Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
1.
J Inherit Metab Dis ; 39(6): 849-857, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27473128

RESUMEN

Vesicular protein sorting-associated proteins (VPS, including VPS11) are indispensable in the endocytic network, in particular the endosome-lysosome biogenesis. Exome sequencing revealed the homozygous variant p.Leu387_ Gly395del in the VPS11 gene in two siblings. On immunoblotting, the mutant VPS11 protein showed a distinctly reduced immunostaining intensity. The children presented with primary and severe developmental delay associated with myoclonic seizures, spastic tetraplegia, trunk and neck hypotonia, blindness, hearing loss, and microcephaly. Neuro-imaging showed severe hypomyelination affecting cerebral and cerebellar white matter and corpus callosum, in the absence of a peripheral neuropathy. Electron microscopy of a skin biopsy revealed clusters of membranous cytoplasmic bodies in dermal unmyelinated nerve axons, and numbers of vacuoles in eccrine sweat glands, similar to what is seen in a classic lysosomal storage disease (LSD). Bone marrow cytology showed a high number of storage macrophages with a micro-vacuolated cytoplasm. Biochemically, changes in urinary glycosphingolipids were reminiscent of those in prosaposin deficiency (another LSD). The clinical and neuro-imaged features in our patients were almost identical to those in some recently reported patients with another variant in the VPS11 gene, p.Cys846Gly; underlining the presumed pathogenic potential of VPS11 defects. A new feature was the morphological evidence for lysosomal storage in VPS11 deficiency: This newly characterised disease can be viewed as belonging to the complex field of LSD.


Asunto(s)
Enfermedades Desmielinizantes/genética , Lisosomas/genética , Proteínas de Transporte Vesicular/deficiencia , Proteínas de Transporte Vesicular/genética , Adolescente , Secuencia de Bases , Catarata/congénito , Catarata/genética , Niño , Endosomas/genética , Femenino , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Humanos , Enfermedades por Almacenamiento Lisosomal/genética , Masculino , Mutación/genética
2.
Eur J Med Genet ; 62(3): 210-216, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30031153

RESUMEN

49,XXXXY syndrome is a rare sex chromosome aneuploidy syndrome. Cognitive impairment with expressive language deficits in combination with developmental and speech dyspraxia are cardinal symptoms. Testicular insufficiency becomes apparent during adolescence. Neurological, musculoskeletal, genital, orthodontic and immunological anomalies are common and a higher incidence of congenital malformations has been described. Here we show the evolving clinical and facial phenotype of eight boys and men with 49,XXXXY, demonstrating an increasingly perceptible distinct facial gestalt over time. In addition, almost all patients had muscular hypotonia, radioulnar synostosis, white matter anomalies, fifth-finger clinodactyly, recurrent respiratory infections in early childhood and teeth anomalies. IQ scores ranged between 40 and 70. Though many boys showed short stature at some point in early childhood, most outgrew it. As more long term data of boys and men with 49,XXXXY become available, parents of affected boys can be counseled more specifically as to the expected course and spectrum of this rare chromosomal disorder. Moreover, the multidisciplinary support can be optimized und unnecessary diagnostics avoided.


Asunto(s)
Síndrome de Klinefelter/patología , Fenotipo , Adolescente , Niño , Preescolar , Humanos , Masculino , Adulto Joven
3.
Hum Mutat ; 29(1): 45-52, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17705300

RESUMEN

Meckel-Gruber syndrome (MKS) is an autosomal recessive, lethal multisystemic disorder characterized by meningooccipital encephalocele, cystic kidney dysplasia, hepatobiliary ductal plate malformation, and postaxial polydactyly. Recently, genes for MKS1 and MKS3 were identified, putting MKS on the list of ciliary disorders (ciliopathies). By positional cloning in a distantly related multiplex family, we mapped a novel locus for MKS to a 3-Mb interval on 12q21. Sequencing of the CEP290 gene located in the minimal critical region showed a homozygous 1-bp deletion supposed to lead to loss of function of the encoded centrosomal protein CEP290/nephrocystin-6. CEP290 is thought to be involved in chromosome segregation and localizes to cilia, centrosomes, and the nucleus. Subsequent analysis of another consanguineous multiplex family revealed homozygous haplotypes and the same frameshift mutation. Our findings add to the increasing body of evidence that ciliopathies can cause a broad spectrum of disease phenotypes, and pleiotropic effects of CEP290 mutations range from single organ involvement with isolated Leber congenital amaurosis to Joubert syndrome and lethal early embryonic multisystemic malformations in Meckel-Gruber syndrome. We compiled clinical and genetic data of all patients with CEP290 mutations described so far. No clear-cut genotype-phenotype correlations were apparent as almost all mutations are nonsense, frameshift, or splice-site changes and scattered throughout the gene irrespective of the patients' phenotypes. Conclusively, other factors than the type and location of CEP290 mutations may underlie phenotypic variability.


