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Rare Genetic Disorder (rare + genetic_disorder)
Selected AbstractsKeratosis Follicularis Spinulosa Decalvans is caused by mutations in MBTPS2,HUMAN MUTATION, Issue 10 2010Emmelien Aten Abstract Keratosis Follicularis Spinulosa Decalvans (KFSD) is a rare genetic disorder characterized by development of hyperkeratotic follicular papules on the scalp followed by progressive alopecia of the scalp, eyelashes, and eyebrows. Associated eye findings include photophobia in childhood and corneal dystrophy. Due to the genetic and clinical heterogeneity of similar disorders, a definitive diagnosis of KFSD is often challenging. Toward identification of the causative gene we reanalyzed a large Dutch KFSD family. SNP arrays (1 M) redefined the locus to a 2.9-Mb region at Xp22.12,Xp22.11. Screening of all 14 genes in the candidate region identified MBTPS2 as the candidate gene carrying a c.1523A>G (p.Asn508Ser) missense mutation. The variant was also identified in two unrelated X-linked KFSD families and cosegregated with KFSD in all families. In symptomatic female carriers, skewed X-inactivation of the normal allele matched with increased severity of symptoms. MBTPS2 is required for cleavage of sterol regulatory element-binding proteins (SREBPs). In vitro functional expression studies of the c.1523A>G mutation showed that sterol responsiveness was reduced by half. Other missense mutations in MBTPS2 have recently been identified in patients with IFAP syndrome. We postulate that both phenotypes are in the spectrum of one genetic disorder with a partially overlapping phenotype. Hum Mutat 31:1,9, 2010. © 2010 Wiley-Liss, Inc. [source] Dysregulation of the BMP-p38 MAPK Signaling Pathway in Cells From Patients With Fibrodysplasia Ossificans Progressiva (FOP),,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2006Jennifer L Fiori Abstract FOP is a disabling disorder in which skeletal muscle is progressively replaced with bone. Lymphocytes, our model system for examining BMP signaling, cannot signal through the canonical Smad pathway unless exogenous Smad1 is supplied, providing a unique cell type in which the BMP,p38 MAPK pathway can be examined. FOP lymphocytes exhibit defects in the BMP,p38 MAPK pathway, suggesting that altered BMP signaling underlies ectopic bone formation in this disease. Introduction: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by progressive heterotopic ossification of connective tissues. Whereas the primary genetic defect in this condition is unknown, BMP4 mRNA and protein and BMP receptor type IA (BMPRIA) protein are overexpressed in cultured lymphocytes from FOP patients, supporting that altered BMP signaling is involved in this disease. In this study, we examined downstream signaling targets to study the BMP,Smad and BMP,p38 mitogen-activated protein kinase (MAPK) pathways in FOP. Materials and Methods: Protein phosphorylation was assayed by immunoblots, and p38 MAPK activity was measured by kinase assays. To examine BMP target genes, the mRNA expression of ID1, ID3, and MSX2 was determined by quantitative real-time PCR. Statistical analysis was performed using Student's t -test or ANOVA. Results: FOP lymphocytes exhibited increased levels of p38 phosphorylation and p38 MAPK activity in response to BMP4 stimulation. Furthermore, in response to BMP4, FOP cells overexpressed the downstream signaling targets ID1 by 5-fold and ID3 by 3-fold compared with controls. ID1 and ID3 mRNA induction was specifically blocked with a p38 MAPK inhibitor, but not extracellular signal-related kinase (ERK) or c-Jun N-terminal kinase (JNK) inhibitors. MSX2, a known Smad pathway target gene, is not upregulated in control or FOP cells in response to BMP, suggesting that lymphocytes do not use this limb of the BMP pathway. However, introduction of Smad1 into lymphocytes made the cells competent to regulate MSX2 mRNA after BMP4 treatment. Conclusions: Lymphocytes are a cell system that signals primarily through the BMP,p38 MAPK pathway rather than the BMP,Smad pathway in response to BMP4. The p38 MAPK pathway is dysregulated in FOP lymphocytes, which may play a role in the pathogenesis of FOP. [source] Cognitive profile in a large french cohort of adults with Prader,Willi syndrome: differences between genotypesJOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 3 2010P. Copet Abstract Background Prader,Willi syndrome (PWS) is a rare genetic disorder characterised by developmental abnormalities leading to somatic and psychological symptoms. These include dysmorphic features, impaired growth and sexual maturation, hyperphagia, intellectual delay, learning disabilities and maladaptive behaviours. PWS is caused by a lack of expression of maternally imprinted genes situated in the 15q11-13 chromosome region. The origin is a ,de novo' deletion in the paternal chromosome in 70% of the cases and a maternal uniparental disomy in 25%. The two main genotypes show differences, notably regarding cognitive and behavioural features, but the mechanisms are not clear. This study assessed cognitive impairment in a cohort of adults with genetically confirmed PWS, analysed their profiles of cognitive strengths and weaknesses, and compared the profiles in terms of genotype. Methods Ninety-nine male and female adults participated, all inpatients on a specialised unit for the multidisciplinary care of PWS. The Wechsler Adult Intelligence Scale (WAIS-III) was administered to all patients in identical conditions by the same psychologist. Eighty-five patients were able to cope with the test situation. Their scores were analysed with non-parametric statistical tools. The correlations with sex, age and body mass index were explored. Two genotype groups were compared: deletion (n = 57) and non-deletion (n = 27). Results The distribution of intelligence quotients in the total cohort was non-normal, with the following values (medians): Full Scale Intelligence Quotient (FSIQ): 52.0 (Q1:46.0; Q3:60.0), Verbal Intellectual Quotient (VIQ): 53.0 (Q1:48; Q3:62) and Performance Intellectual Quotient (PIQ): 52.5 (Q1:48; Q3:61). No correlation was found with sex, age or body mass index. Comparison between groups showed no significant difference in FSIQ or VIQ. PIQ scores were significantly better in the deletion group. The total cohort and the deletion group showed the VIQ = PIQ profile, whereas VIQ > PIQ was