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1.
Oncogene ; 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527668

RESUMO

The basic understanding of the biological effects of eukaryotic translation initiation factors (EIFs) remains incomplete, notably for their roles independent of protein translation. Different EIFs exhibit nuclear localization and DNA-related functions have been proposed, but the understanding of EIFs novel functions beyond protein translation lacks of integrative analyses between the genomic and the proteomic levels. Here, the noncanonical function of EIF3F was studied in human lung adenocarcinoma by combining methods that revealed both the protein-protein and the protein-DNA interactions of this factor. We discovered that EIF3F promotes cell metastasis in vivo. The underpinning molecular mechanisms involved the regulation of a cluster of 34 metastasis-promoting genes including Snail2, as revealed by proteomics combined with immuno-affinity purification of EIF3F and ChIP-seq/Q-PCR analyses. The interaction between EIF3F and signal transducer and activator of transcription 3 (STAT3) controlled the EIF3F-mediated increase in Snail2 expression and cellular invasion, which were specifically abrogated using the STAT3 inhibitor Nifuroxazide or knockdown approaches. Furthermore, EIF3F overexpression reprogrammed energy metabolism through the activation of AMP-activated protein kinase and the stimulation of oxidative phosphorylation. Our findings demonstrate the role of EIF3F in the molecular control of cell migration, invasion, bioenergetics, and metastasis. The discovery of a role for EIF3F-STAT3 interaction in the genetic control of cell migration and metastasis in human lung adenocarcinoma could lead to the development of diagnosis and therapeutic strategies.

4.
Clin Genet ; 96(2): 107-117, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30941742

RESUMO

Fabry disease (FD), a rare X-linked disease, can be treated with bi-monthly infusion of enzyme replacement therapy (ERT) to replace deficient α-galactosidase A (AGAL-A). ERT reduces symptoms, improves quality of life (QoL), and improves clinical signs and biochemical markers. ERT initiation in childhood could slow or stop progressive organ damage. Preventative treatment of FD from childhood is thought to avoid organ damage in later life, prompting a French expert working group to collaborate and produce recommendations for treating and monitoring children with FD. Organ involvement should be assessed by age 5 for asymptomatic boys (age 12-15 for asymptomatic girls), and immediately for children diagnosed via symptoms. The renal, cardiac, nervous and gastrointestinal systems should be assessed, as well as bone, skin, eyes, hearing, and QoL. The plasma biomarker globotriaosylsphingosine is also useful. ERT should be considered for symptomatic boys and girls with neuropathic pain, pathological albuminuria (≥3 mg/mmol creatinine), severe GI involvement and abdominal pain or cardiac involvement. ERT should be considered for asymptomatic boys from the age of 7. Organ involvement should be treated as needed. Early diagnosis and management of FD represents a promising strategy to reduce organ damage, morbidity and premature mortality in adulthood.

5.
Am J Med Genet A ; 179(6): 1030-1033, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30903679

RESUMO

PUM1 has been very recently reported as responsible for a new form of developmental disorder named PADDAS syndrome. We describe here an additional patient with early onset developmental delay, epilepsy, microcephaly, and hair dysplasia, with a de novo heterozygous missense variant of PUM1: c.3439C > T, p.(Arg1147Trp). This variant was absent from databases and predicted deleterious by multiple softwares. The same missense variant has been reported by Gennarino et al., in a girl with much more severe epilepsy. Our report is in favor of a variable expressivity of PADDAS syndrome, and broadens the phenotypic spectrum with the description of hair dysplasia.

6.
J Community Genet ; 2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30919323

RESUMO

The 2011 French Bioethics Law regarding disclosure of genetic information within families enables health professionals to notify any at-risk relatives directly, with the patient's consent, using a template letter. To assess the impact of this template letter in terms of understanding, personal feelings and intent to contact a health professional, we conducted a study interviewing patients, members of the public and genetic professionals. Although the main response to the letter was anxiety, this was associated with good understanding of the content and most individuals mentioned intention to contact a health professional.

