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1.
Hum Mutat ; 42(12): 1548-1566, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34524712

RESUMEN

Hereditary fructose intolerance (HFI) is an inborn error of fructose metabolism of autosomal recessive inheritance caused by pathogenic variants in the ALDOB gene that lead to aldolase B deficiency in the liver, kidneys, and intestine. Patients manifest symptoms, such as ketotic hypoglycemia, vomiting, nausea, in addition to hepatomegaly and other liver and kidney dysfunctions. The treatment consists of a fructose-restricted diet, which results in a good prognosis. To analyze the distribution of ALDOB variants described in patients and to estimate the prevalence of HFI based on carrier frequency in the gnomAD database, a systematic review was conducted to assess ALDOB gene variants among patients with HFI. The prevalence of HFI was estimated from the carrier frequency of variants described in patients, as well as rare variants predicted as pathogenic by in silico tools. The p.(Ala150Pro) and p.(Ala175Asp) variants are the most frequent and are distributed worldwide. However, these variants have particular distribution patterns in Europe. The analysis of the prevalence of HFI showed that the inclusion of rare alleles predicted as pathogenic is a more informative approach for populations with few patients. The data show that HFI has a wide distribution and an estimated prevalence of ~1:10,000.


Asunto(s)
Intolerancia a la Fructosa , Alelos , Intolerancia a la Fructosa/diagnóstico , Intolerancia a la Fructosa/epidemiología , Intolerancia a la Fructosa/genética , Fructosa-Bifosfato Aldolasa/genética , Humanos , Hígado/patología , Mutación
2.
Genet Med ; 23(12): 2369-2377, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34341521

RESUMEN

PURPOSE: Pathogenic variants in GNPTAB and GNPTG, encoding different subunits of GlcNAc-1-phosphotransferase, cause mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma. This study aimed to investigate the cellular and molecular bases underlying skeletal abnormalities in patients with MLII and MLIII. METHODS: We analyzed bone biopsies from patients with MLIII alpha/beta or MLIII gamma by undecalcified histology and histomorphometry. The skeletal status of Gnptgko and Gnptab-deficient mice was determined and complemented by biochemical analysis of primary Gnptgko bone cells. The clinical relevance of the mouse data was underscored by systematic urinary collagen crosslinks quantification in patients with MLII, MLIII alpha/beta, and MLIII gamma. RESULTS: The analysis of iliac crest biopsies revealed that bone remodeling is impaired in patients with GNPTAB-associated MLIII alpha/beta but not with GNPTG-associated MLIII gamma. Opposed to Gnptab-deficient mice, skeletal remodeling is not affected in Gnptgko mice. Most importantly, patients with variants in GNPTAB but not in GNPTG exhibited increased bone resorption. CONCLUSION: The gene-specific impact on bone remodeling in human individuals and in mice proposes distinct molecular functions of the GlcNAc-1-phosphotransferase subunits in bone cells. We therefore appeal for the necessity to classify MLIII based on genetic in addition to clinical criteria to ensure appropriate therapy.


Asunto(s)
Resorción Ósea , Mucolipidosis , Transferasas (Grupos de Otros Fosfatos Sustitutos) , Animales , Humanos , Ratones , Mucolipidosis/genética , Mucolipidosis/patología , Transferasas (Grupos de Otros Fosfatos Sustitutos)/genética
3.
Hum Mutat ; 41(1): 133-139, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31579991

RESUMEN

Mucolipidosis (ML) II and III alpha/beta are inherited lysosomal storage disorders caused by mutations in GNPTAB encoding the α/ß-precursor of GlcNAc-1-phosphotransferase. This enzyme catalyzes the initial step in the modification of more than 70 lysosomal enzymes with mannose 6-phosphate residues to ensure their intracellular targeting to lysosomes. The so-called stealth domains in the α- and ß-subunit of GlcNAc-1-phosphotransferase were thought to be involved in substrate recognition and/or catalysis. Here, we performed in silico alignment analysis of stealth domain-containing phosphotransferases and showed that the amino acid residues Glu389 , Asp408 , His956 , and Arg986 are highly conserved between different phosphotransferases. Interestingly, mutations in these residues were identified in patients with MLII and MLIII alpha/beta. To further support the in silico findings, we also provide experimental data demonstrating that these four amino acid residues are strictly required for GlcNAc-1-phosphotransferase activity and thus may be directly involved in the enzymatic catalysis.


Asunto(s)
Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Predisposición Genética a la Enfermedad , Mucolipidosis/diagnóstico , Mucolipidosis/genética , Mutación Missense , Transferasas (Grupos de Otros Fosfatos Sustitutos)/genética , Alelos , Secuencia de Aminoácidos , Catálisis , Técnica del Anticuerpo Fluorescente , Expresión Génica , Estudios de Asociación Genética , Genotipo , Humanos , Fenotipo , Especificidad por Sustrato , Transferasas (Grupos de Otros Fosfatos Sustitutos)/química , Transferasas (Grupos de Otros Fosfatos Sustitutos)/metabolismo
4.
Genet Mol Biol ; 43(3): 20190298, 2020 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-32706845

RESUMEN

Citrullinemia type 1 (CTLNI), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), and mut0 methylmalonic acidemia (mut0 MMA) are inborn errors of metabolism (IEMs) associated with sudden unexpected death in infancy (SUDI). Its most common pathogenic variants are: c.1168G>A (CTLNI, ASS1 gene), c.1528G>C (LCHADD, HADHA gene), c.655A>T and c.1106G>A (mut0 MMA, MUT gene). Considering the absence of estimates regarding the incidence of these diseases in Brazil, this study sought to investigate the prevalence of its main pathogenic variants in a healthy population in the southern region of the country. A total of 1,000 healthy subjects from Rio Grande do Sul were included. Genotyping was performed by real-time PCR. Individuals found to be heterozygous for c.1528G>C underwent further acylcarnitine profile analysis by tandem mass spectrophotometry. Allele and genotype frequencies were calculated considering Hardy-Weinberg equilibrium. The c.1528G>C variant was detected in heterozygosity in two subjects (carrier frequency = 1:500; allele frequency = 0.001; minimum prevalence of LCHADD = 1: 1,000,000), whose acylcarnitine profiles were normal. Variants c.1168G>A, c.655A>T, and c.1106G>A were not identified. These results denote the rarity of these IEMs in Southern Brazil, highlighting the need to expand the investigation of IEMs in relation to infant morbidity and mortality within the country.

5.
Hum Mutat ; 40(7): 842-864, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30882951

RESUMEN

Mutations in the GNPTAB and GNPTG genes cause mucolipidosis (ML) type II, type III alpha/beta, and type III gamma, which are autosomal recessively inherited lysosomal storage disorders. GNPTAB and GNPTG encode the α/ß-precursor and the γ-subunit of N-acetylglucosamine (GlcNAc)-1-phosphotransferase, respectively, the key enzyme for the generation of mannose 6-phosphate targeting signals on lysosomal enzymes. Defective GlcNAc-1-phosphotransferase results in missorting of lysosomal enzymes and accumulation of non-degradable macromolecules in lysosomes, strongly impairing cellular function. MLII-affected patients have coarse facial features, cessation of statural growth and neuromotor development, severe skeletal abnormalities, organomegaly, and cardiorespiratory insufficiency leading to death in early childhood. MLIII alpha/beta and MLIII gamma are attenuated forms of the disease. Since the identification of the GNPTAB and GNPTG genes, 564 individuals affected by MLII or MLIII have been described in the literature. In this report, we provide an overview on 258 and 50 mutations in GNPTAB and GNPTG, respectively, including 58 novel GNPTAB and seven novel GNPTG variants. Comprehensive functional studies of GNPTAB missense mutations did not only gain insights into the composition and function of the GlcNAc-1-phosphotransferase, but also helped to define genotype-phenotype correlations to predict the clinical outcome in patients.


Asunto(s)
Mucolipidosis/genética , Mutación , Transferasas (Grupos de Otros Fosfatos Sustitutos)/genética , Exones , Humanos , Intrones , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/clasificación , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/genética , Mucolipidosis/clasificación , Fenotipo , Pronóstico , Dominios Proteicos , Transferasas (Grupos de Otros Fosfatos Sustitutos)/química
6.
Mol Genet Metab ; 127(4): 361-367, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31337602