Asunto(s)
Anomalías Múltiples/genética , Antígenos de Neoplasias/genética , Mutación , Proteínas de Neoplasias/genética , Secuencia de Aminoácidos , Secuencia de Bases , Proteínas de Ciclo Celular , Sistema Nervioso Central/anomalías , Proteínas del Citoesqueleto , Análisis Mutacional de ADN , Haplotipos , Humanos , Enfermedades Renales Quísticas/genética , Hígado/anomalías , Datos de Secuencia Molecular , Linaje , Polimorfismo de Nucleótido Simple , Síndrome
4.
Hum Mutat ; 28(6): 638-9, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17437276

RESUMEN

Meckel-Gruber syndrome (MKS) is an autosomal recessive, usually lethal multisystemic disorder characterized by early developmental anomalies of the central nervous system, cystic kidney dysplasia, hepatobiliary ductal plate malformation, and postaxial polydactyly. Three MKS loci have been mapped and recently, two genes were identified: MKS1 on 17q22 in Caucasian kindreds and MKS3 on 8q22 in Omani and Pakistani families, putting MKS on the growing list of ciliary disorders ("ciliopathies"). We performed linkage analysis for MKS1-3 in 14 consanguineous and/or multiplex families of different ethnic origins with histologic diagnosis and at least three classic MKS manifestations in each kindred. Unexpectedly, only five families were linked to any of the known MKS loci, clearly indicating further locus heterogeneity. All five families showed homozygosity for MKS1 and, intriguingly, were of non-Caucasian origin. MKS1 sequencing revealed no mutation in two of these pedigrees, whereas different, novel splicing defects were identified in the three other families and an additional sporadic German patient. Given that all of our mutations and two of the in total four known MKS1 changes cause aberrant splicing (while the other two known mutations were frameshift mutations), we hypothesize that splicing defects are a crucial mutational mechanism in MKS1 which apparently is one of the main loci and key players in MKS. Our results indicate that MKS1 mutations are not restricted to the Caucasian gene pool and suggest further genetic heterogeneity for MKS. Overall, our data have immediate implications for genetic counselling and testing approaches in MKS.


Asunto(s)
Anomalías Múltiples/genética , Empalme Alternativo , Sistema Nervioso Central/anomalías , Enfermedades Renales Quísticas/genética , Mutación , Proteínas/genética , Consanguinidad , Análisis Mutacional de ADN , Exones , Haplotipos , Homocigoto , Humanos , Intrones , Kuwait , Hígado/anomalías , Linaje , Polidactilia/genética , Eliminación de Secuencia , Síndrome , Turquía , Población Blanca/genética
5.
Prenat Diagn ; 25(10): 954-9, 2005 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16088867

RESUMEN

OBJECTIVES: To present the clinical, cytogenetic, and molecular cytogenetic findings of prenatally diagnosed interstitial deletion 10q25.2-q26.1. The majority of distal 10q deletions are pure terminal deletions with breakpoints in 10q25 and 10q26. Only four patients have been described so far with interstitial deletions involving bands 10q25.2-q26.1. METHODS: Postmortem physical examination and autopsy of the foetus after medically terminated pregnancy. GTG-banding, reverse painting, and FISH analysis with BAC clones on amniocyte metaphases were performed to determine the extent of the deletion. RESULTS: At 20 weeks the eutrophic female foetus showed pronounced microretrogeny and hypertelorism, clubfeet as well as minor internal anomalies like pancreas anulare, atypically lobed liver, and missing choleocystis. Cardiac anomalies were not observed and the genitalia were of a normal female. The deletion encompasses 6-Mb and is associated with hemizygosity for 30 genes, including the genes for beta-tectorin, the beta-1 adrenergic receptor, and the alpha-2A adrenergic receptor. CONCLUSION: An interstitial deletion del(10)(q25.2q25.3 approximately 26.11) was confirmed by FISH with mapped BAC clones. Clinical and molecular cytogenetic analyses of further interstitial 10q deletions are necessary to assess whether the phenotypic manifestations differ between deletions that are interstitial compared to those that include also the terminal region of chromosome 10.


Asunto(s)
Cromosomas Humanos Par 10/genética , Eliminación de Gen , Diagnóstico Prenatal , Adulto , Amniocentesis , Bandeo Cromosómico , Pintura Cromosómica , Femenino , Humanos , Hibridación Fluorescente in Situ , Embarazo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA