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Probands
Kinds of Probands Selected AbstractsDopamine transporter gene (DAT1) VNTR polymorphism in major psychiatric disorders: family-based association study in the Bulgarian populationACTA PSYCHIATRICA SCANDINAVICA, Issue 5 2002L. Georgieva Objective:,A 40-bp variable number tandem repeat in the 3,-UTR of dopamine transporter gene (DAT1) has been examined for association with major psychiatric disorders in several case,control studies. No significant results have been found. We used a new collection of parent,offspring trios to test for association with schizophrenia (SZ), bipolar 1 disorder (BPI) and schizoaffective (SA) disorder. Method:,We genotyped trios from Bulgarian origin where the proband had SZ (178 trios), BPI (77 trios) and SA (29 trios). Alleles ranging from 5 to 11 repeats were observed. The results were analysed with the extended TDT (ETDT). Results:,No preferential transmission of alleles was observed for any diagnostic group. The presence of allele DAT*10 was associated with the severity and frequency of auditory hallucinations, however, this result is not significant if corrected for multiple testing. Conclusion:,Our results are in agreement with previous reports of a lack of association between this polymorphism and major psychiatric disorders. [source] Evidence of shared genetic risk factors for migraine and rolandic epilepsyEPILEPSIA, Issue 11 2009Tara Clarke Summary Purpose:, Evidence for a specific association between migraine and rolandic epilepsy (RE) has been conflicting. Children with migraine frequently have electroencephalographic (EEG) abnormalities, including rolandic discharges, and approximately 50% of siblings of patients with RE exhibit rolandic discharges. We assessed migraine risk in RE probands and their siblings. Methods:, We used cohort and reconstructed cohort designs to respectively assess the relative risk of migraine in 72 children with RE and their 88 siblings using International Classification of Headache Disorders (ICHD-2) criteria. Incidences were compared in 150 age and geographically matched nonepilepsy probands and their 188 siblings. We used a Cox proportional hazards model, using age as the time base, adjusting hazard ratios (HRs) for sex in the proband analysis, and for sex and proband migraine status in the sibling analysis. Results:, Prevalence of migraine in RE probands was 15% versus 7% in nonepilepsy probands, and in siblings of RE probands prevalence was 14% versus 4% in nonepilepsy siblings. The sex-adjusted HR of migraine for an RE proband was 2.46 [95% confidence interval (CI) 1.06,5.70]. The adjusted HR of having ,1 sibling with migraine in an RE family was 3.35 (95% CI 1.20,9.33), whereas the HR of any one sibling of a RE proband was 2.86 (95% CI 1.10,7.43). Discussion:, Migraine is strongly comorbid in RE and independently clusters in their siblings. These results suggest shared susceptibility to migraine and RE that is not directly mediated by epileptic seizures. Susceptibility gene variants for RE may be tested as risk factors for migraine. [source] High Risk of Reading Disability and Speech Sound Disorder in Rolandic Epilepsy Families: Case,Control StudyEPILEPSIA, Issue 12 2007Tara Clarke Summary Purpose: Associations between rolandic epilepsy (RE) with reading disability (RD) and speech sound disorder (SSD) have not been tested in a controlled study. We conducted a case,control study to determine whether (1) RD and SSD odds are higher in RE probands than controls and (2) an RE proband predicts a family member with RD or SSD, hence suggesting a shared genetic etiology for RE, RD, and SSD. Methods: Unmatched case,control study with 55 stringently defined RE cases, 150 controls in the same age range lacking a primary brain disorder diagnosis, and their siblings and parents. Odds ratios (OR) were calculated by multiple logistic regression, adjusted for sex and age, and for relatives, also adjusted for comorbidity of RD and SSD in the proband. Results: RD was strongly associated with RE after adjustment for sex and age: OR 5.78 (95% CI: 2.86,11.69). An RE proband predicts RD in family members: OR 2.84 (95% CI: 1.38,5.84), but not independently of the RE proband's RD status: OR 1.30 (95% CI: 0.55,12.79). SSD was also comorbid with RE: adjusted OR 2.47 (95%CI: 1.22,4.97). An RE proband predicts SSD in relatives, even after controlling for sex, age and proband SSD comorbidity: OR 4.44 (95% CI: 1.93,10.22). Conclusions: RE is strongly comorbid with RD and SSD. Both RD and SSD are likely to be genetically influenced and may contribute to the complex genetic etiology of the RE syndrome. Siblings of RE patients are at high risk of RD and SSD and both RE patients and their younger siblings should be screened early. [source] Increased sibling mortality in children with fetal alcohol syndromeADDICTION BIOLOGY, Issue 2 2004Larry Burd We compared the rate of all-cause mortality in siblings of children diagnosed with fetal alcohol syndrome (FAS) with the siblings of matched controls. The siblings of children with FAS had increased mortality (11.4%) compared with matched controls (2.0%), a 530% increase in mortality. The age of death in case siblings deaths occurred later (between 1 day and 7 years) compared with the controls (1 day to 4 years) [odds ratio (OR),=,2.4 (0.4,-,15.6)]. Siblings of children with FAS had increased risk of death due to infectious illness [OR,=,13.7 (1.2,-,361)] and sudden infant death syndrome compared with controls [OR,=,10.2 (1.2,-,75.1)]. A diagnosis of FAS is an important risk marker for mortality in the siblings of the proband even if they do not have FAS. Maternal alcoholism appears to be a useful risk marker for increased mortality risk in diagnosed cases and their siblings. This has important implications in the management of family members of children with FAS. [source] A novel mutation in the PSEN1 gene (L286P) associated with familial early-onset dementia of Alzheimer type and lobar haematomasEUROPEAN JOURNAL OF NEUROLOGY, Issue 12 2007R. Sánchez-Valle The aim of this study was to describe a novel mutation in exon 8 of the presenilin gene (L286P) associated with early-onset autosomal dominant