RESUMEN
Methylmalonic aciduria (MMA-uria) is an autosomal recessive inborn error of amino acid metabolism, involving valine, threonine, isoleucine, and methionine. This organic aciduria may present in the neonatal period with life-threatening metabolic acidosis, hyperammonemia, feeding difficulties, pancytopenia, and coma. Most affected patients have mutations in the methylmalonyl-coenzyme A (methylmalonyl-CoA) mutase gene. Mildly affected patients may present in childhood with failure to thrive and recurrent attacks of metabolic acidosis. Both a higher residual activity of methylmalonyl-CoA mutase as well as the vitamin B12-responsive defects (cblA and cblB) may form the basis of the mild disorder. A few patients with moderate MMA-uria are known in whom no defect could be identified. Here we present a 16-year-old female patient with persisting moderate MMA-uria (approximately 50 mmol/mol creatinine). She was born to consanguineous Caucasian parents. Her fibroblast mutase activity was normal and no effect of vitamin B12 supplementation could be established. Reduced incorporation of 14C-propionate into macromolecules suggested a defect in the propionate-to-succinate pathway. We found a homozygous nonsense mutation (c.139C>T) in the methylmalonyl-CoA epimerase gene (MCEE), resulting in an early terminating signal (p.R47X). Both parents were heterozygous for this mutation; they were found to excrete normal amounts of methylmalonic acid (MMA). This is the first report of methylmalonyl-CoA epimerase deficiency, thereby unequivocally demonstrating the biochemical role of this enzyme in human metabolism.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/genética , Codón sin Sentido , Homocigoto , Ácido Metilmalónico/orina , Racemasas y Epimerasas/genética , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Preescolar , Consanguinidad , Análisis Mutacional de ADN , Femenino , HumanosRESUMEN
AIM: The role of high cholesterol-containing microdomains in the signal transduction cascade leading to the activation of volume-regulated anion channels (VRACs) was studied. METHODS: Osmotic cell swelling-induced efflux of 125I- was determined in human epithelial Intestine 407 cells and in skin fibroblasts obtained from healthy controls or Niemann-Pick type C (NPC) patients. Cellular cholesterol content was modulated by pre-incubation with 2-hydroxypropyl-beta-cyclodextrin in the presence of acceptor lipid vesicles. RESULTS: Osmotic cell swelling of human Intestine 407 cells leads to the rapid activation of a compensatory anion conductance. Treatment of the cells with cyclodextrin enhanced the response to submaximal hypotonic stimulation by approx. twofold, but did not further increase the efflux elicited by a saturating stimulus. In contrast, the volume-sensitive anion efflux was markedly inhibited when cholesterol-loaded cyclodextrin was used. Potentiation of the response by cholesterol depletion was maintained in caveolin-1 deficient Caco-2 colonocytes as well as in sphingomyelinase-treated Intestine 407 cells, indicating that cholesterol-rich microdomains are not crucially involved. However, treatment of the cells with progesterone, an inhibitor of NPC1-dependent endosomal cholesterol trafficking, not only markedly reduced the hypotonicity-provoked anion efflux, but also prevented its potentiation by cyclodextrin. In addition, the volume-sensitive anion efflux from human NPC skin fibroblasts was significantly smaller when compared with control fibroblasts. CONCLUSIONS: The results support a model of regulatory volume decrease involving recruitment of volume-sensitive anion channels from intracellular compartments to the plasma membrane.
Asunto(s)
Canales de Cloruro/metabolismo , Colesterol/metabolismo , Mucosa Intestinal/metabolismo , Enfermedad de Niemann-Pick Tipo C/metabolismo , 2-Hidroxipropil-beta-Ciclodextrina , Transporte Biológico , Estudios de Casos y Controles , Caveolina 1/farmacología , Línea Celular , Membrana Celular/metabolismo , Tamaño de la Célula , Células Cultivadas , Excipientes/farmacología , Fibroblastos/metabolismo , Humanos , Soluciones Hipotónicas , Membrana Dobles de Lípidos , Progesterona/farmacología , Estructura Terciaria de Proteína , Esfingomielina Fosfodiesterasa/farmacología , beta-Ciclodextrinas/farmacologíaRESUMEN
A combined genotype of polymorphisms of methionine metabolism has been associated with CNS demyelination in methotrexate-treated patients. Within a sample of 86 patients with X-linked adrenoleukodystrophy, this genotype was overrepresented in a subgroup of 15 patients with adrenomyeloneuropathy (AMN) with CNS demyelination (adrenoleukomyeloneuropathy) in comparison to 49 AMN patients without CNS demyelination ("pure" AMN; p = 0.002), suggesting that methionine metabolism might contribute to the phenotypic variability in adrenoleukodystrophy.