7.
J Med Genet ; 56(8): 526-535, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30923172

RESUMO

BACKGROUND: Balanced chromosomal rearrangements associated with abnormal phenotype are rare events, but may be challenging for genetic counselling, since molecular characterisation of breakpoints is not performed routinely. We used next-generation sequencing to characterise breakpoints of balanced chromosomal rearrangements at the molecular level in patients with intellectual disability and/or congenital anomalies. METHODS: Breakpoints were characterised by a paired-end low depth whole genome sequencing (WGS) strategy and validated by Sanger sequencing. Expression study of disrupted and neighbouring genes was performed by RT-qPCR from blood or lymphoblastoid cell line RNA. RESULTS: Among the 55 patients included (41 reciprocal translocations, 4 inversions, 2 insertions and 8 complex chromosomal rearrangements), we were able to detect 89% of chromosomal rearrangements (49/55). Molecular signatures at the breakpoints suggested that DNA breaks arose randomly and that there was no major influence of repeated elements. Non-homologous end-joining appeared as the main mechanism of repair (55% of rearrangements). A diagnosis could be established in 22/49 patients (44.8%), 15 by gene disruption (KANSL1, FOXP1, SPRED1, TLK2, MBD5, DMD, AUTS2, MEIS2, MEF2C, NRXN1, NFIX, SYNGAP1, GHR, ZMIZ1) and 7 by position effect (DLX5, MEF2C, BCL11B, SATB2, ZMIZ1). In addition, 16 new candidate genes were identified. Systematic gene expression studies further supported these results. We also showed the contribution of topologically associated domain maps to WGS data interpretation. CONCLUSION: Paired-end WGS is a valid strategy and may be used for structural variation characterisation in a clinical setting.

8.
Genet Med ; 21(9): 2015-2024, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30739908

RESUMO

PURPOSE: Heritable thoracic aortic aneurysms and dissections (hTAAD) are life-threatening complications of well-known syndromic diseases or underdiagnosed nonsyndromic heritable forms (nshTAAD). Both have an autosomal dominant transmission and are genetically heterogeneous. Our objective was to describe the relevance of molecular diagnosis in these patients and the contribution of each gene in nshTAAD. METHODS: Two hundred twenty-six consecutive nshTAAD probands, either young (<45 years) sporadic or familial cases were included. A next-generation sequencing capture panel comprising 23 known disease-causing genes was performed. RESULTS: Class 4 or 5 variants were identified in 18% of the nshTAAD probands, while class 3 variants were found in 10% of them. The yield in familial cases was greater than in sporadic cases. SMAD3 and FBN1 genes were the major disease-causing genes. Unexpectedly, no premature termination codon variant was identified in the FBN1 gene. Furthermore, we report for the first time that aortic dissection or surgery occurred significantly more often and earlier in probands with a class 4 or 5 pathogenic variant. CONCLUSION: This study indicates that genetic screening using NGS is efficient in young and familial nshTAAD. The presence of a pathogenic variant has a possible predictive value, which needs to be further investigated because it may influence care.

9.
Clin Genet ; 95(3): 420-426, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30633342

RESUMO

Rubinstein-Taybi syndrome (RSTS; OMIM 180849) is an autosomal dominant developmental disorder characterized by facial dysmorphism, broad thumbs and halluces associated with intellectual disability. RSTS is caused by alterations in CREBBP (about 60%) and EP300 genes (8%). RSTS is often diagnosed at birth or during early childhood but generally not suspected during antenatal period. We report nine cases of well-documented fetal RSTS. Two cases were examined after death in utero at 18 and 35 weeks of gestation and seven cases after identification of ultrasound abnormalities and termination of pregnancy. On prenatal sonography, a large gallbladder was detected in two cases, and brain malformations were noted in four cases, especially cerebellar hypoplasia. However, the diagnosis of RSTS has not been suggested during pregnancy. Fetal autopsy showed that all fetuses had large thumbs and/or suggestive facial dysmorphism. A CREBBP gene anomaly was identified in all cases. Alterations were similar to those found in typical RSTS children. This report will contribute to a better knowledge of the fetal phenotype to consider the hypothesis of RSTS during pregnancy. Genotyping allows reassuring genetic counseling.

