Twice weekly dosing with Sebelipase alfa (Kanuma®) rescues severely ill infants with Wolman disease.

BACKGROUND: Sebelipase alfa (Kanuma®) is approved for patients with Wolman disease (WD) at a dosage of 3-5 mg/kg once weekly. Survival rates in the second of two clinical trials was greater, despite recruiting more severely ill patients, probably related to higher initial and maximal doses. We aimed to evaluate the effective pharmacokinetics and pharmacodynamics of Sebelipase alfa when administered to patients with severe WD at 5 mg/kg twice weekly, an intensive regimen which was not assessed in the trials. METHODS: We recruited 3 patients receiving Sebelipase alfa 5 mg/kg twice weekly. We measured LAL activity in leukocytes and plasma oxysterol concentration in two patients and LAL activity in fibroblasts in one patient. Clinical follow up was also assessed. RESULTS: Analyses of LAL activity and oxysterols demonstrate that there is short-lived enzyme activity post-dosing which is associated with the release of stored lipids. Clinical data demonstrate that 5 mg/kg twice weekly dosing is well tolerated and effective. CONCLUSION: 5 mg/kg twice weekly dosing with Sebelipase alfa rescues severely ill infants with WD by increasing substrate clearance. There is biologically relevant lipid accumulation in the 'trough' periods before the next dosing, even with this intensive regimen.

Real life data: follow-up assessment on Spanish Gaucher disease patients treated with eliglustat. TRAZELGA project.

BACKGROUND: The availability of multiple treatments for type 1 Gaucher disease increases the need for real-life studies to evaluate treatment efficacy and safety and provide clinicians with more information to choose the best personalized therapy for their patients. AIMS: To determine whether treatment with eliglustat produces, in adult GD1 patients, ans optimal response in daily clinical practice. METHODS: We designed a real-life study with 2 years of follow-up (TRAZELGA [GEE-ELI-2017-01]) to uniformly evaluate the response and adverse events to eliglustat treatment. This study, conducted in 30 patients across Spain and previously treated with other therapies, included the evaluation of safety and efficacy by assessing visceral enlargement, bone disease (DEXA and T and Z scores), concomitant treatments and adverse events, as well as a quality of life evaluation (SF-36). In addition, the quantification of classical biomarkers (chitotriosidase activity, CCL18/PARC and glucosylsphingosine (GluSph)) and new candidates for GD biomarkers (YKL-40, cathepsin S, hepcidin and lipocalin-2 determined by immunoassay) were also assessed. Non-parametric statistical analysis was performed and p < 0.05 was considered statistically significant. MAIN RESULTS: Thirty patients were enrolled in the study. The median age was 41.5 years and the male-female ratio was 1.1:1. 84% of the patients had received ERT and 16% SRT as previous treatment. The most common symptoms at baseline were fatigue (42%) and bone pain (38%), no patient had a bone crisis during the study, and two years after switching, 37% had reduced their use of analgesics. Patient-reported outcomes showed a significant increase in physical function scores (p = 0.027) and physical pain scores (p = 0.010). None of the enrolled patients discontinued treatment due to adverse events, which were mild and transient in nature, mainly gastrointestinal and skin dryness. None of the biomarkers show a significant increase or decompensation after switching. CCL18/PARC (p = 0.0012), YKL-40 (p = 0.00004) and lipocalin-2 (p = 0.0155) improved after two years and GluSph after one year (p = 0.0008) and two years (p = 0.0245) of oral therapy. CONCLUSION: In summary, this real-life study, showed that eliglustat maintains stability and can improve quality of life with few side effects. Significant reductions in classic and other novel biomarkers were observed after two years of therapy.

Accuracy and prognostic impact of FDG PET/CT and biopsy in bone marrow assessment of follicular lymphoma at diagnosis: A Nation-Wide cohort study.