RESUMEN

INTRODUCTION: Biotinidase deficiency (BD), an autosomal recessive disease, is classified into profound (activity <10%) or partial BD (activity 10-30%). The most frequent variant in patients worldwide is c.1330G > C (p.Asp444His), which is associated with partial BD. In vivo studies indicate that this variant reduces the biotinidase activity by 50%. The objective of this study was to evaluate the in vitro effect of p.Asp444His and of five novel variants identified among Brazilian individuals showing low activity of biotinidase in serum. METHODS: The variants c.119 T > C (p.Leu40Pro), c.479G > A (p.Cys160Tyr), c.664G > A (p.Asp222Asn), c.1330G > C (p.Asp444His), c.1337 T > C (p.Leu446Pro), c.1466A > G (p.Asn489Ser) and the wild type (wt) BTD gene were expressed in HEK 293 cells. Biotinidase activity was quantified by colorimetric method in cells homogenates and culture medium. The wtBTD activity was considered 100%. RESULTS: The p.Leu40Pro, p.Cys160Tyr and p.Leu446Pro variants were associated to impaired biotinidase activity (activity in cells: 33%, 14%, 0%, respectively; activity in medium: 7%, 0.3%, 2%, respectively) and undetectable amount of protein in intra and extracellular space. The p.Asn489Ser variant had these effects restricted to the extracellular space (activity in medium: 43%), and the p.Asp222Asn variant showed normal activity. The expression of p.Asp444His variant resulted in detectable protein and slightly reduced activity only in cells (activity in cells: 46%; activity in medium: 115%). CONCLUSION: Our findings suggest that the p.Leu40Pro, p.Cys160Tyr and p.Leu446Pro variants are deleterious; the p.Asn489Ser is probably related to a mild biochemical phenotype; and p.Asp222Asn variant is probably not deleterious. The p.Asp444His variant seems to code for a protein with variable activity.


Asunto(s)
Deficiencia de Biotinidasa/genética , Biotinidasa/genética , Biotinidasa/metabolismo , Variación Genética , Alelos , Colorimetría , Expresión Génica , Células HEK293 , Humanos , Mutación
7.
Intern Med J ; 49(5): 578-591, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30414226

RESUMEN

BACKGROUND: Gaucher disease (GD) presents with a range of signs and symptoms. Physicians can fail to recognise the early stages of GD owing to a lack of disease awareness, which can lead to significant diagnostic delays and sometimes irreversible but avoidable morbidities. AIM: The Gaucher Earlier Diagnosis Consensus (GED-C) initiative aimed to identify signs and co-variables considered most indicative of early type 1 and type 3 GD, to help non-specialists identify 'at-risk' patients who may benefit from diagnostic testing. METHODS: An anonymous, three-round Delphi consensus process was deployed among a global panel of 22 specialists in GD (median experience 17.5 years, collectively managing almost 3000 patients). The rounds entailed data gathering, then importance ranking and establishment of consensus, using 5-point Likert scales and scoring thresholds defined a priori. RESULTS: For type 1 disease, seven major signs (splenomegaly, thrombocytopenia, bone-related manifestations, anaemia, hyperferritinaemia, hepatomegaly and gammopathy) and two major co-variables (family history of GD and Ashkenazi-Jewish ancestry) were identified. For type 3 disease, nine major signs (splenomegaly, oculomotor disturbances, thrombocytopenia, epilepsy, anaemia, hepatomegaly, bone pain, motor disturbances and kyphosis) and one major co-variable (family history of GD) were identified. Lack of disease awareness, overlooking mild early signs and failure to consider GD as a diagnostic differential were considered major barriers to early diagnosis. CONCLUSION: The signs and co-variables identified in the GED-C initiative as potentially indicative of early GD will help to guide non-specialists and raise their index of suspicion in identifying patients potentially suitable for diagnostic testing for GD.


Asunto(s)
Consenso , Técnica Delphi , Enfermedad de Gaucher/diagnóstico , Médicos/normas , Diagnóstico Precoz , Enfermedad de Gaucher/fisiopatología , Humanos
8.
Genet Mol Biol ; 42(3): 571-573, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31188938

RESUMEN

Mucolipidosis II and III (ML II and III) alpha/beta and ML III gamma are lysosomal diseases caused by GlcNAc-1-phosphotransferase deficiency. Previous data indicate that MLII patients have functionally impaired immune system that contributes to predisposition to infections.We evaluated the immunological phenotype of three Brazilian patients with ML III gamma. Our data suggest that the residual activity of GlcNAc-1-phosphotransferase in patients with ML III gamma is enough to allow the targeting of the lysosomal enzymes required for B-cell functions maintenance.

