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Affected Subjects (affected + subject)
Selected AbstractsGenetic variants of insulin receptor substrate-1 (IRS-1) in syndromes of severe insulin resistance.DIABETIC MEDICINE, Issue 10 2002Functional analysis of Ala513Pro, Gly1158Glu IRS- Abstract Aims To define further the role of IRS-1 mutations in human syndromes of severe insulin resistance. Methods The IRS-1 gene was scanned for mutations in 83 unrelated affected subjects and 47 unaffected individuals using fluorescent single-strand conformation polymorphism (fSSCP) analysis. A novel heterozygous mutation, Gly1158Glu, was found in one affected subject. Four and two subjects were heterozygous for the previously reported variants Gly972Arg and Ala513Pro, respectively. The previously identified variant Gly819Arg was found in one affected and one unaffected subject. While Gly972Arg has been described to alter the signalling properties of IRS-1, no functional studies of Ala513Pro or Gly1158Glu have been reported. Results Chinese hamster ovary (CHO) cells stably over-expressing the insulin receptor were transiently transfected with vectors expressing either wild-type, Glu1158 or Pro513 IRS-1. A modest increase in insulin-stimulated tyrosine phosphorylation of Glu1158 IRS-1 was observed. However, this did not result in any significant change in the association of Grb2 or the p85, subunit of PI3-kinase or of PI3-kinase activity. In parallel studies, the Pro513 IRS-1 variant was indistinguishable from wild-type IRS-1. Conclusions While subtle effects of these variants cannot be excluded in this system, it is unlikely that these variants are responsible for the extreme insulin resistance seen in the subjects harbouring them. Although IRS proteins play a central role in insulin signalling, functionally significant mutations in the IRS-1 gene are a rare cause of human syndromes of severe insulin resistance. [source] Mutations in TREM2 lead to pure early-onset dementia without bone cysts,HUMAN MUTATION, Issue 9 2008Eliane Chouery Abstract A genome-wide screen using 382 STR markers to localize and identify the gene implicated in early-onset dementia (EOD) without bone cysts in a Lebanese family with three affected subjects was conducted. A unique locus homozygous by descent at chromosome 6p21.2 locus was identified. Candidate genes were explored by fluorescent sequencing and the effect of the identified mutation was confirmed by qualitative and quantitative RT-PCR. The genetic analysis revealed a novel deletion, c.40+3delAGG, in the 5' consensus donor splice site in intron 1 of TREM2 gene which is known to be responsible for PLOSL (Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy) also designated as Nasu-Hakola disease. In silico analysis predicted a lower strength for the novel donor splice site. Qualitative RT-PCR revealed normal transcript while quantitative RT-PCR showed over twofold down-regulation of TREM2 transcripts. The expression profile of six genes SPP1, NEDD9, FSCN, BCL3, NFKBIA and CCL2 known as disrupted in TREM2-deficient samples was studied and showed same expression profile as TREM2-mutated samples except for CCL2 which was normally regulated. The significantly-reduced expression of TREM2 in our patients and the expression profiles of the six studied genes confirm a role for TREM2 in this distinct phenotype of EOD without bone cysts. To our knowledge, this is the first report of mutations in TREM2 causing a pure dementia. © 2008 Wiley-Liss, Inc. [source] Disease Status in Autosomal Dominant Osteopetrosis Type 2 Is Determined by Osteoclastic Properties,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2006Kang Chu Abstract Asymptomatic gene carriers and clinically affected ADO2 subjects have the same ClCN7 mutation. We examined osteoclastic bone resorption in vitro as well as osteoclast formation, several markers, acid secretion, and cytoskeletal structure. We found that ADO2 expression results from osteoclast specific properties. Introduction: Autosomal dominant osteopetrosis type II (ADO2) is a heritable osteosclerotic disorder that results from heterozygous mutations in the ClCN7 gene. However, of those individuals with a ClCN7 mutation, one third are asymptomatic gene carriers who have no clinical, biochemical, or radiological manifestations. Disease severity in the remaining two thirds is highly variable. Materials and Methods: Human peripheral blood mononuclear cells were isolated and differentiated into osteoclasts by stimulation with hRANKL and human macrophage-colony stimulating factor (hM-CSF). Study subjects were clinically affected subjects, unaffected gene carriers, and normal controls (n = 6 in each group). Pit formation, TRACP staining, RANKL dose response, osteoclast markers, acid secretion, F-actin ring, and integrin ,v,3 expression and co-localization were studied. Results: Osteoclasts