RESUMEN
BACKGROUND: Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) were recently shown to be responsible for autosomal recessive (AR) demyelinating Charcot-Marie-Tooth disease (CMT) type 4A (CMT4A) as well as AR axonal CMT with vocal cord paralysis. METHODS: The coding region of GDAP1 was screened for the presence of mutations in seven families with AR CMT in which the patients were homozygous for markers of the CMT4A locus at chromosome 8q21.1. RESULTS: A nonsense mutation was detected in exon 5 (c.581C>G, S194X), a 1-bp deletion in exon 6 (c.786delG, G262fsX284), and a missense mutation in exon 6 (c.844C>T, R282C). CONCLUSIONS: Mutations in GDAP1 are a frequent cause of AR CMT. They result in an early-onset, severe clinical phenotype. The range of nerve conduction velocities (NCV) is variable. Some patients have normal or near normal NCV, suggesting an axonal neuropathy, whereas others have severely slowed NCV compatible with demyelination. The peripheral nerve biopsy findings are equally variable and show features of demyelination and axonal degeneration.
Asunto(s)
Axones/patología , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedades Desmielinizantes/genética , Genes Recesivos/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Edad de Inicio , Enfermedad de Charcot-Marie-Tooth/patología , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Niño , Preescolar , Cromosomas Humanos Par 8/genética , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/fisiopatología , Electrofisiología , Familia , Femenino , Ligamiento Genético/genética , Pruebas Genéticas , Humanos , Lactante , Masculino , Conducción Nerviosa/fisiología , Linaje , Nervio Sural/patología , TurquíaRESUMEN
Chorea-acanthocytosis (CHAC, MIM 200150) is an autosomal recessive neurodegenerative disorder characterized by the gradual onset of hyperkinetic movements and abnormal erythrocyte morphology (acanthocytosis). Neurological findings closely resemble those observed in Huntington disease. We identified a gene in the CHAC critical region and found 16 different mutations in individuals with chorea-acanthocytosis. CHAC encodes an evolutionarily conserved protein that is probably involved in protein sorting.
Asunto(s)
Corea/genética , Mutación , Proteínas/genética , Proteínas de Saccharomyces cerevisiae , Empalme Alternativo , Animales , Caenorhabditis elegans/genética , Línea Celular , Cromosomas Humanos Par 6 , Eritrocitos/fisiología , Exones , Proteínas Fúngicas/genética , Regulación de la Expresión Génica , Haplotipos , Humanos , Linaje , Transporte de Proteínas , Proteínas/metabolismo , Homología de Secuencia de Aminoácido , Transcripción Genética , Proteínas de Transporte VesicularRESUMEN
OBJECTIVES: This report wants to focus on the risk of severe prematurity in patients with the hypermobility type of the Ehlers-Danlos syndrome (EDS), a heritable disorder of connective tissue. Although various obstetrical complications have been reported in patients with EDS, most reports specifically comment on the severe complications in patients with the vascular type of EDS, including uterine and arterial rupture. Pregnancy outcome in patients presenting the hypermobility type of EDS is poorly documented. CASE: A 33-year-old nullipara was referred for preconceptual genetic counseling with a history of easy bruising, generalized joint hypermobility and chronic arthralgia and myalgia. The diagnosis of the hypermobility type of EDS was confirmed on clinical examination. During her first pregnancy, she underwent a prophylactic McDonald cerclage at 14 weeks' gestation. Premature rupture of membranes occurred at 23 weeks' gestation. A female infant was delivered at 26 weeks and died 3 h after birth. Electron-microscopic examination showed collagen fibre abnormalities in the fetus' skin, which were compatible with the diagnosis of EDS. CONCLUSIONS: Patients with the hypermobility type of EDS can have an increased risk for pregnancy complications, including prematurity due to cervical incompetence and to premature rupture of membranes. We therefore demand the clinician's alertness for possible signs of this underdiagnosed type of EDS and recommend the collaboration between the obstetrician and the medical geneticist in the obstetrical management of these patients.