Alzheimer's disease (AD) and lobar haematomas. The proband was a woman who developed cognitive decline with predominant memory loss at the age of 35 years. The patient died at the age of 54 years and the neuropathological examination confirmed the diagnosis of AD. Three of her four siblings, one parent and one sibling of her parent had suffered from cognitive decline at ages between 35 and 42 years. Three of them also presented lobar haematomas. The neuropathological examination, available in one of them, disclosed the presence of severe amyloid angiopathy as the cause of the haematoma. The study of PSEN1 gene with single strand conformation polymorphism technique failed to show abnormalities suggestive of mutations. Direct sequencing disclosed the presence of a missense mutation in codon 286 (L286P) in the proband and her already affected descendent, which was absent in the healthy sibling. L286P is a novel mutation in PSEN1 that causes familial early-onset AD and brain haematomas related to amyloid angiopathy. [source] Paternal germline mosaicism in Herlitz junctional epidermolysis bullosaEXPERIMENTAL DERMATOLOGY, Issue 5 2002Peter B. Cserhalmi-Friedman Abstract: We studied a single patient with the lethal (Herlitz) type of junctional epidermolysis bullosa (H-JEB). Screening for mutations in the LAMB3 gene in the patient revealed the previously described hotspot mutation R635X and a novel one basepair deletion in exon 10. The single basepair deletion 1094delA could be detected in the clinically unaffected mother, while the nonsense mutation R635X could not be found in the peripheral blood DNA of either parent. After excluding non-paternity by microsatellite analysis using random markers on chromosomes 3, 8 and 18, we determined that the mutation R635X in the proband was most likely the result of a de novo event or alternatively, germline mosaicism. The parents requested prenatal diagnosis for a second pregnancy, and while the maternal mutation 1094delA could not be detected in DNA from the fetus, unexpectedly, the mutation R635X was present in the chorionic villus DNA. These findings were most consistent with paternal germline mosaicism for the recessive mutation R635X. The results have had a significant impact on the genetic counseling in this family. To our knowledge, this study represents the first documented case of germline mosaicism in junctional epidermolysis bullosa, and serves as a reminder that germline mosaicism should be considered in cases in which a ,new' mutation is found in the offspring of a clinically and/or genetically unaffected parent. [source] Familial loading in specific language impairment: patterns of differences across proband characteristics, gender and relative typeGENES, BRAIN AND BEHAVIOR, Issue 3 2007G. Conti-Ramsden There is now little doubt that both environmental factors and genes are likely to make important contributions to the aetiology of specific language impairment (SLI). The most commonly proposed model for understanding these influences is the multifactorial model. In the present study we examine two expectations based on this model: that there will be a systematic relationship between the severity of proband language scores and the rate and severity of SLI in relatives and that relatives will be more strongly affected if they are relatives of a proband of the more rarely affected gender (female) because the latter require a higher genetic liability to become equally impaired. Ninety-three probands and their 300 first-degree relatives participated in this study. Results showed a relationship between proband severity at age 14 and an increased rate of SLI in relatives. This relationship was strong for child siblings and was significant with respect to both rate of SLI and severity over a range of language and literacy measures. In contrast, higher levels of SLI among relatives of female rather than male probands was entirely disproved. [source] Genetic study of the myelin oligodendrocyte glycoprotein (MOG) gene in schizophreniaGENES, BRAIN AND BEHAVIOR, Issue 1 2005G. Zai Schizophrenia (SCZ) is a neuropsychiatric disorder that affects approximately 1% of the general population. The human leukocyte antigen (HLA) system has been implicated in several genetic studies of SCZ. The myelin oligodendrocyte glycoprotein (MOG) gene, which is located close to the HLA region, is considered a candidate for SCZ due to its association with white matter abnormalities and its importance in mediating the complement cascade. Four polymorphisms in the MOG gene (CA)n (TAAA)n, and two intronic polymorphisms, C1334T and C10991T, were investigated for the possibility of association with SCZ using 111 SCZ proband and their families. We examined the transmission of the alleles of each of these polymorphisms with the transmission disequilibrium test. We did not observe significant evidence for biased transmission of alleles at the (CA)n (,2 = 2.430, 6 df, P = 0.876) (TAAA)n (,2 = 3.550, 5 df, P = 0.616), C1334T (,2 = 0.040, 1 df, P = 0.841) and C10991T (,2 = 0.154, 1 df, P = 0.695) polymorphisms. Overall haplotype analysis using the TRANSMIT program was also not significant (,2 = 7.954, 9 df, P = 0.539). Furthermore, our results comparing mean age at onset in the genotype groups using the Kruskal,Wallis Test were not significant. Our case-control analyses (182 cases age-, sex- and ethnicity-matched with healthy controls) and combined z -score [(CA)n: z -score =,1.126, P = 0.130; (TAAA)n: z -score = ,0.233, P = 0.408; C1334T: z -score = 0.703, P = 0.241; C10991T: z -score = 0.551, P = 0.291] were also not significant. Although our data are negative, the intriguing hypothesis for MOG in SCZ may warrant further investigation of this gene. [source] Using a minigene approach to characterize a novel splice site mutation in human F7 gene causing inherited factor VII deficiency in a Chinese pedigreeHAEMOPHILIA, Issue 6 2009T. YU Summary., Factor VII deficiency which transmitted as an autosomal recessive disorder is a rare haemorrhagic condition. The aim of this study was to identify the molecular genetic defect and determine its functional consequences in a Chinese pedigree with FVII deficiency. The proband was diagnosed as inherited