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Background Positron emission tomography (PET) with 18-fluorodeoxyglucose (18FDG) has proven to be highly sensitive in early assessment of tumor response in GIST, especially in cases where there is doubt, or when early prediction of the response could be clinically useful for patient management. As widely known, kinase mutations have an undoubtful predictive value for sensitivity to imatinib and the inclusion of KIT and PDGFRa mutational analysis in the diagnostic work-up of all GIST is now considered as standard practice.Case presentation Herein we detailed described a case of an exon 11 KIT mutated-metastatic GIST patient, who presented an unexpected metabolic progression at the early 18FDG-PET evaluation after one month of first line imatinib, unconfirmed at the liver biopsy performed near after, which has conversely shown a complete pathological response.Conclusions This report aims to be aware of the existence of this metabolic pseudoprogression in GIST at the beginning of imatinib therapy, in order to avoid early treatment discontinuation. Therefore, an early metabolic progression during a molecular-targeted therapy always deserves to be evaluated in the context of the disease molecular profiling and in case of discordant finding between functional imaging and molecular background, a short-term longitudinal control should be suggested.

Context Patients with mutations in thyroid hormone transporter MCT8 have developmental delay and chronic thyrotoxicosis associated with being underweight and having cardiovascular dysfunction. Objective Our previous trial showed improvement of key clinical and biochemical features during 1-year treatment with the T3 analogue Triac, but long-term follow-up data are needed. Methods In this real-life retrospective cohort study, we investigated the efficacy of Triac in MCT8-deficient patients in 33 sites. The primary endpoint was change in serum T3 concentrations from baseline to last available measurement. Secondary endpoints were changes in other thyroid parameters, anthropometric parameters, heart rate, and biochemical markers of thyroid hormone action. Results From October 15, 2014 to January 1, 2021, 67 patients (median baseline age 4.6 years; range, 0.5-66) were treated up to 6 years (median 2.2 years; range, 0.2-6.2). Mean T3 concentrations decreased from 4.58 (SD 1.11) to 1.66 (0.69) nmol/L (mean decrease 2.92 nmol/L; 95% CI, 2.61-3.23; P < 0.0001; target 1.4-2.5 nmol/L). Body-weight-for-age exceeded that of untreated historical controls (mean difference 0.72 SD; 95% CI, 0.36-1.09; P = 0.0002). Heart-rate-for-age decreased (mean difference 0.64 SD; 95% CI, 0.29-0.98; P = 0.0005). SHBG concentrations decreased from 245 (99) to 209 (92) nmol/L (mean decrease 36 nmol/L; 95% CI, 16-57; P = 0.0008). Mean creatinine concentrations increased from 32 (11) to 39 (13) µmol/L (mean increase 7 µmol/L; 95% CI, 6-9; P < 0.0001). Mean creatine kinase concentrations did not significantly change. No drug-related severe adverse events were reported. Conclusions Key features were sustainably alleviated in patients with MCT8 deficiency across all ages, highlighting the real-life potential of Triac for MCT8 deficiency.

In the broader list of cognitive concerns, neuropsychological testing has shown that attentional impairment may have a specific burden in Fibromyalgia Syndrome (FMS). Preliminary observations have reported a subset of FMS patient screened for attention disorders fulfilling the actual diagnosis of ADHD, a neurodevelopmental disorder characterized by developmentally inadequate levels of inattention, hyperactivity and impulsivity that might persist in adulthood. Yet, no study to date has systematically examined the history and the specific contribution of ADHD to FMS in terms of clinical impact and related specific disabilities. In this study, 106 individuals with a FMS diagnosis based on the 2010 criteria of the American College of Rheumatology have been assessed for (a) the presence of ADHD; (b) the burden of disability caused by ADHD versus FMS; (c) the presence of other psychiatric disorders. Results indicated that ADHD was present in 24.5% of FMS individuals, it was associated with higher FMS symptoms severity and a greater functional impairment, particularly in the work/school domain. Moreover, patients with both FMS and ADHD had higher frequency of substance use disorders than those with FMS only (38.5% versus 3.8%) and mainly opioids. Overall, results suggest that ADHD can increase burden adding specific disability in work and social activities, and it is associated with a trend for the excessive use of opioid painkillers. Detection of neurodevelopmental and actual symptoms of ADHD is highly recommended especially in patient prone to increase the dose of anti-pain medication.

Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]–1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066−11G>A (IVS10−11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066−11G>A];[1066−11G>A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome. Fil: Hillert, Alicia. No especifíca; Fil: Anikster, Yair. No especifíca; Fil: Belanger Quintana, Amaya. No especifíca; Fil: Burlina, Alberto. No especifíca; Fil: Burton, Barbara K.. No especifíca; Fil: Carducci, Carla. No especifíca; Fil: Chiesa, Ana Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina Fil: Christodoulou, John. No especifíca; Fil: Dordevic, Maja. No especifíca; Fil: Desviat, Lourdes R.. No especifíca; Fil: Eliyahu, Aviva. No especifíca; Fil: Evers, Roeland A.F.. No especifíca; Fil: Fajkusova, Lena. No especifíca; Fil: Feillet, Francois. No especifíca; Fil: Bonfim Freitas, Pedro E.. No especifíca; Fil: Gizewska, María. No especifíca; Fil: Gundorova, Polina. No especifíca; Fil: Karall, Daniela. No especifíca; Fil: Kneller, Katya. No especifíca; Fil: Kutsev, Sergey I.. No especifíca; Fil: Leuzzi, Vincenzo. No especifíca; Fil: Levy, Harvey L.. No especifíca; Fil: Lichter Koneck, Uta. No especifíca; Fil: Muntau, Ania C.. No especifíca; Fil: Namour, Fares. No especifíca; Fil: Oltarzewsk, Mariusz. No especifíca; Fil: Paras, Andrea. No especifíca; Fil: Perez, Belén. No especifíca; Fil: Polak, Emil. No especifíca; Fil: Polyakov, Alexander V.. No especifíca; Fil: Porta, Francesco. No especifíca; Fil: Rohrbach, Marianne. No especifíca; Fil: Scholl Bürgi, Sabine. No especifíca; Fil: Spécola, Norma. No especifíca; Fil: Stojiljkovic, Maja. No especifíca; Fil: Shen, Nan. No especifíca; Fil: Santana da Silva, Luiz C.. No especifíca; Fil: Skouma, Anastasia. No especifíca; Fil: van Spronsen, Francjan. No especifíca; Fil: Stoppioni, Vera. No especifíca; Fil: Thöny, Beat. No especifíca; Fil: Trefz, Friedrich K.. No especifíca; Fil: Vockley, Jerry. No especifíca; Fil: Yu, Youngguo. No especifíca; Fil: Zschocke, Johannes. No especifíca; Fil: Hoffmann, Georg F.. No especifíca; Fil: Garbade, Sven F.. No especifíca; Fil: Blau, Nenad. No especifíca

Phenylketonuria (PKU) is the most common inborn error of amino acids metabolism. PKU management aims to keep as soon as possible blood phenylalanine (Phe), a non-acutely neurotoxic metabolite, within safe ranges through a dietary Phe restriction tailored to individual dietary Phe tolerance. Information on initial neonatal management of PKU, when Phe tolerance is still unknown, is scanty. We reviewed the metabolic data from 304 patients with PAH deficiency detected at newborn screening within the last 37 years. In keeping with the general neonatal management of intoxication-type inborn errors of metabolism, initial management consisted in a Phe wash-out through the exclusive administration of normocaloric Phe-free formulas until normalization of blood Phe. Based on genotype and Phe tolerance assessed at follow-up, 55 patients had classic PKU (18%), 50 mild PKU (17%), and 199 non-PKU hyperphenylalaninemia (HPA) (65%). The duration of Phe wash-out amounted to 7 ± 2 days in classic PKU, 4 ± 2 days in mild PKU, and

Contains fulltext : 220431.pdf (Publisher’s version ) (Closed access) BACKGROUND: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. METHODS: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1.5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score

MCT8 deficiency is a rare genetic leukoencephalopathy caused by a defect of thyroid hormone transport across cell membranes, particularly through blood brain barrier and into neural cells. It is characterized by a complex neurological presentation, signs of peripheral thyrotoxicosis and cerebral hypothyroidism. Movement disorders (MDs) have been frequently mentioned in this condition, but not systematically studied.Each patient recruited was video-recorded during a routine outpatient visit according to a predefined protocol. The presence and the type of MDs were evaluated. The type of MD was blindly scored by two child neurologists experts in inherited white matter diseases and in MD. Dystonia was scored according to Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). When more than one MD was present, the predominant one was scored.27 patients were included through a multicenter collaboration. In many cases we saw a combination of different MDs. Hypokinesia was present in 25/27 patients and was the predominant MD in 19. It was often associated with hypomimia and global hypotonia. Dystonia was observed in 25/27 patients, however, in a minority of cases (5) it was deemed the predominant MD. In eleven patients, exaggerated startle reactions and/or other paroxysmal non-epileptic events were observed.MDs are frequent clinical features of MCT8 deficiency, possibly related to the important role of thyroid hormones in brain development and functioning of normal dopaminergic circuits of the basal ganglia. Dystonia is common, but usually mild to moderate in severity, while hypokinesia was the predominant MD in the majority of patients.

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common defect of mitochondrial β-oxidation. Confirmation diagnostics after newborn screening (NBS) can be performed either by enzyme testing and/or by sequencing of the ACADM gene. Here, we report the results from enzyme testing in lymphocytes with gene variants from molecular analysis of the ACADM gene and with the initial acylcarnitine concentrations in the NBS sample. From April 2013 to August 2019, in 388 individuals with characteristic acylcarnitine profiles suggestive of MCADD the octanoyl-CoA-oxidation was measured in lymphocytes. In those individuals with residual activities50%, molecular genetic analysis of the ACADM gene was performed. In 50% of the samples (195/388), MCADD with a residual activity ranging from 0% to 30% was confirmed. Forty-five percent of the samples (172/388) showed a residual activity35% excluding MCADD. In the remaining 21 individuals, MCAD residual activity ranged from 30% to 35%. The latter group comprised both heterozygous carriers and individuals carrying two gene variants on different alleles. Twenty new variants could be identified and functionally classified based on their effect on enzyme function. C6 and C8 acylcarnitine species in NBS correlated with MCAD activity and disease severity. MCADD was only confirmed in half of the cases referred suggesting a higher false positive rate than expected. Measurement of the enzyme function in lymphocytes allowed fast confirmation diagnostics and clear determination of the pathogenicity of new gene variants. There is a clear correlation between genotype and enzyme function underlining the reproducibility of the functional measurement in vitro.

