Paolo Picco

Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling

The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.

Efficacy and safety of alendronate for the treatment of osteoporosis in diffuse connective tissue diseases in children: a prospective multicenter study.

OBJECTIVE Osteopenia/osteoporosis is being increasingly reported as a complication of many chronic diseases, even in children. In this preliminary study, we evaluated the effect of an oral bisphosphonate (alendronate) on bone mass in children with diffuse connective tissue diseases. METHODS Thirty-eight children with low bone mass were treated with alendronate for 1 year; 38 children who had the same primary disorders as the study patients but in a less severe form served as untreated control patients. We were also able to evaluate changes in bone mass (before and after alendronate) in 16 of the treated patients whose bone mineral density (BMD) had been routinely measured before the present study was initiated. RESULTS BMD increased by a mean +/- SD of 14.9 +/- 9.8% (P < 0.002 versus baseline) in the treated patients (reaching the normal range in 13 patients), while the BMD was 2.6 +/- 5% (not significant versus baseline) in the control group (15 had a decrease). Most interestingly, there was a large increase in BMD (15.3 +/-9.9%) after alendronate therapy in the 16 children who had their BMD followed up in the year before the study, during which time they had shown little increase in BMD (1.03 +/- 6.3%), and often a decrease. Considering their condition, increases in the height of all patients was satisfactory. No new fractures were observed after alendronate therapy was initiated. CONCLUSION Bisphosphonates can be considered essential components of the treatment of secondary osteoporosis, not only in adults, but also in pediatric patients. Alendronate has a positive effect on secondary osteopenia/osteoporosis in children with connective tissue diseases.

MEFV mutations in Behçet's disease.

Familial Mediterranean fever (FMF) and Behçets disease (BD), both inflammatory diseases, are highly prevalent in the Middle Eastern and Mediterranean populations. FMF is a Mendelian autosomic recessive disease linked to MEFV, a gene of unknown function. BD in contrast is a polyfactorial disease associated with the major histocompatibility complex. Because FMF and BD have epidemiological similarities, we asked whether the FMF gene was implicated in BD. We screened for the common MEFV mutations a cohort of 114 chromosomes from definite BD patients [meeting the criteria of the International study group] and probable cases [meeting at least two of these criteria]. We screened in parallel an ethnically matched cohort of FMF and control chromosomes. The M694V, V726A and E148Q mutations tended to be more frequent in definite BD (2.6%, 2.6%, and 5.2%, respectively) than in controls (0%, 0%, and 2.2%). The P706 polymorphism was found in 10.5% of the probable BD chromosomes, but in only 1.6% of the controls (p=0.01). Because some MEFV mutations were more frequent in BD than in controls, we suggest that they may act as additional susceptibility factors in BD. Hum Mutat 16:271–272, 2000.

Primary Sjögren syndrome in the paediatric age: a multicentre survey.

Abstract Primary Sjögren syndrome (SS) is very rare in childhood. We collected a series of primary paediatric SS cases from different centres. A data collection form was prepared and sent to rheumatologists who were willing to participate. Data on 40 cases of primary SS with onset before the 16th birthday were collected. Almost all patients (35/40) were females, age at onset varied from 9.3 to 12.4 years (mean 10.7 years). Signs and symptoms at disease onset were mainly recurrent parotid swelling followed by sicca symptoms. Abnormal laboratory tests were found in the majority of cases. Regarding treatment, 22 patients were treated at some time with oral corticosteroids, seven with non-steroidal anti-inflammatory drugs, and five with hydroxychloroquine; two patients needed cyclosporine and one cyclophosphamide. Follow-up varied from 0 to 7.5 years from onset, without major complications in the majority of patients. Conclusion: recurrent parotid swelling is a common feature of primary Sjögren syndrome in childhood and often occurs as a presenting feature. Sicca symptoms may be rarer.