Asunto(s)
Adrenoleucodistrofia/genética , Adrenoleucodistrofia/metabolismo , Variación Genética , Metionina/metabolismo , Fenotipo , Adolescente , Adrenoleucodistrofia/clasificación , Niño , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Polimorfismo GenéticoRESUMEN
The detection of echodense fetal bowel on ultrasound examination in the second trimester of pregnancy justifies invasive procedures such as amniocentesis to detect an underlying cause. We present a case in which initial tests identified only one mutation in the cystic fibrosis transmembrane regulator (CFTR)-gene of the fetus, the family history being negative for CF. Strongly reduced intestinal enzyme activities suggested intestinal obstruction and further increased the estimated risk for CF. After the 24th gestational week, a second mutation was found, confirming cystic fibrosis in this child. Problems in counseling in this particular case are discussed.
Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/diagnóstico , Fibrosis Quística/genética , Enfermedades Fetales/diagnóstico por imagen , Asesoramiento Genético , Intestinos/patología , Ultrasonografía Prenatal , Adulto , Femenino , Feto/anomalías , Humanos , Recién Nacido , Intestinos/embriología , Masculino , EmbarazoRESUMEN
Canavan disease is characterised as a rare, neurodegenerative disease that usually causes death in early childhood. It is an autosomal recessive disorder due to an aspartoacylase (ASPA) deficiency. The causative gene has been mapped to chromosome 17 pter-p13. Here we describe three affected children from two Greek families with an unusually mild course of Canavan disease. All children presented with muscular hypotonia and macrocephaly. Diagnosis was based on elevated N-acetylaspartate in urine, reduced aspartoacylase activity in fibroblasts, and marked white matter changes on cerebral imaging. All three affected individuals exhibited continuous psychomotor development without any regression. Genetic analyses revealed compound heterozygous mutations (Y288 C; F295 S) in two individuals. The Y288 C variant was previously described in a child with macrocephaly, mild developmental delay, increased signal intensity in the basal ganglia, partial cortical blindness and retinitis pigmentosa, and slightly elevated N-acetylaspartate in the urine. Demonstration of the same variant in two unusually mildly affected Canavan disease patients and absence of this variant in 154 control chromosomes suggest a possible pathogenic role in mild Canavan disease. In the third individual, two homozygous sequence variants were identified, which comprise the known G274R mutation and a novel K213E variant.
Asunto(s)
Amidohidrolasas/genética , Enfermedad de Canavan/genética , Mutación , Fenotipo , Adolescente , Amidohidrolasas/deficiencia , Enfermedad de Canavan/patología , Enfermedad de Canavan/fisiopatología , Niño , Preescolar , Análisis Mutacional de ADN/métodos , Femenino , Genotipo , Humanos , Imagen por Resonancia Magnética/métodos , MasculinoRESUMEN
Krabbe disease is a devastating lysosomal storage disease with autosomal recessive inheritance. Early symptoms of leukodystrophy, such as irritability and hypertonicity, appear at 3 to 6 months of age, but progress rapidly to severe mental and motor deterioration and death in the second year. The disease is caused by the deficiency of the lysosomal enzyme galactosylceramidase, which is in turn caused by mutations in the GALC gene. The incidence of the infantile form of the disease in the Netherlands is estimated at 1.3 per 100,000 births; 50% of the patients' alleles show the large 30-kb deletion. Early diagnosis by enzyme assay in leukocytes or skin fibroblasts permits timely genetic counselling and prenatal diagnosis, which is reliably made by enzyme or mutation analysis in the chorionic villi.
