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Glucocerebrosidase (GCase) is a lysosomal enzyme that catalyzes the breakdown of glucosylceramide in the presence of its activator saposin C (SapC). SapC arises from the proteolytical cleavage of prosaposin (encoded by PSAP gene), which gives rise to four saposins. GCase is targeted to the lysosomes by LIMP-2, encoded by SCARB2 gene. GCase deficiency causes Gaucher Disease (GD), which is mainly due to biallelic pathogenetic variants in the GCase-encoding gene, GBA1. However, impairment of GCase activity can be rarely caused by SapC or LIMP-2 deficiencies. We report a new case of LIMP-2 deficiency and a new case of SapC deficiency (missing all four saposins, PSAP deficiency), and measured common biomarkers of GD and GCase activity. Glucosylsphingosine and chitotriosidase activity in plasma were increased in GCase deficiencies caused by PSAP and GBA1 mutations, whereas SCARB2-linked deficiency showed only Glucosylsphingosine elevation. GCase activity was reduced in fibroblasts and leukocytes: the decrease was sharper in GBA1- and SCARB2-mutant fibroblasts than PSAP-mutant ones; LIMP-2-deficient leukocytes displayed higher residual GCase activity than GBA1-mutant ones. Finally, we demonstrated that GCase mainly undergoes proteasomal degradation in LIMP-2-deficient fibroblasts and lysosomal degradation in PSAP-deficient fibroblasts. Thus, we analyzed the differential biochemical profile of GCase deficiencies due to the ultra-rare PSAP and SCARB2 biallelic pathogenic variants in comparison with the profile observed in GBA1-linked GCase deficiency.
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Enfermedad de Gaucher , Glucosilceramidasa , Proteínas de Membrana de los Lisosomas , Receptores Depuradores , Saposinas , Glucosilceramidasa/genética , Glucosilceramidasa/deficiencia , Glucosilceramidasa/metabolismo , Humanos , Enfermedad de Gaucher/genética , Enfermedad de Gaucher/metabolismo , Saposinas/deficiencia , Saposinas/genética , Saposinas/metabolismo , Proteínas de Membrana de los Lisosomas/metabolismo , Proteínas de Membrana de los Lisosomas/genética , Receptores Depuradores/genética , Receptores Depuradores/metabolismo , Fibroblastos/metabolismo , Mutación , Lisosomas/metabolismo , Lisosomas/enzimología , Hexosaminidasas/metabolismo , Hexosaminidasas/genética , Hexosaminidasas/deficiencia , Masculino , FemeninoRESUMEN
Neuropathic pain is one of the most invalidating symptoms in patients with Fabry disease (FD), affecting their quality of life, it is linked to small fiber neuropathy and it may not respond to available disease specific treatments. We report the case of a 32 years old man with classic FD and severe neuropathic pain who, after the failure of several standard pharmaceutical approaches, was treated with medical cannabis with relief of nocturnal pain and sleep improvement.
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BACKGROUND: The Italian Medicines Agency (AIFA) demands precise information on benefit/risk profile of home-based enzyme replacement therapy (ERT) for the treatment of patients with Pompe disease and Mucopolysaccharidosis type I (MPS I). This passage is necessary to obtain the authorization for ERT home therapy, even after the coronavirus disease-19 (COVID-19) pandemic period. This research intends to evaluate the safety, treatment satisfaction, and compliance of MPS I patients treated with laronidase (Aldurazyme®) and Pompe Disease patients treated with alglucosidase alfa (Myozyme®) in a homecare setting. RESULTS: We report herein an early interim analysis of the HomERT (Home infusions of ERT) study, a multicenter, non-interventional, double-cohort study that retrospectively analyzed 38 patients from 14 sites in Italy: cohort A (Pompe disease - 32 patients) and cohort B (MPS I - 6 patients). Among the selected patients who started home therapy before enrollment, the average number of missed home-based infusions was 0.7 (1.3) in cohort A and 3.8 (6.4) in cohort B with no return to the hospital setting. Irrespective of the treatment location, 3 prior ADRs per cohort were reported. The majority of patients preferred home-based infusions (cohort A: 96.9%; cohort B: 100%): the main reason was attributed to treatment convenience (cohort A: 81.3%; cohort B: 83.3%). Despite the underlying conditions, most patients self-evaluated their health as "good" (cohort A: 50%; cohort B: 83.3%). CONCLUSIONS: Evidence of favorable safety profile, improved treatment compliance and personal satisfaction validates the use of ERT with laronidase and alglucosidase alfa as a strong candidate for home therapy.
