RESUMEN
BACKGROUND: Mucopolysaccharidosis VI, or Maroteaux-Lamy disease, is an autosomal recessive disease characterized by deficiency of the enzyme arylsulfatase B in the lysosomal catabolism of glycosaminoglycans. Due to reduced (or even null) enzyme activity, glycosaminoglycans (mainly dermatan sulfate) accumulates, leading to a multisystemic disease. Mucopolysaccharidosis VI induces reduced growth, coarse face, audiovisual deficits, osteoarticular deformities, and cardiorespiratory issues, hampering the quality of life of the patient. Enzyme replacement therapy with galsulfase (Naglazyme, BioMarin Pharmaceuticals Inc., USA) is the specific treatment for this condition. Although studies have shown that enzyme replacement therapy slows the progression of the disease, the effects of long-term enzyme replacement therapy remain poorly understood. CASE PRESENTATION: A 29-year-old, Caucasian, male patient diagnosed with mucopolysaccharidosis VI was treated with enzyme replacement therapy for over 15 years. Enzyme replacement therapy was initiated when patient was 13 years old. The patient evolved multiplex dysostosis, carpal tunnel syndrome, thickened mitral valve, and hearing and visual loss. CONCLUSIONS: Although enzyme replacement therapy did not prevent the main signs of mucopolysaccharidosis VI, it slowed their progression. Additionally, enzyme replacement therapy was associated with a longer survival compared with the untreated affected sibling. Taken together, the results indicate that enzyme replacement therapy positively modified the course of the disease.
Asunto(s)
Síndrome del Túnel Carpiano , Mucopolisacaridosis VI , Adolescente , Adulto , Terapia de Reemplazo Enzimático , Glicosaminoglicanos/uso terapéutico , Humanos , Masculino , Mucopolisacaridosis VI/tratamiento farmacológico , Calidad de VidaRESUMEN
Las formas hereditarias de exostosis múltiple, actualmente denominada EXT1 / EXT2-CDG dentro de los desórdenes congénitos de la glicosilación, son los tumores óseos benignos más comunes y se caracterizan por la formación de lesiones óseas cubiertas de cartílago, localizadas en yuxtaposición a epífisis de huesos largos, aunque, en los casos graves, pueden presentar una amplia distribución. El inicio es variable desde los 2-3 años hasta los 13-15 y presenta una incidencia estimada que va de 1/18 000 a 1/50 000 casos en los países europeos. Se presenta el caso de un doble alelo mutante en el gen EXT1 no informado previamente en una adolescente y su familia con exostosis múltiple hereditaria.(AU)
RESUMEN
Las formas hereditarias de exostosis múltiple, actualmente denominada EXT1 / EXT2-CDG dentro de los desórdenes congénitos de la glicosilación, son los tumores óseos benignos más comunes y se caracterizan por la formación de lesiones óseas cubiertas de cartílago, localizadas en yuxtaposición a epífisis de huesos largos, aunque, en los casos graves, pueden presentar una amplia distribución. El inicio es variable desde los 2-3 años hasta los 13-15 y presenta una incidencia estimada que va de 1/18 000 a 1/50 000 casos en los países europeos. Se presenta el caso de un doble alelo mutante en el gen EXT1 no informado previamente en una adolescente y su familia con exostosis múltiple hereditaria.