coagulation FVII deficiency by reduced plasma levels of FVII activity (4.4%) and antigen (38.5%). All nine exons and their flanking sequence of F7 gene were amplified by polymerase chain reaction (PCR) for the proband and the PCR products were directly sequenced. The compound heterozygous mutations of F7 (NM_000131.3) c.572-1G>A and F7 (NM_000131.3) c.1165T>G; p.Cys389Gly were identified in the proband's F7 gene. To investigate the splicing patterns associated with F7 c.572-1G>A, ectopic transcripts in leucocytes of the proband were analyzed. F7 minigenes, spanning from intron 4 to intron 7 and carrying either an A or a G at position -1 of intron 5, were constructed and transiently transfected into human embryonic kidney (HEK) 293T cells, followed by RT-PCR analysis. The aberrant transcripts from the F7 c.572-1G>A mutant allele were not detected by ectopic transcription study. Sequencing of the RT-PCR products from the mutant transfectant demonstrated the production of an erroneously spliced mRNA with exon 6 skipping, whereas a normal splicing occurred in the wide type transfectant. The aberrant mRNA produced from the F7 c.572-1G>A mutant allele is responsible for the factor VII deficiency in this pedigree. [source] Plectin deficiency leads to both muscular dystrophy and pyloric atresia in epidermolysis bullosa simplex,HUMAN MUTATION, Issue 10 2010Ken Natsuga Abstract Plectin is a cytoskeletal linker protein which has a long central rod and N- and C-terminal globular domains. Mutations in the gene encoding plectin (PLEC) cause two distinct autosomal recessive subtypes of epidermolysis bullosa: EB simplex (EBS) with muscular dystrophy (EBS-MD), and EBS with pyloric atresia (EBS-PA). Previous studies have demonstrated that loss of full-length plectin with residual expression of the rodless isoform leads to EBS-MD, whereas complete loss or marked attenuation of expression of full-length and rodless plectin underlies the more severe EBS-PA phenotype. However, muscular dystrophy has never been identified in EBS-PA, not even in the severe form of the disease. Here, we report the first case of EBS associated with both pyloric atresia and muscular dystrophy. Both of the premature termination codon-causing mutations of the proband are located within exon 32, the last exon of PLEC. Immunofluorescence and immunoblot analysis of skin samples and cultured fibroblasts from the proband revealed truncated plectin protein expression in low amounts. This study demonstrates that plectin deficiency can indeed lead to both muscular dystrophy and pyloric atresia in an individual EBS patient. © 2010 Wiley-Liss, Inc. [source] Biochemical and mutational analyses of the cathepsin c gene (CTSC) in three North American families with Papillon Lefèvre syndromeHUMAN MUTATION, Issue 1 2002Y. Zhang Abstract Papillon Lefèvre syndrome (PLS) is an autosomal recessive disorder characterized by palmoplantar hyperkeratosis and severe periodontitis. The disease is caused by mutations in the cathepsin C gene (CTSC) that maps to chromosome 11q14. CTSC gene mutations associated with PLS have been correlated with significantly decreased enzyme activity. Mutational analysis of the CTSC gene in three North American families segregating PLS identified four mutations, including a novel mutation p.G139R. All mutations were associated with dramatically reduced CTSC protease enzyme activity. A homozygous c.96T>G transversion resulting in a p.Y32X change was present in a Mexican PLS proband, while one Caucasian PLS proband was a compound heterozygote for the p.Y32X and p.R272P (c.815G>C) mutations. The other Caucasian PLS proband was a compound heterozygote for c.415G>A transition and c.1141delC mutations that resulted in a p.G139R and a frameshift and premature termination (p.L381fsX393), respectively. The c.415G>A was not present in more than 300 controls, suggesting it is not a CTSC polymorphism. Biochemical analysis demonstrated almost no detectable CTSC activity in leukocytes of all three probands. These mutations altered restriction enzyme sites in the highly conserved CTSC gene. Sequence analysis of CTSC exon 3 confirmed the previously reported p.T153I polymorphism in 4 of the 5 ethnically diverse populations studied. © 2002 Wiley-Liss, Inc. [source] A novel mutation in the ATP2C1 gene is associated with Hailey,Hailey disease in a Chinese familyINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 1 2009Zhou Jiang Liu MD Background, A three-generation Chinese family with Hailey,Hailey disease (HHD) was identified and characterized. The proband developed HHD with severe recurrent blisters and crusted erosions involving the body folds. Skin biopsy studies showed epidermal hyperkeratosis and defects in cell-to-cell adhesion. Three other members in the family were also affected with HHD and had the same clinical manifestations. The purpose of this study was to identify the pathogenic gene or mutation in the family. Methods, All exons and exon,intron boundaries of ATP2C1 were polymerase chain reaction (PCR) amplified and sequenced with DNA samples from the proband. Restriction fragment length polymorphism (RFLP) analysis for the intron 23,exon 24 boundary of ATP2C1 was performed in all family members and in 100 normal control subjects. Results, A novel 2-bp deletion (c.2251delGT) was detected in exon 24 of the ATP2C1 gene. The mutation was present in the three other affected family members and in two asymptomatic young carriers, but not in the other normal family members or the 100 normal controls. The mutation resulted in a frameshift change and led to the formation of a premature termination codon (PTC) four amino acid residues downstream from the sixth transmembrane domain. Conclusions, Our results indicate that the novel c.2251delGT (p.V751fs) mutation in the ATP2C1 gene is responsible for HHD in this Chinese family. This study expands the spectrum of ATP2C1 mutations associated with HHD. [source] Familial aggregation in the night eating syndromeINTERNATIONAL JOURNAL OF EATING DISORDERS, Issue 6 2006Jennifer D. Lundgren PhD Abstract Objective: This study examined the extent to which the night eating syndrome (NES) affects first-degree relatives of NES and control probands. Method: NES