The X-linked Cyclin-Dependent Kinase-Like 5 (CDKL5) gene encodes a serine-threonine kinase highly expressed in the developing brain. Loss of function of CDKL5 is pointed out to underlie the CDKL5 Deficiency Disorder (CDD), an X-linked dominant disease characterized by early-onset epileptic encephalopathy and developmental delay, usually affecting females more than males. To the best to our knowledge, only 45 males with CDD have been reported so far. Type and position of CDKL5 variants with different impact on the protein are reported to influence the clinical presentation. X-chromosome inactivation occurring in females and post-zygotic mosaicism in males are also believed to contribute to this variability. Based on these issues, genotype-phenotype correlations are still challenging. Here, we describe clinical features of five additional affected males with unreported CDKL5 variants, expanding the molecular spectrum of the disorder. We also reviewed the clinical profile of the previously reported 45 males with molecularly confirmed CDD. Severe developmental delay, cortical visual impairment, and early-onset refractory epilepsy characterize the CDD picture in males. By assessing the molecular spectrum, we confirm that germ-line truncating CDKL5 variants, equally distributed across the coding sequence, are the most recurrent mutations in CDD, and cause the worsen phenotype. While recurrence and relevance of missense substitutions within C-terminal remain still debated, disease-causing missense changes affecting the N-terminal catalytic domain correlate to a severe clinical phenotype. Finally, our data provide evidence that post-zygotic CDKL5 mosaicism may result in milder phenotypes and, at least in a subset of subjects, in variable response to antiepileptic treatments.

Due to the low efficiency of nitrogen fertilizers in flooded rice paddies, there is a rising demand for tools able to detect crop nitrogen status in space and time to allow farmers to use the technical novelties of precision agriculture to improve fertilizer management in extensive fields. This work sets up an operational approach to increase nitrogen use efficiency of top-dressing fertilization by supporting variable rate fertilization in rice cropping systems. The procedure exploits (i) crop modelling to identify best periods for fertilization (When), (ii) Sentinel-2 imagery to draw management zones (MZ) and lead field scouting (Where), and (iii) smartphone app to measure nitrogen nutritional index (NNI) (How much). Automatically generated MZ from Sentinel-2 data were able to identify within field patches with different nutritional status and NNI data well described the crop temporal dynamic in relation to crop development and nutritional needs. The workflow was implemented to provide farmers with timely information on plant nutritional status during the 2018 growing season to define site-specific fertilization strategies implemented with variable rate technology (VRT). Tests conducted on 6 fields over 30 ha in 3 farms showed the feasibility of the proposed workflow in real farming conditions allowing a reduction of applied fertilizer up to 25% in the areas with sufficient nutritional status. Demonstration revealed that VRT based on geospatial information from integrated in-field and satellite data can provide agronomic and environmental benefits compared with standard fertilization resulting in promising outcomes both in terms of yield (increase in the range 0.2–0.5 t ha−1) and nitrogen use efficiency (increase up to 7.8%).

Tetrahydrobiopterin (BHAlthough the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH

Objectives Phenylalanine (Phe) hydroxylase (PAH) deficiency leads to hyperphenylalaninemia (HPA) and tyrosine (Tyr) depletion. We investigated Tyr homeostasis in patients with PAH deficiency and the effect of a slow-release amino acids therapy in phenylketonuria (PKU). Methods We performed four complementary investigations: (1) Tyr concentrations were monitored in 114 patients (10.6 ± 11.9 years) with PKU on dietary treatment supplemented with traditional amino acid formulations (n=52, 1175 samples) or non-PKU HPA on a free diet (n=62, 430 samples); (2) Tyr metabolism in PKU was quantitatively evaluated in three patients by a simple Tyr oral loading test (100 mg/kg); (3) diurnal and (4) long-term Tyr concentrations were evaluated in 5 and 13 patients with PKU, respectively, who switched from traditional to slow-release amino acids therapy. Results 1) Tyr concentrations in the PKU population were subnormal and significantly lower than in non-PKU HPA (p Conclusions Slow-release amino acids therapy can improve Tyr homeostasis in PKU. If associated to optimized Phe control, such a metabolic goal may allow long-term clinical benefits in patients with PKU.