Hereditary forms of multiple exostoses, now called EXT1/EXT2-CDG within Congenital Disorders of Glycosylation, are the most common benign bone tumors in humans and clinical description consists of the formation of several cartilage-capped bone tumors, usually benign and localized in the juxta-epiphyseal region of long bones, although wide body dissemination in severe cases is not uncommon. Onset of the Alelo doble mutante en el gen EXT1 no informado previamente en una adolescente con exostosis múltiple hereditariaDouble mutant alleles in the EXT1 gene not previously reported in a teenager with hereditary multiple exostosesdisease is variable ranging from 2-3 years up to 13-15 years with an estimated incidence ranging from 1/18 000 to 1/50 000 cases in European countries. We present a double mutant alleles in the EXT1 gene not previously reported in a teenager and her family with hereditary multiple exostoses
Asunto(s)
Humanos , Femenino , Adolescente , Pediatría , Exostosis Múltiple Hereditaria , AdolescenteRESUMEN
Hereditary forms of multiple exostoses, now called EXT1/EXT2-CDG within Congenital Disorders of Glycosylation, are the most common benign bone tumors in humans and clinical description consists of the formation of several cartilage-capped bone tumors, usually benign and localized in the juxta-epiphyseal region of long bones, although wide body dissemination in severe cases is not uncommon. Onset of the disease is variable ranging from 2-3 years up to 13-15 years with an estimated incidence ranging from 1/18,000 to 1/50,000 cases in European countries. We present a double mutant alleles in the EXT1 gene not previously reported in a teenager and her family with hereditary multiple exostoses.
Asunto(s)
Exostosis Múltiple Hereditaria/genética , Mutación , N-Acetilglucosaminiltransferasas/genética , Adolescente , Alelos , Femenino , HumanosAsunto(s)
Neoplasias Óseas/genética , Codón sin Sentido , Exostosis Múltiple Hereditaria/genética , Exostosis Múltiple Hereditaria/patología , N-Acetilglucosaminiltransferasas/genética , Osteocondroma/genética , Adulto , Argentina , Biopsia con Aguja , Neoplasias Óseas/patología , Neoplasias Óseas/cirugía , Exostosis Múltiple Hereditaria/diagnóstico por imagen , Exostosis Múltiple Hereditaria/cirugía , Femenino , Fémur/diagnóstico por imagen , Fémur/patología , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética/métodos , Osteocondroma/patología , Osteocondroma/cirugía , Linaje , Huesos Pélvicos/diagnóstico por imagen , Huesos Pélvicos/patología , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Medición de Riesgo , Tomografía Computarizada por Rayos X/métodos , Resultado del TratamientoRESUMEN
Homocystinuria due to CBS deficiency is a rare autosomal recessive disorder characterized by elevated plasma levels of homocysteine (Hcy) and methionine (Met). Here we present the analysis of 22 unrelated patients of different geographical origins, mainly Spanish and Argentinian. Twenty-two different mutations were found, 10 of which were novel. Five new mutations were missense and five were deletions of different sizes, including a 794-bp deletion (c.532-37_736 + 438del794) detected by Southern blot analysis. To assess the pathogenicity of these mutations, seven were expressed heterologously in Escherichia coli and their enzyme activities were assayed in vitro, in the absence and presence of the CBS activators PLP and SAM. The presence of the mutant proteins was confirmed by Western blotting. Mutations p.M173del, p.I278S, p.D281N, and p.D321V showed null activity in all conditions tested, whereas mutations p.49L, p.P200L and p.A446S retained different degrees of activity and response to stimulation. Finally, a minigene strategy allowed us to demonstrate the pathogenicity of an 8-bp intronic deletion, which led to the skipping of exon 6. In general, frameshifting deletions correlated with a more severe phenotype, consistent with the concept that missense mutations may recover enzymatic activity under certain conditions.
