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1.
J Intellect Disabil Res ; 67(7): 679-689, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37129092

RESUMO

BACKGROUND: Investigating copy number variations (CNVs) such as microdeletions or microduplications can significantly contribute to discover the aetiology of neurodevelopmental disorders. 15q11.2 genomic region, including NIPA1 and NIPA2 genes, contains a recurrent but rare CNV, flanked by the break points BP1 and BP2. Both BP1-BP2 microdeletion and microduplication have been associated with intellectual disability (ID), neuropsychiatric/behavioural disturbances and mild clinical features, even if with incomplete penetrance and variable expressivity. The pathogenic role of this CNV is quite unclear though. Unknown variants in other DNA regions and parent-of-origin effect (POE) are some of the mechanisms that have been proposed as an explanation of the wide phenotypic variability. As NIPA1 and NIPA2 encode for proteins that mediate magnesium (Mg2+ ) metabolism, it has been suggested that urinary Mg2+ levels could potentially represent informative and affordable biomarkers for a rapid screening of 15q11.2 duplications or deletions. Furthermore, magnesium supplementation has been proposed as possible therapeutic strategy. METHODS: Thirty one children with ID and/or other neurodevelopmental disorders carrying either a duplication or a deletion in 15q11.2 BP1-BP2 region have been recruited. When available, blood samples from parents have been analysed to identify the CNV origin. All participants underwent family and medical data collection, physical examination and neuropsychiatric assessment. Electroencephalogram (EEG) and brain magnetic resonance imaging (MRI) scan were performed in 15 children. In addition, 11 families agreed to participate to the assessment of blood and urinary Mg2+ levels. RESULTS: We observed a highly variable phenotypic spectrum of developmental issues encompassing ID in most subjects as well as a variety of behavioural disorders such as autism and attention-deficit disorder/attention-deficit hyperactivity disorder. Dysmorphic traits and malformations were detected only in a minority of the participants, and no clear association with growth anomalies was found. Abnormal brain MRI and/or EEG were reported respectively in 64% and 92% of the subjects. Inheritance assessment highlighted an excess of duplication of maternal origin, while cardiac alterations were detected only in children with 15q11.2 CNV inherited from the father. We found great variability in Mg2+ urinary values, without correlation with 15q11.2 copy numbers. However, the variance of urinary Mg2+ levels largely increases in individuals with 15q11.2 deletion/duplication. CONCLUSIONS: This study provides further evidence that 15q11.2 BP1-BP2 CNV is associated with a broad spectrum of neurodevelopmental disorders and POE might be an explanation for clinical variability. However, some issues may question the real impact of 15q11.2 CNV on the phenotype in the carriers: DNA sequencing could be useful to exclude other pathogenic gene mutations. Our results do not support the possibility that urinary Mg2+ levels can be used as biomarkers to screen children with neurodevelopmental disorders for 15q11.2 duplication/deletion. However, there are evidences of correlations between 15q11.2 BP1-BP2 CNV and Mg2+ metabolism and future studies may pave the way to new therapeutic options.


Assuntos
Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Humanos , Aberrações Cromossômicas , Magnésio , Variações do Número de Cópias de DNA/genética , Transtornos do Neurodesenvolvimento/genética , Deficiência Intelectual/genética , Biomarcadores
2.
Clin Genet ; 92(6): 624-631, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28485813

RESUMO

Classical Ehlers-Danlos syndrome (cEDS) is characterized by marked cutaneous involvement, according to the Villefranche nosology and its 2017 revision. However, the diagnostic flow-chart that prompts molecular testing is still based on experts' opinion rather than systematic published data. Here we report on 62 molecularly characterized cEDS patients with focus on skin, mucosal, facial, and articular manifestations. The major and minor Villefranche criteria, additional 11 mucocutaneous signs and 15 facial dysmorphic traits were ascertained and feature rates compared by sex and age. In our cohort, we did not observe any mandatory clinical sign. Skin hyperextensibility plus atrophic scars was the most frequent combination, whereas generalized joint hypermobility according to the Beighton score decreased with age. Skin was more commonly hyperextensible on elbows, neck, and knees. The sites more frequently affected by abnormal atrophic scarring were knees, face (especially forehead), pretibial area, and elbows. Facial dysmorphism commonly affected midface/orbital areas with epicanthal folds and infraorbital creases more commonly observed in young patients. Our findings suggest that the combination of ≥1 eye dysmorphism and facial/forehead scars may support the diagnosis in children. Minor acquired traits, such as molluscoid pseudotumors, subcutaneous spheroids, and signs of premature skin aging are equally useful in adults.