participants and controls were assessed with the Night Eating Questionnaire (NEQ), the Night Eating Syndrome History and Inventory (NESHI), 10 day sleep and food records, the Eating Disorder Examination (EDE), the Structured Clinical Interview for DSM IV Axis I Disorders (SCID I), and a Family History Questionnaire (FHQ) to assess the presence of NES among first-degree relatives. A proband predictive model, using logistic regression analyses and the generalized estimating equation to control for correlation among observations within families was used to assess familial aggregation. Results: The odds of an NES proband having an affected first-degree relative were significantly greater than that of a control proband (odds ratio = 4.9, p < .001). A number of covariates were included in the model: proband body mass index (BMI) (kg/m2), proband gender, proband age, proband ethnicity, first-degree relative gender, relationship to proband (i.e., mother, father, or sibling), and the interaction between relationship to proband and proband status (night eater or control); none was statistically significant (p > .05). Conclusion: The study showed a strong aggregation of NES in families. © 2006 by Wiley Periodicals, Inc. Int J Eat Disord 2006 [source] Familial Hypocalciuric Hypercalcemia Caused by an R648stop Mutation in the Calcium-Sensing Receptor Gene ,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2002Mika Yamauchi Abstract In this study, we report an 84-year-old female proband in a Japanese family with familial hypocalciuric hypercalcemia (FHH) caused by an R648stop mutation in the extracellular calcium-sensing receptor (CaR) gene. At the age of 71 years, she presented with hypercalcemia (11.4 mg/dl), hypocalciuria (Cca/Ccr = 0.003), hypermagnesemia (2.9 mg/dl), and a high-serum parathyroid hormone (PTH) level (midregion PTH, 3225 [160,520] pg/ml). At the age of 74 years, a family screening was carried out and revealed a total of 9 hypercalcemic individuals (all intact PTH values <62 pg/dl) among 17 family members tested, thus, being diagnosed as FHH. Two and one-half of three clearly enlarged parathyroid glands were resected, because persistently high PTH levels (intact PTH, 292 pg/ml; midregion PTH, 5225 pg/ml) and the presence of a markedly enlarged parathyroid gland by several imaging modalities (ultrasonography, computed tomography [CT], magnetic resonance imaging [MRI], and subtraction scintigraphy) suggested coexistent primary hyperparathyroidism (pHPT); however, hypercalcemia persisted postoperatively. Histological and immunohistochemical examination revealed that the resected parathyroid glands showed lipohyperplasia as well as normally expressed Ki67, vitamin D receptor (VDR), and the CaR. Sequence analysis disclosed that the proband and all affected family members had a heterozygous nonsense (R648stop) mutation in the CaR gene. This mutation is located in the first intracellular loop; thus, it would be predicted to produce a truncated CaR having only one transmembrane domain (TMD) and lacking its remaining TMDs, intracellular loops, and C-terminal tail. Western analysis of biotinylated HEK293 cells transiently transfected with this mutant receptor showed cell surface expression of the truncated protein at a level comparable with that of the wild-type CaR. The mutant receptor, however, exhibited no increase in intracellular free calcium concentration (Ca2+i) when exposed to high extracellular calcium concentrations (Ca2+o). The proband's clinical course was complicated because of associated renal tubular acidosis (RTA) and nephrotic syndrome. However, it was unclear whether their association affected the development of elevated serum PTH and parathyroid gland enlargement. This report is the first to show that an R648stop CaR mutation yields a truncated receptor that is expressed on the cell surface but is devoid of biological activity, resulting in FHH. [source] Canine COL1A2 Mutation Resulting in C-Terminal Truncation of Pro-,2(I) and Severe Osteogenesis ImperfectaJOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2001Bonnie G. Campbell Abstract RNA and type I collagen were analyzed from cultured skin fibroblasts of a Beagle puppy with fractures consistent with type III osteogenesis imperfecta (OI). In a nonisotopic RNAse cleavage assay (NIRCA), the proband's RNA had a unique cleavage pattern in the region of COL1A2 encoding the C-propeptide. DNA sequence analyses identified a mutation in which nucleotides 3991-3994 ("CTAG") were replaced with "TGTCATTGG." The first seven bases of the inserted sequence were identical to nucleotides 4002-4008 of the normal canine COL1A2 sequence. The resulting frameshift changed 30 amino acids and introduced a premature stop codon. Reverse-transcription polymerase chain reaction (RT-PCR) with primers flanking the mutation site amplified two complementary DNA (cDNA) fragments for the proband and a single product for the control. Restriction enzyme digestions also were consistent with a heterozygous mutation in the proband. Type I procollagen labeled with [3H]proline was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Increased density of pC-,2(I) suggested comigration with the similarly sized pro-,2(I) derived from the mutant allele. Furthermore, ,-chains were overhydroxylated and the ratio of ,1(I):,2(I) was 3.2:1, consistent with the presence of ,1(I) homotrimers. Analyses of COL1A2 and type I collagen were both consistent with the described heterozygous mutation affecting the pro-,2(I) C-propeptide and confirmed a diagnosis of OI. [source] Monozygotic twins are discordant for chronic periodontitis: clinical and bacteriological findingsJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 2 2010Gaudy L. Torres de Heens Torres de Heens GL, Loos BG, van der Velden U. Monozygotic twins are discordant for chronic periodontitis: clinical and bacteriological findings. J Clin Periodontol 2010; 37: 120,128. doi: 10.1111/j.1600-051X.2009.01511.x. Abstract Objectives: The aim of this study was to assess, in monozygotic (MZ) and dizygotic (DZ) twin pairs in whom the proband of the twin pair was suffering from moderate to severe chronic periodontitis, the contribution of genetics, periodontal pathogens