9.
Genet Mol Biol ; 42(1 suppl 1): 197-206, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30985853

RESUMEN

Lysosomal storage disorders (LSDs) constitute a heterogeneous group of approximately 50 genetic disorders. LSDs diagnosis is challenging due to variability in phenotype penetrance, similar clinical manifestations, and a high allelic heterogeneity. A powerful tool for the diagnosis of the disease could reduce the "diagnostic odyssey" for affected families, leading to an appropriate genetic counseling and a better outcome for current therapies, since enzyme replacement therapies have been approved in Brazil for Gaucher, Fabry, and Pompe diseases, and are under development for Niemann-Pick Type B. However, application of next-generation sequencing (NGS) technology in the clinical diagnostic setting requires a previous validation phase. Here, we assessed the application of this technology as a fast, accurate, and cost-effective method to determine genetic diagnosis in selected LSDs. We have designed two panels for testing simultaneously 11 genes known to harbor casual mutations of LSDs. A cohort of 58 patients was used to validate those two panels, and the clinical utility of these gene panels was tested in four novel cases. We report the assessment of a NGS approach as a new tool in the diagnosis of LSDs in our service.

11.
Hum Mol Genet ; 24(12): 3497-505, 2015 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-25788519

RESUMEN

Mucolipidosis II (MLII) and III alpha/beta are autosomal-recessive diseases of childhood caused by mutations in GNPTAB encoding the α/ß-subunit precursor protein of the GlcNAc-1-phosphotransferase complex. This enzyme modifies lysosomal hydrolases with mannose 6-phosphate targeting signals. Upon arrival in the Golgi apparatus, the newly synthesized α/ß-subunit precursor is catalytically activated by site-1 protease (S1P). Here we performed comprehensive expression studies of GNPTAB mutations, including two novel mutations T644M and T1223del, identified in Brazilian MLII/MLIII alpha/beta patients. We show that the frameshift E757KfsX1 and the non-sense R587X mutations result in the retention of enzymatically inactive truncated precursor proteins in the endoplasmic reticulum (ER) due to loss of cytosolic ER exit motifs consistent with a severe clinical phenotype in homozygosity. The luminal missense mutations, C505Y, G575R and T644M, partially impaired ER exit and proteolytic activation in accordance with less severe MLIII alpha/beta disease symptoms. Analogous to the previously characterized S399F mutant, we found that the missense mutation I403T led to retention in the ER and loss of catalytic activity. Substitution of further conserved residues in stealth domain 2 (I346 and W357) revealed similar biochemical properties and allowed us to define a putative binding site for accessory proteins required for ER exit of α/ß-subunit precursors. Interestingly, the analysis of the Y937_M972del mutant revealed partial Golgi localization and formation of abnormal inactive ß-subunits generated by S1P which correlate with a clinical MLII phenotype. Expression analyses of mutations identified in patients underline genotype-phenotype correlations in MLII/MLIII alpha/beta and provide novel insights into structural requirements of proper GlcNAc-1-phosphotransferase activity.


Asunto(s)
Estudios de Asociación Genética , Mutación , Proproteína Convertasas/metabolismo , Dominios y Motivos de Interacción de Proteínas , Serina Endopeptidasas/metabolismo , Transferasas (Grupos de Otros Fosfatos Sustitutos)/genética , Transferasas (Grupos de Otros Fosfatos Sustitutos)/metabolismo , Animales , Línea Celular , Retículo Endoplásmico/metabolismo , Activación Enzimática , Expresión Génica , Humanos , Espacio Intracelular/metabolismo , Masculino , Proproteína Convertasas/genética , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Transporte de Proteínas , Proteolisis , Serina Endopeptidasas/genética , Transferasas (Grupos de Otros Fosfatos Sustitutos)/química
12.
J Hum Genet ; 61(6): 555-60, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26935170