Assuntos
Colágeno Tipo V/genética , Síndrome de Ehlers-Danlos/genética , Anormalidades do Olho/genética , Instabilidade Articular/genética , Anormalidades da Pele/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Colágeno Tipo V/metabolismo , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/metabolismo , Síndrome de Ehlers-Danlos/patologia , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/metabolismo , Anormalidades do Olho/patologia , Face/anormalidades , Feminino , Expressão Gênica , Humanos , Instabilidade Articular/diagnóstico , Instabilidade Articular/metabolismo , Instabilidade Articular/patologia , Articulações/anormalidades , Articulações/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Anormalidades da Pele/diagnóstico , Anormalidades da Pele/metabolismo , Anormalidades da Pele/patologia
3.
J Inorg Biochem ; 153: 253-258, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26387966

RESUMO

Cisplatin is a widely used chemotherapy drug which exerts cytotoxic activity by affecting both nuclear and cytosolic pathways. Herewith, we report, for the first time, that cisplatin inhibits proteasome activity in vitro. Cisplatin induces a dose dependent inhibition of the three enzymatic activities of proteasome (i.e., the chymotrypsin-like activity, the trypsin-like activity and the caspase-like activity). Moreover, cisplatin administration to neuroblastoma cells brings about a fast loss of proteasome particle activity, which is followed by a de novo synthesis of proteasome. Lastly, we report that the simultaneous administration of lactacystin and cisplatin enhances the cytotoxicity of cisplatin alone. The overall bulk of data opens to an intriguing scenario, concerning the biological effects of cisplatin in the control of cellular life, which goes beyond the well established genotoxic effect.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Inibidores de Cisteína Proteinase/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Acetilcisteína/análogos & derivados , Acetilcisteína/farmacologia , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Ubiquitinação
4.
Pediatr Med Chir ; 25(4): 289-91, 2003.
Artigo em Italiano | MEDLINE | ID: mdl-15070275

RESUMO

Familial Mediterranean Fever is an autosomal recessive disease occurring in Mediterranean and Middle Eastern populations. It is caused by mutations affecting both alleles of MEFV, a gene that encodes a neutrophil protein called pyrin. We describe a case of dominant transmission with variable penetrance.


Assuntos
Febre Familiar do Mediterrâneo/genética , Humanos , Lactente , Masculino , Penetrância
5.
Am J Physiol Cell Physiol ; 279(6): C1870-9, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11078702

RESUMO

In previous work (McKee EE, Bentley AT, Smith RM Jr, and Ciaccio CE, Biochem Biophys Res Commun 257: 466-472, 1999), the transport of guanine nucleotides into the matrix of intact isolated heart mitochondria was demonstrated. In this study, the time course and mechanisms of guanine nucleotide transport are characterized. Two distinct mechanisms of transport were found to be capable of moving guanine nucleotides across the inner membrane. The first carrier was saturable, displayed temperature dependence, preferred GDP to GTP, and did not transport GMP or IMP. When incubated in the absence of exogenous ATP, this carrier had a V(max) of 946 +/- 53 pmol. mg(-1). min(-1) with a K(m) of 2.9 +/- 0.3 mM for GDP. However, transport of GTP and GDP on this carrier was completely inhibited by physiological concentrations of ATP, suggesting that this carrier was not involved with guanine nucleotide transport in vivo. Because transport on this carrier was also inhibited by atractyloside, this carrier was consistent with the well-characterized ATP/ADP translocase. The second mechanism of guanine nucleotide uptake was insensitive to atractyloside, displayed temperature dependence, and was capable of transporting GMP, GDP, and GTP at approximately equal rates but did not transport IMP, guanine, or guanosine. GTP transport via this mechanism was slow, with a V(max) of 48.7 +/- 1.4 pmol. mg(-1). min(-1) and a K(m) = 4.4 +/- 0.4 mM. However, because the requirement for guanine nucleotide transport is low in nondividing tissues such as the heart, this transport process is nevertheless sufficient to account for the matrix uptake of guanine nucleotides and may represent the physiological mechanism of transport.


Assuntos
Atractilosídeo/farmacologia , Inibidores Enzimáticos/farmacologia , Nucleotídeos de Guanina/farmacocinética , Mitocôndrias/metabolismo , Miocárdio/metabolismo , Trifosfato de Adenosina/farmacologia , Animais , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/fisiologia , Relação Dose-Resposta a Droga , Metabolismo Energético/fisiologia , Etilmaleimida/farmacologia , Guanosina Difosfato/farmacocinética , Guanosina Monofosfato/farmacocinética , Guanosina Trifosfato/farmacocinética , Hidroximercuribenzoatos/farmacologia , Cinética , Inibidores de Proteases/farmacologia , Ratos , Ratos Sprague-Dawley , Trítio
6.
Acta Neurol Scand ; 102(3): 162-8, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10987375

RESUMO

OBJECTIVES: To assess cognitive functioning in patients affected by beta-thalassemia major (beta-th) by using a neuropsychological battery, and to identify clinical correlates. MATERIAL AND METHODS: Forty-six beta-th patients and 46 controls similar for age, sex, and education participated in the study. All subjects performed a comprehensive neuropsychological battery including tests of abstract reasoning, attention, executive functions, language, constructional/visuospatial skills, and memory. RESULTS: Compared to controls beta-th patients, in particular those showing signs of hemosiderosis, were significantly impaired on all neuropsychological tests. There was no relationship between cognitive performances and signs of deferoxamine toxicity, deferoxamine dosage, and levels of hemoglobin and ferritin, while duration of transfusional therapy and time interval between onset of blood transfusions and onset of chelating treatment correlated with performances of tests assessing abstract reasoning, attention, constructional/visuospatial skills, memory and with the scores of the Mini Mental State Examination. CONCLUSION: Our findings suggest that beta-th is associated with neuropsychological impairment involving multiple cognitive domains and argue for a potential role of hemosiderosis on cognitive functioning.


Assuntos
Percepção Auditiva , Cognição , Hemossiderose/psicologia , Talassemia beta/complicações , Talassemia beta/psicologia , Adulto , Análise de Variância , Transfusão de Sangue , Estudos de Casos e Controles , Terapia por Quelação , Feminino , Hemossiderose/etiologia , Humanos , Masculino , Testes Neuropsicológicos , Talassemia beta/fisiopatologia , Talassemia beta/terapia
7.
Biochem Biophys Res Commun ; 257(2): 466-72, 1999 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-10198236

RESUMO

Presence of guanine nucleotide within the matrix of mitochondria is uncontested; the mechanism by which GTP takes up residence in the matrix is unknown. In this report, we demonstrate for the first time that direct transport of guanine nucleotide across the inner membrane of heart mitochondria is possible. Transport of guanine nucleotides from the medium to the matrix was suggested by inhibition of translation in isolated rat heart mitochondria when GTP-gamma-S was added to the medium. This result suggested that GTP was one source of matrix GTP. Other sources were investigated by measuring matrix uptake and conversion to GTP of several purines, purine nucleosides, and purine nucleotides. Results demonstrated that [14C]-guanine and [3H]-guanosine were not taken up by isolated mitochondria and were not converted to any other compound. While [14C]-ATP and [3H]-AMP were taken up readily into the matrix, radioactivity was never associated with a guanine compound. [3H]-IMP was not taken up into the matrix and was never converted to another compound. Our data showed that label added as [3H]-GTP, [3H]-GDP, or [3H]-GMP was readily taken up and concentrated in the matrix of isolated mitochondria.


Assuntos
Nucleotídeos de Guanina/metabolismo , Mitocôndrias Cardíacas/metabolismo , Difosfato de Adenosina/metabolismo , Difosfato de Adenosina/farmacologia , Monofosfato de Adenosina/metabolismo , Monofosfato de Adenosina/farmacologia , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Animais , Transporte Biológico , Guanina/metabolismo , Guanina/farmacologia , Guanosina/metabolismo , Guanosina/farmacologia , Guanosina 5'-O-(3-Tiotrifosfato)/farmacologia , Guanosina Difosfato/análogos & derivados , Guanosina Difosfato/metabolismo , Guanosina Difosfato/farmacologia , Guanosina Monofosfato/metabolismo , Guanosina Monofosfato/farmacologia , Guanosina Trifosfato/metabolismo , Guanosina Trifosfato/farmacologia , Inosina Monofosfato/farmacologia , Membranas Intracelulares/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Tionucleotídeos/farmacologia , Fatores de Tempo
9.
Blood ; 90(6): 2207-12, 1997 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-9310471

RESUMO

Hepatitis C virus (HCV) infection is a common cause of liver disease among polytransfused thalassemics. We treated a cohort of subjects with beta-thalassemia major and chronic hepatitis C with alpha-interferon. The aims of the study were to assess the long-term biochemical and virologic efficacy of alpha-interferon and to evaluate the influence of HCV type and liver siderosis on the outcome of therapy. Seventy subjects (mean age, 14.1 years) with chronic HCV infection and abnormal aminotransferases received recombinant alpha-interferon for 12 months and were observed after therapy for at least 24 months. Sixty-three subjects (90%) were HCV-RNA positive at the start of therapy. HCV type 1b was found in 41 subjects (65.1%), non-1b types in 13 (20.6%), and mixed HCV types in 9 (14.3%). Liver biopsy showed cirrhosis in 11 subjects (15.7%) and siderosis grade 3-4 in 24 patients (34.2%). Three patients stopped therapy due to adverse events. Twenty-eight subjects (40%) had normal aminotransferases and had cleared HCV-RNA when last observed (mean follow-up, 36.5 months; range, 25 to 49 months). Of 41 patients who did not normalize aminotransferases, 9 had become HCV-RNA negative at the end of follow-up. The absence of cirrhosis, low liver iron content, and infection with non-1b HCV type were independently associated to complete sustained response upon multivariable analysis. In conclusion, alpha-interferon may induce a sustained virologic and biochemical remission of hepatitis in beta-thalassemic patients with chronic HCV infection and nonadvanced liver disease.


Assuntos
Hepatite C/tratamento farmacológico , Interferon-alfa/uso terapêutico , Talassemia beta/complicações , Adolescente , Adulto , Alanina Transaminase/sangue , Criança , Pré-Escolar , Doença Crônica , Feminino , Hepatite C/complicações , Humanos , Interferon alfa-2 , Ferro/metabolismo , Fígado/metabolismo , Masculino , Análise Multivariada , Proteínas Recombinantes , Siderose/patologia , Fatores de Tempo
10.
Gut ; 34(2 Suppl): S142-3, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-8314484

RESUMO

In this open, pilot study, interferon (IFN) alpha-2b seemed effective in the treatment of hepatitis C virus (HCV) infection in patients with beta-thalassaemia. In seven of nine patients who completed the study alanine aminotransferase activities returned to normal, and a completely stable response 24 months after treatment was seen in five. Liver biopsy specimen showed a clear reduction in portal, periportal, and lobular necroinflammation in all five cases. Three patients stopped treatment early because of side effects.


Assuntos
Hepatite C/terapia , Interferon-alfa/uso terapêutico , Talassemia beta/complicações , Adolescente , Aspartato Aminotransferases/sangue , Criança , Feminino , Hepatite C/complicações , Hepatite C/enzimologia , Hepatite C/patologia , Humanos , Interferon alfa-2 , Fígado/patologia , Masculino , Projetos Piloto , Proteínas Recombinantes , Talassemia beta/enzimologia , Talassemia beta/patologia
11.
Haematologica ; 77(6): 502-6, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1289187

RESUMO

BACKGROUND: Chronic infection with the hepatitis C virus (HCV) and iron overload are the main causes of chronic liver disease in subjects with homozygous beta-thalassemia (HBT). Iron overload can be counteracted by intensive chelation. alpha-interferon reduces viremia and necroinflammation in patients with chronic HCV hepatitis. METHODS: To assess the effectiveness and safety of alpha 2b-Interferon (IFN), we enrolled in an open pilot trial of treatment 12 patients with HBT and biopsy-proven anti-HCV positive chronic hepatitis. IFN was given at a dose of 5 MU/m2 thrice weekly for 8 weeks, then 3 MU/m2 thrice weekly for 18 weeks. Patients were followed up to 24 months after stopping treatment when a second liver biopsy was performed in subjects with sustained response (normal ALT during follow-up). RESULTS: Two patients discontinued IFN at 7 weeks because of haemolytic anemia and one after 8 weeks due to persistent fever. Among 9 subjects completing the protocol, 5 normalized ALT while on treatment and a further 2 within two months after stopping IFN. A sustained response was obtained altogether in 5 patients, since ALT relapsed in 2 responders. None of the 3 subjects who discontinued IFN and of the 2 patients who did not respond to treatment normalized ALT over a 24 months follow-up. Post-treatment liver histology in long-term responders showed a reduction of portal, periportal and lobular necroinflammation, while siderosis was essentially unchanged. CONCLUSIONS: Although the pattern of response to IFN in HCV-infected subjects with HBT might differ from that of non-thalassemics, due to peculiar side effects and delayed response, the drug appears to be effective and deserves further investigation.