and lifestyle factors towards the clinical phenotype. Material and Methods: For this study, 18 adult twin pairs were selected on the basis of interproximal attachment loss (AL) 5 mm in 2 non-adjacent teeth in one twin member. The study included 10 MZ and eight DZ twin pairs, in whom the periodontal condition, presence of periodontal pathogens, educational level, smoking behaviour and body mass index (BMI) were evaluated. Results: Both MZ and DZ twins were discordant regarding AL and alveolar bone loss. Discordance was greater in DZ compared with MZ twins. In MZ twins, the discordance could not be explained by education, smoking, BMI and periodontal pathogens. In DZ twins, 45.6% of the discordance could be explained by more pack-years of the probands. Conclusion: The results confirm a possible role of genetic factors in periodontitis. However, the magnitude of the genetic effects on disease severity may have been overestimated previously. [source] Newborn screening in Fragile X syndromeJOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 10 2008F. Tassone Background: Screening for the FMR1 mutations has been a topic of considerable discussion since the FMR1 gene was identified. However, Fragile X has not been recommended for newborn screening mainly because of the lack of an accurate screening test and of data on potential benefits. We have recently developed an improved Polymerase Chain Reaction (PCR) method for the identification of premutation and full mutation alleles for the FMR1 gene. Method: The method is inexpensive, accurate and quick and can be performed on a number of sample templates including, importantly, blood spots. We have applied this method for international screening. Specifically, we have screened 5267 anonymous blood spot samples from newborn males from the centre-northwest region of Spain. We have also used this technology to a pilot ,high risk' screening program of individuals with autism and/or intellectual disabilities and family members of a proband with fragile X initiated in Guatemala. This project is a prototype for future screening endeavours. Results: One important outcome from this study is that the frequency of premutation alleles (1 per 250) appears to be higher than previously reported. This is of importance, especially in view of the different phenotypic involvement observed in carriers of premutation alleles, including neurological problems such as FXTAS. Here, we present data on the frequency of premutation/full alleles found in this population and their size distribution. Conclusion: This project is a prototype for future screening endeavours. Results from our pilot program in both Spain and Guatemala will lend strong support for implementing this technology for rapid screening to a much larger scale population screening. [source] De novo mutation in the mitochondrial tRNALeu(UUR) gene (A3243G) with rapid segregation resulting in MELAS in the offspringJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 1 2001CH Ko Abstract: A 14-year-old Chinese boy with a normal perinatal and early developmental history presented at 5 years of age with migraine, intractable epilepsy, ataxia, supraventricular tachycardia, paralytic ileus and progressive mental deterioration. Computerized tomography revealed multiple cerebral infarcts in the parieto-occipital region without basal ganglial calcification. Magnetic resonance imaging showed increased signal intensity in T2 weighted images in the same regions. A cerebral digital subtraction angiogram was normal. Venous lactate, pyruvate, lactate to pyruvate ratio and cerebrospinal fluid lactate were elevated. Muscle biopsy did not reveal any ragged red fibres; dinucleotide,tetrazolium reductase activity was normal. Mitochondrial DNA analysis detected an adenine to guanine mutation at nucleotide position 3243 of tRNALeu(UUR). All four tissues analysed demonstrated heteroplasmy: leucocyte 56%, hair follicle 70%; buccal cell 64%; muscle 54%. The mother and brother of the proband, both asymptomatic, were also found to have a heteroplasmic A3243G mutation in the leucocytes, hair follicle and buccal cells. Other members of the maternal lineage, including the maternal grandmother, did not have the mutation. This report describes a patient with mitochondrial encephalopathy, lactic acidosis, stroke-like episodes, who presented with multisystem involvement. The absence of ragged red fibres in muscle biopsy did not preclude the diagnosis. Mutational analysis of mitochodrial DNA conveniently confirmed the diagnosis of the disorder. A de novo mutaton is demonstrated in this family. [source] A novel Phe171Cys mutation in integrin ,IIb causes Glanzmann thrombasthenia by abrogating ,IIb,3 complex formationJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 7 2004N. Rosenberg Summary.,Background: Glanzmann thrombasthenia (GT) is an autosomal recessive bleeding disorder characterized by lack of platelet aggregation induced by most agonists. The disease is caused by mutations in either ,IIb[glycoprotein (GP) IIb] or ,3 (GPIIIa) genes that lead to a lack or dysfunction of the integrin ,IIb,3 which serves as a fibrinogen receptor. Patients Mucocutaneous bleeding manifestations and platelet dysfunction consistent with GT were observed in three members of a Cypriot family: a 3-year-old proband, her father and her paternal uncle. Objective: To determine the molecular basis of GT in this family and to characterize possible biochemical and structural defects. Results: Analysis of the patients' platelets by fluorescence-activated cell sorting demonstrated trace amounts of ,3, no ,IIb and no ,IIb,3 on the membrane. Sequence analysis revealed a novel T607G transversion in exon 5 of the ,IIb gene predicting a Phe171Cys alteration that created a PstI recognition site. All three patients were homozygous for the mutation, the mother and paternal grandparents of the proband were heterozygous, whereas 110 healthy subjects lacked this transversion. Chinese hamster ovary cells cotransfected with cDNAs of mutated ,IIb and wild-type ,3 failed to express ,IIb,3 as shown by immunoprecipitation and immunohistochemistry experiments. Structural analysis of the ,IIb,3 model, which was based on the crystal