Asunto(s)
Galactosilceramidasa/deficiencia , Leucodistrofia de Células Globoides/genética , Galactosilceramidasa/genética , Asesoramiento Genético , Humanos , Países Bajos , Mutación Puntual , Diagnóstico Prenatal , Eliminación de SecuenciaAsunto(s)
Síndrome de Down/diagnóstico , Enfermedades Fetales/diagnóstico , Enfermedad de Tay-Sachs/diagnóstico , Aborto Inducido , Diagnóstico Diferencial , Síndrome de Down/genética , Femenino , Enfermedades Fetales/genética , Humanos , Cariotipificación , Embarazo , Primer Trimestre del Embarazo , Diagnóstico PrenatalAsunto(s)
Anomalías Múltiples/genética , Cara/anomalías , Trastornos del Crecimiento/patología , Discapacidad Intelectual/patología , Proteínas Tirosina Quinasas , Anomalías Múltiples/etiología , Anomalías Múltiples/patología , Preescolar , ADN/química , ADN/genética , Análisis Mutacional de ADN , Femenino , Humanos , Lactante , Masculino , Polimorfismo Genético , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos , Receptores de Factores de Crecimiento de Fibroblastos/genética , Anomalías Cutáneas/patología , SíndromeRESUMEN
Ataxia telangiectasia (AT) is an autosomal recessive disorder characterised by cerebellar ataxia, telangiectasia, immune defects, and a predisposition to malignancy. Chromosomal breakage is a feature. AT cells are abnormally sensitive to cell kill by ionising radiation and abnormally resistant to inhibition of DNA synthesis by ionising radiation. The responsible gene, 'ataxia telangiectasia mutated' (ATM) plays a crucial role in a signal transduction pathway, regulating the cell cycle, and in preventing damaged DNA from being reproduced. This rare genetic disorder manifests itself during childhood. The illness is progressive and most individuals die in their second or third decade of life due to infections or cancer. AT is difficult to diagnose due to its rarity and clinical heterogeneity. Both a physical examination and several laboratory tests are necessary for establishing its proper diagnosis.
Asunto(s)
Ataxia Telangiectasia/genética , Mutación , Proteínas Serina-Treonina Quinasas/genética , Formación de Anticuerpos/genética , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/inmunología , Proteínas de la Ataxia Telangiectasia Mutada , Ciclo Celular/genética , Proteínas de Ciclo Celular , Proteínas de Unión al ADN , Diagnóstico Diferencial , Humanos , Inmunidad Celular/genética , Examen Físico , Tolerancia a Radiación/genética , Tolerancia a Radiación/fisiología , Transducción de Señal , Proteínas Supresoras de TumorRESUMEN
Prenatal diagnosis of the Hunter syndrome (mucopolysaccharidosis type II; MPS II) is preferably achieved by the assay of iduronate-2-sulphate sulphatase (IDS) in uncultured chorionic villi (CV) as this allows early (12th week), rapid (2-3 days) and reliable results. We summarize the results of 174 prenatal analyses in the past 30 years, using various methods such as radiolabelled sulphate incorporation in amniotic fluid (AF) cells, glycosaminoglycan (GAG)-electrophoresis in AF and IDS assay in CV, CV-cells, AF and AF-cells. Twenty-seven fetuses with MPS II were diagnosed after finding clearly abnormal results in pregnancies with a male fetus; very low IDS activity has also been measured in some pregnancies with a (heterozygous) female fetus, emphasizing the need to combine enzyme assay with fetal sex determination. IDS activity has until recently been assessed by a cumbersome radioactive enzyme assay. Here we describe the use of a novel fluorigenic 4-methylumbelliferyl substrate, which allows a sensitive, rapid and convenient assay of IDS activity and reliable early prenatal diagnosis. This novel IDS assay was validated in retrospective analyses of 14 CV, CV-cell, AF and AF-cell samples from affected pregnancies in addition to prospective prenatal diagnosis in eight pregnancies at risk with one MPS II-affected fetus.