Objectives Biallelic mutations in the SLC25A19 gene impair the function of the thiamine mitochondrial carrier, leading to two distinct clinical phenotypes. Homozygosity for the c.530G > C mutation is invariably associated to Amish lethal microcephaly. The second phenotype, reported only in 8 patients homozygous for different non-Amish mutations (c.373G > A, c.580T > C, c.910G > A, c.869T > A, c.576G > C), is characterized by bilateral striatal necrosis and peripheral polyneuropathy. We report a new patient with the non-Amish SLC25A19 phenotype showing compound heterozygosity for the new variant c.673G > A and the known mutation c.373G > A. Case presentation The natural history of non-Amish SLC25A19 deficiency is characterized by acute episodes of fever-induced encephalopathy accompanied by isolated lactic acidosis and Leigh-like features at magnetic resonance imaging (MRI). Acute episodes are prevented by high-dose thiamine treatment (600 mg/day). As shown in the new case, both mild clinical signs and basal ganglia involvement can precede the acute encephalopathic onset of the disease, potentially allowing treatment anticipation and prevention of acute brain damage. Peripheral axonal neuropathy, observed in 7 out of 9 patients, is not improved by thiamine therapy. In two early treated patients, however, peripheral neuropathy did not occur even on long-term follow-up, suggesting a potential preventive role of treatment anticipation also at the peripheral level. Conclusions Non-Amish SLC25A19 deficiency is an extra-rare cause of Leigh syndrome responsive to thiamine treatment. Ex adiuvantibus thiamine treatment is mandatory in any patient with Leigh-like features.

DNAJC12 deficiency is a new cause of inherited hyperphenylalaninemia (HPA), besides phenylalanine hydroxylase (PAH) deficiency and tetrahydrobiopterin (BH4) deficiencies. Differently from other inherited HPAs, no quantitative data on peripheral phenylalanine (Phe) and tyrosine (Tyr) metabolism are currently available in DNAJC12 deficiency. Phe and Tyr metabolism in a patient with DNAJC12 after a simple Phe oral loading test (100 mg/kg) and a combined Phe (100 mg/kg) + BH4 (20 mg/kg) loading test is presented and compared to patients with disorders of BH4 metabolism, PAH deficiency, and healthy controls. Phe and Tyr metabolism in DNAJC12 deficiency is similar to non-PKU HPA. Differently from BH4 deficiency, BH4 administration in DNAJC12 deficiency does not firmly enhance the rate of Phe hydroxylation. A central effect of BH4 treatment in DNAJC12 deficiency cannot be excluded.

BackgroundTetrahydrobiopterin (BH4) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH4biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH4deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world and therefore these guidelines have been developed aiming to harmonize and optimize patient care. Representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) developed the guidelines according to the SIGN (Scottish Intercollegiate Guidelines Network) methodology by evaluating all available evidence for the diagnosis and treatment of BH4deficiencies.ConclusionAlthough the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH4deficient patients.

Introduction 6-Pyruvoyl-tetrahydropterin synthase deficiency (PTPSd) is a rare autosomal recessive disorder of synthesis of biogenic amines, which is characterized by variable neurological impairment and hyperphenylalaninemia. We aimed to assess the long-term clinical outcome of this disorder and the factors affecting it. Methods At total of 28 PTPSd patients (aged 19.9 ± 10.9 years) underwent clinical (neurological and psychiatric) and neuropsychological assessment (BRIEF, VABS-II, and IQ). Based on CSF homovanillic (HVA) and 5-hydroxyindolacetic acid (5-HIAA) and pterin concentrations at diagnosis, patients were classified as having either a severe [SF; low level of CSF, HVA, and 5-HIAA with altered neopterin/biopterin (Neo/Bio)] or mild form (MF; normal HVA and 5-HIAA with altered Neo/Bio) of PTPSd. Results Approximately 36% of patients had MF PTPSd. At the last examination, 43% of patients had movement disorders (2 MF, 10 SF), 43% of patients had variable degrees of intellectual disability (SF only), 39% met the criteria for a psychiatric disorder (3 MF, 9 SF). Applying a linear regression model, we found that HVA and phenylalanine levels at birth had a significant influence on IQ, BRIEF, and VABS-II variability. Lastly, 5-HIAA further contributed to VABS-II variability. The disease showed a self-limiting clinical course and its treatment, although delayed, is effective in improving the neurological status. Conclusions Neurodevelopmental impairment due to PTPSd shows a self-limiting course. A continuous improvement in the neurological condition has been observed in patients receiving treatment, even when delayed. The severity of brain biogenic amine depletion at diagnosis predicts neurological and psychiatric outcomes.

Background Pompe disease (PD) is a rare condition caused by mutations in gene encoding for the enzyme alpha-glucosidase, resulting in an abnormal intracellular accumulation of glycogen. The disease clinical spectrum ranges from severe infantile forms to adult-onset forms with minor limitations. Since 2000 enzyme replacement therapy (ERT) is available and disease natural history has changed, with prolonged survival and evidence of myopathic features. Methods In this study, we monitored disease progression up to three years in eight young patients with PD. Based on the literature data and the long term personal experience, we selected validated functional scales for neuromuscular disorders and compared the results to identify a simple and reliable protocol for the follow-up of children with PD. Moreover, we evaluated cognitive functions using developmental/cognitive tests. Results Based on study results, we suggest that motor functions in children with PD could be better assessed by Chop Intend, MFM20 (Motor Function Measure Scale for Neuromuscular Diseases 20) and NSAA (North Star Ambulatory Assessment), according to age and functional level. Evaluation should be completed with ROM (Range Of Motion) measurement, MRC (Medical Research Council) evaluation and 6MWT (6 Minute Walk test) when possible. Conclusions The proposed protocol seems to be reliable and should be done every six months, because of the progressive natural history of the disease, the rapid changes typical of developmental age and the need to document ERT effects. About cognitive functions, additional tests to classical intelligence scales (WISC, WPPSI) should be useful to better describe specific neuropsychological profile.