from clinically affected subjects had severely attenuated bone resorption compared with those from normal controls. However, osteoclasts from unaffected gene carriers displayed similar bone resorption to those from normal controls. In addition, the resorption lacunae from both unaffected gene carriers and normal controls appeared much earlier and spread much more rapidly than those from clinically affected subjects. As time progressed, the distinction between clinically affected subjects and the other two groups increased. No significant difference was found in acidic secretion or osteoclast formation between the three groups. Osteoclast cytoskeletal organization showed no difference between the three groups but there was low cellular motility in clinically affected subjects. Conclusions: Osteoclasts from the unaffected gene carriers, in contrast to those from the clinically affected subjects, functioned normally in cell culture. This finding supports the hypothesis that intrinsic osteoclast factors determine disease expression in ADO2. Further understanding of this mechanism is likely to lead to the development of new approaches to the treatment of clinically affected patients. [source] Novel PRKCG/SCA14 mutation in a Dutch spinocerebellar ataxia family: Expanding the phenotypeMOVEMENT DISORDERS, Issue 7 2006Monique H.M. Vlak MD Abstract We report on a family with an autosomal dominant cerebellar ataxia in which we identified a novel mutation in exon 5 of the PRKCG/SCA14 gene that results in a Val138Glu substitution in the encoded protein PKC,. While most affected subjects displayed a late-onset uncomplicated form of spinocerebellar ataxia with occasional mild extrapyramidal features (such as postural tremor), one patient presented with a very mild nonprogressive ataxia since the age of 3 years and predominant multifocal myoclonus. © 2006 Movement Disorder Society [source] Neurofibromatosis 2 with peripheral neuropathies: Electrophysiological, pathological and genetic studies of a Taiwanese familyNEUROPATHOLOGY, Issue 5 2010Hung-Chou Kuo The objective of this study was to assess peripheral nerve involvement and DNA mutation of the neurofibromatosis type 2 (NF2) gene (NF2) in a Taiwanese family with classic NF2. Eleven members (six symptomatic and five asymptomatic) of a family carrying NF2 underwent clinical examination, neuroimaging, and electrophysiological analysis. Mutation and linkage analyses were conducted on DNA samples prepared from peripheral blood (all individuals), a sural nerve biopsy specimen (one symptomatic member), and a tumor specimen (another symptomatic member). Six of the 11 members were diagnosed with classic NF2. DNA sequencing of the tumor specimen demonstrated a frameshift mutation with 756delC on exon 8 of NF2. Three affected subjects showed clinical variability of the neuropathic disorders. Electrophysiological studies demonstrated variation in the disease pattern and severity of peripheral nerve involvement in five affected subjects. The morphometric assessment of the sural nerve biopsy specimen showed a marked reduction in both large myelinated and unmyelinated fibre density and increased density of non-myelinating Schwann cell nuclei. Apart from numerous pathological nuclei of isolated Schwann cells, multiple profiles of non-myelinating Schwann cell subunits were apparent in the endoneurium. Schwann cell proliferation in association with first-hit mutation of the merlin gene might be responsible for the NF2-associated neuropathy. Sural nerve biopsy showed a progressive neuropathy in the disease. Further, we suggest nonmyelinating Schwann cells are involved in NF2 neuropathy. [source] Hereditary cerebral hemorrhage with amyloidosis-Dutch typeNEUROPATHOLOGY, Issue 4 2005Marion Maat-Schieman The amyloid ,-protein (A,) E22Q mutation of the rare disorder hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) causes severe cerebral amyloid angiopathy (CAA) with hemorrhagic strokes of mid-life onset and dementia. The mutation does not affect total A, production but may alter the A,1,42:A,1,40 ratio, and affect the proteolytic degradation of A, and its transport across the blood,brain barrier. A, E22Q aggregates faster into more stable amyloid-like fibrils than wild-type A,. Non-fibrillar A,(x-42) deposits precede the appearance of fibrils and the deposition of A,(x-40) in the vascular basement membrane. CAA severity tends to increase with age but may vary greatly among patients of comparable ages. Lumenal narrowing of affected blood vessels, leukoencephalopathy, CAA-associated vasculopathies, and perivascular astrocytosis, microgliosis, and neuritic degeneration complicate the development of HCHWA-D CAA. Parenchymal A, deposition is also enhanced in the HCHWA-D brain with non-fibrillar membrane-bound A,(x-42) deposits evolving into relatively fibrillar diffuse plaques variously associated