Asunto(s)
Amniocentesis , Muestra de la Vellosidad Coriónica , Iduronato Sulfatasa/análisis , Mucopolisacaridosis II/diagnóstico , Mucopolisacaridosis II/enzimología , Adulto , Líquido Amniótico/citología , Líquido Amniótico/metabolismo , Células Cultivadas , Electroforesis en Gel Bidimensional , Femenino , Fluorometría , Glicosaminoglicanos/metabolismo , Heterocigoto , Humanos , Masculino , Embarazo , Embarazo de Alto Riesgo , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
A biochemical variant of argininosuccinate lyase deficiency, found in five individuals, is introduced. In comparison to classical patients, the variant cases of argininosuccinate lyase deficiency were characterized by residual enzyme activity as measured by the incorporation of [14C]citrulline into proteins. The five patients of different ethnic backgrounds presented with relatively mild clinical symptoms, variable age of onset, marked argininosuccinic aciduria and severe, but not complete, deficiency of argininosuccinate lyase. [14C]Citrulline incorporation into proteins, which is completely blocked in classical argininosuccinic aciduria, was only partially reduced in fibroblasts of these patients. Further investigation showed that previous standard conditions of the assay were not optimal. Higher concentrations of citrulline in the incubation medium strongly stimulated 14C incorporation in normal cells, but not in the patients; as a result, the relative incorporation level in the patients dropped to 6-28% compared to 18-75% of normal in the original procedure. Prenatal diagnosis was successfully performed in three of the families. Affected pregnancies were indicated by (partial) deficiency of [14C]citrulline incorporation in chorionic villi and/or increased levels of argininosuccinate in amniotic fluid. Analysis of the ASL gene in the five patients revealed a considerable allelic heterogeneity. Three novel mutations--R385C (2 patients), V178M and R379C--were detected in homozygous states, whereas one patient was compound heterozygous for the known mutations R193Q and Q286R. In conclusion, there are patients of different ethnic backgrounds who are characterized by residual activity of argininosuccinate lyase and who present with less severe clinical courses. In addition, we present an improved biochemical assay for accurate prenatal and postnatal diagnosis.
Asunto(s)
Ácido Argininosuccínico/orina , Citrulinemia/diagnóstico , Adulto , Argininosuccinatoliasa/análisis , Niño , Citrulina/metabolismo , Citrulinemia/genética , Fibroblastos/enzimología , Humanos , Lactante , Recién Nacido , Masculino , Diagnóstico PrenatalRESUMEN
Deficiency of argininosuccinate synthetase (ASS) causes citrullinemia, an autosomal recessive inherited defect of the urea cycle. Most patients described so far have presented with the classical form of the disease. There are also patients with a mild form of citrullinemia in whom the exact molecular basis and clinical relevance are uncertain. Mutations in the human ASS gene have not yet been described in mildly affected or asymptomatic patients with citrullinemia. The genomic sequence of the human ASS gene is not precisely known making mutation analysis difficult. Here, the entire genomic DNA sequence and mutations in the ASS gene of patients with the classical and mild form of the disease are described. The mutations c.1168G-->A (G390R) and IVS13+5 G-->A and the novel mutation c.323G-->T (R108L) have been found to be associated with classical citrullinemia, whereas the novel mutations c.535T-->G (W179R), and c.1085G-->T (G362V) have been detected on alleles of the mildly affected patients. Thus, mutations found in the human ASS gene of asymptomatic children with biochemical abnormalities and in some cases enzymatically proven citrullinemia have allowed us to classify these cases as ASS-deficient patients. The elucidation of the structure of the human ASS gene has made possible the use of intronic primers for molecular analysis of patients with mild disease and the classical form, and provides another option for prenatal diagnostics in affected families with the severe type.
Asunto(s)
Argininosuccinato Sintasa/genética , Citrulinemia/diagnóstico , Secuencia de Aminoácidos , Argininosuccinato Sintasa/química , Secuencia de Bases , Citrulinemia/genética , Cartilla de ADN , ADN Complementario , Humanos , Datos de Secuencia Molecular , Homología de Secuencia de AminoácidoRESUMEN
We report on a sibship with protein-losing enteropathy related to intestinal lymphangiectasia, a peculiar face, and genital anomalies. The parents are distantly related and from Dutch ancestry. The first patient was born with a protein-losing enteropathy, craniofacial anomalies, and renal defects. At 1 year of age, she died of severe complications of the protein-losing enteropathy and respiratory distress. Her brother was a cytogenetically normal male fetus identified by prenatal ultrasound at 19 weeks with similar anomalies. The pregnancy was terminated at 20 weeks. Autopsy showed müllerian duct remnants. These cases seem to confirm the Urioste syndrome [Urioste et al., 1993: Am J Med Genet 47:494-503]. Although it was previously only reported in 46,XY individuals, this report of a consanguineous family with an affected sibship of both sexes suggests it to be an autosomal recessive entity.
Asunto(s)
Anomalías Múltiples/genética , Trastornos de los Cromosomas/genética , Linfangiectasia Intestinal/complicaciones , Conductos Paramesonéfricos/anomalías , Enteropatías Perdedoras de Proteínas/etiología , Anomalías Múltiples/patología , Amniocentesis , Femenino , Genes Recesivos , Humanos , Cariotipificación , Linfangiectasia Intestinal/patología , Linfedema/etiología , Masculino , Enteropatías Perdedoras de Proteínas/fisiopatología , SíndromeRESUMEN
The recent development of simple, fluorogenic enzyme assays for infantile and late infantile neuronal ceroid lipofuscinosis (INCL and LINCL; CLN1 and CLN2) has greatly facilitated the diagnostic process for these diseases. In leucocytes and fibroblasts from INCL (n = 38) patients we found profound deficiencies of palmitoyl-protein thioesterase I (PPT1), the residual activity was < 5% of mean control activity. In fibroblasts from LINCL patients we found a similar deficiency of tripeptidyl-peptidase I activity (TPP-I), with < 2% activity in 16 patients. The residual TPP-I activity in leucocytes from LINCL patients seemed substantially higher. We also showed the feasibility of reliable prenatal enzyme analysis. In five first-trimester and two second-trimester prenatal analyses for INCL, four affected foetuses were detected (PPT activity 3-6%). Two first trimester pregnancies at risk for LINCL were analysed and a clear TPP-I deficiency was detected in both cases (TPP-I activity 3-4%). The first patient with adult neuronal ceroid lipofuscinosis (ANCL) due to a deficiency of PPT is presented; her present age is 53 years and the onset of the disease was at 38 years with psychiatric symptoms.
Asunto(s)
Endopeptidasas/deficiencia , Lipofuscinosis Ceroideas Neuronales/diagnóstico , Lipofuscinosis Ceroideas Neuronales/enzimología , Tioléster Hidrolasas/deficiencia , Adulto , Aminopeptidasas , Células Cultivadas , Muestra de la Vellosidad Coriónica , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas , Endopeptidasas/metabolismo , Femenino , Fibroblastos/citología , Fibroblastos/enzimología , Humanos , Leucocitos/enzimología , Persona de Mediana Edad , Embarazo , Serina Proteasas , Tioléster Hidrolasas/metabolismo , Tripeptidil Peptidasa 1RESUMEN
Androgen insensitivity syndrome encompasses a wide range of phenotypes, which are caused by numerous different mutations in the AR gene. Detailed information on the genotype/phenotype relationship in androgen insensitivity syndrome is important for sex assignment, treatment of androgen insensitivity syndrome patients, genetic counseling of their families, and insight into the functional domains of the AR. The commonly accepted concept of dependence on fetal androgens of the development of Wolffian ducts was studied in complete androgen insensitivity syndrome (CAIS) patients. In a nationwide survey in The Netherlands, all cases (n = 49) with the presumptive diagnosis androgen insensitivity syndrome known to pediatric endocrinologists and clinical geneticists were studied. After studying the clinical phenotype, mutation analysis and functional analysis of mutant receptors were performed using genital skin fibroblasts and in vitro expression studies. Here we report the findings in families with multiple affected cases. Fifty-nine percent of androgen insensitivity syndrome patients had other affected relatives. A total of 17 families were studied, seven families with CAIS (18 patients), nine families with partial androgen insensitivity (24 patients), and one family with female prepubertal phenotypes (two patients). No phenotypic variation was observed in families with CAIS. However, phenotypic variation was observed in one-third of families with partial androgen insensitivity resulting in different sex of rearing and differences in requirement of reconstructive surgery. Intrafamilial phenotypic variation was observed for mutations R846H, M771I, and deletion of amino acid N682. Four newly identified mutations were found. Follow-up in families with different AR gene mutations provided information on residual androgen action in vivo and the development of the prepubertal and adult phenotype. Patients with a functional complete defective AR had some pubic hair, Tanner stage P2, and vestigial Wolffian duct derivatives despite absence of AR expression. Vaginal length was functional in most but not all CAIS patients. The minimal incidence of androgen insensitivity syndrome in The Netherlands, based on patients with molecular proof of the diagnosis is 1:99,000. Phenotypic variation was absent in families with CAIS, but distinct phenotypic variation was observed relatively frequent in families with partial androgen insensitivity. Molecular observations suggest that phenotypic variation had different etiologies among these families. Sex assignment of patients with partial androgen insensitivity cannot be based on a specific identified AR gene mutation because distinct phenotypic variation in partial androgen insensitivity families is relatively frequent. In genetic counseling of partial androgen insensitivity families, this frequent occurrence of variable expression resulting in differences in sex of rearing and/or requirement of reconstructive surgery is important information. During puberty or normal dose androgen therapy, no or only minimal virilization may occur even in patients with significant (but still deficient) prenatal virilization. Wolffian duct remnants remain detectable but differentiation does not occur in the absence of a functional AR. In many CAIS patients, surgical elongation of the vagina is not indicated.
Asunto(s)
Síndrome de Resistencia Androgénica/genética , Adolescente , Adulto , Síndrome de Resistencia Androgénica/epidemiología , Síndrome de Resistencia Androgénica/patología , Niño , Preescolar , ADN/genética , Electroforesis en Gel de Poliacrilamida , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Inmunohistoquímica , Lactante , Masculino , Países Bajos/epidemiología , Linaje , Fenotipo , Fosforilación , Receptores Androgénicos/genética , Vagina/cirugíaRESUMEN
An inherited deficiency in beta-galactosidase can result in GM1 gangliosidosis, with several phenotypes of generalized or chronic psychomotor deterioration, as well as in Morquio disease type B, a characteristic mucopolysaccharidosis free of neurological symptoms. We performed mutation analyses in 17 juvenile and adult patients from various European regions with a deficiency in beta-galactosidase and skeletal abnormalities. Fifteen of these had the Morquio B phenotype and have remained neurologically healthy until now while the two others exhibited psychomotor retardation of juvenile onset. A two-base substitution (851-852TG-->CT; W273L) was present in 14 of the 15 Morquio B cases. Even if one excludes alleles from patients with possible common descent, there was a much higher frequency (79%) among those with Morquio B phenotype for the W273L mutation than previously reported in the literature (37%). That the Morquio phenotype is also expressed in heterozygotes for W273L and alleles typically found in GM1 gangliosidosis makes it possible to predict the phenotype and reliably detect heterozygotes. A single French patient had a novel missense point mutation (Q408P) together with a known mutation (T500A) while the mentally retarded patients were both heterozygous for two mutations known in chronic GM1 gangliosidosis together with two novel missense point mutations (Y270D and H281Y) in the vicinity of W273L. Our results confirm the high impact of Trp 273 for the function of beta-galactosidase and the expression of the Morquio B phenotype. In addition, a second domain around the amino acids 400-500 may also be of significance.
Asunto(s)
Análisis Mutacional de ADN , Mucopolisacaridosis IV/genética , Mutación Puntual , beta-Galactosidasa/deficiencia , Adolescente , Adulto , Niño , Preescolar , Cartilla de ADN/química , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Linaje , Fenotipo , ARN Mensajero/metabolismo , Mapeo Restrictivo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , beta-Galactosidasa/genéticaRESUMEN
Cerebro-oculo-facio-skeletal (COFS) syndrome is a recessively inherited rapidly progressive neurologic disorder leading to brain atrophy, with calcifications, cataracts, microcornea, optic atrophy, progressive joint contractures, and growth failure. Cockayne syndrome (CS) is a recessively inherited neurodegenerative disorder characterized by low to normal birth weight, growth failure, brain dysmyelination with calcium deposits, cutaneous photosensitivity, pigmentary retinopathy and/or cataracts, and sensorineural hearing loss. Cultured CS cells are hypersensitive to UV radiation, because of impaired nucleotide-excision repair (NER) of UV-induced damage in actively transcribed DNA, whereas global genome NER is unaffected. The abnormalities in CS are caused by mutated CSA or CSB genes. Another class of patients with CS symptoms have mutations in the XPB, XPD, or XPG genes, which result in UV hypersensitivity as well as defective global NER; such patients may concurrently have clinical features of another NER syndrome, xeroderma pigmentosum (XP). Clinically observed similarities between COFS syndrome and CS have been followed by discoveries of cases of COFS syndrome that are associated with mutations in the XPG and CSB genes. Here we report the first involvement of the XPD gene in a new case of UV-sensitive COFS syndrome, with heterozygous substitutions-a R616W null mutation (previously seen in patients in XP complementation group D) and a unique D681N mutation-demonstrating that a third gene can be involved in COFS syndrome. We propose that COFS syndrome be included within the already known spectrum of NER disorders: XP, CS, and trichothiodystrophy. We predict that future patients with COFS syndrome will be found to have mutations in the CSA or XPB genes, and we document successful use of DNA repair for prenatal diagnosis in triplet and singleton pregnancies at risk for COFS syndrome. This result strongly underlines the need for screening of patients with COFS syndrome, for either UV sensitivity or DNA-repair abnormalities.
Asunto(s)
Anomalías Múltiples/genética , ADN Helicasas , Reparación del ADN/genética , Proteínas de Unión al ADN , Enfermedades Fetales/genética , Mutación Missense/genética , Diagnóstico Prenatal , Proteínas/genética , Factores de Transcripción , Trillizos/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/fisiopatología , Secuencia de Aminoácidos , Disparidad de Par Base/genética , Secuencia de Bases , Preescolar , Síndrome de Cockayne/genética , Síndrome de Cockayne/fisiopatología , Análisis Mutacional de ADN , Replicación del ADN/genética , Replicación del ADN/efectos de la radiación , Femenino , Enfermedades Fetales/diagnóstico , Enfermedades Fetales/fisiopatología , Humanos , Lactante , Recién Nacido , Judíos/genética , Masculino , Datos de Secuencia Molecular , Embarazo , Proteínas/metabolismo , Síndrome , Rayos Ultravioleta/efectos adversos , Xerodermia Pigmentosa/genética , Xerodermia Pigmentosa/fisiopatología , Proteína de la Xerodermia Pigmentosa del Grupo DRESUMEN
Late-infantile neuronal ceroid lipofuscinosis (LINCL) is a progressive neurodegenerative disorder caused by the deficiency of lysosomal tripeptidyl peptidase I (TPP-I) encoded by the CLN2 gene. We report the first case of early prenatal diagnosis of LINCL by combined enzyme and mutation analysis. TPP-I activity in chorionic villi (CV) was less than 2% of the mean normal control level and g.1946A > G and g.3670C > T mutations were demonstrated, as in the two previously affected children. After termination of pregnancy, TPP-I deficiency was confirmed in cultured CV cells and in the fetal skin fibroblasts. The expression of unequivocal TPP-I deficiency in CV demonstrates that enzyme assay is a reliable option for prenatal diagnosis of LINCL.
Asunto(s)
Análisis Mutacional de ADN , Endopeptidasas/deficiencia , Endopeptidasas/genética , Lipofuscinosis Ceroideas Neuronales/diagnóstico , Diagnóstico Prenatal , Aminopeptidasas , Vellosidades Coriónicas/enzimología , Muestra de la Vellosidad Coriónica , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas , Femenino , Humanos , Lipofuscinosis Ceroideas Neuronales/enzimología , Lipofuscinosis Ceroideas Neuronales/genética , Embarazo , Primer Trimestre del Embarazo , Tripeptidil Peptidasa 1RESUMEN
The xeroderma pigmentosum group D (XPD) helicase subunit of TFIIH functions in DNA repair and transcription initiation. Different mutations in XPD give rise to three ultraviolet-sensitive syndromes: the skin cancer-prone disorder xeroderma pigmentosum (XP), in which repair of ultraviolet damage is affected; and the severe neurodevelopmental conditions Cockayne syndrome (CS) and trichothiodystrophy (TTD). In the latter two, the basal transcription function of TFIIH is also presumed to be affected. Here we report four unusual TTD patients with fever-dependent reversible deterioration of TTD features such as brittle hair. Cells from these patients show an in vivo temperature-sensitive defect of transcription and DNA repair due to thermo-instability of TFIIH. Our findings reveal the clinical consequences of impaired basal transcription and mutations in very fundamental processes in humans, which previously were only known in lower organisms.