BACKGOUND: In the workup of follicular lymphoma (FL), bone marrow biopsy (BMB) assessment is a key component of FLIPI and FLIPI2, the most widely used outcome scores. During the previous decade, several studies explored the role of FDG-PET/CT for detecting nodal and extranodal disease, with only one large study comparing both techniques. METHODS: The aim of our study was to evaluate the diagnostic accuracy and the prognostic impact of both procedures in a retrospective cohort of 299 FL patients with both tests performed at diagnosis. In order to avoid a collinearity bias, FLIPI2 was deconstructed in its founding parameters, and the bone marrow involvement (BMI) parameter separately included as: a positive BMB, a positive PET/CT, the combined "PET/CT and BMB positive" or "PET/CT or BMB positive". These variables were also confronted independently with the POD24 in 233 patients treated with intensive regimens. RESULTS: In the total cohort, bone marrow was involved in 124 and 60 patients by BMB and PET/CT, respectively. In terms of overall survival, age > 60 y.o. and the combined "PET/CT or BMB positive" achieved statistical independence as a prognostic factor. In patients treated with an intensive regimen, only the combined "PET/CT or BMB positive" added prognostic value for a shorter overall survival, when confronted with the POD24. CONCLUSION: Our results show that in FL both BMB and PET/CT should be considered at diagnosis, as their combined assessment provides independent prognostic value in the context of the most widely use clinical scores.

Serum Phospholipid Profile Changes in Gaucher Disease and Parkinson's Disease.

Alterations in the levels of serum sphingolipids and phospholipids have been reported in Gaucher disease and in Parkinson's disease, suggesting a potential role of these lipids as biomarkers. This project's objective is to detect novel associations and novel candidate biomarkers in the largest Spanish Gaucher and Parkinson diseases of the Iberian Peninsula. For that, 278 participants were included: 100 sporadic Parkinson's patients, 70 Gaucher patients, 15 GBA1-mutation-carrier Parkinson's patients and 93 controls. A serum lipidomics array including 10 phospholipid groups, 368 species, was performed using high-performance liquid chromatography-mass spectrometry. Lipid levels were compared between groups via multiple-regression analyses controlling for clinical and demographic parameters. Additionally, lipid levels were compared within the Gaucher and Parkinson's groups controlling for medication and/or disease severity. Results were controlled for robustness by filtering of non-detectable lipid values. There was an increase in the levels of phosphatidylcholine, with a simultaneous decrease in lyso-phosphatidylcholine, in the Gaucher, Parkinson's and GBA1-mutation-carrier Parkinson's patients vs. controls. Phosphatidylethanolamine, lyso- and plasmalogen-phosphatidylethanolamine were also increased in Gaucher and Parkinson's. Gaucher patients also showed an increase in lyso-phosphatidylserine and phosphatidylglycerol. While in the Gaucher and Parkinson's groups, velaglucerase alpha and dopamine agonists, respectively, showed positive associations with the lipid changes, miglustat treatment in Gaucher patients normalized the altered phosphatidylcholine/lyso-phosphatidylcholine ratio. In conclusion, Gaucher and Parkinson's patients showed changes in various serum phospholipid levels when compared with healthy controls, further supporting the role of such lipids in disease development and, possibly, as putative biomarkers. This hypothesis was reinforced by the normalizing effect of miglustat, and by controlling for data robustness, even though the limited number of participants, especially in the sub-distribution by treatment groups in GD requires validation in a larger number of patients.

Gaucher Disease: Identification and Novel Variants in Mexican and Spanish Patients.

BACKGROUND: Gaucher disease (GD) is the most prevalent lysosomal storage disorder, affecting all ethnic groups, although its prevalence is higher in Ashkenazi Jewish populations. Three clinical forms of GD have been described: Type 1 non-neuronopathic, type 2 acute neuronopathic, and type 3 subacute neuronopathic. An autosomal recessive disorder is caused by variants in the human glucocerebrosidase gene (GBA; MIM*606463) located on chromosome 1q21, resulting from deficit or lack of activity of the ß-glucocerebrosidase enzyme, leading to the accumulation of glucocerebroside substrate in the cells of the macrophage-monocyte system. The aim was to determine variants in Mexican and Spanish populations with GD. METHODS: We report the molecular analysis by a direct automatic method sequenced of both chains of the GBA gene, in 69 Mexican and 369 Spanish patients with GD. RESULTS: We detected 75 variants with pathogenic or likely pathogenic effect and, identified 3 new variants c.408_412del/p.Asn136Lysfs*15; c.820G>A/p.Glu274Lys and c.1058T>G/p*. The most frequent variants were c.1448T>C/p.Leu483Pro/L444P and c.1226A>G/p.Asn409Ser/N370S. The detected genotypes were compared with data from both GD registries to define similarities and differences in both populations. CONCLUSIONS: We defined the variant profile in patients with GD in a Mexican and a Spanish population and compared them. The screening permitted the detection of common variants and the report of three new variants, in addition to a variant associated with Parkinson disease but not with GD. Since molecular diagnosis has considerable predictive value in GD, it is important to study the genotype-phenotype correlations, establishing the severity of the variant.

