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Carrier Females (carrier + female)
Selected AbstractsAutism and other neuropsychiatric symptoms are prevalent in individuals with MeCP2 duplication syndrome,ANNALS OF NEUROLOGY, Issue 6 2009Melissa B. Ramocki MD Objective There have been no objective assessments to determine whether boys with MECP2 duplication have autism or whether female carriers manifest phenotypes. This study characterizes the clinical and neuropsychiatric phenotypes of affected boys and carrier females. Methods Eight families (9 males and 9 females) with MECP2 duplication participated. A detailed history, physical examination, electroencephalogram, developmental evaluation, Autism Diagnostic Observation Schedule, and Autism Diagnostic Interview,Revised were performed for each boy. Carrier females completed the Symptom Checklist-90-R, Wechsler Abbreviated Scale of Intelligence, Broad Autism Phenotype Questionnaire, and detailed medical and mental health histories. Size and gene content of each duplication were determined by array comparative genome hybridization. X-chromosome inactivation patterns were analyzed using leukocyte DNA. MECP2 and IRAK1 RNA levels were quantified from lymphoblast cell lines, and western blots were performed to assess MeCP2 protein levels. Results All of the boys demonstrated mental retardation and autism. Poor expressive language, gaze avoidance, repetitive behaviors, anxiety, and atypical socialization were prevalent. Female carriers had psychiatric symptoms, including generalized anxiety, depression, and compulsions that preceded the birth of their children. The majority exhibited features of the broad autism phenotype and had higher nonverbal compared to verbal reasoning skills. Interpretation Autism is a defining feature of the MECP2 duplication syndrome in boys. Females manifest phenotypes despite 100% skewing of X-inactivation and normal MECP2 RNA levels in peripheral blood. Analysis of the duplication size, MECP2 and IRAK1 RNA levels, and MeCP2 protein levels revealed that most of the traits in affected boys are likely due to the genomic region spanning of MECP2 and IRAK1. The phenotypes observed in carrier females may be secondary to tissue-specific dosage alterations and require further study. Ann Neurol 2009;66:771,782 [source] Mutation frequencies of X-linked mental retardation genes in families from the EuroMRX consortium,,HUMAN MUTATION, Issue 2 2007Arjan P.M. de Brouwer Abstract The EuroMRX family cohort consists of about 400 families with non-syndromic and 200 families with syndromic X-linked mental retardation (XLMR). After exclusion of Fragile X (Fra X) syndrome, probands from these families were tested for mutations in the coding sequence of 90 known and candidate XLMR genes. In total, 73 causative mutations were identified in 21 genes. For 42% of the families with obligate female carriers, the mental retardation phenotype could be explained by a mutation. There was no difference between families with (lod score >2) or without (lod score <2) significant linkage to the X chromosome. For families with two to five affected brothers (brother pair=BP families) only 17% of the MR could be explained. This is significantly lower (P=0.0067) than in families with obligate carrier females and indicates that the MR in about 40% (17/42) of the BP families is due to a single genetic defect on the X chromosome. The mutation frequency of XLMR genes in BP families is lower than can be expected on basis of the male to female ratio of patients with MR or observed recurrence risks. This might be explained by genetic risk factors on the X chromosome, resulting in a more complex etiology in a substantial portion of XLMR patients. The EuroMRX effort is the first attempt to unravel the molecular basis of cognitive dysfunction by large-scale approaches in a large patient cohort. Our results show that it is now possible to identify 42% of the genetic defects in non-syndromic and syndromic XLMR families with obligate female carriers. © 2007 Wiley-Liss, Inc. [source] H intragenic polymorphisms and haplotype analysis in the ornithine transcarbamylase (OTC) gene and their relevance for tracking the inheritance of OTC deficiency,,HUMAN MUTATION, Issue 5 2002Consuelo Climent Abstract The "private" nature of most mutations causing ornithine transcarbamylase (OTC) deficiency makes mutation identification in the patients difficult. Further, the PCR-amplification technology generally used for the genetic diagnosis of the deficiency misses large deletions in carrier females. Intragenic OTC polymorphisms may allow detection of these deletions and may