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Rigoldi M.,Rare Metabolic Diseases Unit | Concolino D.,University of Catanzaro | Morrone A.,University of Florence | Morrone A.,Paediatric Neurology Unit and Laboratories | And 7 more authors.
Clinical Genetics | Year: 2014

We analysed the clinical history of 16 hemizygous males affected by Anderson-Fabry Disease, from four families, to verify their intrafamilial phenotypic variability. Seven male patients, ranging from 26 to 61years of age, died, whereas nine (age range 23-55) are alive. Eleven patients have undergone enzyme replacement therapy (ERT) for a period of 5-10years. We have found a wide range of intrafamilial phenotypic variability in these families, both in terms of target-organs and severity of the disease. Overall, our findings confirm previous data from the literature showing a high degree of intrafamilial phenotypic variability in patients carrying the same mutation. Furthermore, our results underscore the difficulty in giving accurate prognostic information to patients during genetic counselling, both in terms of rate of disease progression and involvement of different organs, when such prognosis is solely based on the patient's family history. © 2013 John Wiley & Sons A/S.

Verrecchia E.,Catholic University of the Sacred Heart | Zampetti A.,Imperial College London | Antuzzi D.,A. Gemelli Policlinic | Ricci R.,A. Gemelli Policlinic | And 8 more authors.
European Journal of Internal Medicine | Year: 2016

Background Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency of alpha-galactosidase A enzyme, which leads to the accumulation of its substrate, the globotriaosylceramide or Gb3, in many organs and tissues. Main clinical manifestations of FD are neuropathic pain, angiokeratomas, proteinuria and renal failure, left ventricular hypertrophy and stroke. Fever is also a possible symptom at the onset of the disease during childhood and adolescence, but it is frequently misdiagnosed, causing a delay in FD diagnosis. Methods We retrospectively analysed the medical records in our series of 58 Fabry patients, focusing on the proportion of patients who exhibited fever as the main symptom at the onset of FD in order to evaluate the diagnostic delay in these patients. Findings In our series, we found a significant proportion of patients with a history of fevers at the beginning of their medical history (20.7%; 12/58). 83% of patients with fever also exhibited acroparesthesias (10/12). Inflammatory markers were elevated in few of those cases (2/12). The mean diagnostic delay was 15.6 ± SD 12.8 years. Interpretation Fever emerged to be common as part of the FD clinical spectrum and it significantly contributed to the diagnostic delay encountered with this rare disease. Furthermore, our retrospective analysis indicated that FD patients commonly exhibit episodes of fever in association with other symptoms suggestive of FD (such as episodic pain crisis, acroparesthesias, hypo/anhydrosis, heat intolerance, fatigue and gastrointestinal distress). A careful analysis of the medical history in patients suffering fever could lead to an early and correct FD diagnosis. We believe that fever/hyperthermia, acroparesthesias and angiokeratoma should be considered for inclusion in the algorithm for Intermittent Fever of Unknown Origin (FUO) in order to improve the recognition of FD. © 2016 European Federation of Internal Medicine.

Sardi I.,University of Florence | Fantappie O.,University of Florence | la Marca G.,Paediatric Neurology Unit and Laboratories | Giovannini M.G.,University of Florence | And 7 more authors.
Cancer Letters | Year: 2014

Doxorubicin (Dox) has got a limited efficacy in the treatment of central nervous system tumors because of its poor penetration through blood-brain barrier mediated by MDR efflux transporters. We investigated the possibility that ondansetron (Ond) enhances Dox cytotoxicity in cell lines interfering with P-glycoprotein and increases Dox concentration in rat brain tissues.The MDR phenotype was studied using human hepatocellular carcinoma cell line PLC/PRF/5 (P5 and P1(0.5) clones), two subclones of NIH 3T3 cells (PSI-2 and PN1A) and two glioblastoma cell lines (A172, U87MG). Rats were pretreated with Ond before injection of Dox. Quantitative analysis of Dox was performed by mass spectrometry. Our in vitro experiments demonstrated that Ond at 10 μg/ml is not toxic to all cell lines. However, Ond reverses the MDR phenotype in P1(0.5) and PN1A cell lines. In addition, we showed that pretreatment with Ond increases Dox concentration in rat brain tissues, without increasing acute heart and renal toxicity. © 2014 Elsevier Ireland Ltd.