Assessing tumor response to neoadjuvant chemoradiation in rectal cancer with rectoscopy and 18F-FDG PET/CT: results from a prospective series.

INTRODUCTION: rectoscopy and 18F-FDG PET/CT as a diagnostic algorithm for the assessment of tumor response in rectal cancer after neoadjuvant chemoradiation therapy (CRT) is very useful. MATERIAL AND METHODS: this was a prospective longitudinal study in patients with locally advanced rectal cancer treated with neoadjuvant CRT. Patients were assessed after CRT completion with a digital rectal examination, proctoscopy and 18F-FDG PET/CT. Patients were subdivided as clinical (cCR) or radiologic (rCR) responders and non-responders according to tumor response. Clinical and radiological re-assessment was compared with the surgical specimen. Pathological tumor regression (pCR) grade was determined according to Mandard's classification. Of the 68 patients included, 15 (22 %) presented pCR in the surgical specimen and tumor persistence (non-PCR) was detected in the remaining 53 (78 %). Clinical assessment (DRE+ rectoscopy) identified 15 patients as cCR and 53 as non-cCR, two were false positives and two were false negatives. The overall accuracy was 94 %. 18F-FDG PET/CT identified 18 patients as rCR and 50 as non-rCR, one was a false positive and four were false negatives. The overall accuracy was 92 %. A combination of clinical findings and 18F-FDG PET/CT resulted in an accuracy of 96 %. The combination of clinical findings + 18F-FDG PET/CT was able to correctly identify all cases of pCR, with the exception of one case that presented a tumor regression of 80 %. In this series, 18F-PET-CT and clinical assessment had excellent accuracies in differentiating PCR from non-PCR after CRT completion. PET-CT combined with clinical assessment had a better accuracy than both modalities independently. 18F-FDG PET/CT is a valid tool that complements the clinical assessment of tumor response.

Identification of risk features for complication in Gaucher's disease patients: a machine learning analysis of the Spanish registry of Gaucher disease.

BACKGROUND: Since enzyme replacement therapy for Gaucher disease (MIM#230800) has become available, both awareness of and the natural history of the disease have changed. However, there remain unmet needs such as the identification of patients at risk of developing bone crisis during therapy and late complications such as cancer or parkinsonism. The Spanish Gaucher Disease Registry has worked since 1993 to compile demographic, clinical, genetic, analytical, imaging and follow-up data from more than 400 patients. The aims of this study were to discover correlations between patients' characteristics at diagnosis and to identify risk features for the development of late complications; for this a machine learning approach involving correlation networks and decision trees analyses was applied. RESULTS: A total of 358 patients, 340 type 1 Gaucher disease and 18 type 3 cases were selected. 18% were splenectomyzed and 39% had advanced bone disease. 81% of cases carried heterozygous genotype. 47% of them were diagnosed before the year 2000. Mean age at diagnosis and therapy were 28 and 31.5 years old (y.o.) respectively. 4% developed monoclonal gammopathy undetermined significance or Parkinson Disease, 6% cancer, and 10% died before this study. Previous splenectomy correlates with the development of skeletal complications and severe bone disease (p = 0.005); serum levels of IgA, delayed age at start therapy (> 9.5 y.o. since diagnosis) also correlates with severe bone disease at diagnosis and with the incidence of bone crisis during therapy. High IgG (> 1750 mg/dL) levels and age over 60 y.o. at diagnosis were found to be related with the development of cancer. When modelling the decision tree, patients with a delayed diagnosis and therapy were the most severe and with higher risk of complications. CONCLUSIONS: Our work confirms previous observations, highlights the importance of early diagnosis and therapy and identifies new risk features such as high IgA and IgG levels for long-term complications.

Serum protein profile analysis in lysosomal storage disorders patients.