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COVID-19 , Enfermedad del Almacenamiento de Glucógeno Tipo II , Mucopolisacaridosis I , Mucopolisacaridosis VI , Humanos , Terapia de Reemplazo Enzimático/efectos adversos , Mucopolisacaridosis I/tratamiento farmacológico , Estudios de Cohortes , Estudios Retrospectivos , Prioridad del Paciente , alfa-GlucosidasasRESUMEN
The rapid expansion of the number of adult patients with inherited metabolic diseases (IMDs) has created demand for physicians with expertise in the field of adult metabolic medicine (AMM). Unfortunately, existing accredited training programs in this field are rare, and training programs in pediatric metabolic medicine cannot fully meet the needs of AMM physicians as the types of patients and the problems they face are different in the adult setting. We surveyed a group of working practitioners in AMM for input on what medical expert competencies they feel should be included as part of training programs in AMM. Through a modified Delphi process, 66 physicians from six continents reached consensus on a comprehensive list of training competencies in AMM. This list includes competencies from the fields of adult internal medicine, neurology, medical genetics, and pediatric metabolic medicine but also includes competencies not found in any of those programs, leading to the conclusion that the training needs for specialists in AMM cannot be met from any of these existing programs. We propose that AMM be considered a subspecialty separate from pediatric metabolic medicine and that accredited training programs in AMM be created using these medical expert competencies as part of a broader program design.
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BACKGROUND: Since the beginning of the COVID-19 pandemic, MetabERN has been monitoring the SARS-CoV-2 infection rates within its metabolic community. To gather data on the total number of cases and the severity of symptoms among IMD patients one year into the pandemic, an online survey was distributed among all MetabERN healthcare providers (HCP). Epidemiological analysis was performed by integrating the survey's data with the MetabERN database. RESULTS: Survey's respondents reported a total of 452 cases of COVID-19 among their IMD patients (213 paediatric and 239 adults). Considering the total number of patients followed by the respondents (n = 26,347), the registered prevalence of COVID-19 in the IMD population was of 1716 × 100,000. Italy emerged as the most affected country (25.4% of cases), followed by the United Kingdom (14.2% of cases). Most of the paediatric cases of COVID-19 displayed no or mild symptoms during the disease: 34% of HCP reported having asymptomatic patients in 75-100% of cases, while 37.5% reported mild symptoms in about a quarter of their patients. Similarly to paediatric cases, most adult IMD patients with COVID-19 were asymptomatic or had mild symptoms: about one third of respondents reported 75-100% asymptomatic patients and about 65% of HCP had between 0 and 50% of patients with mild symptoms. The majority of the respondents reported no deaths due to COVID-19 in adult and paediatric patients with IMDs. CONCLUSIONS: Most of MetabERN's IMD patients who got COVID-19 during the first year of the pandemic had mild symptoms and a positive outcome of the disease. However, fatal events were recorded in paediatric patients; this, together with the lack of information on the long-term effects of COVID-19 in IMDs, call for caution in the metabolic population.