RESUMEN

Mucolipidosis (ML) III gamma is a rare autosomal-recessive disorder caused by pathogenic mutations in the GNPTG gene. GNPTG encodes the γ-subunit of GlcNAc-1-phosphotransferase that catalyzes mannose 6-phosphate targeting signal synthesis on soluble lysosomal enzymes. ML III gamma patients are characterized by missorting of lysosomal enzymes. In this report, we describe the probable occurrence of mRNA editing in two ML III gamma patients. Patients A and B (siblings) presented at the adult age with a typical clinical picture of ML III gamma, mainly compromising bone and joints, and high levels of lysosomal enzymes in plasma and low levels in fibroblasts. Both were found to be homozygous for c.-112C>G and c.328G>T (p.Glu110Ter) mutations in genomic DNA (gDNA) analysis of GNPTG. Analysis of complementary DNA (cDNA), however, showed normal genotypes for both patients. Low GNPTG mRNA expression was observed in both patients. The mRNA editing can explain the differences found in patients A and B regarding gDNA and cDNA analysis, and the mild clinical phenotype associated with homozygosity for a nonsense mutation. Our results suggest that mRNA editing can be more frequent than expected in monogenic disorders and that GNPTG analysis should be performed on gDNA.


Asunto(s)
Codón sin Sentido , Homocigoto , Mucolipidosis/diagnóstico , Mucolipidosis/genética , Mutación , ARN Mensajero/genética , Hermanos , Transferasas (Grupos de Otros Fosfatos Sustitutos)/genética , Adulto , Alelos , Sustitución de Aminoácidos , Biomarcadores , Variaciones en el Número de Copia de ADN , Femenino , Expresión Génica , Genotipo , Humanos , Masculino , Fenotipo , Polimorfismo de Longitud del Fragmento de Restricción , Edición de ARN , Análisis de Secuencia de ADN
13.
J Inherit Metab Dis ; 39(5): 713-723, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27287710

RESUMEN

INTRODUCTION: Alpha-1,3-glucosyltransferase congenital disorder of glycosylation (ALG6-CDG) is a congenital disorder of glycosylation. The original patients were described with hypotonia, developmental disability, epilepsy, and increased bleeding tendency. METHODS: Based on Euroglycan database registration, we approached referring clinicians and collected comprehensive data on 41 patients. RESULTS: We found hypotonia and developmental delay in all ALG6-CDG patients and epilepsy, ataxia, proximal muscle weakness, and, in the majority of cases, failure to thrive. Nine patients developed intractable seizures. Coagulation anomalies were present in <50 % of cases, without spontaneous bleedings. Facial dysmorphism was rare, but seven patients showed missing phalanges and brachydactyly. Cyclic behavioral change, with autistic features and depressive episodes, was one of the most significant complaints. Eleven children died before the age of 4 years due to protein losing enteropathy (PLE), sepsis, or seizures. The oldest patient was a 40 year-old Dutch woman. The most common pathogenic protein alterations were p.A333V and p.I299Del, without any clear genotype-phenotype correlation. DISCUSSION: ALG6-CDG has been now described in 89 patients, making it the second most common type of CDG. It has a recognizable phenotype and a primary neurologic presentation.


Asunto(s)
Ataxia/patología , Trastornos Congénitos de Glicosilación/patología , Epilepsia/patología , Glucosiltransferasas/genética , Deformidades Congénitas de las Extremidades/patología , Proteínas de la Membrana/genética , Trastornos Mentales/patología , Debilidad Muscular/patología , Adolescente , Adulto , Ataxia/genética , Niño , Preescolar , Trastornos Congénitos de Glicosilación/genética , Epilepsia/genética , Femenino , Estudios de Asociación Genética/métodos , Glicosilación , Humanos , Lactante , Recién Nacido , Deformidades Congénitas de las Extremidades/genética , Masculino , Trastornos Mentales/genética , Hipotonía Muscular/genética , Hipotonía Muscular/patología , Debilidad Muscular/genética , Fenotipo , Estudios Retrospectivos , Convulsiones/genética , Convulsiones/patología , Adulto Joven
15.
J Inherit Metab Dis ; 38(3): 529-36, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25224825

