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Catia Cavicchi

Bio: Catia Cavicchi is an academic researcher from Boston Children's Hospital. The author has contributed to research in topics: Newborn screening & Gene mutation. The author has an hindex of 10, co-authored 18 publications receiving 316 citations.

Papers
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Journal ArticleDOI
TL;DR: The classical form is mainly characterised, in affected hemizygous males, by angiokeratoma, acroparaesthesias, hypohidrosis, pains, fever crises, and involvement of the kidneys, brain, and heart, while the cardiac variant is characterised by symptoms restricted to cardiac abnormalities.
Abstract: Anderson-Fabry disease (E C 3.2.1.22, MIM 301500) is an X linked lysosomal storage disorder caused by a deficiency of the enzyme α-galactosidase A (GLA).1,2 The onset of the disease and the severity of clinical manifestations depend principally on residual GLA enzymatic activity.1 Fabry disease can be classified into two clinical phenotypes: the classical form and the cardiac variant.1,3 The classical form is mainly characterised, in affected hemizygous males, by angiokeratoma, acroparaesthesias, hypohidrosis, pains, fever crises, and involvement of the kidneys, brain, and heart. Neurological and/or psychological manifestations with personality disturbances can also occur.1 The cardiac variant is characterised by symptoms restricted to cardiac abnormalities, including conduction defects and/or late onset cardiomyopathy with left ventricular hypertrophy.1,3,4 A prevalence of Fabry disease in a referral population of male patients with a clinical diagnosis of late onset hypertrophic cardiomyopathy (HCM) has also been reported.5 The X linked disorders affect males, while the female carriers are generally asymptomatic, owing in part to the random inactivation of the X chromosome.6 Fabry female carriers can be asymptomatic or clinically affected, usually with a late onset and mild form of the disease. Corneal abnormalities are the most frequent clinical manifestations.1 The human GLA gene, mapped on Xq22, is organised in seven exons encompassing over 12 kb.7 So far, about 265 mutations spread throughout the GLA gene in all exons have been reported in the Human Gene Mutation Database Web site and, in addition, a further 65 have been published.8,9 ### Key points

62 citations

Journal ArticleDOI
TL;DR: The hypothesis that an active site-specific chemical chaperone, which could be administered orally, might be effective in treating GAL-A conformational defects is endorsed, paving the way for conformational FD.

51 citations

Journal ArticleDOI
TL;DR: The genetic characterization of two patients with Type II sialidosis exhibiting the congenital (P1) and infantile forms (P2) showed one known NEU1 missense mutation, and the new c.807 + 1G > A splicing defect (detected in P1), a genetic lesion that is extremely rare in this disease.
Abstract: Sialidosis is a lysosomal storage disease caused by the deficiency of alpha-N-acetyl neuraminidase-1 (NEU1). Sialidosis is classified into two main clinical variants: Type I, the milder form of the disease, and Type II, which can in turn be subdivided into three forms: congenital, infantile and juvenile. We report herein the clinical, biochemical and molecular characterisation of two patients with Type II sialidosis exhibiting the congenital (P1) and infantile forms (P2). We also review clinical data on the rare Type II forms of sialidosis in the hope of improving understanding of the disorder and facilitating its diagnosis. The genetic characterization of the two patients showed one known [c. 679G > A (p.G227R)] NEU1 missense mutation (detected in P2), and the new c.807 + 1G > A splicing defect (detected in P1), a genetic lesion that is extremely rare in this disease. Interestingly, P2 presented an extremely elevated level of chitotriosidase in plasma. This is the first pathological detection of chitotriosidase in sialidosis patients.

35 citations

Journal ArticleDOI
TL;DR: In an expanded newborn screening program for inborn errors of metabolism by LC-MS/MS in Tuscany, six newborns showed decreased blood citrulline levels, and molecular analysis of the OTC gene identified the known p.Trp265Leu mutation, which is correlated with late-onset ornithine transcarbamylase deficiency (OTCD).