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COVID-19 , Enfermedades Metabólicas , Adulto , Niño , Personal de Salud , Humanos , Enfermedades Metabólicas/epidemiología , Pandemias , SARS-CoV-2RESUMEN
Acid sphingomyelinase deficiency (ASMD) is a rare metabolic disorder due to biallelic mutation in the SMPD1 gene. The defect leads to the accumulation of sphingomyelin within the cells of the reticulo-endothelial system, particularly in the spleen, liver, lungs, and bone marrow causing hepato-splenomegaly, lung disease and hematological abnormalities. At present, data on abdominal imaging in ASMD are limited. Here we describe the characteristics of focal liver lesions observed in a 30 years old female. During the Magnetic Resonance follow up an increase in number and size of the lesions, showing T1 hypointensity and T2 hyperintensity with contrast enhancement, was observed. Contrast enhanced ultrasound evidenced rapid wash-in and steady isoecogenicity without appreciable wash-out at 80 seconds. The main lesion was biopsied to rule out the presence of a hepatocellular carcinoma, and showed to be a benign foamy macrophages aggregate. In this report, we discuss the possible pathogenesis of focal hepatic lesions in ASMD and their differential diagnosis.
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(1) Background: Niemann-Pick type C disease (NPCD) is an autosomal recessive lysosomal storage disorder caused by mutations in the NPC1 or NPC2 genes. The clinical presentation is characterized by visceral and neurological involvement. Apart from a small group of patients presenting a severe perinatal form, all patients develop progressive and fatal neurological disease with an extremely variable age of onset. Different biomarkers have been identified; however, they poorly correlate with neurological disease. In this study we assessed the possible role of plasma NfL as a neurological disease-associated biomarker in NPCD. (2) Methods: Plasma NfL levels were measured in 75 healthy controls and 26 patients affected by NPCD (24 NPC1 and 2 NPC2; 39 samples). (3) Results: Plasma NfL levels in healthy controls correlated with age and were significantly lower in pediatric patients as compared to adult subjects (p = 0.0017). In both pediatric and adult NPCD patients, the plasma levels of NfL were significantly higher than in age-matched controls (p < 0.0001). Most importantly, plasma NfL levels in NPCD patients with neurological involvement were significantly higher than the levels found in patients free of neurological signs at the time of sampling, both in the pediatric and the adult group (p = 0.0076; p = 0.0032, respectively). Furthermore, in adults the NfL levels in non-neurological patients were comparable with those found in age-matched controls. No correlations between plasma NfL levels and NPCD patient age at sampling or plasma levels of cholestan 3ß-5α-6ß-triol were found. (4) Conclusions: These data suggest a promising role of plasma NfL as a possible neurological disease-associated biomarker in NPCD.
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Glycogen storage disease type Ia (GSDIa) is an inherited metabolic disorder caused by mutations in the enzyme glucose-6-phosphatase-α (G6Pase-α). Affected individuals develop renal and liver complications, including the development of hepatocellular adenoma/carcinoma and kidney failure. The purpose of this study was to identify potential biomarkers of the evolution of the disease in GSDIa patients. To this end, we analyzed the expression of exosomal microRNAs (Exo-miRs) in the plasma exosomes of 45 patients aged 6 to 63 years. Plasma from age-matched normal individuals were used as controls. We found that the altered expression of several Exo-miRs correlates with the pathologic state of the patients and might help to monitor the progression of the disease and the development of late GSDIa-associated complications.