10.
Sci Rep ; 8(1): 17492, 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30504818

RESUMO

Syndromes that display craniofacial anomalies comprise a major class of birth defects. Both genetic and environmental factors, including prenatal retinoic acid (RA) exposure, have been associated with these syndromes. While next generation sequencing has allowed the discovery of new genes implicated in these syndromes, some are still poorly characterized such as Oculo-Auriculo-Vertebral Spectrum (OAVS). Due to the lack of clear diagnosis for patients, developing new strategies to identify novel genes involved in these syndromes is warranted. Thus, our study aimed to explore the link between genetic and environmental factors. Owing to a similar phenotype of OAVS reported after gestational RA exposures in humans and animals, we explored RA targets in a craniofacial developmental context to reveal new candidate genes for these related disorders. Using a proteomics approach, we detected 553 dysregulated proteins in the head region of mouse embryos following their exposure to prenatal RA treatment. This novel proteomic approach implicates changes in proteins that are critical for cell survival/apoptosis and cellular metabolism which could ultimately lead to the observed phenotype. We also identified potential molecular links between three major environmental factors known to contribute to craniofacial defects including maternal diabetes, prenatal hypoxia and RA exposure. Understanding these links could help reveal common key pathogenic mechanisms leading to craniofacial disorders. Using both in vitro and in vivo approaches, this work identified two new RA targets, Gnai3 and Eftud2, proteins known to be involved in craniofacial disorders, highlighting the power of this proteomic approach to uncover new genes whose dysregulation leads to craniofacial defects.

11.
Eur J Hum Genet ; 2018 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-30374058

RESUMO

The organization of mammalian genomes into sub-megabase sized Topologically Associated Domains (TADs) has recently been revealed by techniques derived from Chromosome Conformation Capture (3 C), such as High Chromosome Contact map (Hi-C). Disruption of this organization by structural variations can lead to ectopic interactions between enhancers and promoters, and to alteration of genes expression patterns. This mechanism has already been described as the main pathophysiological mechanism in several syndromes with congenital malformations. We describe here the case of a fetus with a severe multiple congenital anomalies syndrome, including extensive polydactyly of the four limbs. This fetus carries a de novo deletion next to the IHH gene, encompassing a TAD boundary. Such an IHH TAD boundary deletion has already been described in the Dbf mouse model, which shows a quite similar, but less severe phenotype. We hypothesize that the deletion harbored by this fetus results in the same pathophysiological mechanisms as those of the Dbf model. The description of this case expands the spectrum of the disruption of chromatin architecture of WNT6/IHH/EPHA4/PAX3 locus, and could help to understand the mechanisms of chromatin interactions at this locus.

12.
Prenat Diagn ; 2018 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-30328630

RESUMO

OBJECTIVE: The aim of this study is to evaluate the diagnostic utility of prenatal diagnosis using the chromosomal microarray analysis (CMA) for fetuses presenting with isolated or associated intrauterine growth restriction (IUGR). METHOD: We retrospectively included all fetuses with IUGR referred for prenatal testing and studied by rapid fluorescence in situ hybridization (FISH), karyotype, and CMA. RESULTS: Among the 162 IUGR fetuses (78 associated and 84 isolated IUGR) included, 15 had an abnormal FISH result: 10 associated and five isolated fetal IUGRs. Among the 143 fetuses studied by CMA, 10 (7%) presented pathogenic copy number variations (CNVs). All 10 were in the associated fetal IUGR group (10/65 or 15.4%; 95% confidence interval [CI]: 8.4%-26.2%) versus 0/78 in the isolated fetal IUGR group (95% CI: 0%-5.6%). Six fetuses (4.2%) carried variants of unknown significance (VOUS) (three associated and three isolated fetal IUGRs). CONCLUSION: Our study highlights the added value of CMA in the case of associated fetal IUGR with an incremental yield of 6.1% (4/65) over karyotyping. No pathogenic CNVs were reported in the isolated fetal IUGR group. More studies must be conducted to determine when and whether CMA would be wisely indicated in this population.