structure of ,v,3, indicated that Phe171 plays an essential role in the interface between the ,-propeller domain of ,IIb and the ,A domain of ,3. Conclusions: A novel Phe171Cys mutation in the ,IIb gene of patients with GT is associated with abrogation of ,IIb,3 complex formation. [source] Characterization of an immunologic polymorphism (D79H) in the heavy chain of factor VJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 6 2004M. Van Der Neut Kolfschoten Summary.,Background: During the study of a family with hereditary factor (F)V deficiency (FV Amersfoort, 1102 A > T in exon 7) we identified an individual with 5% FV heavy chain antigen (FVHC) and 50% FV light chain antigen (FVLC). Further testing revealed that apart from the FV Amersfoort allele a second variant FV allele was segregating in this family, which encodes for a FV molecule with a reduced affinity for mAb V-23 used in the FV heavy chain ELISA (ELISAHC). Objective: Identification and characterization of the molecular basis responsible for the reduced affinity of the variant FV for mAb V-23. Methods: Family members of the proband were screened for mutations in the exons coding for the heavy chain of FV, after which the recombinant variant FV could be generated and characterized. Next, the cases and controls of the Leiden Thrombophilia Study (LETS) were genotyped for carriership of the variant FV. Results: In the variant FV allele a polymorphism in exon 3 (409G > C) was identified, which predicts the replacement of aspartic acid 79 by histidin (D79H). Introduction of this mutation in recombinant FV confirmed that it reduces the affinity for binding to mAb V-23. The substitution has no effect on FV(a) stability and Xa-cofactor activity. In Caucasians the frequency of the FV-79H allele is ,5%. Analysis of the LETS revealed that the FV-79H allele is not associated with FV levels (FVLC), activated protein C sensitivity (using an activated partial thromboplastin time-based test) or risk of venous thrombosis (OR 1.07, CI 95: 0.7,1.7). Conclusion: The D79H substitution in FV should be considered as a neutral polymorphism. The monoclonal antibody V-23, which has a strongly reduced affinity for FV-79H, is not suitable for application in diagnostic tests. [source] Safety aspects for public access defibrillation using automated external defibrillators near high-voltage power linesACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 5 2004C. J. Schlimp Background:, Automated external defibrillators (AEDs) must combine easy operability and high-quality diagnosis even under unfavorable conditions. This study determined the influence of electromagnetic interference caused by high-voltage power lines with 16.7-Hz alternating current on the quality of AEDs' rhythm analysis. Methods:, Two AEDs frequently used in Austria were tested near high-voltage power lines (15 kV or 110 kV, alternating current with 16.7 Hz). The defibrillation electrodes were attached either to a proband with true sinus rhythm or to a resuscitation dummy with generated sinus rhythm, ventricular fibrillation, ventricular tachycardia or asystole. Results:, Electromagnetic interference was much more prominent in a human's than in a dummy's electrocardiogram and depended on the position of the electrodes and cables in relation to the power line. Near high-voltage power lines the AEDs showed a significant operational fault. One AED interpreted the interference as a motion artifact, even when underlying rhythms were clearly detectable. The other AED interpreted 16.7-Hz oscillation as ventricular fibrillation with consequent shock advice when no underlying rhythm was detected. Conclusion:, The tested AEDs neither filter nor recognize a technical interference of 16.7 Hz caused by 15-kV power lines above railway tracks or 110-kV overland power lines, as run by railway companies in Austria, Germany, Norway, Sweden and Switzerland. These failures in AEDs' algorithms for rhythm analysis may cause substantial harm to patients undergoing public access defibrillation. The proper function of AEDs needs to be reconsidered to guarantee patients' safety near high-voltage power lines. [source] Variance components analyses of multiple asthma traits in a large sample of Australian families ascertained through a twin probandALLERGY, Issue 2 2006M. A. R. Ferreira Background:, Intermediate phenotypes are often measured as a proxy for asthma. It is largely unclear to what extent the same set of environmental or genetic factors regulate these traits. Objective:, Estimate the environmental and genetic correlations between self-reported and clinical asthma traits. Methods:, A total of 3073 subjects from 802 families were ascertained through a twin proband. Traits measured included self-reported asthma, airway histamine responsiveness (AHR), skin prick response to common allergens including house dust mite (Dermatophagoides pteronyssinus [D. pter]), baseline lung function, total serum immunoglobulin E (IgE) and eosinophilia. Bivariate and multivariate analyses of eight traits were performed with adjustment for ascertainment and significant covariates. Results:, Overall 2716 participants completed an asthma questionnaire and 2087 were clinically tested, including 1289 self-reported asthmatics (92% previously diagnosed by a doctor). Asthma, AHR, markers of allergic sensitization and eosinophilia had significant environmental correlations with each other (range: 0.23,0.89). Baseline forced expiratory volume in 1 s (FEV1) showed low environmental correlations with most traits. Fewer genetic correlations were significantly different from zero. Phenotypes with greatest genetic similarity were asthma and atopy (0.46), IgE and eosinophilia (0.44), AHR and D. pter (0.43) and AHR and airway obstruction (,0.43). Traits with greatest genetic dissimilarity were FEV1 and atopy (0.05), airway obstruction and IgE (0.07) and FEV1 and D. pter (0.11). Conclusion:, These results suggest that the same set of environmental factors regulates the variation of many asthma traits. In addition, although most traits are regulated to great extent by specific genetic factors, there is still some degree of genetic overlap that could be exploited by multivariate linkage