represent an alternative to mutation detection for prenatal diagnosis and carrier identification in families with a history of inherited OTC deficiency. A new highly informative polymorphism (allele frequencies, 0.66/0.34) in intron 3 of the OTC gene (IVS3-39_40insT) is reported here, and allelic frequencies of 16 additional intragenic OTC polymorphisms are determined in 133-35 (average per polymorphism, 72) unrelated chromosomes. In addition to the novel polymorphism, only three of the studied polymorphisms (Lys46Arg, allelic frequency 0.68/0.32; IVS3-8A>T, 0.34/0.66; Gln270Arg, 0.97/0.03) are confirmed to be informative. These provide, together with another reported polymorphism (IVS4-7A>G; reported allelic frequency 0.71/0.29; Plante and Tuchman, 1998), a set of highly valuable markers of the OTC gene. Nevertheless, the combined informativity of the studied polymorphisms is limited by their distribution in only four haplotypes with one of them predominating (65% of the sampled chromosomes). Although this haplotype composition may be restricted to the Iberian peninsula (the origin of the samples), more informative polymorphisms are required to increase the diagnostic potential and, particularly, to identify large deletions affecting OTC gene exons 5-10, where only one polymorphism of weak diagnostic value is known. © 2002 Wiley-Liss, Inc. [source] The expanding clinical spectrum of Anderson,Fabry disease: a challenge to diagnosis in the novel era of enzyme replacement therapyJOURNAL OF INTERNAL MEDICINE, Issue 6 2004A. C. Hauser Abstract. Anderson,Fabry disease is an X-linked recessive lysosomal storage disease resulting from deficient ,-galactosidase A activity. The conception of the disease has changed within the last decade. Studies of the last years have shown that the disease is not limited to the classical full-blown manifestation in affected males, which is well known since more than a century, but may also occur in carrier females. The phenomenology may differ in severity and kind of organ manifestation. Cardiac and renal variants with solely disease manifestation of these organs have also been described in an increasing number. It is likely that a spectrum exists regarding ,-galactosidase A activity in both genders on the one hand, and an additional one regarding the severity and the number of organs affected on the other. The purpose of this review is to sharpen physicians' perception of this disease. Early and accurate diagnosis is mandatory considering that this disorder is now, after introduction of the novel enzyme replacement therapy, a treatable disease. [source] CMTX: heterozygosity for a GJB1/CX32 mutation in a XXY male results in a mild phenotypeJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 2 2004M Milani Mutations in the GJB1/Cx32 gene (Xq13.1) cause the most common X-linked form of CMT (CMTX1) and are the most frequent cause of CMT disease after the CMT1A duplication. The disorder is characterized by a moderate-to-severe neuropathy in affected males and mild-to-no symptoms in carrier females. We report here a CMT1A-negative family in which 4 females and 2 males were affected, exhibiting different disease severity. Molecular analysis of the GJB1/Cx32 gene uncovered a nonsense mutation (Arg22stop) in exon 2. The mutation, which had been previously described by others and observed by us in numerous other families, occurred in heterozygous form in the 4 females. However, while one of the two male patients was severely affected and shown to be hemizygous, as expected, the other was mildly affected and found to carry the mutation in heterozygous form. Genotyping at the SRY (Yp11.3) and DMD (Xp21) loci suggested the occurrence of the XXY genotype associated with Klinefelter syndrome. Microsatellite analysis indicated that the nondysjunctional error was of paternal origin, as it is usually observed in about half the cases. The patient had no children. At clinical examination, he exhibited a very mild neurologic phenotype and showed signs of hypogonadism (mild gynecomastia and small testes) as well as moderate cognitive impairment. Electrophysiologic, cytogenetic and endocrinologic investigations are in progress in order to define the unusual phenotype in this patient. [source] Autism and other neuropsychiatric symptoms are prevalent in individuals with MeCP2 duplication syndrome,ANNALS OF NEUROLOGY, Issue 6 2009Melissa B. Ramocki MD Objective There have been no objective assessments to determine whether boys with MECP2 duplication have autism or whether female carriers manifest phenotypes. This study characterizes the clinical and neuropsychiatric phenotypes of