Asunto(s)
Cistationina betasintasa/genética , Homocistinuria/genética , Eliminación de Secuencia/genética , Alelos , Argentina , Femenino , Mutación del Sistema de Lectura/genética , Expresión Génica , Homocisteína/genética , Homocistinuria/enzimología , Humanos , Intrones , Masculino , Mutagénesis Sitio-Dirigida , Sitios de Empalme de ARN/genética , España , Relación Estructura-ActividadRESUMEN
Maroteaux-Lamy syndrome, or mucopolysaccharidosis VI (MPS VI), is an autosomal recessive lysosomal storage disorder caused by a deficiency of N-acetylgalactosamine-4-sulfatase or arylsulfatase B (ARSB). We aimed to analyze the spectrum of mutations responsible for the disorder in Spanish and Argentinian patients, not previously studied. We identified all the ARSB mutant alleles, nine of them novel, in 12 Spanish and 4 Argentinian patients. The new changes were as follows: six missense mutations: c.245T>G [p.L82R], c.413A>G [p.Y138C], c.719C>T [p.S240F], c.922G>A [p.G308R], c.1340G>T [p.C447F] and c.1415T>C [p.L472P]; one nonsense mutation: c.966G>A [p.W322X]; and two intronic changes involving splice sites: c.1142+2T>A, in the donor splice site of intron 5, which promotes skipping of exon 5, and c.1143-1G>C, which disrupts the acceptor site of intron 5, resulting in skipping of exon 6. We also report 10 previously described mutations as well as several non-pathogenic polymorphisms. Haplotype analysis indicated a common origin for most of the mutations found more than once. Most of the patients were compound heterozygotes, whereas only four of them were homozygous. These observations confirm the broad allelic heterogeneity of the disease, with 19 different mutations in 16 patients. However, the two most frequent mutations, c.1143-1G>C and c.1143-8T>G, present in both populations, accounted for one-third of the mutant alleles in this group of patients.
Asunto(s)
Mucopolisacaridosis VI/genética , Mutación/genética , N-Acetilgalactosamina-4-Sulfatasa/genética , Argentina , Células Cultivadas , Análisis Mutacional de ADN , Fibroblastos/enzimología , Fibroblastos/patología , Haplotipos , Humanos , Mucopolisacaridosis VI/enzimología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , EspañaRESUMEN
Homocystinuria is an autosomal recessive disease most commonly caused by mutations in cystathionine beta-synthase (CBS). In this study we present the mutation analysis of 36 Colombian individuals from 10 unrelated kindred, with 11 individuals clinically classified as homocystinuric. Mutation analysis of the CBS gene revealed p.T191M, a prevalent mutation in Spain and Portugal, in the homozygous state in seven of the unrelated patients. Genotype-phenotype assessment of the p.T191M homozygous patients showed a high level of variability, including different severity in one pair of affected siblings. None of the patients responded biochemically to treatment with pharmacological doses of pyridoxine and folic acid as revealed by essentially unchanged homocysteine levels. This study offered a unique opportunity to study 18 heterozygous (p.T191M/wt) relatives of the homocystinuric patients. One atypical finding was that many of them presented with above average total homocysteine levels, putting them at an increased risk for vascular disease. Cryptorchidism was present in three of the cases, one of which presented also with Klinefelter syndrome. In addition to the previously described p.T191M mutation, a new mutation, p.A288T, was identified in a single individual. In this paper we present the first characterization, at a molecular level, of patients with homocystinuria from Colombia.
Asunto(s)
Cistationina betasintasa/genética , Homocistinuria/genética , Adolescente , Niño , Preescolar , Colombia , Criptorquidismo/genética , Análisis Mutacional de ADN , Femenino , Homocigoto , Humanos , Lactante , MasculinoRESUMEN
Classical homocystinuria is due to cystathionine beta-synthase (CBS) deficiency. More than 130 mutations, which differ in prevalence and severity, have been described at the CBS gene. Mutation p.I278T is very prevalent, has been found in all European countries where it has been looked for with the exception of the Iberian peninsula, and is known to respond to vitamin B6. On the other hand, mutation p.T191M is prevalent in Spain and Portugal and does not respond to B6. We analysed 30 pedigrees from Spain, Portugal, Colombia and Argentina, segregating for homocystinuria. The p.T191M mutation was detected in patients from all four countries and was particularly prevalent in Colombia. The number of p.T191M alleles described in this study, together with those previously published, is 71. The prevalence of p.T191M among CBS mutant alleles in the different countries was: 0.75 in Colombia, 0.52 in Spain, 0.33 in Portugal, 0.25 in Venezuela, 0.20 in Argentina and 0.14 in Brazil. Haplotype analyses suggested a double origin for this mutation. No genotype-phenotype correlation other than the B6-nonresponsiveness could be established for the p.T191M mutation. Additionally, three new mutations, p.M173V, p.I429del and c.69_70+8del10, were found. The p.M173V was associated with a mild, B6-responsive, phenotype.