13.
Gene ; 679: 305-313, 2018 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-30217758

RESUMO

Histone lysine methylation influences processes such as gene expression and DNA repair. Thirty Jumonji C (JmjC) domain-containing proteins have been identified and phylogenetically clustered into seven subfamilies. Most JmjC domain-containing proteins have been shown to possess histone demethylase activity toward specific histone methylation marks. One of these subfamilies, the KDM5 family, is characterized by five conserved domains and includes four members. Interestingly, de novo loss-of-function and missense variants in KDM5B were identified in patients with intellectual disability (ID) and autism spectrum disorder (ASD) but also in unaffected individuals. Here, we report two novel de novo splice variants in the KDM5B gene in three patients with ID and ASD. The c.808 + 1G > A variant was identified in a boy with mild ID and autism traits and is associated with a significant reduced KDM5B mRNA expression without alteration of its H3K4me3 pattern. In contrast, the c.576 + 2T > C variant was found in twins with global delay in developmental milestones, poor language and ASD. This variant causes the production of an abnormal transcript which may produce an altered protein with the loss of the ARID1B domain with an increase in global gene H3K4me3. Our data reinforces the recent observation that the KDM5B haploinsufficiency is not a mechanism involved in intellectual disability and that KDM5B disorder associated with LOF variants is a recessive disorder. However, some variants may also cause gain of function, and need to be interpreted with caution, and functional studies should be performed to identify the molecular consequences of these different rare variants.


Assuntos
Processamento Alternativo , Transtorno do Espectro Autista/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Histona Desmetilases com o Domínio Jumonji/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Adolescente , Transtorno do Espectro Autista/metabolismo , Linhagem Celular , Criança , Deficiências do Desenvolvimento/metabolismo , Regulação para Baixo , Feminino , Predisposição Genética para Doença , Haploinsuficiência , Humanos , Deficiência Intelectual/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Masculino , Proteínas Nucleares/metabolismo , Linhagem , Proteínas Repressoras/metabolismo
14.
Eur J Med Genet ; 2018 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-30142438

RESUMO

The CACNA1A gene encodes a calcium-dependent voltage channel, localized in neuronal cells. Pathogenic variants in this gene are known to lead to a broad clinical spectrum including episodic ataxia type 2, spinocerebellar ataxia type 6, familial hemiplegic migraine, and more recently epileptic encephalopathy. We report a large family revealing a wide variability of neurological manifestations associated with a CACNA1A missense pathogenic variant. The index case had early-onset epileptic encephalopathy with progressive cerebellar atrophy, although his mother and his great-grandmother suffered from paroxystic episodic ataxia. His grandfather and great grand-aunt reported no symptoms, but two of her sons displayed early-onset ataxia with intellectual disability. Two of her little daughters suffered from gait disorders, and also from epilepsy for one of them. All these relatives were carriers of the previously described heterozygous variant in CACNA1A gene. We report here the first family leading to major clinical variability and incomplete penetrance. Our family highlights the difficulties to provide accurate genetic counselling concerning prenatal diagnosis regarding highly variable severity of the clinical presentation.