34 citations

Journal ArticleDOI
TL;DR: Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene.
Abstract: Ferri L, Guido C, la Marca G, Malvagia S, Cavicchi C, Fiumara A, Barone R, Parini R, Antuzzi D, Feliciani C, Zampetti A, Manna R, Giglio S, Della Valle CM, Wu X, Valenzano KJ, Benjamin ER, Donati MA, Guerrini R, Genuardi M, Morrone A. Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene. Fabry disease (FD) is an X-linked lysosomal storage disorder with a heterogeneous spectrum of clinical manifestations that are caused by the deficiency of α-galactosidase A (α-Gal-A) activity. Although useful for diagnosis in males, enzyme activity is not a reliable biochemical marker in heterozygous females due to random X-chromosome inactivation, thus rendering DNA sequencing of the α-Gal-A gene, alpha-galactosidase gene (GLA), the most reliable test for the confirmation of diagnosis in females. The spectrum of GLA mutations is highly heterogeneous. Many polymorphic GLA variants have been described, but it is unclear if haplotypes formed by combinations of such variants correlate with FD, thus complicating molecular diagnosis in females with normal α-Gal-A activity. We tested 67 female probands with clinical manifestations that may be associated with FD and 110 control males with normal α-Gal-A activity. Five different combinations of GLA polymorphic variants were identified in 14 of the 67 females, whereas clearcut pathogenetic alterations, p.Met51Ile and p.Met290Leu, were identified in two cases. The latter has not been reported so far, and both mutant forms were found to be responsive to the pharmacological chaperone deoxygalactonojirimycin (DGJ; migalastat hydrochloride). Analysis of the male control population, as well as male relatives of a suspected FD female proband, permitted the identification of seven different GLA gene haplotypes in strong linkage disequilibrium. The identification of haplotypes in control males provides evidence against their involvement in the development of FD phenotypic manifestations.

30 citations


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TL;DR: The updated HPO database is described, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO, allowing integration of existing datasets and interoperability with multiple biomedical resources.
Abstract: The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online.

801 citations

Journal ArticleDOI
TL;DR: Treatment of individual symptoms in addition to enzyme replacement therapy seems to be needed for many patients, especially those who have had some degree of organ dysfunction, and additional data are needed to document long-term treatment outcomes.

613 citations

Journal ArticleDOI
TL;DR: This work reviews the main mechanisms responsible for increased immune activity in females, which provides a survival advantage in the face of pathogenic insult but can also enhance the susceptibility of females to autoimmunity.
Abstract: In response to various immune challenges, females show better survival than males; the X chromosome has an important role in this immunological advantage. X chromosome-linked diseases are usually restricted to males, who have only one copy of the X chromosome; however, females are more prone to autoimmune diseases, and the X chromosome may be involved in the breakdown of self tolerance. Several hypotheses have been proposed in recent years that support a role for the X chromosome in shaping autoimmune responses. Here, we review the main mechanisms responsible for increased immune activity in females. This provides a survival advantage in the face of pathogenic insult but can also enhance the susceptibility of females to autoimmunity.

582 citations

Journal ArticleDOI
TL;DR: These guidelines aim at providing a trans-European consensus to guide practitioners, set standards of care and help awareness campaigns, and help to harmonise practice, set common standards and spread good practices with a positive impact on the outcomes of UCD patients.
Abstract: Urea cycle disorders (UCDs) are inborn errors of ammonia detoxification/arginine synthesis due to defects affecting the catalysts of the Krebs-Henseleit cycle (five core enzymes, one activating enzyme and one mitochondrial ornithine/citrulline antiporter) with an estimated incidence of 1:8.000. Patients present with hyperammonemia either shortly after birth (~50%) or, later at any age, leading to death or to severe neurological handicap in many survivors. Despite the existence of effective therapy with alternative pathway therapy and liver transplantation, outcomes remain poor. This may be related to underrecognition and delayed diagnosis due to the nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity. These guidelines aim at providing a trans-European consensus to: guide practitioners, set standards of care and help awareness campaigns. To achieve these goals, the guidelines were developed using a Delphi methodology, by having professionals on UCDs across seven European countries to gather all the existing evidence, score it according to the SIGN evidence level system and draw a series of statements supported by an associated level of evidence. The guidelines were revised by external specialist consultants, unrelated authorities in the field of UCDs and practicing pediatricians in training. Although the evidence degree did hardly ever exceed level C (evidence from non-analytical studies like case reports and series), it was sufficient to guide practice on both acute and chronic presentations, address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues. Also, it identified knowledge voids that must be filled by future research. We believe these guidelines will help to: harmonise practice, set common standards and spread good practices with a positive impact on the outcomes of UCD patients.

485 citations

Journal ArticleDOI
TL;DR: Among all randomly assigned patients with Fabry's disease (with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy), the percentage of patients who had a response at 6 months did not differ significantly between the migAlastat group and the placebo group.
Abstract: BackgroundFabry’s disease, an X-linked disorder of lysosomal α-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of α-galactosidase, increasing enzyme trafficking to lysosomes. MethodsThe initial assay of mutant α-galactosidase forms that we used to categorize 67 patients with Fabry’s disease for randomization to 6 months of double-blind migalastat or placebo (stage 1), followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional year, had certain limitations. Before unblinding, a new, validated assay showed that 50 of the 67 participants had mutant α-galactosidase forms suitable for targeting by migalastat. The primary end point was the percentage of patients who had a response (≥50% reduction in the number of globotriaosylceramide inclusions per kidney interstitial capillary) at 6 months. We assessed safety along with disease substrates and renal, cardiovascular, and patient-re...

350 citations