Genetic Mapping to 10q23.3-q24.2, in a Large Italian Pedigree, of a New Syndrome Showing Bilateral Cataracts, Gastroesophageal Reflux, and Spastic Paraparesis with Amyotrophy

We have recently observed a large pedigree with a new rare autosomal dominant spastic paraparesis. In three subsequent generations, 13 affected individuals presented with bilateral cataracts, gastroesophageal reflux with persistent vomiting, and spastic paraparesis with amyotrophy. Bilateral cataracts occurred in all affected individuals, with the exception of one patient who presented with a chorioretinal dystrophy, whereas clinical signs of spastic paraparesis showed a variable expressivity. Using a genomewide mapping approach, we mapped the disorder to the long arm of chromosome 10 on band q23.3-q24.2, in a 12-cM chromosomal region where additional neurologic disorders have been localized. The spectrum of phenotypic manifestations in this family is reminiscent of a smaller pedigree, reported recently, confirming the possibility of a new syndrome. Finally, the anticipation of symptoms suggests that an unstable trinucleotide repeat may be responsible for the condition.

MVK mutations and associated clinical features in Italian patients affected with autoinflammatory disorders and recurrent fever

Autosomal recessive autoinflammatory disorder caused by mutations of the mevalonate kinase gene (MVK), leading to mild, incomplete MK enzyme deficiency (MKD), has been known so far as Hyper-IgD and periodic fever syndrome (HIDS) and regarded as mostly occurring in Northern Europe. Here we report the results of the molecular characterization of the first Italian series of patients affected with autoinflammatory disorders and periodic fever. A total of 13 different mutations, scattered throughout the MVK coding region, were identified in either homozygous or compound heterozygous state in 15 patients. The mutation leading to the V377I amino-acid change, already described also in other series, resulted the most common with a frequency of 50% of all MKD alleles. Among the other mutations, eight had never been described before, including an interstitial deletion of 19 nucleotides in exon 2. In addition to these nucleotide changes, private and polymorphic MVK variants have been detected in the patients under analysis and checked also in a set of control individuals. Clinical features are reported for each of the 15 MKD patients, and life-threatening infections and systemic amyloidosis presented as unexpected MKD-related complications. Our study demonstrates that MKD is a common cause of recurrent fever also in the Italian population, where it is associated with both a wide spectrum of previously unreported MVK mutations and peculiar phenotypic features.

Role of haematological, pulmonary and renal complications in the long-term prognosis of patients with lysinuric protein intolerance

Three patients with lysinuric protein intolerance are reported. The first patient displayed severe haemolytic anaemia, bone marrow erythroblastophagocytosis, renal tubular disease and interstitial lung disease. Despite treatment with citrulline and low-protein diet, this child died at the age of 18 months. The second patient is now 24 years old and has chronic interstitial lung disease and focal renal glomerulosclerosis. The third patient, now 5 years old, has severe chronic interstitial lung disease. A 6-month treatment with prednisone was ineffective in the second and third patients.

Whole-body MRI in the assessment of disease activity in juvenile dermatomyositis

Objective To compare whole-body MRI (WB-MRI) with clinical examination in the assessment of disease activity in juvenile dermatomyositis (JDM). Methods WB-MR images were obtained from 41 JDM patients and 41 controls using a 1.5 T MRI scanner and short τ inversion recovery sequences. 18 patients had follow-up WB-MRI. Muscle, subcutaneous tissue and myofascial signal abnormalities were scored in 36 muscular groups and on proximal and distal extremities. WB-MRI and clinical assessments were performed concurrently and results compared. Validation procedures included analysis of feasibility, reliability, construct validity, discriminative ability and responsiveness. Results WB-MRI revealed distal legs (26/41 patients) and forearm (19/41 patients) muscle inflammation undetected during clinical examination and allowed an accurate assessment of subcutaneous (23/41 patients) and myofascial involvement (13/41 patients). 27 patients showed a patchy distribution of muscle inflammation while in seven the abnormal hyperintense areas tended to be homogeneously distributed. The inter-reader agreement for muscular, subcutaneous and myofascial WB-MRI scores was excellent. Correlations between WB-MRI muscle score and disease activity measures were excellent (Manual Muscle Test: rs=−0.84, Childhood Myositis Assessment Scale: rs=−0.81). WB-MRI score was higher in JDM active patients when compared with the control group (pB<0.0001) and the inactive patients (pB=0.004), and showed an excellent responsiveness (standardised response mean=1.65). Follow-up WB-MRI showed resolution of inflammation in nine patients whereas clinical criteria for remission were satisfied in five. Conclusions WB-MRI provides additional information to clinical evaluation and represents a promising tool to estimate total inflammatory burden, tailor treatment and monitor its efficacy.