Caciotti A.,Paediatric Neurology Unit and Laboratories | Catarzi S.,Paediatric Neurology Unit and Laboratories | Catarzi S.,University of Florence | Tonin R.,Paediatric Neurology Unit and Laboratories | And 11 more authors.
Orphanet Journal of Rare Diseases | Year: 2013

Background: Mutations in the CTSA gene, that encodes the protective protein/cathepsin A or PPCA, lead to the secondary deficiency of β-galactosidase (GLB1) and neuraminidase 1 (NEU1), causing the lysosomal storage disorder galactosialidosis (GS). Few clinical cases of GS have been reported in the literature, the majority of them belonging to the juvenile/adult group of patients. Methods. The correct nomenclature of mutations for this gene is discussed through the analysis of the three PPCA/CTSA isoforms available in the GenBank database. Phenotype-genotype correlation has been assessed by computational analysis and review of previously reported single amino acid substitutions. Results: We report the clinical and mutational analyses of four cases with the rare infantile form of GS. We identified three novel nucleotide changes, two of them resulting in the missense mutations, c.347A>G (p.His116Arg), c.775T>C (p.Cys259Arg), and the third, c.1216C>T, resulting in the p.Gln406* stop codon, a type of mutation identified for the first time in GS. An Italian founder effect of the c.114delG mutation can be suggested according to the origin of the only three patients carrying this mutation reported here and in the literature. Conclusions: In early reports mutations nomenclature was selected according to all CTSA isoforms (three different isoforms), thus generating a lot of confusion. In order to assist physicians in the interpretation of detected mutations, we mark the correct nomenclature for CTSA mutations. The complexity of pathology caused by the multifunctions of CTSA, and the very low numbers of mutations (only 23 overall) in relation to the length of the CTSA gene are discussed.In addition, the in silico functional predictions of all reported missense mutations allowed us to closely predict the early infantile, late infantile and juvenile phenotypes, also disclosing different degrees of severity in the juvenile phenotype. © 2013 Caciotti et al.; licensee BioMed Central Ltd.

Ferri L.,University of Florence | Ferri L.,Paediatric Neurology Unit and Laboratories | Donati M.A.,Metabolic and Muscular Unit | Funghini S.,Paediatric Neurology Unit and Laboratories | And 12 more authors.
European Journal of Human Genetics | Year: 2015

Infantile-onset skeletal myopathy Barth syndrome (OMIM #302060) is caused by mutations in the X-linked TAZ gene and hence usually manifests itself only in hemizygous males. Confirmatory testing is provided by mutational analysis of the TAZ gene and/or by biochemical dosage of the monolysocardiolipin/tetralinoleoyl cardiolipin ratio. Heterozygous females do not usually display a clinical phenotype but may undergo molecular genetic prenatal diagnosis during pregnancy. We characterized two novel and non-identical TAZ gene rearrangements in the offspring of a single female carrier of Barth syndrome. The hg19chrX:g.153634427-153644361delinsKP-123427.1 TAZ gene rearrangement was identified in her affected son, whereas the NM-000116.3(TAZ)c.-72-109+51del TAZ gene deletion was identified in a male foetus during a subsequent pregnancy. The unaffected mother was surprisingly found to harbour both variants in addition to a wild-type TAZ allele. A combination of breakpoint junction sequencing, linkage analysis and assessment of allelic dosage revealed that the two variants had originated independently from an apparently unstable/mutable TAZ maternal allele albeit via different mutational mechanisms. We conclude that molecular prenatal diagnosis in Barth syndrome families with probands carrying TAZ gene rearrangements should include investigation of the entire coding region of the TAZ gene. The identification of the breakpoint junctions of such gross gene rearrangements is important to ensure accurate ascertainment of carriership with a view to providing appropriate genetic counselling. © 2015 Macmillan Publishers Limited.

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