RESUMEN

Uncooked cornstarch (UCCS) is a widely used treatment strategy for patients with hepatic glycogen storage disease (GSD). It has been observed that GSD-patients display different metabolic responses to different cornstarches. The objective was to characterize starch fractions and analyze the digestion of different starches in a dynamic gastrointestinal in vitro model. The following brands of UCCS were studied: Argo and Great Value from the United States of America; Brazilian Maizena Duryea and Yoki from Brazil; Dutch Maizena Duryea from the Netherlands. Glycosade, a modified starch, and sweet polvilho, a Brazilian starch extracted from cassava, were also studied. The starch fractions were analyzed by glycemic TNO index method and digestion analyses were determined by the TIM-1 system, a dynamic, computer-controlled, in vitro gastrointestinal model, which simulates the stomach and small intestine. The final digested amounts were between 84 and 86% for the UCCS and Glycosade, but was 75.5% for sweet povilho. At 180 min of the experiment, an important time-point for GSD patients, the digested amount of the starches corresponded to 67.9-71.5 for the UCCS and Glycosade, while it was 55.5% for sweet povilho. In an experiment with a mixture of sweet polvilho and Brazilian Maizena Duryea, a final digested amount of 78.4% was found, while the value at 180 min was 61.7%. Sweet polvilho seems to have a slower and extended release of glucose and looks like an interesting product to be further studied as it might lead to extended normoglycemia in GSD-patients.


Asunto(s)
Digestión/fisiología , Glucosa/metabolismo , Enfermedad del Almacenamiento de Glucógeno Tipo I/dietoterapia , Almidón/análisis , Almidón/clasificación , Humanos , Modelos Biológicos , Almidón/uso terapéutico
16.
Health Qual Life Outcomes ; 13: 41, 2015 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-25889100

RESUMEN

BACKGROUND: Osteogenesis imperfecta (OI) is a group of genetic disorders of collagen biosynthesis, characterized by low bone density leading to fractures. Most patients exhibit functional impairment and require the aid of a caregiver. The aim of this study is to assess the quality of life (QoL) of caregivers of patients with OI. METHODS: In this cross-sectional study, a convenience sampling strategy was used to enroll adult caregivers of children and adolescents with OI who attended a referral center in southern Brazil. The WHOQOL-BREF instrument was used to assess QoL. RESULTS: Twenty-four caregivers of 27 patients (10 with type I, 4 with type III, and 13 with type IV OI) were included in the study. Eighteen caregivers were the patients' mothers, two had OI, and 22 cared for only one patient. Mean WHOQOL-BREF scores were 14.59 for the physical health domain, 13.80 for the psychological domain, 15.19 for the social relationships domain, and 12.87 for the environmental domain; the mean total QoL score was 14.16. QoL scores did not differ significantly according to patients' OI type or number of fractures. Economic status was not correlated significantly with QoL scores. CONCLUSIONS: QoL appears to be impaired in caregivers of patients with OI. Additional studies are required to confirm these findings and to ascertain which factors account for this phenomenon.


Asunto(s)
Cuidadores/psicología , Osteogénesis Imperfecta/enfermería , Osteogénesis Imperfecta/psicología , Relaciones Padres-Hijo , Calidad de Vida/psicología , Adaptación Psicológica , Adolescente , Adulto , Brasil , Niño , Estudios Transversales , Femenino , Humanos , Masculino
17.
An Acad Bras Cienc ; 87(2 Suppl): 1375-88, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26247150

RESUMEN

With the advance and popularization of molecular techniques, the identification of genetic mutations that cause diseases has increased dramatically. Thus, the number of laboratories available to investigate a given disorder and the number of subsequent diagnosis have increased over time. Although it is necessary to identify mutations and provide diagnosis, it is also critical to develop specific therapeutic approaches based on this information. This review aims to highlight recent advances in mutation-targeted therapies with chemicals that mitigate mutational pathology at the molecular level, for disorders that, for the most part, have no effective treatment. Currently, there are several strategies being used to correct different types of mutations, including the following: the identification and characterization of translational readthrough compounds; antisense oligonucleotide-mediated splicing redirection; mismatch repair; and exon skipping. These therapies and other approaches are reviewed in this paper.


Asunto(s)
Técnicas de Silenciamiento del Gen , Enfermedades Genéticas Congénitas/tratamiento farmacológico , Oligonucleótidos Antisentido , Empalme del ARN , Enfermedades Raras/tratamiento farmacológico , Humanos , Mutación/genética , Enfermedades Raras/genética
18.
BMC Med Genet ; 15: 96, 2014 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-25174816