with reactive astrocytes, activated microglia, and degenerating neurites. Plaque density tends ,to ,decrease ,with ,age. ,Neurofibrillary ,degeneration is absent or limited. HCHWA-D dementia is associated with CAA severity independently of Braak stage, age, and plaque density. Particularly, microaneurysms may contribute to the development of (small) hemorrhages/infarcts and the latter to cognitive decline in affected subjects. However, the relative importance of cerebral hemorrhages/infarcts, white matter damage and/or other CAA- or A,-related factors for cognitive deterioration in HCHWA-D remains to be determined. [source] Agreement between clinical examination and quantitative tests of neurologic function among 384 subjects,AMERICAN JOURNAL OF INDUSTRIAL MEDICINE, Issue 4 2001Kyle Steenland Abstract Background Quantitative neurological tests are often cheaper and easier than clinical examinations, and provide continuous data which may discriminate between exposed and nonexposed groups with more sensitivity than dichotomous (normal/abnormal) examination data. Methods We compare clinical examinations and analogous quantitative tests for arm tremor, postural sway, and vibrotactile sensitivity (finger and toe), for 384 subjects. Results The "abnormal" clinical outcomes studied were relatively common (range, 3,36%), and did not result in impairment of daily activity for affected subjects. All the quantitative tests were reasonably good predictors of the corresponding clinical outcome. The most predictive test was for toe vibrotactile sensitivity. The probability of an abnormal clinical result for those in the worst quartile for the toe test was 0.63, compared with 0.36 for all subjects. Conclusions Our results suggest that certain quantitative tests might be used in epidemiologic studies instead of a physical examination. Am. J. Ind. Med. 39:361,368, 2001. Published 2001 Wiley-Liss, Inc. [source] Deafness Due to A1555G Mitochondrial Mutation Without Use of Aminoglycoside,THE LARYNGOSCOPE, Issue 6 2004Tatsuo Matsunaga MD Abstract Objectives/Hypothesis: The objective was to clarify the characteristics of deafness associated with the A1555G mutation within mitochondrial 12S ribosomal RNA gene in the absence of aminoglycoside exposure. Study Design: Clinical and genetic studies in family members with the A1555G mitochondrial mutation were performed. Methods: The subjects were 123 maternally related members of a large Japanese family with the A1555G mutation. All subjects had no previous history of exposure to aminoglycosides. Hearing disability and handicap, tinnitus, and medical histories were analyzed by interviews in all of the subjects, genetic testing was performed in 41 subjects, and pure-tone audiometry was conducted in 26 subjects with hearing disability and handicap. Results: The A1555G mutation was detected in a homoplasmic form (meaning that all the mitochondrial DNA carries the mutation) in all 41 subjects who were screened. The risk for developing postlingual hearing loss was likely to be much higher in the present subjects than in the general population. Both the severity and age at onset of the phenotype were similar in affected subjects within the same sibling group. Pure-tone averages were significantly worse in subjects who developed hearing loss before age 10 years than in those who developed hearing loss later. Conclusion: The present study demonstrated that the prevalence of deafness in individuals with the A1555G mitochondrial mutation was likely to be high even in the absence of aminoglycoside exposure and clearly showed the association of severe to profound hearing loss with the onset of hearing loss before age 10 years. [source] Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein,ANNALS OF NEUROLOGY, Issue 2 2010Wen-Quan Zou MD Objective: The objective of the study is to report 2 new genotypic forms of protease-sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV). The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV). Methods: Fifteen affected subjects with 129MM, 129MV, and 129VV underwent comparative evaluation at the National Prion Disease Pathology Surveillance Center for clinical, histopathologic, immunohistochemical, genotypical, and PrP characteristics. Results: Disease duration (between 22 and 45 months) was significantly different in the 129VV and 129MV subjects. Most other phenotypic features along with the PrP electrophoretic profile were similar but distinguishable in the 3 129 genotypes. A major difference laid in the sensitivity to protease digestion of the disease-associated PrP, which was high in 129VV but much lower, or altogether lacking, in 129MV and 129MM. This difference prompted the substitution of the original designation with "variably protease-sensitive prionopathy" (VPSPr). None of the subjects had mutations in the PrP gene coding region. Interpretation: Because