Previous studies have shown that human liver stem-like cells (HLSCs) may undergo differentiation in vitro into urea producing hepatocytes and in vivo may sustain liver function in models of experimentally induced acute liver injury. The aim of this study was to assess the safety of HLSCs intrahepatic administration in inherited neonatal-onset hyperammonemia. The study was approved by the Agenzia Italiana del Farmaco on favorable opinion of the Italian Institute of Health as an open-label, prospective, uncontrolled, monocentric Phase I study (HLSC 01–11, EudraCT-No. 2012–002120-33). Three patients affected by argininosuccinic aciduria (patient 1) and methylmalonic acidemia (patients 2 and 3) and included in the liver transplantation list were enrolled. In all patients, HLSCs were administered by percutaneous intrahepatic injections (once a week for two consecutive weeks) within the first months of life. The first patient received 125,000 HLSCs x gram of liver/dose while the other two patients received twice this dose. No immunosuppression was administered since HLSCs possess immunomodulatory activities. None of the patients experienced infections, hyperammonemia decompensation, or other adverse events during the whole observation period. No donor specific antibodies (DSA) against HLSCs were detected. Patients were metabolic stable despite an increase (~30%) in protein intake. Two patients underwent liver transplantation after 19 and 11 months respectively, and after explantation, the native livers showed no histological alterations. In conclusion, percutaneous intrahepatic administration of HLSCs was safe in newborn with inherited neonatal-onset hyperammonemia. These data pave the way for Phase II studies in selected inherited and acquired liver disorders.

Background Interstitial lung disease (ILD) evaluation is challenging, given the low sensitivity of X-ray and pulmonary function tests, and limited accessibility and radiation linked to repetitive HRCT. Lung Ultrasound (US) has shown potential in the evaluation of ILD of autoimmune diseases including systemic sclerosis. Objectives To define and asses the reliability of definitions of US-detected findings in ILD. Methods A taskforce (TF) within the OMERACT US WG performed a literature review (LR) to identify US lesions in ILD, a Delphi exercise to define these lesions and a web-based exercise to test the reliability of these definitions by using either intraclass correlation coefficient (ICC) or kappa statistics. Prior to the Delphi exercise all participants received training files and were subsequently asked to provide clips on BL, PLI and normal findings. Based on the results of the LR, which identified B-lines (BL) and pleural line irregularity (PLI) as main US findings in ILD, the Delphi exercise contained statements on US definitions on BL and PLI. After reaching agreement (> 75%) on the above mentioned items, a set of 80 high-quality clips (30 for PLI, 50 for BL), was selected and distributed to the TF members in order to score them (semiquantitatively, 0-2 for PLI and total number for BL) Results The 3 Delphi rounds and the web-based exercise were completed by 24 and 22 sonographers, respectively. Final definitions are reported in Table I. The web-based exercise showed moderate inter-reader reliability for both BL (ICC=0.61) and PLI (kappa=0.69). Table I: definitions of PLI and BL Pleural line irregularity (PLI): a loss of regularity that may be associated with an increase in thickness, focal, diffuse, or nodular B-line (BL): a vertical hyperechoic reverberation artifacts that arise from the pleural line, extend to the bottom of the screen without fading, and move synchronously with lung sliding Conclusion US is a candidate imaging modality to identify and monitor ILD in rheumatic diseases; US consensus based definitions of main US findings were defined and endorsed. Further development is planned for validating US as an outcome measurement instrument for ILD. Disclosure of Interests Andrea Delle Sedie Speakers bureau: Abbvie, UCB, Celgene, MSD, Lene Terslev Speakers bureau: Speakers fee from : Roche, Novartis, Pfizer, MSD, BMS, Celgene, George Bruyn : None declared, Tomas Cazenave: None declared, stavros chrysidis: None declared, Mario Diaz: None declared, Marco Di Carlo: None declared, Marilena Frigato: None declared, Luna Gargani: None declared, Marwin Gutierrez: None declared, ALOJZIJA HOCEVAR: None declared, Annamaria Iagnocco: None declared, Aaron Juche: None declared, Peter Mandl: None declared, Esperanza Naredo Consultant for: Abbvie, Speakers bureau: AbbVie, Roche, Bristol-Myers Squibb, Pfizer, UCB, Lilly, Novartis, Janssen, and Celgene GmbH, Mohammed A Mortada: None declared, Carlos Pineda: None declared, Francesco Porta: None declared, Viviana Ravagnani: None declared, Carlo Alberto Scire: None declared, Teodora Serban: None declared, Kate Smith: None declared, Maria Stoenoiu Grant/research support from: Abbvie, Roche, Wyeth, Marika Tardella: None declared, Karina Torralba: None declared, Richard Wakefield: None declared, Maria-Antonietta d’Agostino: None declared

Liver transplant (LT) is a therapeutic option for a growing number of inborn errors of metabolism (IEM), including some disorders not confined to the liver. Clinical advantages of LT in maple syrup urine disease (MSUD), methylmalonic acidemia (MMA), and argininosuccinic aciduria (ASA) have been reported. However, no information on the early metabolic effect of LT after portal reperfusion is available in these disorders. Here we describe the intraoperative differential metabolic outcome of LT in MSUD, MMA, and ASA. In these IEM, LT promptly cleared toxic metabolites to safe concentrations. In MSUD, leucine concentration reached physiological concentration within 12 hours after portal reperfusion. In MMA and ASA, LT allowed faster clearance of methylmalonate and argininosuccinate, respectively, both dropping by ∼90% within the first hour after portal reperfusion. The early biochemical benefits of LT in MSUD, MMA, and ASA demonstrate its immediate effectiveness in protecting patients from intercurrent metabolic decompensations.

