RESUMO
Warburg Micro Syndrome is a rare, autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornia, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism. We have found five new mutations in the RAB3GAP1 gene in seven patients with suspected Micro Syndrome from families with Turkish, Palestinian, Danish, and Guatemalan backgrounds. A thorough clinical investigation of the patients has allowed the delineation of symptoms that are consistently present in the patients and may aid the differential diagnosis of Micro Syndrome for patients in the future. All patients had postnatal microcephaly, micropthalmia, microcornia, bilateral congenital cataracts, short palpebral fissures, optic atrophy, severe mental retardation, and congenital hypotonia with subsequent spasticity. Only one patient had microcephaly at birth, highlighting the fact that congenital microcephaly is not a consistent feature of Micro syndrome. Analysis of the brain magnetic resonance imagings (MRIs) revealed a consistent pattern of polymicrogyria in the frontal and parietal lobes, wide sylvian fissures, a thin hypoplastic corpus callosum, and increased subdural spaces. All patients were homozygous for the mutations detected and all mutations were predicted to result in a truncated RAB3GAP1 protein. The analysis of nine polymorphic markers flanking the RAB3GAP1 gene showed that the mutation c.1410C>A (p.Tyr470X), for which a Danish patient was homozygous, occurred on a haplotype that is shared by the unrelated heterozygous parents of the patient. This suggests a possible founder effect for this mutation in the Danish population.
Assuntos
Encéfalo/patologia , Mutação , Proteínas rab3 de Ligação ao GTP/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Árabes , Encéfalo/anormalidades , Encéfalo/fisiopatologia , Catarata/congênito , Catarata/genética , Catarata/patologia , Cromossomos Humanos Par 2/genética , Córnea/anormalidades , Córnea/patologia , Dinamarca , Efeito Fundador , Marcadores Genéticos , Predisposição Genética para Doença , Guatemala , Humanos , Hipogonadismo/genética , Hipogonadismo/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Imageamento por Ressonância Magnética , Microcefalia/genética , Microcefalia/patologia , Atrofia Óptica/genética , Atrofia Óptica/patologia , TurquiaRESUMO
Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurodegenerative disorders characterized by progressive spasticity and weakness in the lower limbs. The most common forms of autosomal dominant HSP, SPG4 and SPG3, are caused by sequence variants in the SPAST and SPG3A genes, respectively. The pathogenic variants are scattered all over these genes and many variants are unique to a specific family. The phenotype in SPG4 patients can be modified by a variant in SPAST (p.Ser44Leu) and recently, a variant in HSPD1, the gene underlying SPG13, was reported as a second genetic modifier in SPG4 patients. In this study HSP patients were screened for variants in SPG3A, SPAST and HSPD1 in order to identify disease causing variations. SPAST was sequenced in all patients whereas subsets were sequenced in HSPD1 and in selected exons of SPG3A. SPG4 patients and their HSP relatives were genotyped for the modifying variant in HSPD1. We report six new sequence variants in SPAST including a fourth non synonymous sequence variant in exon 1 and two synonymous changes of which one has been found in a HSP patient previously, but never in controls. Of the novel variants in SPAST four were interpreted as disease causing. In addition one new disease causing sequence variant and one non pathogenic non synonymous variant were found in SPG3A. In HSPD1 we identified a sporadic patient homozygote for the potential modifying variation. The effect of the modifying HSPD1 variation was not supported by identification in one SPG4 family.
Assuntos
Adenosina Trifosfatases/genética , Substituição de Aminoácidos , Chaperonina 60/genética , GTP Fosfo-Hidrolases/genética , Heterogeneidade Genética , Variação Genética , Polimorfismo de Nucleotídeo Único , Paraplegia Espástica Hereditária/genética , Adenosina Trifosfatases/química , Adenosina Trifosfatases/fisiologia , Motivos de Aminoácidos , Células Cultivadas/química , Chaperonina 60/química , Chaperonina 60/fisiologia , Análise Mutacional de DNA , Dinamarca/epidemiologia , Feminino , Fibroblastos/química , GTP Fosfo-Hidrolases/química , GTP Fosfo-Hidrolases/fisiologia , Proteínas de Ligação ao GTP , Genótipo , Humanos , Masculino , Proteínas de Membrana , Proteínas Mitocondriais , Linhagem , Fenótipo , Sítios de Splice de RNA/genética , Análise de Sequência de DNA , Deleção de Sequência , Paraplegia Espástica Hereditária/epidemiologia , Paraplegia Espástica Hereditária/patologia , EspastinaRESUMO
Twenty-seven preterm infants were compared to 10 full-term infants at term equivalent age using a voxel-based analysis of diffusion tensor imaging of the brain. Preterm infants exhibited higher fractional anisotropy values, which may suggest accelerated maturation, in the location of the sagittal stratum. While some earlier findings in preterm infants have suggested developmental delays, the results of this study are more consistent with accelerated white matter development, possibly as a result of increased sensorimotor stimulation in the extrauterine environment. These results are the first to suggest that the increased intensity of stimulation associated with preterm birth may advance the process of white matter maturation in the human brain. Questions remain about whether these findings reflect acceleration of the process of white matter maturation generally, or localized alterations induced specifically by activity in affected pathways.