INTRODUCTION: Serum protein electrophoresis (SPE) is a well-established technique to identify alterations in plasma protein profiles, caused by diseases as multiple myeloma (MM). In addition, it could be a cost-effective technique to discover new plasma biomarkers. Relation between MM and lysosomal storage diseases (LSDs) as Gaucher disease has been set out but, it has not been evaluated on other LSDs nor the utility of the SPE as first step on LSDs biomarkers discovery projects. MATERIALS AND METHODS: Stored plasma samples at diagnosis from several LSDs patients underwent analysis. Quality control was checked prior to the SPE was analyzed by capillary electrophoresis. The analysis for monoclonal spikes and the differences between each fraction on patients' samples vs the control data previously published, were evaluated. Furthermore, immunoprotein quantification and free light chains ratio were done by nephelometry and turbidimetry. RESULTS: Seventy-five samples of LSD patients at diagnosis, were assessed. The frequency of the MGUS on LSDs patients was not higher than in general population whereas one lysosomal acid lipase deficiency infant showed increased IgA and kappa deviation. Regarding to the usefulness of SPE in biomarkers discovery, statistically significant differences were observed on SPE fractions between LSDs and healthy population. DISCUSSION: The evaluation of SPE fractions can be a useful tool to understand pathophysiologic aspects in LDSs and, to simplify new marker discovery projects. In some of them, the MGUS appearance is a risk factor for the MM development despite its frequency is not increased on the studied LSDs at diagnosis.

Direct and indirect effects of the SARS-CoV-2 pandemic on Gaucher Disease patients in Spain: Time to reconsider home-based therapies?

OBJECTIVE: An analysis of the SARS-CoV-2 pandemic impact in the Spanish Gaucher Disease (GD) community is presented here. PATIENTS & METHODS: The Spanish GD foundation (FEETEF) surveyed 113 GD patients from March 30 to April 27; all patients provided a verbal consent. RESULTS: 110 surveys were analyzed. The median age was 47 years old (y.o.), 31 patients were ≥ 60 y.o.; and 34% of patients reported comorbidities. 46% (51/110) of patients were treated by enzyme replacement therapy (ERT), 48 of them at hospitals; 45.1% (45/110) were on substrate reduction therapy (SRT) and 9% (10/110) receive no therapy. 25% (11/48) of ERT-hospital-based patients reported therapy interruptions, while SRT-patients did not report missing doses. No bone crises were reported. However, 50% (55/110) of patients reported being worried about their predisposition to a severe SARS-COV-2 infection and 29% (16/55) of them took anxiolytics or antidepressants for this. While 6 patients reported to have contact with an infected person, another two confirmed SARS-CoV-2 infections were reported in splenectomyzed patients, one of them (a 79-year-old diabetic) died. CONCLUSIONS: One quarter of the patients treated at hospitals reported dose interruptions. Home-based therapy may need to be considered in order to minimize the impact of the COVID-19 pandemic.

Allelic and phenotypic characterization of CYP2D6 and its encoded P450 cytochrome enzyme in a serie of Spanish type 1 Gaucher disease patients.

BACKGROUND: Cytochrome p450 is the main drug metabolic pathway. CYP2D6 is a highly polymorphic gene that encodes a cytochrome p450 enzyme with three activity levels: null, reduced and normal. Apart from another type of mutations CYP2D6 can suffer duplications and deletions of the entire gene. This is the pathway to metabolize one of the Gaucher disease treatments, whose dose administration is regulated according to the metabolizer phenotype, this being one of the administration limitations. OBJECTIVES: The aim of this paper is to evaluate the allelic frequencies and the metabolizer status of Gaucher type 1 patients in the Spanish population and compare it with the general Spanish population and other Gaucher disease groups. METHODS: In this study, 109 type 1 Gaucher disease patients were analyzed with the xTAG®CYP2D6 kit to identify the CYP2D6 gene alleles. RESULTS: We observed that eighty-seven patients could be classified as extensive, 14 as intermediate, 6 as poor and 2 as ultra-rapid metabolizers. The allelic duplication frequency is 5.5% and deletion is 4.5%. The most common allele is wild-type and the second is the null *4 allele. Intermediate phenotype frequency is higher than expected (p<0.05). CONCLUSIONS: Our Spanish GD series shows an unexpected distribution of some alleles and phenotypic metabolizer status, in contrast to that previously reported in the Spanish population.

LC-MS/MS analysis of plasma glucosylsphingosine as a biomarker for diagnosis and follow-up monitoring in Gaucher disease in the Spanish population.