ObjectiveTo evaluate the level of agreement on ultrasonographic (US) lesions among highly experienced sonographers as well as the intraobserver and interobserver reliability of inflammatory and structural US lesions in patients with osteoarthritis (OA) of the foot.MethodsAfter a systematic literature review, a Delphi survey was performed to test definitions of US lesions in OA of the foot, including inflammatory lesions (ie, synovial hypertrophy [SH], joint effusion [JE], power Doppler signal [PD]), and structural abnormalities (ie, cartilage damage [CD] and osteophytes). Subsequently, the reliability of US in assessing the aforementioned lesions was tested on static images as well as during a live exercise. Reliability was assessed by kappa analyses and prevalence-adjusted bias-adjusted kappa (PABAK) on a dichotomous and an ordinal scale.ResultsIntraobserver and interobserver reliability for SH and JE evaluated by binary scoring was good for both components, while the intraobserver reliability for semiquantitative scoring of SH ranged from moderate in the web-based exercise (PABAK 0.49) to good (PABAK 0.8) in the live exercise. Reliability for CD and PD assessments were respectively good and excellent in all exercises (ranged from PABAK 0.61 to 0.79 for CD and 0.88 to 0.95 for PD). The interobserver reliability for the semiquantitative scoring of osteophytes was fair in the live exercise (PABAK 0.36) and moderate in the static exercise (PABAK 0.60).ConclusionsConsensual US definitions were found to be reliable for assessing inflammatory lesions in OA of the foot, while the use of US to assess structural damage requires further studies.

Background:According to guidelines, the use of steroid and/or hyaluronate (HA) intra-articular injections for knee osteoarthritis (KOA) is controversial. Heterogeneity of studies and difference in HAs characteristics does not allow to draw safe conclusions. One of the major concerns is the accuracy of the procedure as up to 1/3 of injections could miss joint space when performed blindly (1), negatively affecting the efficacy of HA that needs to be placed correctly in the joint spaceObjectives:The aim of our study was to evaluate the longterm efficacy of a novel association of a Cross-Linked Sodium Hyaluronate Combined With Triamcinolone Hexacetonide (SHCTH) in patients with KOA in a real life setting.Methods:We retrospectively evaluated the clinical and ultrasonographic (US) data of patients (pts) affected by symptomatic KOA with intra-articular injections of SHCTH (1 injection every 6 months). Pts with concomitant inflammatory arthropaties were excluded. US guidance was carried out with the “in plane” technique choosing either the lateral suprapatellar or midpatellar approach. All pts were evaluated for pain with a VAS 0-10 for pain at baseline and after 2 weeks, 1, 3, 6, 9 and 12 months, with the WOMAC questionnaire and with US, scoring joint effusion, synovial hypertrophy (SH) and power Doppler (PD) synovial signal. Due to the retrospective design, the WOMAC data were available as VAS or Likert scales; to allow comparability these values were standardized. Clinical and US variables at different time points were compared using the Wilcoxon rank sing test, the McNemar test or the paired samples t-test, depending on the variable.Results:49 knees (43 pts, median age 70.6 years, 24 women) were included in the study. Kellgren Lawrence grade was 1 for 5 knees, 2 for 10, 3 for 17 and 4 for 9. SHCTH was delivered correctly in the joint space in all patients as assessed by US check during the injection and no side effects occurred. Of the 49 knees, 28 had an available 6 months follow-up, while 21 completed the 12 months follow-up, with an attrition mostly related to the COVID 19 pandemic. A rapid and sustained statistically significant decrease of both VAS pain and the WOMAC subscales was observed. The reduction of pain was already significant at 2 weeks, probably thanks to the corticosteroid component. At US evaluation, effusion significantly decreased at all time points. Although SH scores also significantly decreased, the effect on the proportion of affected joints was not as relevant. The reduction of PD was significant until month 9. Detailed results are presented in Table 1.Conclusion:Our data show that US guided SHCTH injections provide a rapid and sustained clinical response in patients with symptomatic OA. Besides the effect on pain, the US data confirm the effect of the drug on the inflammation. US guidance guaranteed the correct placement of the product in all patients and eliminated the bias of wrong placement that may occur with blind injections, thus allowing to draw safe conclusions on the efficacy of SHCTH for the treatment of KOA.References:[1]Jones A, Regan M, Ledingham J, et al. Importance of placement of intra-articular steroid injections. BMJ 1993;307:1329–30.Table 1.Table 1. Clinical and US measures. p values refer to the comparison with baseline. WOMAC subscales were compared by paired samples t test. *hypothesis test not applicablebaseline2 weeks1 month3 months6 months9 months12 monthsVAS (median,IQR)6 (5-8)3 (1-4.25) p2 (0.5-3-5) p1.5 (0-3) p1.5 (0-4) p1 (0-2.75) p1 (0-3.25) pWOMAC pain--p 0.028p 0.0004p 0.0036p 0.0096p 0.0064WOMAC stiffness--p 0.048p 0.040p 0.0388pp 0.0083WOMAC function--p 0.043p 0.0005p 0.0014p 0.01p 0.007Effusion 0-3 (median,IQR)2 (1-2)-1 (0-1) p1 (0-1) p1 (0-1) p 0.00010 (0-1) p1 (0-1) pSynovial Hypertrophy 0-3 (median,IQR)1 (1-2)-1 (1-1) p 0.0021 (1-1) p 0.00011 (1-1) p 0.00011 (0-1) p 0.00011 (0.5-1) p 0.0001PD 0-3 (median,IQR)0 (0-0)-0 (0-0) p 0.030 (0-0) p 0.030 (0-0) P 0.061 (0-1) p 0.010 (0-0) p 0.31Disclosure of Interests:None declared.