RESUMEN

BACKGROUND: Biotinidase deficiency (BD) is an inborn error of metabolism in which some genetic variants correlate with the level of enzyme activity. Biotinidase activity, however, may be artifactually low due to enzyme lability, premature birth, and jaundice; this hinders both phenotypic classification and the decision to implement therapy. This study sought to characterize the clinical and genetic profile of a sample of Brazilian patients exhibiting reduced biotinidase activity. METHODS: This observational, multicenter study used a convenience sampling strategy, with sequencing of exons 2, 3, and 4 of the BTD gene. RESULTS: The sample comprised 38 individuals with biochemical phenotypes defined a priori on the basis of biotinidase activity in serum/plasma (2 with profound deficiency, 9 with partial deficiency, 15 heterozygous, 1 borderline between partial deficiency and heterozygosity, 2 borderline between heterozygous and normal) or dried blood spot sample (n = 9, all with unspecified deficiency). Most patients were from Southern Brazil (n = 29/38) and were identified by neonatal screening (n = 33/38). Parental consanguinity was reported in two cases. The most commonly found genetic variants were c.1330G > C (p.D444H), c.755A > G (p.D252G), and c.[511G > A;1330G > C] (p.[A171T;D444H]), with allele frequencies of 50%, 9.4%, and 5.4% respectively. Three novel pathogenic variants were identified (c.119 T > C or p.L40P, c.479G > A or p.C160Y, and c.664G > A or p.D222N). Twenty-nine patients had two pathogenic variants detected (with cis/trans status ascertained in 26/29), six had only one variant, and three had no pathogenic variants detected. Genotyping confirmed the original phenotypic classification based on enzyme activity in 16/26 cases. Three polymorphic variants were identified in control individuals, of which two were nonpathogenic (c.1171C > T or p.P391S and c.1413 T > C or p.C471C, with a frequency of 1.5% and 5.5% respectively) and one pathogenic (c.1330G > C, frequency 4%). CONCLUSIONS: Our findings suggest that partial BD is the most common form of BD in Brazil, and expand current knowledge on the allelic heterogeneity of this condition.


Asunto(s)
Deficiencia de Biotinidasa/genética , Deficiencia de Biotinidasa/patología , Biotinidasa/genética , Polimorfismo de Nucleótido Simple , Brasil , Estudios Transversales , Exones , Femenino , Heterogeneidad Genética , Variación Genética , Humanos , Recién Nacido , Masculino , Tamizaje Neonatal
19.
Front Genet ; 15: 1355962, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38425716

RESUMEN

Classic galactosemia (CG, OMIM #230400, ORPHA: 79,239) is a hereditary disorder of galactose metabolism that, despite treatment with galactose restriction, affects brain function in 85% of the patients. Problems with cognitive function, neuropsychological/social emotional difficulties, neurological symptoms, and abnormalities in neuroimaging and electrophysiological assessments are frequently reported in this group of patients, with an enormous individual variability. In this review, we describe the role of impaired galactose metabolism on brain dysfunction based on state of the art knowledge. Several proposed disease mechanisms are discussed, as well as the time of damage and potential treatment options. Furthermore, we combine data from longitudinal, cross-sectional and retrospective studies with the observations of specialist teams treating this disease to depict the brain disease course over time. Based on current data and insights, the majority of patients do not exhibit cognitive decline. A subset of patients, often with early onset cerebral and cerebellar volume loss, can nevertheless experience neurological worsening. While a large number of patients with CG suffer from anxiety and depression, the increased complaints about memory loss, anxiety and depression at an older age are likely multifactorial in origin.

20.
Genet Mol Biol ; 35(4 (suppl)): 947-54, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23413206

RESUMEN

The specific treatment available for Fabry disease (FD) is enzyme replacement therapy (ERT) with agalsidase alfa or beta. A systematic review and meta-analysis was conducted to assess the efficacy and safety of ERT for FD. Only double-blind, randomized clinical trials (RCTs) comparing agalsidase alfa or beta and placebo were included. ERT with either agalsidase alfa or beta was considered similar for the purposes of analysis. Ten RCTs were identified, which showed improvements in neuropathic pain, in heart abnormalities and in globotriaosylceramide (GL-3) levels. A meta-analysis showed increased odds for fever, rigors, development of IgG antibodies to agalsidase, and no significant association with development of hypertension or reduction in the QRS complex duration on electrocardiogram. The RCTs included in this comparison enrolled few patients, were highly heterogeneous, and were focused mainly on surrogate endpoints, limiting any conclusions as to the real effect of ERT for FD. The available evidence suggests that response to ERT is variable across patient subgroups and that agalsidase may slow progression of FD, with slight improvement of existing changes. Nevertheless, many uncertainties remain, and further studies are necessary.

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