Red flags for appropriate referral to the gastroenterologist and the rheumatologist of patients with inflammatory bowel disease and spondyloarthritis.

Collaboration between gastroenterologists and rheumatologists is recommended for the correct management of patients with associated spondyloarthritis (SpA) and inflammatory bowel disease (IBD). We aimed to establish the appropriateness of several red flags for a prompt specialist referral. A systematic review of the literature was performed using the GRADE method to describe the prevalence of co-existing IBD-SpA and the diagnostic accuracy of red flags proposed by a steering committee. Then, a consensus among expert gastroenterologists and rheumatologists (10 in the steering committee and 13 in the expert panel) was obtained using the RAND method to confirm the appropriateness of each red flag as 'major' (one sufficient for patient referral) or 'minor' (at least three needed for patient referral) criteria for specialist referral. The review of the literature confirmed the high prevalence of co-existing IBD-SpA. Positive and negative predictive values of red flags were not calculated, given the lack of available data. A consensus among gastroenterology and rheumatology specialists was used to confirm the appropriateness of each red flag. Major criteria to refer patients with SpA to the gastroenterologist included: rectal bleeding, chronic abdominal pain, perianal fistula or abscess, chronic diarrhoea and nocturnal symptoms. Major criteria to refer patients with IBD to the rheumatologist included: chronic low back pain, dactylitis, enthesitis and pain/swelling of peripheral joints. Several major and minor red flags have been identified for the diagnosis of co-existing IBD-SpA. The use of red flags in routine clinical practice may avoid diagnostic delay and reduce clinic overload.

Consensus on the management of patients with psoriatic arthritis in a dermatology setting.

BACKGROUND: Psoriatic arthritis (PsA) is a chronic inflammatory disease associated with psoriasis (PsO). Early diagnosis and prompt therapeutic intervention are crucial for limiting PsA progression and prevention of disability. Dermatologists are in a privileged position to detect early PsA. The management of patients with PsA in the dermatology setting is widely variable. OBJECTIVE: To provide practical recommendations for the management of patients with PsA in the dermatology setting including early diagnosis and treatment. METHODS: A consensus document was written by an expert panel composed by dermatologists (n = 12) and rheumatologists (n = 6). Eleven highly relevant questions were selected and elaborated with answers/statements based on a narrative literature review. The resulting document was discussed in a face-to-face meeting adopting a nominal group technique to reach consensus (i.e. 100% agreement) using the Delphi method. RESULTS: A consensus was achieved in defining the following: the clinical characteristics differentiating inflammatory and non-inflammatory signs and symptoms of joint disease; the most important differential diagnoses of PsA in clinical practice; the most useful screening questionnaires, serum laboratory tests and imaging techniques for the detection of early PsA; the criteria for dermatologist to refer patients with PsO to rheumatologist; the criteria for the diagnosis of PsA; the selection of the indices that the dermatologist could use for measuring the activity and severity of PsA in clinical practice; when systemic steroids and/or intra-articular steroid injections are indicated in the treatment of PsA. Finally, systemic treatments including synthetic and biologic disease-modifying antirheumatic drugs to be considered for the treatment of PsA have been reported. CONCLUSIONS: The implementations of these practical recommendations could be very helpful for the management of patients with PsA in the dermatology setting including early diagnosis and treatment.

The -308 TNFα and the -174 IL-6 promoter polymorphisms associate with effective anti-TNFα treatment in seronegative spondyloarthritis.

The genetic predisposition to a long-term efficacy of anti-tumor necrosis factor (TNF)α treatment in seronegative spondyloarthritis (SpA) was investigated by analysing the possible correlation between several single nucleotide gene polymorphisms and the retention rate of anti-TNFα therapies. We compared patients needing to switch the first anti-TNFα (Sw, No. 64) within at least 12 months of follow-up with patients not needing to switch (NSw, No. 123), observing at least 6 months of treatment to establish anti-TNFα failure, leading to treatment change. Response to treatment was evaluated by standardised criteria (BASDAI for axial involvement, DAS28-EULAR for peripheral involvement). The TNFα -308 A allele and the interleukin (IL)-6 -174GG homozygosis resulted as independent biomarkers predicting survival of the first anti-TNFα therapy in SpA patients (P=0.007, odds ratio (OR): 4.4, 95% confidence interval (CI)=1.5-13.1 and P=0.035, OR: 2.1, 95% CI=1.1-4.4). Also, the male gender (P=0.001, OR: 3.4, 95% CI=1.6-7.1) associated with the NSw phenotype, whereas no association was found either with the specific diagnosis or the predominant joint involvement.