Background:Imaging has been extensively used for the Calcium Pyrophosphate Deposition Disease (CPPD) diagnosis but the prevalence of joint calcifications at imaging in CPPD patients has not been thoroughly assessed.Objectives:This systematic literature review (SLR) is aimed to estimate the prevalence of calcium crystal deposition in peripheral joints by imaging in suspected or definite CPPD patients to establish relevant joints for CPPD monitoringMethods:After defining PICOs, Pubmed and Embase were searched from inception to October 2020 for identifying studies that evaluated the use of Conventional Radiography (CR), Ultrasound (US), Computed Tomography (CT) and Dual Energy Computed Tomography (DECT) in detecting calcifications at peripheral joints in patients with defined or probable CPPD. Search strategies based on MeSH terms and free text were applied. Six reviewers independently screened titles and abstracts, eligible article full texts were evaluated for inclusion and data extraction.Results:The SLR identified 1149 manuscripts. 524 papers entered in the full text evaluation and 181 articles were finally included. Considering excluded abstracts and full texts, 23 and 17 were excluded as duplicate, 156 and 9 for language, 171 and 48 for population, 171 and 20 for intervention, 57 and 117 for outcome, 47 and 70 for study type and 76 for full text unavailability. Among included, 41 papers considered patients with definite CPPD with a total population of 1239 patients, 908 cases and 331 controls and 140 papers referred to patients with suspected CPPD with a total population of 26785 patients, 2896 affected by CPPD and 23889 controls. The results about all joints are summarized in the Table 1. In patients with definite diagnosis, knee and wrist are the joints with the highest prevalence of calcifications at all imaging types, followed by hip and acromion-clavicular joint while in patients with suspected CPPD, the knee is the most prevalent followed by the wrist, hip and ankle (only sites with more than 50 patients assessed considered). The hand joints are characterized by CPPD lowest prevalence at imaging. Bilateral imaging findings varies depending on the technique used, the site and the patient’s type.Table 1.Definite CPPD DiagnosisKNEEWRISTHANDELBOWSHOULDERACHIPANKLEFOOTTMXRImaging positive cases/all cases330/584 57%214/409 52%43/158 27%54/212 25%65/249 26%37/84 44%140/293 48%30/255 12%15/59 25%0Cases positivebilaterally99/146 68%30/79 38%0/104/12 33%2/2 100%9/17 53%7/10 70%7/10 70%00USImaging positive cases/all cases155/252 62%86/118 75%4/42 9%2/2 100%0/304/30 13%47/80 59%30/255 12%15/59 25%0Cases positivebilaterally83/96 86%33/47 70%1/ 4 25%003/ 4 75%29/47 62%7/10 70%00CTImaging positive cases/all cases41/50 82%22/28 78%00000000Cases positivebilaterally27/30 90%000000000DECTImaging positive cases/all cases8/10 80%9/10 90%1/1 100%0000000Cases positivebilaterally001/1 100%0000000Suspected CPPD diagnosisKNEEWRISTHANDELBOWSHOULDERACHIPANKLEFOOTTMXRImaging positive cases/all cases1989/2442 81%549/1024 54%98/602 16%29/72 40%75/185 41%27/31 87%322/887 36%56/116 48%24/42 57%0Cases positive bilaterally611/1068 57%209/334 63%64/85 75%22/23 96%41/46 89%0/294/196 48%44/53 83%18/19 95%0USImaging positive cases/all cases241/261 93%125/185 68%2/39 5%1/1 100%4/12 33%02/2 100%27/78 35%8/37 22%0Cases positivebilaterally4/9 44%74/93 80%00000000CTImaging positive cases/all cases019/23 83%002/2 100%02/2 100%001/1 100%Cases positivebilaterally0000000001/1 100%DECTImaging positive cases/all cases1/1 100%2/2 100%00000000Cases positivebilaterally1/1 100%000000000Table 1 For each joint, are summarized the ratio between positive joints and overall evaluated joints and the ratio between the joints positive bilaterally and overall joints evaluated bilaterally.AC Acromion Clavicular, TM temporo mandibularConclusion:According to the results of this SLR, knees and wrists could be the sentinel joints for CPPD detection by imaging.Disclosure of Interests:None declared.