Background Gaucher disease (GD), caused by a deficiency in acid ß-glucosidase, leads to the accumulation of glucosylsphingosine (GluSph), which has been used as a powerful biomarker for the diagnosis and follow-up of GD. Our aim was to perform the first retrospective study of GluSph in Spanish patients, analyzing its relationship with classical biomarkers and other parameters of disease and its utility regarding treatment monitoring. Methods Classical biomarkers were evaluated retrospectively by standard methods in a total of 145 subjects, including 47 GD patients, carriers, healthy controls and patients suffering from other lysosomal lipidoses. GluSph was also measured using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method developed as part of the present study. Results The optimized method presented intra- and inter-assay variations of 3.1 and 11.5%, respectively, overall recovery higher than 96% and linearity up to plasma concentrations of 1000 ng/mL with 100% specificity and sensitivity. Only GD patients displayed GluSph levels above 5.4 ng/mL at diagnosis and this was significantly correlated with the classical biomarkers chitotriosidase (r = 0.560) and the chemokine CCL18/PARC (CCL18/PARC) (ρ = 0.515), as well as with the Spanish magnetic resonance imaging index (S-MRI, r = 0.364), whereas chitotriosidase correlated with liver volume (r = 0.372) and CCL18/PARC increased in patients with bone manifestations (p = 0.005). GluSph levels decreased with treatment in naïve patients. Conclusions Plasma GluSph is the most disease-specific biomarker for GD with demonstrated diagnostic value and responsiveness to therapy. GluSph in the present series of patients failed to demonstrate better correlations with clinical characteristics at onset than classical biomarkers.

New variants in Spanish Niemann-Pick type c disease patients.

Niemann-Pick type C (NPC) disease is a rare inherited disease, with progressive neurodegeneration as the main symptom. It is a lysosomal storage disorder caused by mutations in NPC1 or NPC2 genes, leading to a lysosomal cholesterol trafficking impairment. Disease indicators are the clinical suspicion and biomarker levels. However, a genetic study is mandatory for the diagnosis, which is complicated due to the different variants with unknown significance. The aim of this work was to identify the variants responsible for NPC in our pediatric population. Twenty-two samples from non-related infants believed to have NPC disease were analyzed during the last 3 years. Surrogate biomarkers of the disease were evaluated whenever possible. Sanger sequencing for both genes is reported for all samples. Complementary genetic studies were performed when necessary. NPC disease was confirmed in 31.8% of subjects due to homozygous or compound heterozygous genetic variants in NPC1. The following four novel variants were identified: a gross deletion variant composed of the gene promoter and the first exon, NM_000271.3:c.385delT, NM_000271.3:c.1553+1342_1655-291del, and NM_000271.3:c.1757delA. None had functional activity and all resulted in important structural changes in the protein.

Tenosinovitis de De Quervain: nueva plástica de aumento del continente del primer compartimento dorsal. Estudio anatómico y experiencia clínica inicial / De Quervain tenosynovitis: new enlargement plasty of the first dorsal compartment. Anatomical study and clinical retrospective study

Objetivos: Determinar la viabilidad anatómica del aumento del continente del primer compartimento dorsal y comunicar la ex-periencia clínica de esta nueva técnica comparada con la liberación clásica. materiales y métodos: Estudio anatómico de 12 muñecas cadavéricas para comprobar el aumento del continente del primer compartimento y su relación con la rama sensitiva radial. Estudio clínico retrospectivo que incluyó a pacientes >18 años, sin cirugías previas, con tenosinovitis de De Quervain sin respuesta al tratamiento ortopédico, operados entre enero de 2014 y enero de 2019, y con un seguimiento mínimo de 12 meses. Veintidós pacientes fueron divididos en: grupo A (aumento) y grupo B(liberación simple). La edad promedio era 47 (grupo A) y 50 años (grupo B). La evaluación subjetiva incluyó la escala analógica visual para dolor, el puntaje QuickDASH y el cuestionario de satisfacción PSQ-18; el examen objetivo consistió en evaluaciones goniométrica y dinamométrica. Resultados: El estudio ana-tómico demostró un aumento del continente del primer compartimento dorsal y una íntima relación con la rama sensitiva radial. El seguimiento promedio del estudio clínico fue 24 y 50 meses, en los grupos A y B, respectivamente. El puntaje promedio de la escala analógica visual para dolor fue 0,5/10 (grupo A) y 1/10 (grupo B). El índice de satisfacción fue del 97% en ambos grupos. El puntaje QuickDASH, las evaluaciones goniométrica y dinamométrica no arrojaron diferencias significativas. Conclusión: La nueva plástica de aumento del continente del primer compartimento dorsal para tratar la tenosinovitis de De Quervain en este estudio anatomoclínico resultó eficaz y reproducible. Nivel de Evidencia: III

