 gene. KI and wild-type mice received PPIs or PBS intraperitoneally and were analyzed for survival, inflammation, cytokine secretion, and amyloidosis development. RESULTS: Mutant Nlrp3 KI mice displayed features that recapitulate the immunologic and clinical phenotype of CAPS. They showed systemic inflammation with high levels of serum proinflammatory cytokines, inflammatory infiltrates in various organs, and amyloid deposits in the spleen, liver, and kidneys. Toll-like receptor stimulated macrophages from KI mice secreted high levels of IL-1ß, IL-18, and IL-1α but low amounts of IL-1 receptor antagonist. Treatment of KI mice with PPIs had a clear clinical effect, showing a reduction in inflammatory manifestations, regression of amyloid deposits, and normalization of proinflammatory and anti-inflammatory cytokine production by macrophages. CONCLUSION: Nlrp3 KI mice displayed a CAPS phenotype with many characteristics of autoinflammation, including amyloidosis. The therapeutic effectiveness of PPIs associated with a lack of toxicity indicates that these drugs could represent relevant adjuvants to the anti-IL-1 drugs in patients with CAPS and other IL-1-driven diseases.