15.
Orphanet J Rare Dis ; 13(1): 127, 2018 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-30064518

RESUMO

BACKGROUND: Fabry disease (OMIM #301500) is an X-linked disorder caused by alpha-galactosidase A deficiency with two major clinical phenotypes: classic and non-classic of different prognosis. From 2001, enzyme replacement therapies (ERT) have been available. We aimed to determine the epidemiology and the functional characteristics of anti-drug antibodies. Patients from the French multicenter cohort FFABRY (n = 103 patients, 53 males) were prospectively screened for total anti-agalsidase IgG and IgG subclasses with a home-made enzyme-linked immunosorbent assay (ELISA), enzyme-inhibition assessed with neutralization assays and lysoGb3 plasma levels, and compared for clinical outcomes. RESULTS: Among the patients exposed to agalsidase, 40% of men (n = 18/45) and 8% of women (n = 2/25) had antibodies with a complete cross-reactivity towards both ERTs. Antibodies developed preferentially in men with non-missense GLA mutations (relative risk 2.88, p = 0.006) and classic phenotype (58.6% (17/29) vs 6.7% (1/16), p = 0.0005). Specific anti-agalsidase IgG1 were the most frequently observed (16/18 men), but the highest concentrations were observed for IgG4 (median 1.89 µg/ml, interquartile range (IQR) [0.41-12.24]). In the men exposed to agalsidase, inhibition was correlated with the total IgG titer (r = 0.67, p < 0.0001), especially IgG4 (r = 0.75, p = 0.0005) and IgG2 (r = 0.72, p = 0.001). Inhibition was confirmed intracellularly in Fabry patient leucocytes cultured with IgG-positive versus negative serum (median: 42.0 vs 75.6%, p = 0.04), which was correlated with IgG2 (r = 0.67, p = 0.017, n = 12) and IgG4 levels (r = 0.59, p = 0.041, n = 12). Plasma LysoGb3 levels were correlated with total IgG (r = 0.66, p = 0.001), IgG2 (r = 0.72, p = 0.004), IgG4 (r = 0.58, p = 0.03) and IgG1 (r = 0.55, p = 0.04) titers. Within the classic group, no clinical difference was observed but lysoGb3 levels were higher in antibody-positive patients (median 33.2 ng/ml [IQR 20.6-55.6] vs 12.5 [10.1-24.0], p = 0.005). CONCLUSION: Anti-agalsidase antibodies preferentially develop in the severe classic Fabry phenotype. They are frequently associated with enzyme inhibition and higher lysoGb3 levels. As such, they could be considered as a hallmark of severity associated with the classic phenotype. The distinction of the clinical phenotypes should now be mandatory in studies dealing with Fabry disease and its current and future therapies.

16.
Genet Med ; 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-29997391

RESUMO

PURPOSE: To investigate the genetic basis of congenital ataxias (CAs), a unique group of cerebellar ataxias with a nonprogressive course, in 20 patients from consanguineous families, and to identify new CA genes. METHODS: Singleton -exome sequencing on these 20 well-clinically characterized CA patients. We first checked for rare homozygous pathogenic variants, then, for variants from a list of genes known to be associated with CA or very early-onset ataxia, regardless of their mode of inheritance. Our replication cohort of 180 CA patients was used to validate the new CA genes. RESULTS: We identified a causal gene in 16/20 families: six known CA genes (7 patients); four genes previously implicated in another neurological phenotype (7 patients); two new candidate genes (2 patients). Despite the consanguinity, 4/20 patients harbored a heterozygous de novo pathogenic variant. CONCLUSION: Singleton exome sequencing in 20 consanguineous CA families led to molecular diagnosis in 80% of cases. This study confirms the genetic heterogeneity of CA and identifies two new candidate genes (PIGS and SKOR2). Our work illustrates the diversity of the pathophysiological pathways in CA, and highlights the pathogenic link between some CA and early infantile epileptic encephalopathies related to the same genes (STXBP1, BRAT1, CACNA1A and CACNA2D2).

17.
Redox Biol ; 18: 33-42, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29935387

RESUMO

Anti-cancer effects of local anesthetics have been reported but the mode of action remains elusive. Here, we examined the bioenergetic and REDOX impact of levobupivacaine on human prostate cancer cells (DU145) and corresponding non-cancer primary human prostate cells (BHP). Levobupivacaine induced a combined inhibition of glycolysis and oxidative phosphorylation in cancer cells, resulting in a reduced cellular ATP production and consecutive bioenergetic crisis, along with reactive oxygen species generation. The dose-dependent inhibition of respiratory chain complex I activity by levobupivacaine explained the alteration of mitochondrial energy fluxes. Furthermore, the potency of levobupivacaine varied with glucose and oxygen availability as well as the cellular energy demand, in accordance with a bioenergetic anti-cancer mechanism. The levobupivacaine-induced bioenergetic crisis triggered cytostasis in prostate cancer cells as evidenced by a S-phase cell cycle arrest, without apoptosis induction. In DU145 cells, levobupivacaine also triggered the induction of autophagy and blockade of this process potentialized the anti-cancer effect of the local anesthetic. Therefore, our findings provide a better characterization of the REDOX mechanisms underpinning the anti-effect of levobupivacaine against human prostate cancer cells.