European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update.

BACKGROUND: Since the publication of the European League Against Rheumatism recommendations for the pharmacological treatment of psoriatic arthritis (PsA) in 2012, new evidence and new therapeutic agents have emerged. The objective was to update these recommendations. METHODS: A systematic literature review was performed regarding pharmacological treatment in PsA. Subsequently, recommendations were formulated based on the evidence and the expert opinion of the 34 Task Force members. Levels of evidence and strengths of recommendations were allocated. RESULTS: The updated recommendations comprise 5 overarching principles and 10 recommendations, covering pharmacological therapies for PsA from non-steroidal anti-inflammatory drugs (NSAIDs), to conventional synthetic (csDMARD) and biological (bDMARD) disease-modifying antirheumatic drugs, whatever their mode of action, taking articular and extra-articular manifestations of PsA into account, but focusing on musculoskeletal involvement. The overarching principles address the need for shared decision-making and treatment objectives. The recommendations address csDMARDs as an initial therapy after failure of NSAIDs and local therapy for active disease, followed, if necessary, by a bDMARD or a targeted synthetic DMARD (tsDMARD). The first bDMARD would usually be a tumour necrosis factor (TNF) inhibitor. bDMARDs targeting interleukin (IL)12/23 (ustekinumab) or IL-17 pathways (secukinumab) may be used in patients for whom TNF inhibitors are inappropriate and a tsDMARD such as a phosphodiesterase 4-inhibitor (apremilast) if bDMARDs are inappropriate. If the first bDMARD strategy fails, any other bDMARD or tsDMARD may be used. CONCLUSIONS: These recommendations provide stakeholders with an updated consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes in PsA, based on a combination of evidence and expert opinion.

Typing TREX1 gene in patients with systemic lupus erythematosus.

An impaired expression of interferon-α regulated genes has been reported in patients with either systemic lupus erythematosus (SLE) or Aicardi-Goutières syndrome (AGS), a rare monogenic encephalopathy with onset in infancy. One of mutations causing AGS is located in the TREX1 gene on chromosome 3. Heterozygous mutations in TREX1 were reported in SLE patients. TREX1 is a DNA exonuclease with specificity for ssDNA. An impairment of its activity may result in the accumulation of nucleid acid. A recent study described a significant association between a haplotype including several common single nucleotide polymorphisms (SNPs) of TREX1 and neurological manifestations in European SLE patients. Fifty-one SLE patients were screened for TREX1 gene, and the corresponding data were collected from clinical charts. A novel heterozygous variant (p.Asp130Asn) was identified in one patient and in none of 150 controls. A missense variation was located in one of the three active sites of the gene and was classified as probably damaging. Variations of SNP rs11797 were detected in 33 SLE patients and a variation of rs3135944 in one. A significantly higher rate of the minor allele (T nucleotide) of SNP rs11797 was found in SLE patients with neuropsychiatric manifestations [12/16 (75%) vs 28/86 (32.5%) O=0.002, odds ratio=6.42 95% confidence interval (1.7-26.2)]. Only 1 out of 8 patients (12.5%) with neuropsychiatric SLE carried the wild-type form in homozygosity. Although we analyzed a small number of patients, we found a novel variation of TREX1, which may be pathogenic. The polymorphism of rs11797 was more frequent in SLE patients with neurological manifestations.

Dispersal distance is influenced by parental and grand-parental density.

Non-genetic transmission of information across generations, so-called parental effects, can have significant impacts on offspring morphology, physiology, behaviour and life-history traits. In previous experimental work using the two-spotted spider mite Tetranychus urticae Koch, we demonstrated that dispersal distances increase with local density and levels of genetic relatedness. We here show that manipulation of parental and grand-parental density has a significant effect on offspring dispersal distance, of the same order of magnitude as manipulation of offspring density. We demonstrate that offspring exposed to the same density disperse further if they were born to parents exposed to higher density compared with parents exposed to low density. Offspring dispersal distance also increases when grand-parents were exposed to higher density, except for offspring exposed to low densities, which disperse at shorter distances whatever the grand-parental density. We also show that offspring from mothers exposed to higher densities were overall larger, which suggests that parents in high densities invest more in individual offspring, enabling them to disperse further. We propose that our findings should be included in models investigating the spread rate of invasive species or when predicting the success of conservation measures of species attempting to track changing climates.