Assuntos
Hepatite C/terapia , Hepatite Crônica/terapia , Fatores Imunológicos/uso terapêutico , Interferon-alfa/uso terapêutico , Talassemia beta/complicações , Adolescente , Alanina Transaminase/sangue , Criança , Feminino , Hemocromatose/complicações , Hepatite C/complicações , Hepatite C/patologia , Hepatite Crônica/complicações , Hepatite Crônica/patologia , Homozigoto , Humanos , Interferon alfa-2 , Masculino , Proteínas Recombinantes , Indução de Remissão , Reação Transfusional , Viremia/complicações , Viremia/terapia
12.
Haematologica ; 77(1): 82-3, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1398286

RESUMO

During a screening program to identify at risk couples for beta-thalassemia first-trimester prenatal diagnosis, we were able to detect, by polymerase chain reaction (PCR) and direct genomic sequencing of the PCR product, a homozygosis for the G-T substitution at the first nucleotide of codon 27 of the delta-globin gene in a pregnant Sicilian woman. The possibility of showing an interaction between delta and beta thalassemia is relevant for a thalassemia prevention program because it may hide a beta-thal carrier state.


Assuntos
Globinas/genética , Complicações Hematológicas na Gravidez/etiologia , Talassemia/genética , Sequência de Bases , Análise Mutacional de DNA , Feminino , Humanos , Dados de Sequência Molecular , Linhagem , Reação em Cadeia da Polimerase , Gravidez , Diagnóstico Pré-Natal
13.
Radiol Med ; 80(6): 823-9, 1990 Dec.
Artigo em Italiano | MEDLINE | ID: mdl-2281161

RESUMO

Recently, a new type of skeletal lesions has been described in Cooley's anemia as a possible complication secondary to therapy. In 12 children affected with thalassemia major, who received an intensive transfusional regimen combined with continuous iron chelation therapy (desferoxamine-B: 50-80 mg/kg/day), some radiological abnormalities of the long bones were observed similar to those described in rickets and scurvy. These rickets and/or scurvy-like lesions had never been reported before the introduction of high-dose desferoxamine therapy. The pathogenesis of these lesions is uncertain, but the toxic effect of desferoxamine probably plays an important role in their development. The association of growth retardation and rickets and/or scurvy-like skeletal lesions in Cooley's anemia patients may be used as a valuable clinical criterion in long-term chelation management.


Assuntos
Doenças Ósseas/diagnóstico por imagem , Raquitismo/diagnóstico por imagem , Escorbuto/diagnóstico por imagem , Talassemia/complicações , Adolescente , Doenças Ósseas/etiologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Radiografia , Raquitismo/etiologia , Escorbuto/etiologia
15.
Boll Ist Sieroter Milan ; 62(3): 292-7, 1983 Jul.
Artigo em Italiano | MEDLINE | ID: mdl-6639781

RESUMO

Serum levels of Lactic dehydrogenase (LDH) were determined at weekly intervals, in 52 patients with Boutonneuse Fever: 33 adults (23 uncomplicated and 10 complicated cases) and 19 children (no complication occurred in these patients). In the first week of illness, LDH was increased in 86 and 100% of adults (uncomplicated and complicated cases respectively) and in 89% of children. Mean values were 419 and 472 U/l for adults (uncomplicated and complicated) and 423 for children (normal values until 240 U/l). In total (adults plus children), in the first week, pathological findings were observed in 90% of patients. In the second week, LDH was increased in 53 and 100% for adults, and 66% for children. Mean values were 252 and 306 for adults, and 291 U/l for children. The significance of this increase is related to the pathophysiology of rickettsial diseases. Rickettsiae cause endothelial injury with platelet aggregation, activation of inflammation as well as coagulation mechanisms and subsequently damage of various organ systems at various degree (from silent to evident forms). From a general point of view LDH increase appears in part of platelet origin, at first stage of illness, in part from other organ systems involved in the vasculitic process.


Assuntos
Febre Botonosa/enzimologia , L-Lactato Desidrogenase/sangue , Infecções por Rickettsiaceae/enzimologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prognóstico
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