approaches. [source] The first two Japanese cases of severe type I congenital plasminogen deficiency with ligneous conjunctivitis: Successful treatment with direct thrombin inhibitor and fresh plasma,,AMERICAN JOURNAL OF HEMATOLOGY, Issue 6 2009Takashi Suzuki A 71-year-old woman and her elder sister developed ligneous conjunctivitis after ocular surgery. Laboratory tests demonstrated that the proband and her sister had 6.6% and 8.1% of plasminogen activity, and 1.2 and 1.4 mg/dl of antigen, respectively. Thus, they were diagnosed as having severe type I plasminogen deficiency, for the first time, in Japan. DNA sequencing and PCR-RFLP analyses revealed that these two cases are homozygotes of a novel A-to-G mutation at the obligatory splicing acceptor site in intron-C. Both cases were satisfactorily treated with a direct thrombin inhibitor, topical Argatroban, and topical plasma obtained from their healthy family members. Am. J. Hematol. 2009. © 2009 Wiley-Liss, Inc. [source] Familial neuroendocrine cell hyperplasia of infancy,,PEDIATRIC PULMONOLOGY, Issue 8 2010J. Popler MD Abstract Background Neuroendocrine cell hyperplasia of infancy (NEHI) is a recently described children's interstitial lung disease (chILD) disorder of unknown etiology. It manifests clinically with tachypnea, retractions, hypoxemia, and crackles. The characteristic radiographic appearance consists of pulmonary hyperexpansion and ground-glass densities on high-resolution computed tomography (HRCT). Lung histology shows hyperplasia of bombesin-immunopositive neuroendocrine cells within distal bronchioles and alveolar ducts without other identifiable lung pathology or developmental anomaly. Methods We describe four families with multiple siblings diagnosed with NEHI. Cases were identified at three pediatric centers. Inclusion criteria included clinical findings consistent with NEHI, lung biopsy confirmation in the index case, and a diagnostic HRCT or biopsy in other siblings. Results Each family had a proband diagnosed with NEHI based upon pathologic review, and at least one additional sibling diagnosed either by pathologic review or HRCT. All patients presented between 2 and 15 months of age. Both male and female children were affected. The majority of the patients underwent both HRCT and lung biopsy. There were no deaths among affected children. No environmental exposures or other potential etiologies were identified as a cause of presenting symptoms. Conclusions The familial occurrence of NEHI suggests the possibility of a genetic etiology for this disorder and highlights the importance of taking a complete family medical history for infants presenting with a suggestive clinical picture. Identification of familial NEHI patients allows for the opportunity to further our understanding of this disorder, its natural history, the phenotypic spectrum, and potential genetic causes. Pediatr. Pulmonol. 2010; 45:749,755. © 2010 Wiley-Liss, Inc. [source] Congenital central hypoventilation syndrome from past to future: Model for translational and transitional autonomic medicine,PEDIATRIC PULMONOLOGY, Issue 6 2009Debra E. Weese-Mayer Abstract The modern story of CCHS began in 1970 with the first description by Mellins et al., came most visibly to the public eye with the ATS Statement in 1999, and continues with increasingly fast paced advances in genetics. Affected individuals have diffuse autonomic nervous system dysregulation (ANSD). The paired-like homeobox gene PHOX2B is the disease-defining gene for CCHS; a mutation in the PHOX2B gene is requisite to the diagnosis of CCHS. Approximately 90% of individuals with the CCHS phenotype will be heterozygous for a polyalanine repeat expansion mutation (PARM); the normal allele will have 20 alanines and the affected allele will have 24,33 alanines (genotypes 20/24,20/33). The remaining ,10% of individuals with CCHS will have a non-PARM (NPARM), in the PHOX2B gene; these will be missense, nonsense, or frameshift. CCHS and PHOX2B are inherited in an autosomal dominant manner with a stable mutation. Approximately 8% of parents of a CCHS proband will be mosaic for the PHOX2B mutation. A growing number of cases of CCHS are identified after the newborn period, with presentation from infancy into adulthood. An improved understanding of the molecular basis of the PHOX2B mutations and of the PHOX2B genotype/CCHS phenotype relationship will allow physicians to anticipate the clinical phenotype for each affected individual. To best convey the remarkable history of CCHS, and to describe the value of recognizing CCHS as a model for translational and transitional autonomic medicine, we present this review article in the format of a chronological story, from 1970 to the present day. Pediatr Pulmonol. 2009; 44:521,535. © 2009 Wiley-Liss, Inc. [source] Genetic counseling and "molecular" prenatal diagnosis of holoprosencephaly (HPE),AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Sandra Mercier Abstract Holoprosencephaly (HPE) is a structural anomaly of the developing brain in which the forebrain fails to divide into two separate hemispheres and ventricles. The poor prognosis in the most severe forms justifies the importance of genetic counseling in affected families. The genetic counseling requires a thorough clinical approach given the extreme variability of phenotype and etiology. The karyotype is an essential diagnostic tool. Since mutations in the four major genes (SHH, ZIC2, SIX3, and TGIF) have been identified in HPE patients, molecular study is performed routinely in nonsyndromic HPE. New molecular tools, such as array-CGH analysis, are now part of the diagnostic process. Prenatal diagnosis is based primarily on fetal imaging, but "molecular" prenatal diagnosis can be performed if a mutation has been previously identified in a proband. Interpretations of molecular diagnosis must be given with caution, given the lack of strict genotype,phenotype correlation, and should be offered in addition to fetal imaging, using ultrasound followed by fetal MRI. We report on our experience of 15 molecular prenatal diagnoses from chorionic villi or amniotic fluid sampling. In eight instances, we were able to reassure the parents after taking into account the absence