Treating axial and peripheral spondyloarthritis, including psoriatic arthritis, to target: results of a systematic literature search to support an international treat-to-target recommendation in spondyloarthritis.

BACKGROUND: Current recommendations for the management of axial spondyloarthritis (SpA) and psoriatic arthritis are to monitor disease activity and adjust therapy accordingly. However, treatment targets and timeframes of change have not been defined. An international expert panel has been convened to develop 'treat-to-target' recommendations, based on published evidence and expert opinion. OBJECTIVE: To review evidence on targeted treatment for axial and peripheral SpA, as well as for psoriatic skin disease. METHODS: We performed a systematic literature search covering Medline, Embase and Cochrane, conference abstracts and studies in http://www.clinicaltrials.gov. RESULTS: Randomised comparisons of targeted versus routine treatment are lacking. Some studies implemented treatment targets before escalating therapy: in ankylosing spondylitis, most trials used a decrease in Bath Ankylosing Spondylitis Disease Activity Index; in psoriatic arthritis, protocols primarily considered a reduction in swollen and tender joints; in psoriasis, the Modified Psoriasis Severity Score and the Psoriasis Area and Severity Index were used. Complementary evidence correlating these factors with function and radiographic damage at follow-up is sparse and equivocal. CONCLUSIONS: There is a need for randomised trials that investigate the value of treat-to-target recommendations in SpA and psoriasis. Several trials have used thresholds of disease activity measures to guide treatment decisions. However, evidence on the effect of these data on long-term outcome is scarce. The search data informed the expert committee regarding the formulation of recommendations and a research agenda.

Do mites evolving in alternating host plants adapt to host switch?

A fluctuating environment may be perceived as a composition of different environments, or as an environment per se, in which it is the fluctuation itself that poses a selection pressure. If so, then organisms may adapt to this alternation. We tested this using experimental populations of spider mites that have been evolving for 45 generations in a homogeneous environment (pepper or tomato plants), or in a heterogeneous environment composed of an alternation of these two plants approximately at each generation. The performance (daily oviposition rate and juvenile survival) of individuals from these populations was tested in each of the homogeneous environments, and in two alternating environments, one every 3 days and the other between generations. To discriminate between potential genetic interactions between alleles conferring adaptation to each host plant and environmental effects of evolving in a fluctuating environment, we compared the performance of all lines with that of a cross between tomato and pepper lines. As a control, two lines within each selection regime were also crossed. We found that crosses between alternating lines and between pepper and tomato lines performed worse than crosses between lines evolving in homogeneous environments when tested in that environment. In contrast, alternating lines performed either better or similarly to lines evolving in homogeneous environments when tested in a fluctuating environment. Our results suggest that fluctuating environments are more than the juxtaposition of two environments. Hence, tests for adaptation of organisms evolving in such environments should be carried out in fluctuating conditions.

Combining experimental evolution and field population assays to study the evolution of host range breadth.

Adapting to specific hosts often involves trade-offs that limit performance on other hosts. These constraints may either lead to narrow host ranges (i.e. specialists, able to exploit only one host type) or wide host ranges often leading to lower performance on each host (i.e. generalists). Here, we combined laboratory experiments on field populations with experimental evolution to investigate the impact of adaptation to the host on host range evolution and associated performance over this range. We used the two-spotted spider mite, Tetranychus urticae, a model organism for studies on the evolution of specialization. Field mite populations were sampled on three host plant species: tomato, citrus tree and rosebay (Nerium oleander). Testing these populations in the laboratory revealed that tomato populations of mites could exploit tomato only, citrus populations could exploit citrus and tomato whereas Nerium populations could exploit all three hosts. Besides, the wider niche ranges of citrus and Nerium populations came at the cost of low performance on their non-native hosts. Experimental lines selected to live on the same three host species exhibited similar patterns of host range and relative performance. This result suggests that adaptation to a new host species may lead to wider host ranges but at the expense of decreased performance on other hosts. We conclude that experimental evolution may reliably inform on evolution in the field.

Predictive factors for partial remission according to the Ankylosing Spondylitis Assessment Study working group in patients with ankylosing spondylitis treated with anti-TNFα drugs.