Objective: To establish the anatomical feasibility of the first dorsal compartment (FDC) enlargement and to report our clinical experience with this new technique compared with the traditional release. materials and methods: Anatomical study of 12 ca-daver wrists to corroborate first compartment enlargement and its relationship to the sensitive branch of the radial nerve. Clinical retrospective study of patients who had undergone surgery between 2014 and 2019 due to De Quervain tenosynovitis (DQT) refractory to nonsurgical management, over 18 years of age, with no previous surgical history and a 12-month minimum follow-up. The 22-patient series was divided into two groups: enlargement (Group A) and simple release (Group B). Average ages were 47 years (Group A) and 50 years (Group B). Subjective outcome was evaluated by the visual analogue scale (VAS) for pain, the Quick-DASH score, and the Patient Satisfaction Questionnaire Short Form (PSQ-18). Objective outcome was evaluated by goniometry and dynamometry tests. Results: The anatomical study proved the increase of the FDC laxity and its close relationship to the sensitive branch of the radial nerve. The clinical study follow-up periods were of 24 months in Group A and 50 months in Groups B. Average VAS scores were 0.5/10 in Group A and 1/10 in Group B). Satisfaction index was 97% in both groups. Quick-DASH scores, and goniometry and dynamometry tests yielded no significant differences. Conclusions: The new enlargement plasty of the FDC for the surgical treatment of DQT in this anatomical and clinical study proved to be a reproducible and effective technique. Level of Evidence: III

Muscle-tendon weakness contributes to chronic fatigue syndrome in Gaucher's disease.

BACKGROUND: Chronic fatigue (CFg) is a prevalent symptom in Gaucher disease (GD) at diagnosis (79%) and remains in a quarter of patients after years of therapy. Bone abnormalities are present in over 70% and peripheral neuropathy in about 11% of the patients, which contributes to the disabling and debilitating complications. Our hypothesis is that other factors such as muscle-tendinous weakness could have influence in the development of CFg. METHODS: We have evaluated the fiber structure and elasticity of muscle-tendinous unit by strain-elastography (S-ELA) and analyzed their influence in the CFg. S-ELA study was performed in Achilles tendon in 25 type 1 and two type 3 GD patients, all of them with fatigue and were on enzymatic replacement therapy for mean 13 years; simultaneously, bone marrow burden by MRI and calcaneus ultrasound densitometry were evaluated. Blood cell counts, plasma biomarkers, GBA1 genotyping, and SF36 quality of life scale (QoL) were also performed. STATISTICAL ANALYSIS: descriptive and comparative test. RESULTS: All patients showed a normal Achilles tendinous structure. Abnormal stiff grade 2-3 was found in 17/27 (62.9%); in 11/27 (40.7%) of patients, the alteration was bilateral. There were no correlations between the S-ELA results to other variables; nevertheless, a significant correlation between the degree of tendon hardness and the low score on the QoL scales (p = 0.0035) was found. The S-ELA is a sensitive painless, fast, and low cost method to detect muscle-tendinous subclinical dysfunction that could contribute to CFg in GD. The identification of subclinical tendon alteration would be a sign of alarm, focused on the risk of development of bone complications. CONCLUSION: Intratendinous alteration in strain-elastography is an independent variable in GD patients with persistent fatigue.

Web-Based Bioinformatics Predictors: Recommendations to Assess Lysosomal Cholesterol Trafficking Diseases-Related Genes.