Assuntos
Anestésicos Locais/farmacologia , Antineoplásicos/farmacologia , Bupivacaína/análogos & derivados , Glicólise/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Bupivacaína/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Respiração Celular/efeitos dos fármacos , Células Cultivadas , Metabolismo Energético/efeitos dos fármacos , Humanos , Levobupivacaína , Masculino , Oxirredução/efeitos dos fármacos , Próstata/efeitos dos fármacos , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Espécies Reativas de Oxigênio/metabolismo
18.
Cell Rep ; 23(10): 2852-2863, 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29874573

RESUMO

The ubiquitin proteasome system (UPS) regulates many cellular functions by degrading key proteins. Notably, the role of UPS in regulating mitochondrial metabolic functions is unclear. Here, we show that ubiquitination occurs in different mitochondrial compartments, including the inner mitochondrial membrane, and that turnover of several metabolic proteins is UPS dependent. We specifically detailed mitochondrial ubiquitination and subsequent UPS-dependent degradation of succinate dehydrogenase subunit A (SDHA), which occurred when SDHA was minimally involved in mitochondrial energy metabolism. We demonstrate that SDHA ubiquitination occurs inside the organelle. In addition, we show that the specific inhibition of SDHA degradation by UPS promotes SDHA-dependent oxygen consumption and increases ATP, malate, and citrate levels. These findings suggest that the mitochondrial metabolic machinery is also regulated by the UPS.

19.
J Med Genet ; 55(6): 359-371, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29618507

RESUMO

The Xq28 duplication involving the MECP2 gene (MECP2 duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitial MECP2 duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype of MECP2 duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life.

20.
Dig Liver Dis ; 50(5): 429-437, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29602572

RESUMO

Non-specific gastrointestinal symptoms, including pain, diarrhoea, nausea, and vomiting, can be the first symptoms of Fabry disease. They may suggest more common disorders, e.g. irritable bowel syndrome or inflammatory bowel disease. The confounding clinical presentation and rarity of Fabry disease often cause long diagnostic delays and multiple misdiagnoses. Therefore, specialists involved in the clinical evaluation of non-specific upper and lower gastrointestinal symptoms should recognize Fabry disease as a possible cause of the symptoms, and should consider Fabry disease as a possible differential diagnosis. When symptoms or family history suggest Fabry disease, in men, low alpha-galactosidase A enzyme levels, and in women, specific Fabry mutations confirm the diagnosis. In addition to symptomatic treatments, disease-specific enzyme replacement therapy with recombinant human alpha-galactosidase A enzyme or chaperone therapy (migalastat) in patients with amenable mutations can improve the disease, including gastrointestinal symptoms, and should be initiated as early as possible after Fabry disease has been confirmed; starting enzyme replacement therapy at as young an age as possible after diagnosis improves long-term clinical outcomes. Improved diagnostic tools, such as a modified gastrointestinal symptom rating scale, may facilitate diagnosing Fabry disease in patients with gastrointestinal symptoms of unknown cause and thus assure timely initiation of disease-specific treatment.


Assuntos
Doença de Fabry/diagnóstico , Doença de Fabry/tratamento farmacológico , alfa-Galactosidase/sangue , alfa-Galactosidase/uso terapêutico , Dor Abdominal/etiologia , Diagnóstico Diferencial , Diarreia/etiologia , Doença de Fabry/complicações , Doença de Fabry/genética , Feminino , Humanos , Masculino , Náusea/etiologia , Avaliação de Sintomas , Vômito/etiologia
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