The objective of this study was to evaluate the predictive factors for achieving partial remission (PR) in patients with ankylosing spondylitis (AS) treated with anti-TNFα. We longitudinally enrolled in a multi-center study 214 AS patients, classified according to New York criteria, treated with anti-TNFα drugs adalimumab (ADA), etanercept (ETA) and infliximab (INF) with at least 12 months of follow up. PR was reached when the score was <20 mm (on a visual analogue scale of 0-100 mm) in each of the following 4 domains: 1) patient global assessment (in the last week); 2) pain (spinal pain); 3) function [measured by the bath ankylosing spondylitis functional index (BASFI)]; 4) inflammation [mean of intensity and duration of morning stiffness, from the bath ankylosing spondylitis disease activity index (BASDAI)]. Two hundred fourteen AS patients (M/F=160/54; median age/range=43.2/19-78 years; median disease duration/ range=96/36-189 months) were treated with ADA (15.8%), ETA (28.9%) and INF (55.1%). At 12 and 24 months, high serum level of C reactive protein (CRP) (≥2 vs ≤0.8 mg/dL) were associated with higher rate of PR in AS patients treated with anti-TNFα drugs. At 24 months, PR was associated with shorter disease duration (≤36 vs ≥189 months) and higher erythrosedimentation rate (ESR) values (≥45 vs ≤17 mm/h). In male patients lower bath ankylosing spondylitis metrology index (BASMI) (≤2 vs ≥6) and absence of psoriasis were associated with higher PR rate only at 12 months. Other parameters assessed before treatment, such as BASDAI, BASFI, peripheral arthritis, inflammatory bowel disease and uveitis were not associated with PR. Our long-term longitudinal study in a setting of clinical practice showed that inflammatory parameters (i.e. CRP, ESR) and disease duration represent the most important predictive variables to achieve PR with an anti-TNFα treatment.

Density and genetic relatedness increase dispersal distance in a subsocial organism.

Although dispersal distance plays a major role in determining whether organisms will reach new habitats, empirical data on the environmental factors that affect dispersal distance are lacking. Population density and kin competition are two factors theorised to increase dispersal distance. Using the two-spotted spider mite as a model species, we altered these two environmental conditions and measured the mean dispersal distance of individuals, as well as other attributes of the dispersal kernel. We find that both density and relatedness in the release patch increase dispersal distance. Relatedness, but not density, changes the shape of the dispersal kernel towards a more skewed and leptokurtic shape including a longer 'fat-tail'. This is the first experimental demonstration that kin competition can shape the whole distribution of dispersal distances in a population, and thus affect the geographical spread of dispersal phenotypes.

Inhibition of the de-myelinating properties of Aicardi-Goutières syndrome lymphocytes by cathepsin D silencing.

Molecular mechanisms relating interferon-alpha (IFN-alpha) to brain damage have recently been identified in a microarray analysis of cerebrospinal fluid lymphocytes from patients with Aicardi-Goutières Syndrome (AGS). These findings demonstrate that the inhibition of angiogenesis and the activation of neurotoxic lymphocytes are the major pathogenic mechanisms involved in the brain damage consequent to elevated interferon-alpha levels. Our previous study demonstrated that cathepsin D, a lysosomal aspartyl endopeptidase, is the primary mediator of the neurotoxicity exerted by AGS lymphocytes. Cathepsin D is a potent pro-apoptotic, neurotoxic, and demyelinating protease if it is not properly inhibited by the activities of leukocystatins. In central nervous system white matter, demyelination results from cathepsin over-expression when not balanced by the expression of its inhibitors. In the present study, we used RNA interference to inhibit cathepsin D expression in AGS lymphocytes with the aim of decreasing the neurotoxicity of these cells. Peripheral blood lymphocytes collected from an AGS patient were immortalized and co-cultured with astrocytes in the presence of interferon alpha with or without cathepsin D RNA interference probes. Cathepsin D expression was measured by qPCR, and neurotoxicity was evaluated by microscopy. RNA interference inhibited cathepsin D over-production by 2.6-fold (P<0.01) in AGS lymphocytes cultured in the presence of interferon alpha. AGS lymphocytes treated using RNA interference exhibited a decreased ability to induce neurotoxicity in astrocytes. Such neurotoxicity results in the inhibition of astrocyte growth and the inhibition of the ability of astrocytes to construct web-like aggregates. These results suggest a new strategy for repairing AGS lymphocytes in vitro by inhibiting their ability to induce astrocyte damage and leukodystrophy.

Optimal life-history schedule in a metapopulation with juvenile dispersal.

Previous models have predicted that when mortality increases with age, older individuals should invest more of their resources in reproduction and produce less dispersive offspring, as both their future reproductive value and their prospect of competing with their own sib decline. Those models assumed stable population sizes. We here study for the first time the evolution of age-specific reproductive effort and of age-specific offspring dispersal rate in a metapopulation with extinction-recolonization dynamics and juvenile dispersal. Our model explores the evolutionary consequences of disequilibrium in the age structure of individuals in local populations, generated by disturbances. Life-history decisions are then shaped both by changes with age in individual performances, and by changes in ecological conditions, as young and old individuals do not live on average in the same environments. Lower juvenile dispersal favours the evolution of higher reproductive effort in young adults in a metapopulation with extinction-recolonization compared with a well-mixed population. Contrary to previous predictions for stable structured populations, we find that offspring dispersal should generally increase with maternal age. This is because young individuals, who are overrepresented in recently colonized populations, should allocate more to reproduction and less to dispersal as a strategy to exploit abundant recruitment opportunities in such populations.

Dysregulation of the immune system in Aicardi-Goutières syndrome: another example in a TREX1-mutated patient.

Aicardi-Goutières syndrome (AGS) is a rare genetic encephalopathy characterized by neurological and extraneurological involvement. A clinical overlap between AGS and systemic lupus erythematosus (SLE) has been reported. We describe an AGS patient who developed autoimmune manifestations: thyroiditis, cANCA positivity, antiphospholipid antibodies and cerebral ischemia. This first description of antiphospholipid syndrome in a TREX1-mutated patient further expands the clinical spectrum of AGS. Although the clinical overlap with SLE may indicate common pathogenic mechanisms, the autoimmune manifestations in AGS are so extensive that we suggest they should be considered a clinical feature of the disease, rather than a sign of coexistent SLE.

Psoriatic arthritis: treatment strategies using biologic agents.

The traditional management of psoriatic arthritis (PsA) includes NSAIDs, corticosteroids and DMARDs. Advancement in the knowledge of the immunopathogenesis of PsA has been associated with the development of biologic agents which have revolutionized the management of the disease. Among biologics drugs, there are the 4 currently available anti-TNFα blocking agents (etanercept, infliximab, adalimumab and golimumab) which are more effective than traditional DMARDs on symptoms/signs of inflammation, quality of life, function, and in inhibiting the progression of the structural joint damage. Despite of the high cost, TNF inhibitors are cost-effective on both the musculoskeletal and skin manifestations of psoriatic disease.

The Assessment of SpondyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general.

OBJECTIVE: To evaluate new classification criteria for peripheral spondyloarthritis (SpA) in patients with SpA with peripheral manifestations only. METHODS: In this Assessment of SpondyloArthritis international Society (ASAS) study, two prespecified sets of criteria were compared against the European Spondylarthropathy Study Group (ESSG) and Amor criteria in newly referred consecutive patients with undiagnosed peripheral arthritis, and/or enthesitis, and/or dactylitis that usually began before 45 years of age. The clinical diagnosis (SpA vs no SpA) made by the ASAS rheumatologist served as reference standard. RESULTS: In all, 24 ASAS centres included 266 patients, with a final diagnosis of SpA being made in 66.2%. After adjustments a final set of criteria showed the best balance between sensitivity (77.8%) and specificity (82.9%): arthritis and/or enthesitis and/or dactylitis plus (A) one or more of the following parameters: psoriasis, inflammatory bowel disease, preceding infection, human leucocyte antigen B27, uveitis, sacroiliitis on imaging, or (B) two or more other parameters: arthritis, enthesitis, dactylitis, inflammatory back pain in the past, family history of SpA. The new criteria performed better than modified versions of the ESSG (sensitivity 62.5%, specificity 81.1%) and the Amor criteria (sensitivity 39.8%, specificity 97.8%), particularly regarding sensitivity. In the entire ASAS population of 975 patients the combined use of ASAS criteria for axial SpA and ASAS criteria for peripheral SpA also had a better balance (sensitivity 79.5%, specificity 83.3%) than the modified ESSG (sensitivity 79.1%, specificity 68.8%) and Amor criteria (sensitivity 67.5%, specificity 86.7%), respectively. CONCLUSIONS: The new ASAS classification criteria for peripheral SpA performed well in patients presenting with peripheral arthritis, enthesitis and/or dactylitis.

2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis.

This first update of the ASAS/EULAR recommendations on the management of ankylosing spondylitis (AS) is based on the original paper, a systematic review of existing recommendations and the literature since 2005 and the discussion and agreement among 21 international experts, 2 patients and 2 physiotherapists in a meeting in February 2010. Each original bullet point was discussed in detail and reworded if necessary. Decisions on new recommendations were made - if necessary after voting. The strength of the recommendations (SOR) was scored on an 11-point numerical rating scale after the meeting by email. These recommendations apply to patients of all ages that fulfill the modified NY criteria for AS, independent of extra-articular manifestations, and they take into account all drug and non-drug interventions related to AS. Four overarching principles were introduced, implying that one bullet has been moved to this section. There are now 11 bullet points including 2 new ones, one related to extra-articular manifestations and one to changes in the disease course. With a mean score of 9.1 (range 8-10) the SOR was generally very good.

Environmental effects on the detection of adaptation.

Detecting adaptation involves comparing the performance of populations evolving in different environments. This detection may be confounded by effects due to the environment experienced by organisms prior to the test. We tested whether such confounding effects occur, using spider-mite selection lines on two novel hosts and one ancestral host, after 15 generations of selection. Mites were either sampled directly from the selection lines or subjected to a common juvenile or to a common maternal environment, mimicking the most frequent environmental manipulations. These environments strongly affected all life-history traits. Moreover, the detection of adaptation and correlated responses on the ancestral host was inconsistent among environments in almost 20% of the cases. Indeed, we did not detect responses unambiguously for any life-history trait. This inconsistency was due to differential environmental effects on lines from different selection regimes. Therefore, the detection of adaptation requires a careful control of these environmental effects.

Diversification in temporally heterogeneous environments: effect of the grain in experimental bacterial populations.

Although theory established the necessary conditions for diversification in temporally heterogeneous environments, empirical evidence remains controversial. One possible explanation is the difficulty of designing experiments including the relevant range of temporal grains and the appropriate environmental trade-offs. Here, we experimentally explore the impact of the grain on the diversification of the bacterium Pseudomonas fluorescens SBW25 in a temporally fluctuating environment by including 20 different pairs of environments and four temporal grains. In general, higher levels of diversity were observed at intermediate temporal grains. This resulted in part from the enhanced capacity of disruptive selection to generate negative genotypic correlations in performance at intermediate grains. However, the evolution of reciprocal specialization was an uncommon outcome. Although the temporal heterogeneity is in theory less powerful than the spatial heterogeneity to generate and maintain the diversity, our results show that diversification under temporal heterogeneity is possible provided appropriate environmental grains.

The Aicardi-Goutières syndrome. Molecular and clinical features of RNAse deficiency and microRNA overload.

Intracellular RNAses are involved in various functions, including microRNA maturation and turnover. Mutations occurring in genes encoding RNAses cause Aicardi-Goutiéres syndrome (AGS). AGS mutations silence RNAse activity, thus inducing accumulation of endogenous RNAs, mainly consisting of short RNAs and microRNAs. Overload of intracellular RNA triggers Toll like receptor-dependent interferon-alpha production in the brain, which in turn activates neurotoxic lymphocytes and inhibits angiogenesis thus inducing the typical clinical phenotype of AGS. However, these pathogenic mechanisms are attenuated after three years of age by the endogenous production of DNAJP58IPK and Cystatin F, which arrest AGS progression. Because RNAses are involved in microRNA turnover, we evaluated the expression of 957 microRNAs in lymphocytes from AGS patients and control patients. Our results indicate that microRNA overload occurs in AGS patients. This upregulation inhibits microRNA turnover impeding the synthesis of the novel microRNAs required for the differentiation and myelination of the brain during the initial period of postnatal life. These pathogenic mechanisms result in AGS, a neurological syndrome characterized by irritability, mild hyperpyrexia, pyramidal and extrapyramidal signs, and spastic-dystonic tetraplegia. Typical cerebrospinal fluid alterations include lymphocytosis and elevated interferon-alpha levels. Brain imaging demonstrates cerebral calcifications, white matter abnormalities, and progressive cerebral atrophy.Thus, evidence exists that mutations silencing intracellular RNases affect microRNA turnover resulting in the severe clinical consequences in the brain characterizing the clinical feature of AGS.