Introduction: Viscosupplementation with hyaluronic acid (HA) is indicated for non-responders to non-pharmacological therapy, to analgesics or when non-steroidal anti-inflammatory drugs (NSAIDs) are contraindicated. The aim of this study is to compare the efficacy, safety and costs of three different HA treatments ( Sinovial® Forte, sinovial one and hyalgan). Patients and methods: Ninety patients with grade I/II Kellgren–Lawrence knee osteoarthritis were included in three groups, the first was treated with hyalgan (weekly for 5 weeks), the second with Sinovial® Forte (weekly for 3 weeks) and the third group with a single injection of sinovial one. Results: All three treatments were effective, with an average reduction in the Western Ontario and McMaster Universities osteoarthritis index (WOMAC) score of 18.9 points for hyalgan, 18.04 points for Sinovial® Forte and 17.92 points for sinovial one. The comparison of the three groups did not show any statistical difference in terms of efficacy. National health system (NHS) and social costs are, respectively, €419.12 and €853.43 for hyalgan, €338.64 and €599.22 for Sinovial® Forte, €221.56 and €308.42 for sinovial one. Conclusion: All three treatments were equally effective with no statistically significant differences; thus, the treatment with sinovial one may be considered as clinically effective as the other two regimens, but with a very efficient cost profile in early symptomatic knee osteoarthritis.

Background Short/branched-chain acyl-CoA dehydrogenase (SBCAD) deficiency is a rare inborn error of metabolism with uncertain clinical significance. As it leads to C5-carnitine (i.e. isovalerylcarnitine, 2methylbutyrilcarnitine, or pivaloylcarnitine) elevation, SBCAD deficiency is detectable at newborn screening, requiring differential diagnosis from isovaleric acidemia and pivalic acid administration. Increased urinary excretion of 2-methylbutyrylglycine (2MBG) is the hallmark of SBCAD deficiency. Methods We report two cases of SBCAD deficiency and provide a review of the available literature on this condition. Results Two siblings newly diagnosed with SBCAD deficiency are reported. Newborn screening allowed the early diagnosis in the second-born (C5=0.5 μmol/L, normal 0.05–0.3 μmol/L) and addressed selective screening in the 5-year asymptomatic brother (C5=1.9 μmol/L). Both patients showed increased urinary excretion of 2MBG and two mutations in the ACADSB gene (c.443C>T/c.1145C>T). Currently, both the patients are asymptomatic. Longitudinal biochemical monitoring of the two patients while on treatment with carnitine (100 mg/kg/day) was provided. Based on our experience and the literature review (162 patients), SBCAD deficiency is symptomatic in about 10% of reported patients. Clinical onset occurs in newborns or later in life with seizures, developmental delay, hypotonia, and failure to thrive. On longitudinal follow-up, epilepsy, developmental delay, microcephaly, and autism can develop. Acute metabolic decompensation due to catabolic stressors can occur, as observed in one newly reported patient. Fifteen mutations in the ACADSB gene are known, including the newly identified variant c.1145C>T (p.Thr382Met), variably associated to the phenotype. In the Hmong population, SBCAD deficiency is highly prevalent, mostly due to the founder mutation c.1165A>G, and is largely asymptomatic. Conclusions Although mostly asymptomatic, considering SBCAD deficiency as a non-disease in non-Hmong subjects appears unsafe. Catabolic situations can precipitate acute metabolic decompensation. Carnitine supplementation and valproate avoidance appear to be indicated. Providing an emergency protocol for the management of acute catabolic episodes seems reasonable in asymptomatic patients with SBCAD deficiency. Longitudinal follow-up is recommended.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive metabolic disorder of GABA catabolism. SSADH is a mitochondrial homotetrameric enzyme encoded by ALDH5A1 gene. We report the molecular characterization of ALDH5A1 gene in an Italian SSADHD patient, showing heterozygosity for four missense mutations: c.526G>A (p.G176R), c.538C>T (p.H180Y), c.709G>T (p.A237S) and c.1267A>T (p.T423S), the latter never described so far. The patient inherited c.526A in cis with c.538T from the mother and c.709T in cis with c.1267T from the father. To explore the effects of the two allelic arrangements on SSADH activity and protein level, wild type, single or double mutated cDNA constructs were expressed in a cell system. The p.G176R change, alone or in combination with p.H180Y, causes the abolishment of enzyme activity. Western blot analysis showed a strongly reduced amount of the p.176R-p.180Y double mutant protein, suggesting increased degradation. Indeed, in silico analyses confirmed high instability of this mutant homotetramer. Enzyme activity relative to the other p.423S-p.237S double mutant is around 30% of wt. Further in silico analyses on all the possible combinations of mutant monomers suggest the lowest stability for the tetramer constituted by p.176R-p.180Y monomers and the highest stability for that constituted by p.237S-p.423S monomers. The present study shows that when a common SNP, associated with a slight reduction of SSADH activity, is inherited in cis with a mutation showing no consequences on the enzyme function, the activity is strongly affected. In conclusion, the peculiar arrangement of four missense mutations occurring in this patient is responsible for the SSADHD phenotype.