observed in the non-deletion group. The subtest scores in the two groups showed significant differences, with the deletion group scoring better in three subtests: object assembly, picture arrangement and digit symbol coding. Some relative strengths and weaknesses concerned the total cohort, but others concerned only one genotype. Discussion We documented a global impairment in the intellectual abilities of a large sample of French PWS patients. The scores were slightly lower than those reported in most other studies. Our data confirmed the previously published differences in the cognitive profiles of the two main PWS genotypes and offer new evidence to support this hypothesis. These results could guide future neuropsychological studies to determine the cognitive processing in PWS. This knowledge is essential to improve our understanding of gene-brain-behaviour relationships and to open new perspectives on therapeutic and educational programmes. [source] Familial Currarino syndrome presenting with peripheral primitive neuroectodermal tumour arising with a sacral teratomaPEDIATRIC BLOOD & CANCER, Issue 1 2008G. Sen MD Abstract This report illustrates a rare genetic disorder, Currarino syndrome, in association with an unusual malignant transformation to a peripheral primitive neuroectodermal tumour within a sacral teratoma. The triad of features consists of a presacral mass, partial sacral agenesis and anorectal anomalies. The most common presentation is constipation. In this case there was a history of constipation, teratomas and spinal abnormalities in many of the family members over three generations. Detailed family history taken at time of initial presentation may have prevented delay in diagnosis and averted the need for intensive treatment, which may well cause late sequelae. Pediatr Blood Cancer 2008;50:172,175. © 2006 Wiley-Liss, Inc. [source] Block Design Performance in the Williams Syndrome Phenotype: A Problem with Mental Imagery?THE JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY AND ALLIED DISCIPLINES, Issue 6 2001Emily K. Farran Williams syndrome (WS) is a rare genetic disorder which, among other characteristics, has a distinctive cognitive profile. Nonverbal abilities are generally poor in relation to verbal abilities, but also show varying levels of ability in relation to each other. Performance on block construction tasks represents arguably the weakest nonverbal ability in WS. In this study we examined two requirements of block construction tasks in 21 individuals with WS and 21 typically developing (TD) control individuals. The Squares tasks, a novel twodimensional block construction task, manipulated patterns by segmentation and perceptual cohesiveness to investigate the first factor, processing preference (local or global), and by obliqueness to examine the second factor, the ability to use mental imagery. These two factors were investigated directly by the Children's Embeded Figures Test (CEFT; Witkin, Oltman, Raskin, & Karp, 1971) and a mental rotation task respectively. Results showed that individuals with WS did not differ from the TD group in their processing style. However, the ability to use mental imagery was significantly poorer in the WS group than the TD group. This suggests that weak performance on the block construction tasks in WS may relate to an inability to use mental imagery. [source] Peri-operative management of a patient with hereditary angioedema undergoing laparoscopic cholecystectomyANAESTHESIA, Issue 1 2010A. Spyridonidou Summary Hereditary angioedema is a rare genetic disorder resulting from an inherited deficiency or dysfunction of the C1-esterase inhibitor of the classic complement pathway. It is characterised by recurrent episodes of angioedema, without urticaria or pruritus, most often affecting the skin or the mucosal tissues of the upper respiratory and gastrointestinal tracts. We describe the peri-operative care of a woman with hereditary angioedema undergoing laparoscopic cholecystectomy with emphasis on the role of anaesthetists as peri-operative physicians. [source] A case of focal dermal hypoplasia (Goltz) syndrome with exophytic granulation tissue treated by curettage and photodynamic therapyCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 2 2006R. Mallipeddi Summary Focal dermal hypoplasia (Goltz) syndrome is a rare genetic disorder characterized by cutaneous, ectodermal and mesodermal defects. We present a case in which painful, exophytic granulation tissue has been the main symptom over the past 15 years. After unsatisfactory results with a number of treatment modalities including topical steroids, silver-nitrate applications, cryotherapy, curettage, excision and pulsed-dye laser, we achieved significant benefit with curettage in combination with photodynamic therapy. Although impaired wound healing has been described in focal dermal hypoplasia, this is, to our knowledge, the first time that pyogenic granuloma-like lesions have been reported. [source] Congenital central hypoventilation syndrome: genotype,phenotype correlation in parents of affected children carrying a PHOX2B expansion mutationCLINICAL GENETICS, Issue 3 2010S Parodi Parodi S, Vollono C, Baglietto MP, Balestri M, Di Duca M, Landri PA, Ceccherini I, Ottonello G, Cilio MR. Congenital central hypoventilation syndrome: genotype,phenotype correlation in parents of affected children carrying a PHOX2B expansion mutation. Congenital Central Hypoventilation Syndrome (CCHS) is a rare genetic disorder. Although most CCHS associated PHOX2B mutations occur de novo, about 10% of the cases are inherited from apparently asymptomatic parents, thus confirming variable expressivity and incomplete penetrance of PHOX2B mutations. Three asymptomatic parents of children affected with CCHS, and found to carry the same PHOX2B expansion mutations as their siblings, were studied by overnight polysomnography and somatic mosaicism analysis. In one case, significant sleep breathing control anomalies were detected, while the other two resulted in normal. In tissue-specific allele studies, mosaicism with a comparatively low mutant allele proportion was showed in the two unaffected adult carriers. Accurate polysomnography and assessment of the degree of somatic mosaicism should be conducted in asymptomatic carriers of PHOX2B mutations, as they may unmask subclinical but significant anomalies [source] | |||||||||||||