Asunto(s)
Síndrome de Ehlers-Danlos/complicaciones , Rotura Prematura de Membranas Fetales/etiología , Complicaciones del Embarazo , Adulto , Síndrome de Ehlers-Danlos/clasificación , Síndrome de Ehlers-Danlos/genética , Femenino , Humanos , Recién Nacido , Recien Nacido Prematuro , Inestabilidad de la Articulación/complicaciones , Inestabilidad de la Articulación/genética , Embarazo , Factores de Riesgo , Incompetencia del Cuello del Útero/etiologíaRESUMEN
We observed a missense mutation in the peripheral myelin protein zero gene (MPZ, Thr124Met) in seven Charcot-Marie-Tooth (CMT) families and in two isolated CMT patients of Belgian ancestry. Allele-sharing analysis of markers flanking the MPZ gene indicated that all patients with the Thr124Met mutation have one common ancestor. The mutation is associated with a clinically distinct phenotype characterized by late onset, marked sensory abnormalities and, in some families, deafness and pupillary abnormalities. Nerve conduction velocities of the motor median nerve vary from <38 m/s to normal values in these patients. Clusters of remyelinating axons in a sural nerve biopsy demonstrate an axonal involvement, with axonal regeneration. Phenotype-genotype correlations in 30 patients with the Thr124Met MPZ mutation indicate that, based on nerve conduction velocity criteria, these patients are difficult to classify as CMT1 or CMT2. We therefore conclude that CMT patients with slightly reduced or nearly normal nerve conduction velocity should be screened for MPZ mutations, particularly when additional clinical features such as marked sensory disturbances, pupillary abnormalities or deafness are also present.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Proteína P0 de la Mielina/genética , Mutación Puntual , Anciano , Biopsia , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Análisis Mutacional de ADN , Electromiografía , Salud de la Familia , Femenino , Haplotipos , Humanos , Masculino , Nervio Mediano/fisiología , Metionina , Neuronas Motoras/patología , Neuronas Motoras/fisiología , Neuronas Aferentes/patología , Neuronas Aferentes/fisiología , Linaje , Fenotipo , Polimorfismo Conformacional Retorcido-Simple , Nervio Sural/patología , Treonina , Nervio Cubital/fisiologíaRESUMEN
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors in parathyroids, enteropancreatic endocrine tissues, anterior pituitary, and other tissues. The gene for MEN1 has recently been cloned and shown to code for a 610-amino acid protein of enigmatic function which probably acts as a tumor suppressor. Several mutations causing the MEN1 phenotype have been recently identified. In order to determine the spectrum of MEN1 gene mutations in a sample of 25 Belgian patients, we have systematically screened the 10 exons and adjacent sequences of the MEN1 gene by means of an automatic sequencing protocol. Twelve different mutations were identified including nonsense, frameshift, splicing, and missense mutations. Two of these mutations (D172Y and 357del4) occurred more than once. A missense mutation was also found in a kindred with familial hyperparathyroidism. We observed no significant correlation between the nature or position of mutation and the clinical status. We have also detected 6 intragenic polymorphisms and DNA sequence variants and have analyzed their frequencies in our population.
Asunto(s)
Mutación del Sistema de Lectura/genética , Mutación de Línea Germinal/genética , Neoplasia Endocrina Múltiple Tipo 1/genética , Mutación Missense/genética , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas , Bélgica , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Repeticiones de Microsatélite/genética , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo GenéticoRESUMEN
The responsibility of cerebral cholinergic lesions for the weak clinical response to cholinergic neurotransmission enhancement of Alzheimer's disease (AD) was studied by measuring the effects of physostigmine on glucose consumption and neuropsychological tests. Ten AD and ten aged normals (AN) were examined twice, under placebo and under maximal tolerated dose of physostigmine, in randomized order and blind fashion. Under physostigmine, both groups showed better performances in tests measuring attention (P < 0.05-0.001) but not long-term memory, and cerebral glucose consumption was regionally modified (P < 0.0001). We observed a regional decrease in AD and in AN which was larger in AD, where each patient exhibited a mean metabolic decrease. With normalized values, AD and AN showed a similar decrease in the metabolic values of prefrontal cortex and striatum (P = 0.0003). These findings suggest that cholinergic neurotransmission enhancement depresses glucose consumption and increases selective attention in similar ways in both groups, but to a larger extent in AD. This suggests that brain metabolism in AD over-responds to enhancement of cholinergic neurotransmission. The observed weak response of clinical symptomatology to anticholinesterase agents does not appear to be due to the failure to enhance the activity of the cholinergic system in AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Química Encefálica/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Glucosa/metabolismo , Fisostigmina/farmacología , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Apolipoproteínas E/metabolismo , Atención/efectos de los fármacos , Femenino , Humanos , Masculino , Memoria/efectos de los fármacos , Tiempo de Reacción/efectos de los fármacos , Sistema Nervioso Simpático/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Tomografía Computarizada de EmisiónRESUMEN
Chorea-acanthocytosis (CHAC) is a rare autosomal recessive disorder characterized by progressive neurodegeneration and unusual red-cell morphology (acanthocytosis), with onset in the third to fifth decade of life. Neurological impairment with acanthocytosis (neuroacanthocytosis) also is seen in abetalipoproteinemia and X-linked McLeod syndrome. Whereas the molecular etiology of McLeod syndrome has been defined (Ho et al. 1994), that of CHAC is still unknown. In the absence of cytogenetic rearrangements, we initiated a genomewide scan for linkage in 11 families, segregating for CHAC, who are of diverse geographical origin. We report here that the disease is linked, in all families, to a 6-cM region of chromosome 9q21 that is flanked by the recombinant markers GATA89a11 and D9S1843. A maximum two-point LOD score of 7.1 (theta = .00) for D9S1867 was achieved, and the linked region has been confirmed by homozygosity-by-descent, in offspring from inbred families. These findings provide strong evidence for the involvement of a single locus for CHAC and are the first step in positional cloning of the disease gene.