INTRODUCTION: The growing number of genetic variants of unknown significance (VUS) and availability of several in silico prediction tools make the evaluation of potentially deleterious gene variants challenging. MATERIALS AND METHODS: We evaluated several programs and software to determine the one that can predict the impact of genetic variants found in lysosomal storage disorders (LSDs) caused by defects in cholesterol trafficking best. We evaluated the sensitivity, specificity, accuracy, precision, and Matthew's correlation coefficient of the most common software. RESULTS: Our findings showed that for exonic variants, only MutPred1 reached 100% accuracy and generated the best predictions (sensitivity and accuracy = 1.00), whereas intronic variants, SROOGLE or Human Splicing Finder (HSF) generated the best predictions (sensitivity = 1.00, and accuracy = 1.00). DISCUSSION: Next-generation sequencing substantially increased the number of detected genetic variants, most of which were considered to be VUS, creating a need for accurate pathogenicity prediction. The focus of the present study is the importance of accurately predicting LSDs, with majority of previously unreported specific mutations. CONCLUSION: We found that the best prediction tool for the NPC1, NPC2, and LIPA variants was MutPred1 for exonic regions and HSF and SROOGLE for intronic regions and splice sites.

A Rare Case of Giant Intraperitoneal Lipoma Found Incidentally on 18F-FDG PET/CT in a Patient with Nodular Fasciitis.

We report a case of concurrent nodular fasciitis and incidental giant intraperitoneal lipoma diagnosed on whole-body 18F-FDG PET/CT, an imaging modality that has the advantage of being able to detect unsuspected lesions.

Food Components with the Potential to be Used in the Therapeutic Approach of Mental Diseases.

BACKGROUND: Neurological disorders represent a high influence in our society throughout the world. Although the symptoms arising from those diseases are well known, the causes and mechanisms are complex and depending on multiple factors. Some food components consumed as part of our diet have been studied regarding their incidence in different common neurological diseases such as Alzheimer disease, major depression, Parkinson disease, autism and schizophrenia among others. OBJECTIVE: In this review, information has been gathered on the main evidences arising from studies on the most promising food components, related to their therapeutic potential, as part of dietary supplements or through the diet, as an alternative or a complement of the traditional drug treatments. Those food components include vitamins, minerals, fatty acids, carotenoids, polyphenols, bioactive peptides, probiotics, creatine and saponins. RESULTS: Many in vitro and in vivo animal studies, randomized and placebo control trials, and systematic reviews on the scientific results published in the literature, have been discussed, highlighting the more recent advances, also with the aim to explore the main research needs. Particular attention has been paid to the mechanisms of action of the compounds regarding their anti-inflammatory, antioxidative properties and neuronal protection. CONCLUSION: More research is needed to prove the therapeutic potential of the food components based on scientific evidence, also on intervention studies to demonstrate the improvement of neuronal and cognitive impairments.

Gaucher disease and chronic myeloid leukemia: first reported patient receiving enzyme replacement and tyrosine kinase inhibitor therapies simultaneously.

Report a female diagnosed as type 1 Gaucher disease after a femoral pathologic fracture when she was 55 years old. Enzyme replacement therapy was started, and she achieved therapeutic goals. In 2015, a Ph' CML with numerous pseudo-Gaucher cells in bone marrow appears. BCR/ABL was not present at GD diagnosis.

The erythrocyte osmotic resistance test as screening tool for cholesterol-related lysosomal storage diseases.

BACKGROUND: Erythrocyte volume regulation and membrane elasticity are essential for adaptation to osmotic and mechanical stress, and life span. Here, we evaluated whether defective cholesterol trafficking caused by the rare lysosomal storages diseases (LSDs), Niemann-Pick type C (NPC) and Lysosomal acid lipase (LAL) deficiency (LALD) impairs these properties. Moreover, we tested whether measurements of cholesterol membrane content and osmotic resistance serve as a screening test for these LSDs. METHODS: Patients were genotyped for mutations in NPC1, NPC2, or LIPA genes. We measured LSD plasma biomarkers and LAL activity. Red blood cells (RBC) membrane cholesterol content was evaluated in 73 subjects. Osmotic resistance tests (ORT) were conducted in 121 blood samples from LSD suspected patients and controls. RESULTS: We did not find statistically significant differences between RBC cholesterol content between subjects and controls. However, the ORT, particularly at 0.49% (w/v) hypotonic sodium chloride solution, revealed a significant higher osmotic resistance in LSDs patients than in controls. We established a cut-off value of ≤51% of haemolysis with sensibility and specificity values of 80% and 70%, respectively. CONCLUSIONS: NPC and LALD do not alter cholesterol content in the RBC membrane but increase osmotic resistance. Therefore, ORT serves as screening test for the studied LSDs.