affected boys and carrier females. Methods Eight families (9 males and 9 females) with MECP2 duplication participated. A detailed history, physical examination, electroencephalogram, developmental evaluation, Autism Diagnostic Observation Schedule, and Autism Diagnostic Interview,Revised were performed for each boy. Carrier females completed the Symptom Checklist-90-R, Wechsler Abbreviated Scale of Intelligence, Broad Autism Phenotype Questionnaire, and detailed medical and mental health histories. Size and gene content of each duplication were determined by array comparative genome hybridization. X-chromosome inactivation patterns were analyzed using leukocyte DNA. MECP2 and IRAK1 RNA levels were quantified from lymphoblast cell lines, and western blots were performed to assess MeCP2 protein levels. Results All of the boys demonstrated mental retardation and autism. Poor expressive language, gaze avoidance, repetitive behaviors, anxiety, and atypical socialization were prevalent. Female carriers had psychiatric symptoms, including generalized anxiety, depression, and compulsions that preceded the birth of their children. The majority exhibited features of the broad autism phenotype and had higher nonverbal compared to verbal reasoning skills. Interpretation Autism is a defining feature of the MECP2 duplication syndrome in boys. Females manifest phenotypes despite 100% skewing of X-inactivation and normal MECP2 RNA levels in peripheral blood. Analysis of the duplication size, MECP2 and IRAK1 RNA levels, and MeCP2 protein levels revealed that most of the traits in affected boys are likely due to the genomic region spanning of MECP2 and IRAK1. The phenotypes observed in carrier females may be secondary to tissue-specific dosage alterations and require further study. Ann Neurol 2009;66:771,782 [source] 2466: Blue cone nonochromacy gene mutation in Asia: phenotype variabilityACTA OPHTHALMOLOGICA, Issue 2010P BITOUN Purpose A far East asian family with 4 affected maternal cousin males with congenital nystagmus, low vision and dyschromatopsia was investigated for a genetic cause after informed consent. Blue cone monochromacy is a rare form of X-linked visual handicap with dyschromatopsia. Methods Family members had ophthalmologic examination including visual acuity, fundoscopy , slit lamp, biomicroscopy,colour vision testing and ERG and VEP recordings.DNA analysis of the composition of the cone ospin gene cluster was performed by PCR and PCR/RFLP as well as direct sequencing of LWS opsin gene. Results A novel nonsense Mutation in the single Long wave sensitive opsin gene was identified in all affected males and carrier females. The variability of the phenotype as well as the added role of parental myopia transmission in the phenotype will be discussed. Conclusion This is the first reported molecular diagnosis of blue cone monochromacy in the Asian population. The compound effect of dominantly inherited myopia offers insight of the effect of the added mutational load in these patients. [source] Identification of a novel deletion in the OA1 gene: report of the first Spanish family with X-linked ocular albinismCLINICAL & EXPERIMENTAL OPHTHALMOLOGY, Issue 5 2010Monica Martinez-Garcia PhD Abstract Background:, This study was undertaken to analyse the OA1 gene (GPR143) and its involvement in a Spanish family presenting with nystagmus, a common symptom of X-linked ocular albinism (XLOA). Methods:, DNA samples from the index case and eight relatives were analysed by multiplex ligation-dependent probe amplification (MLPA). Sequence analysis and restriction assay were used to confirm the results. In addition, an analysis of a STR located in intron 1 of the OA1 gene (OA-CA) was performed. Results:, The father of the proband presented with nystagmus, a feature consistent with XLOA. Mutation screening by multiplex ligation-dependent probe amplification and sequence analysis of the exon 2 of the OA1 gene led to the identification of the novel p.Glu129fsX35 (g.5815delA) mutation in two affected males and four carrier females. Three relatives were found to be non-mutated. The deletion detected resulted in a truncated protein 35 codons downstream and generated a new restriction site for the XcmI endonuclease. Additionally, microsatellite analysis showed co-segregation with the disease in the family. Conclusions:, A novel deletion in the OA1 gene was identified in a Spanish family with ocular albinism. The mutation detected is likely a loss-of-function alteration. To the best of our knowledge, we describe the first Spanish family known to present with XLOA due to mutations in the OA1 gene. [source] | ||||||||||