Asunto(s)
Acantocitos/patología , Corea/genética , Cromosomas Humanos Par 9 , Adulto , Edad de Inicio , Corea/sangre , Mapeo Cromosómico , Femenino , Genes Recesivos , Ligamiento Genético , Marcadores Genéticos , Genotipo , Humanos , Escala de Lod , Masculino , Persona de Mediana Edad , Linaje , Recombinación GenéticaRESUMEN
Three Down syndrome patients for whom karyotypic analysis showed a "mirror" (reverse tandem) duplication of chromosome 21 were studied by phenotypic, cytogenetic, and molecular methods. On high-resolution R-banding analysis performed in two cases, the size of the fusion 21q22.3 band was apparently less than twice the size of the normal 21q22.3, suggesting a partial deletion of distal 21q. The evaluation of eight chromosome 21 single-copy sequences of the 21q22 region--namely, SOD1, D21S15, D21S42, CRYA1, PFKL, CD18, COL6A1, and S100B--by a slot blot method showed in all three cases a partial deletion of 21q22.3 and partial monosomy. The translocation breakpoints were different in each patient, and in two cases the rearranged chromosome was found to be asymmetrical. The molecular definition of the monosomy 21 in each patient was, respectively, COL6A1-S100B, CD18-S100B, and PFKL-S100B. DNA polymorphism analysis indicated in all cases a homozygosity of the duplicated material. The duplicated region was maternal in two patients and paternal in one patient. These data suggest that the reverse tandem chromosomes did not result from a telomeric fusion between chromosomes 21 but from a translocation between sister chromatids. The phenotypes of these patients did not differ significantly from that of individuals with full trisomy 21, except in one case with large ears with an unfolded helix. The fact that monosomy of distal 21q22.3 in these patients resulted in a phenotype very similar to Down syndrome suggests that the duplication of the genes located in this part of chromosome 21 is not necessary for the pathogenesis of the Down syndrome features observed in these patients, including most of the facial and hand features, muscular hypotonia, cardiopathy of the Fallot tetralogy type, and part of the mental retardation.
Asunto(s)
Aberraciones Cromosómicas , Trastornos de los Cromosomas , Cromosomas Humanos Par 21 , Síndrome de Down/genética , Monosomía , Adulto , Niño , Femenino , Genotipo , Humanos , Recién Nacido , Cariotipificación , Masculino , FenotipoRESUMEN
Paramyotonia congenita (PMC), a dominant disorder featuring cold-induced myotonia (muscle stiffness), has recently been genetically linked to a candidate gene, the skeletal muscle sodium channel gene SCN4A. We have now established that SCN4A is the disease gene in PMC by identifying two different single-base coding sequence alterations in PMC families. Both mutations affect highly conserved residues in the III-IV cytoplasmic loop, a portion of the sodium channel thought to pivot in response to membrane depolarization, thereby blocking and inactivating the channel. Abnormal function of this cytoplasmic loop therefore appears to produce the Na+ current abnormality and the unique temperature-sensitive clinical phenotype in this disorder.
Asunto(s)
Frío , Proteínas Musculares/genética , Miotonía Congénita/genética , Canales de Sodio/genética , Secuencia de Aminoácidos , Secuencia de Bases , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Linaje , Alineación de SecuenciaRESUMEN
We report the occurrence of a leiomyoma of the suprarenal gland in a 10-year-old girl with ataxia-telangiectasia (A-T). Muscle cell tumors are very uncommon in this gland as they are in A-T. Possible reasons for developing nonhematologic tumors in this syndrome are reviewed. A defect in DNA repair mechanisms probably favors, in young children, the expression of tumors normally expected in the aged.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/patología , Ataxia Telangiectasia/complicaciones , Leiomioma/patología , Neoplasias de las Glándulas Suprarrenales/etiología , Neoplasias de las Glándulas Suprarrenales/genética , Ataxia Telangiectasia/genética , Niño , Inversión Cromosómica , Femenino , Pruebas Hematológicas , Humanos , Leiomioma/etiología , Leiomioma/genética , Estadificación de Neoplasias , Translocación GenéticaRESUMEN
We report the case of an adolescent girl who presents with the 18q-syndrome, primary hypothyroidism, pernicious anemia and IgM hypogammaglobulinemia. Her karyotype was performed during infancy because of malformations and showed deletion of the long arm of chromosome 18. The patient had been treated with levothyroxine (Elthyrone) since age 13 when primary hypothyroidism was documented. A close hematological follow-up was then undertaken due to the presence of anti-parietal cell antibodies. A megaloblastic anemia of sudden offset led to the diagnosis of pernicious anemia by age 16, which was confirmed by a positive Shilling's test. Recently, the patient was found to have antimicrosome antibodies and moderate IgM hypogammaglobulinemia.