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Exosomas/genética , Enfermedad del Almacenamiento de Glucógeno Tipo I/genética , Enfermedades Renales/genética , Hígado/lesiones , Hígado/metabolismo , MicroARNs/genética , Adolescente , Adulto , Factores de Edad , Animales , Biomarcadores/metabolismo , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Exosomas/metabolismo , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Ontología de Genes , Glucosa-6-Fosfatasa/metabolismo , Enfermedad del Almacenamiento de Glucógeno Tipo I/sangre , Enfermedad del Almacenamiento de Glucógeno Tipo I/patología , Humanos , Enfermedades Renales/sangre , Enfermedades Renales/patología , Masculino , Ratones , MicroARNs/metabolismo , Persona de Mediana Edad , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: Late onset Pompe disease (LOPD) is a lysosomal neuromuscular disorder which can progressively impair the patients' exercise tolerance, motor and respiratory functions, and quality of life. The available enzyme replacement therapy (ERT) does not completely counteract disease progression. We investigated the effect of exercise training alone, or associated with a high-protein diet, on the exercise tolerance, muscle and pulmonary functions, and quality of life of LOPD patients on long term ERT. METHODS: The patients were asked to participate to a crossover randomized study comprehending a control period (free diet, no exercise) followed by 2 intervention periods: exercise or exercise + diet, each lasting 26 weeks and separated by 13 weeks washout periods. Exercise training included moderate-intensity aerobic exercise on a cycle ergometer, stretching and balance exercises, strength training. The diet was composed by 25-30% protein, 30-35% carbohydrate and 35-40% fat. Before and after each period patients were assessed for: exercise tolerance test on a cycle-ergometer, serum muscle enzymes, pulmonary function tests and SF36 questionnaire for quality of life. Compliance was evaluated by training and dietary diaries. Patients were contacted weekly by researchers to optimize adherence to treatments. RESULTS: Thirteen LOPD patients, median age 49 ± 11 years, under chronic ERT (median 6.0 ± 4.0 years) were recruited. Peak aerobic power (peak pulmonary O2 uptake) decreased after control, whereas it increased after exercise, and more markedlyafter exercise + diet. Serum levels of lactate dehydrogenase (LDH) significantly decreased after exercise + diet; both creatine kinase (CK) and LDH levels were significantly reduced after exercise + diet compared to exercise. Pulmonary function showed no changes after control and exercise, whereas a significant improvement of forced expiratory volume in 1 sec (FEV1) was observed after exercise + diet. SF36 showed a slight improvement in the "mental component" scale after exercise, and a significant improvement in "general health" and "vitality" after exercise + diet. The compliance to prescriptions was higher than 70% for both diet and exercise. CONCLUSIONS: Exercise tolerance (as evaluated by peak aerobic power) showed a tendency to decrease in LOPD patients on long term ERT. Exercise training, particularly if combined with high-protein diet, could reverse this decrease and result in an improvement, which was accompanied by improved quality of life. The association of the two lifestyle interventions resulted also in a reduction of muscle enzyme levels and improved pulmonary function.
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Dieta Rica en Proteínas , Enfermedad del Almacenamiento de Glucógeno Tipo II , Adulto , Estudios Cruzados , Ejercicio Físico , Humanos , Persona de Mediana Edad , Calidad de VidaRESUMEN
The direct and indirect effects of Coronavirus Disease-19 (COVID-19) pandemic, on Italian patients with lysosomal storage disorders receiving therapy, were analyzed by a phone questionnaire. No proved COVID-19 emerged among 102 interviewed. No problems were reported by patients receiving oral treatments. Forty-nine% of patients receiving enzyme replacement therapy in hospitals experienced disruptions, versus 6% of those home-treated. The main reasons of missed infusions were fear of infection (62.9%) and re-organization of the infusion centers (37%).
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Infecciones por Coronavirus/epidemiología , Enfermedades por Almacenamiento Lisosomal/terapia , Neumonía Viral/epidemiología , Adulto , COVID-19 , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/psicología , Infecciones por Coronavirus/terapia , Terapia de Reemplazo Enzimático , Miedo , Femenino , Humanos , Italia/epidemiología , Enfermedades por Almacenamiento Lisosomal/complicaciones , Masculino , Persona de Mediana Edad , Pandemias , Aceptación de la Atención de Salud , Manejo de Atención al Paciente , Neumonía Viral/complicaciones , Neumonía Viral/psicología , Neumonía Viral/terapia , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal storage disorder caused by mutations in NPC1 or NPC2 genes. In 2009, the molecular characterization of 44 NPC Italian patients has been published. Here, we present an update of the genetic findings in 105 Italian NPC patients belonging to 83 unrelated families (77 NPC1 and 6 NPC2). NPC1 and NPC2 genes were studied following an algorithm recently published. Eighty-four different NPC1 and five NPC2 alleles were identified. Only two NPC1 alleles remained non detected. Sixty-two percent of NPC1 alleles were due to missense variants. The most frequent NPC1 mutation was the p.F284Lfs*26 (5.8% of the alleles). All NPC2 mutations were found in the homozygous state, and all but one was severe. Among newly diagnosed patients, 18 novel NPC1 mutations were identified. The pathogenic nature of 7/9 missense alleles and 3/4 intronic variants was confirmed by filipin staining and NPC1 protein analysis or mRNA expression in patient's fibroblasts. Taken together, our previous published data and new results provide an overall picture of the molecular characteristics of NPC patients diagnosed so far in Italy.
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Adult metabolic medicine (AMM) is an expanding medical subspecialty, due to the increasing number of adult patients with inherited metabolic diseases (IMD). However, a formal training and postgraduate education in this field is not available in the majority of countries. Existing adult metabolic specialists (AMS) come from many different backgrounds. The aim of this survey was to assess the state of play as regards education and training in AMM worldwide. Members of the Society for the Study of Inborn Error of Metabolism adult metabolic group (n = 89) were asked to take part in this survey. Forty-two AMS (47.2%) from 18 different countries completed the questionnaire. The most common specialties were internal medicine (38.1%), endocrinology (26.2%), genetics (21.4%), and neurology (21.4%). Ninety-five percent of respondents considered that practical clinical experience had contributed importantly for their professional development, while only 27% felt the same for formal academic education. The current state of available education and training was judged as generally poor or fair (73% of the respondents). The most suggested ways of improving education and training in AMM were: to facilitate international internships; to implement courses on adult-IMD; and to create a formal academic education. The skills considered most important for AMS were: recognition of signs and symptoms of diseases, knowledge of the available treatments, and ability to perform a correct follow up. In conclusion, worldwide, current available education and training in AMM is considered inadequate. This survey emphasizes the need for development of new, formal training opportunities to improve knowledge, and competence in this rapidly expanding field.
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Endocrinología/educación , Necesidades y Demandas de Servicios de Salud , Enfermedades Metabólicas/diagnóstico , Enfermedades Metabólicas/terapia , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/terapia , Especialización/normas , Adulto , Competencia Clínica , Servicios de Salud , Humanos , Enfermedades Metabólicas/genética , Errores Innatos del Metabolismo/genéticaRESUMEN
X-linked hypophosphatemia (XLH) is the most common monogenic disorder causing hypophosphatemia. This case-note review documents the clinical features and the complications of treatment in 59 adults (19 male, 40 female) with XLH. XLH is associated with a large number of private mutations; 37 different mutations in the PHEX gene were identified in this cohort, 14 of which have not been previously reported. Orthopaedic involvement requiring surgical intervention (osteotomy) was frequent. Joint replacement and decompressive laminectomy were observed in those older than 40 years. Dental disease (63%), nephrocalcinosis (42%), and hearing impairment (14%) were also common. The rarity of the disease and the large number of variants make it difficult to discern specific genotype-phenotype relationships. A new treatment, an anti-FGF23 antibody, that may affect the natural history of the disease is currently being investigated in clinical trials.
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Raquitismo Hipofosfatémico Familiar/genética , Raquitismo Hipofosfatémico Familiar/terapia , Enfermedades Genéticas Ligadas al Cromosoma X , Mutación , Endopeptidasa Neutra Reguladora de Fosfato PHEX/genética , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/uso terapéutico , Raquitismo Hipofosfatémico Familiar/fisiopatología , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Factores de Crecimiento de Fibroblastos/inmunología , Estudios de Asociación Genética , Pérdida Auditiva/etiología , Humanos , Laminectomía , Masculino , Persona de Mediana Edad , Nefrocalcinosis/etiología , Osteotomía , Ensayos Clínicos Controlados Aleatorios como Asunto , Enfermedades Estomatognáticas/etiología , Adulto JovenRESUMEN
Tangier disease is an autosomal recessive disorder caused by mutations in the ABCA1 gene and characterized by the accumulation of cholesteryl ester in various tissues and a near absence of high-density lipoprotein. The subject in this investigation was a 36-year-old Italian man with Tangier disease. He and his wife had come to the In Vitro Fertilization Unit, Pesaro Hospital (Azienda Ospedaliera Ospedali Riuniti Marche Nord) seeking help regarding fertility issues. The man was diagnosed with severe oligoasthenoteratozoospermia. Testosterone is the sex hormone necessary for spermatogenesis and cholesterol is its precursor; hence, we hypothesized that the characteristic cholesterol deficiency in Tangier disease patients could compromise their fertility. The aim of the study was to therefore to determine if there is an association between Tangier disease and male infertility. After excluding viral, infectious, genetic and anatomical causes of the subject's oligoasthenoteratozoospermia, we performed a hormonal analysis to verify our hypothesis. The patient was found to be negative for frequent bacteria and viruses. The subject showed a normal male karyotype and tested negative for Yq microdeletions and Cystic Fibrosis Transmembrane Conductance Regulator gene mutations. A complete urological examination was performed, and primary hypogonadism was also excluded. Conversely, hormonal analyses showed that the subject had a high level of follicle stimulating hormone and luteinizing hormone, low total testosterone and a significant decline in inhibin B. We believe that the abnormally low cholesterol levels typically found in subjects with Tangier disease may result in a reduced testosterone production which in turn could affect the hormonal axis responsible for spermatogenesis leading to a defective maturation of spermatozoa.
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Colesterol/genética , Infertilidad Masculina/genética , Enfermedad de Tangier/genética , Testosterona/biosíntesis , Transportador 1 de Casete de Unión a ATP/genética , Adulto , Colesterol/deficiencia , Ésteres del Colesterol/genética , Ésteres del Colesterol/metabolismo , Humanos , Infertilidad Masculina/complicaciones , Infertilidad Masculina/fisiopatología , Masculino , Mutación , Oligospermia/complicaciones , Oligospermia/genética , Oligospermia/fisiopatología , Espermatogénesis/genética , Enfermedad de Tangier/complicaciones , Enfermedad de Tangier/fisiopatologíaRESUMEN
This study aims to assess the proinflammatory interleukin 1ß (IL-1ß) and anti-inflammatory IL-10 production by monocytes from 38 patients with type 2 diabetes and 31 controls in different glucose concentrations. Monocytes were incubated in low (2.5 mmol/L)-, normal (5.0 mmol/L)-, and high (20 mmol/L)-glucose conditions in the presence and absence of lipopolysaccharide (LPS). Monocytes from both patients and controls only produced a significant increase in IL-1ß in low-glucose conditions (p < 0.01), and this phenomenon was amplified in the presence of LPS, while it was not seen in normal- or high-glucose conditions, not even in the presence of LPS stimulation. There was no increase in IL-10 production by monocytes from either diabetic patients or controls using whatever glucose concentrations, except when treated with LPS in normal-glucose conditions. These findings seem to suggest that low-glucose conditions induce an inflammatory response in monocytes in all individuals, as an intrinsic capacity of this cell line. On the other hand, monocytes only retain their anti-inflammatory ability in response to known inflammatory stimuli such as LPS, under normal-glucose concentrations. In conclusion, human monocytes express an inflammatory pattern in low-glucose conditions in vitro. This response could contribute to explaining the higher cardiovascular risk induced by hypoglycemia in diabetic patients.
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Diabetes Mellitus Tipo 2/patología , Glucosa/farmacología , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Anciano , Estudios de Casos y Controles , Células Cultivadas , Diabetes Mellitus Tipo 2/inmunología , Ensayo de Inmunoadsorción Enzimática , Voluntarios Sanos , Humanos , Interleucina-10/análisis , Interleucina-1beta/análisis , Lipopolisacáridos/farmacología , Persona de Mediana Edad , Monocitos/citología , Monocitos/efectos de los fármacos , Monocitos/metabolismoRESUMEN
Exercise intolerance is one of the clinical hallmarks of late-onset Pompe disease (LOPD). We studied the acute effects of ERT on the physiological variables associated with exercise tolerance in patients chronically ERT treated. Moreover, we assessed the influence of clinical severity on the investigated variables. The day before (B) and the day after (A) ERT injection, 11 LOPD patients performed on a cycle-ergometer an exercise tolerance test to voluntary exhaustion; VO2, HR, RPE, and GAA activity were determined in B and A. The disease severity was characterized by Walton scale, 6MWT, and pulmonary function tests. No significant differences in the variables related to exercise tolerance were found in A vs B, despite a significant increase in GAA activity in peripheral lymphocytes. No differences in VO2 peak were observed between patients with only skeletal muscle impairment and patients with both skeletal and respiratory muscle impairment. Distance walked at 6MWT was significantly higher than VO2 peak expressed as percentage of normal values. In conclusion, in LOPD patients the exercise tolerance test is not acutely affected by ERT administration; the peripheral muscle component seems more prominent in determining the VO2 peak decrease than the respiratory component; VO2 peak might be more sensitive than 6MWT in estimating exercise tolerance in LOPD.
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Terapia de Reemplazo Enzimático , Tolerancia al Ejercicio/efectos de los fármacos , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , alfa-Glucosidasas/uso terapéutico , Adolescente , Adulto , Prueba de Esfuerzo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
The small interstitial deletion in the long arm of chromosome 15 causing Prader-Willi/Angelman syndrome is well known, whereas cases that report terminal deletions in 15q in association with the Prader-Willi-like phenotype are very rare. By using GTG-banding analysis, metaphase FISH, MLPA analysis, and genome-wide array CGH, we detected an unbalanced translocation involving a microdeletion of the distal part of 15q and a microduplication of the distal part of 18q. The unbalanced translocation was found in a boy that was referred with clinical suspicion of Prader-Willi syndrome. In the 15q-deleted region, 23 genes have been identified, and 13 of them are included in the OMIM database. Among these, the deleted IGFR1, MEF2A, CHSY1, and TM2D3 genes could contribute to the patient's phenotype. Seven genes are included in the duplicated chromosome segment 18q, but only one (CTDP1) is present in the OMIM database. We suggest that the deleted chromosome segment 15q26.2qter may be responsible for the phenotype of our case and may also be a candidate locus of Prader-Willi-like syndrome.
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Deleción Cromosómica , Cromosomas Humanos Par 15/genética , Cromosomas Humanos Par 18/genética , Duplicación de Gen/genética , Síndrome de Prader-Willi/genética , Translocación Genética/genética , Adulto , Preescolar , Bandeo Cromosómico , Hibridación Genómica Comparativa , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Masculino , Edad Materna , Fenotipo , Síndrome de Prader-Willi/fisiopatología , Adulto JovenRESUMEN
Niemann-Pick C disease (NPCD) is a rare autosomal recessive neurovisceral disorder with a heterogeneous clinical presentation. Cholestan-3ß,5α,6ß-triol and 7-ketocholesterol have been proposed as biomarkers for the screening of NPCD. In this work, we assessed oxysterols levels in a cohort of Italian patients affected by NPCD and analyzed the obtained results in the context of the clinical, biochemical and molecular data. In addition, a group of patients affected by Niemann-Pick B disease (NPBD) were also analyzed. NPC patients presented levels of both oxysterols way above the cut off value, except for 5 siblings presenting the variant biochemical phenotype who displayed levels of 3ß,5α,6ß-triol below or just above the cut-off value; 2 of them presented also normal levels of 7-KC. Both oxysterols were extremely high in a patient presenting the neonatal systemic lethal phenotype. All NPB patients showed increased oxysterols levels. In conclusion, the reported LC-MS/MS assay provides a robust non-invasive screening tool for NPCD. However, false negative results can be obtained in patients expressing the variant biochemical phenotype. These data strengthen the concept that the results should always be interpreted in the context of the patients' clinical picture and filipin staining and/or genetic studies might still be undertaken in patients with normal levels of oxysterols if symptoms are highly suggestive of NPCD. Both oxysterols are significantly elevated in NPB patients; thus a differential diagnosis should always be performed in patients presenting isolated hepatosplenomegaly, a common clinical sign of both NPCD and NPBD.