all 3 129 genotypes are involved, and are associated with distinguishable phenotypes, VPSPr becomes the second sporadic prion protein disease with this feature after Creutzfeldt-Jakob disease, originally reported in 1920. However, the characteristics of the abnormal prion protein suggest that VPSPr is different from typical prion diseases, and perhaps more akin to subtypes of Gerstmann-Sträussler-Scheinker disease. ANN NEUROL 2010;68:162,172 [source] Longterm visual prognosis in Usher syndrome types 1 and 2ACTA OPHTHALMOLOGICA, Issue 4 2006André M. Sadeghi Abstract. Purpose:, To estimate the age at diagnosis of retinitis pigmentosa and to determine visual acuity deterioration, visual field impairment and the frequency of cataracts in Usher syndrome types 1 and 2. Methods:, We carried out a retrospective study of 328 affected subjects with Usher syndrome types 1 and 2. Study subjects were divided into seven different age groups by decade. Data were analysed using descriptive statistics, general linear model anova and survival analysis. Results:, Retinitis pigmentosa was diagnosed significantly earlier in subjects with Usher syndrome type 1 than in those with type 2. Visual acuity was significantly more impaired in affected subjects with Usher syndrome type 1 than in those with type 2 from 50 years of age onwards. Survival analysis revealed a significant difference in visual field loss (, 10 degrees) between the two groups, with type 2 subjects tending to be more impaired, while comparison indicated no significant differences between the groups in any of the other visual field categories. Cataract was found to be generally more common in Usher syndrome type 1 than type 2. Conclusions:, Progressive loss of visual acuity and visual field begins to be substantial between the second and third decades of life in both Usher types. The rate of degeneration varies between individuals in both groups. The data are useful for the counselling of affected subjects with Usher syndrome types 1 and 2. [source] A novel deletion mutation in LIPH gene causes autosomal recessive hypotrichosis (LAH2)CLINICAL GENETICS, Issue 2 2008M Jelani Autosomal recessive hypotrichosis is a rare hereditary disorder characterized by sparse hair on scalp and rest of the body of affected subjects. Recently, three clinically similar autosomal recessive forms of hypotrichosis [localized autosomal recessive hypotrichosis (LAH)1], LAH2 and LAH3 have been mapped on chromosomes 18q12.1, 3q27.3, and 13q14.11-q21.32, respectively. For these three loci, two genes DSG4 for LAH1 and LIPH for LAH2 have been identified. To date, only five mutations in DSG4 and two in LIPH genes have been reported. In this study, we have ascertained two large unrelated consanguineous Pakistani families with autosomal recessive form of hypotrichosis. Affected individuals showed homozygosity to the microsatellite markers tightly linked to LIPH gene on chromosome 3q27. Sequence analysis of the gene in the affected subjects from both the families revealed a novel deletion mutation in exon 5 (c.659-660delTA) causing frameshift and downstream premature termination codon. All the three mutations identified in the LIPH gene, including the one in this study, are deletion mutations. [source] Genetic heterogeneity and minor CYP1B1 involvement in the molecular basis of primary congenital glaucoma in GypsiesCLINICAL GENETICS, Issue 1 2008P Sivadorai Primary congenital glaucoma (PCG) is a genetically heterogeneous disorder of autosomal recessive inheritance, with mutations in the cytochrome P450 1B1 (CYP1B1) gene detected in an average of ,50% of cases worldwide. The Roma/Gypsies are considered to be a rare example of a single founder CYP1B1 mutation, E387K (identified in the Slovak Roma), accounting for 100% of disease alleles. Contrary to this concept, unusual genetic heterogeneity was revealed in this study of 21 Gypsy PCG patients from Bulgaria and 715 controls from the general Gypsy population. In our small sample of affected subjects, we identified five different CYP1B1 mutations , four known (E229K, R368H, E387K and R390C) and one novel and potentially pathogenic (F445I), which together accounted for ,30% of disease alleles. E387K was rare in both the patient and the control group, indicating that its high frequency in the Slovak Roma is the product of local founder effect not representative of the overall molecular pattern of PCG in the Gypsy population. Data on other Mendelian disorders and on the population genetics of the Gypsies suggest that a true founder mutation is likely to exist and has remained undetected. Our analysis of another candidate gene, MYOC, and the GLC3B and GLC3C loci did not provide support for their involvement. The molecular basis of PCG in the Gypsies is thus unresolved, and diagnostic analyses should be extended beyond the E387K mutation. [source] | |||||||||||||