Outcome of primary antiphospholipid syndrome in childhood

The objective of this paper is to investigate the long-term outcome of primary antiphospholipid syndrome (APS) in the paediatric age. The features of unselected patients with primary APS who had disease onset before the age of 16 years were retrospectivelyanalysed in three Italian referral centres. Clinical and laboratory manifestationswere assessed to establish whether, at the end of follow-up, the final diagnosis was still primary APS or whether they had developed definite SLE or lupus-like syndrome.Fourteen patients, nine boys and five girls, who had the presentingclinical manifestationof APS between three and 13 years of age (median nine years) and were followed for two to 16 years (median six years). Six patients presented with deep vein thrombosis, five with cerebral stroke, two with peripheral artery occlusion and one with myocardial infarction. During follow-up, four patients had one or more recurrences of vascular thrombosis. At last observation, 10 patients could still be classified as having primary APS, two had developed SLE, one lupus-like syndrome and one Hodgkin’s lymphoma. In conclusion; our analysis suggests that some children who present with the features of primary APS may progress to develop SLE or lupus-like syndrome.

Serum p55 and p75 tumour necrosis factor receptors as markers of disease activity in juvenile chronic arthritis.

OBJECTIVE: To determine the expression of tumour necrosis factor alpha (TNF alpha) and its soluble receptors (p55 and p75) in the sera and synovial fluid of patients with juvenile chronic arthritis (JCA), and their correlation with disease activity parameters. METHODS: Ninety eight sera from 45 patients with JCA (14 systemic, 12 polyarticular, 19 pauciarticular), 20 sera from age matched healthy controls, and five synovial fluids from five antinuclear antibody (ANA) positive pauciarticular JCA patients were tested for the presence of TNF alpha, soluble TNF receptors p55 and p75 (sTNFRp55, sTNFRp75), and interleukin-6 (IL-6) by an enzyme amplified sensitivity immunoassay. Physician global estimate of disease activity, weekly fever score and joint score, C reactive protein (CRP), erythrocyte sedimentation rate (ESR), and haemoglobin concentration were evaluated as parameters of disease activity. The expression of p55 and p75 on peripheral mononuclear cells (MNCs) from five patients with systemic JCA and synovial MNCs from five ANA positive patients with pauciarticular JCA was evaluated by flow cytometry. RESULTS: TNF alpha serum concentrations did not differ significantly between the patients with active JCA and the control group. No correlation was found between TNF alpha and parameters of disease activity, but both p55 and p75 showed a significant positive correlation with the physician global estimate of disease activity (p < 0.001), ESR (p < 0.001), CRP (p < 0.001), and serum concentrations of IL-6 (p < 0.001). Serum concentrations of haemoglobin correlated inversely with the concentrations of p55 and p75 (p < 0.001). Synovial lymphocytes selectively expressed the p75 surface receptor. CONCLUSIONS: sTNFRp55 and sTNFRp75 each represent a sensitive marker of disease activity in JCA. Their increased expression in biological fluids may support the hypothesis that TNF alpha has a role in the pathogenesis of JCA.