of the mutation in the fetus, previously identified before in a parent and/or a proband. Fetal RMI was normal later in pregnancy, and no child had medical problems after birth. The mutation was found in the seven other cases: four children were born, either without brain malformation and asymptomatic, or had a less severe form than the index case. © 2010 Wiley-Liss, Inc. [source] Prenatal diagnosis of oculocutaneous albinism type II and novel mutations in two Chinese familiesPRENATAL DIAGNOSIS, Issue 6 2007Li Hongyi Abstract Objective The prenatal genetic diagnosis and counseling of oculocutaneous albinism type II (OCA2) by detecting mutations in the OCA2 gene Methods DNA samples were extracted from peripheral whole blood and amniocentesis-derived cells. Polymerase chain reaction and automatic sequence analysis were used to screen the OCA2 gene. Results Case 1: Two novel heterozygous mutations (p.N476D and p.Y827H) in the P gene were detected in the proband. Molecular prenatal diagnosis on fetal DNA revealed N476D. The pregnancy progressed uneventfully to a normal outcome. Case 2: Mutation analysis of the DNA of family 2 revealed compound heterozygosities for two novel P gene mutations (p.N476D and p.G775R). The pregnant female and the fetus each presented with a single P gene mutation (p.V443I and G775R, respectively). The pregnancy was continued. Conclusion This is the first report of prenatal diagnosis performed in families with oculocutaneous albinism type II (OCA2). Also, this report reveals three novel mutations of the P gene. Copyright © 2007 John Wiley & Sons, Ltd. [source] Perinatal findings and molecular cytogenetic analyses of de novo interstitial deletion of 9q (9q22.3,q31.3) associated with Gorlin syndromePRENATAL DIAGNOSIS, Issue 8 2006Chih-Ping Chen Abstract Objectives To present the perinatal findings and the molecular cytogenetic analyses of a de novo interstitial deletion of 9q (9q22.3,q31.3) associated with Gorlin syndrome. Methods Amniocentesis was performed at 18 weeks' gestation on a 27-year-old woman at a community hospital because of a high Down syndrome risk of 1/178, a low maternal serum ,-fetoprotein (MSAFP) level of 0.66 multiples of the median (MoM), and a high maternal serum human chorionic gonadotrophin (MShCG) level of 3.13 MoM. The karyotype was initially determined to be 46,XY. However, fetal macrocephaly and overgrowth were found at 30 weeks' gestation. Postnatally, the infant manifested characteristic features of Gorlin syndrome. High-resolution chromosomal bandings of the peripheral blood lymphocytes, polymorphic DNA marker analysis to determine the parental origin of the deletion, array comparative genomic hybridization (CGH) to determine the extent of the chromosomal deletion, and fluorescence in situ hybridization (FISH) to determine the deletion of the PTCH gene were performed. Results The 850-band level of resolution showed an interstitial deletion of 9q (9q22.3,q31.3). The parental karyotypes were normal. The karyotype of the proband was 46,XY,del(9)(q22.3q31.3)de novo. Polymorphic DNA marker analysis revealed that the deletion was of paternal origin. Array CGH revealed that the deleted region was about 12 Mb, encompassing the segment from 9q22.32 to 9q31.3. FISH analysis using the BAC probe RP11-34D4 and the probe RP11-43505 indicated the deletion of the PTCH gene. Conclusions Fetuses with an interstitial deletion of 9q (9q22.3,q31.3) may be associated with a low level of MSAFP and a high level of MShCG in the second trimester, and sonographic findings of overgrowth and macrocephaly in the third trimester. Copyright © 2006 John Wiley & Sons, Ltd. [source] Trisomy 15 mosaicism owing to familial reciprocal translocation t(1;15): implication for prenatal diagnosisPRENATAL DIAGNOSIS, Issue 6 2006Paolo Prontera Abstract We describe a 4-year-old female child with severe global mental retardation, myoclonic epilepsy, proximal hypotonia and dysmorphisms, whose prenatal diagnosis following amniocentesis revealed a constitutional female karyotype carrying a t(1;15)(q10;p11) familial reciprocal translocation. Post-natal high-resolution karyotype, Fluorescence in situ hybridization (FISH) screening for subtelomeric rearrangements, VNTR search for UPD15 in the blood and fibroblast, and WCP1 and 15 in the mother, failed to provide an explanation for the complex clinical phenotype of the proband. Since the pachytene configuration of the translocated chromosomes defines a high probability of 3:1 segregation, an extensive workup was undertaken to look for a possibly cryptic mosaicism. Four percent of the cells with trisomy 15 was found in the peripheral blood lymphocytes examined by classical cytogenetic technique and interphase FISH analysis. The clinical features associated with cryptic trisomy 15 mosaicism and the problems concerning prenatal diagnosis and genetic counselling for carriers of translocations at high risk of 3:1 segregation are discussed. Copyright © 2006 John Wiley & Sons, Ltd. [source] Prenatal diagnosis for arginase deficiency by second-trimester fetal erythrocyte arginase assay and first-trimester ARG1 mutation analysisPRENATAL DIAGNOSIS, Issue 11 2004Stanley H. Korman Abstract Hyperargininemia is a progressive neurometabolic disorder caused by deficiency of hepatic cytosolic arginase I, resulting from mutations in the ARG1 gene. We diagnosed arginase deficiency in a three-year-old male child of first-cousin Palestinian Arab parents. Prenatal diagnosis of an unaffected fetus was achieved in the second trimester of a subsequent pregnancy by cordocentesis and analysis of arginase activity in fetal erythrocytes. ARG1 mutation analysis in the proband revealed homozygosity for a deletion of 10 753 bp extending from the first intron to beyond the poly (A) site of the gene. This is the first gross deletion in the ARG1 gene to be identified and the first mutation to be described in an arginase-deficient patient of this ethnic origin. The identification of the ARG1 deletion in this family enabled first-trimester prenatal diagnosis in a subsequent pregnancy by multiplex PCR analysis performed on chorionic villous DNA. Copyright © 2004 John Wiley & Sons, Ltd. [source] | ||||||||||||||||||||||||||||||||||