scholarly journals A PEX6-Defective Peroxisomal Biogenesis Disorder with Severe Phenotype in an Infant, versus Mild Phenotype Resembling Usher Syndrome in the Affected Parents

2002 ◽  
Vol 70 (4) ◽  
pp. 1062-1068 ◽  
Author(s):  
Annick Raas-Rothschild ◽  
Ronald J.A. Wanders ◽  
Petra A.W. Mooijer ◽  
Jeannette Gootjes ◽  
Hans R. Waterham ◽  
...  
Keyword(s):  
Usher Syndrome ◽  
Severe Phenotype ◽  
Mild Phenotype ◽  
Peroxisomal Biogenesis ◽  
Peroxisomal Biogenesis Disorder

scholarly journals Successful management of multiple pregnancies in a family with varying severity of Von Willebrand disease

2018 ◽  
Vol 11 (4) ◽  
pp. 192-194
Author(s):  
Patrick Harrington ◽  
Pippa Kyle ◽  
Jacky Cutler ◽  
Bella Madan
Keyword(s):  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
The Other ◽  
Severe Phenotype ◽  
Mild Phenotype ◽  
History Of ◽  
Specialist Treatment ◽  
Factor Concentrate ◽  
Von Willebrand ◽  
Willebrand Factor

We present the obstetric history of a family of three sisters with Von Willebrand disease, managed in our centre over the course of nine successful pregnancies. The abnormalities result from inheritance of an exon 50 skipping mutation in the Von Willebrand factor gene, resulting from consanguinity. Two of the sisters were identified as having a severe phenotype with a Von Willebrand factor level of less than 5 IU/dl, with the other having a mild phenotype. Of the sisters with a severe phenotype, one had a number of prenatal complications and required early onset prophylaxis with Von Willebrand factor concentrate, whilst the other had a less complicated clinical course, only requiring Von Willebrand factor concentrate to cover labour. The sister with mild Von Willebrand disease had a rise in Von Willebrand factor levels during pregnancy and required no specialist treatment. The report highlights the markedly different clinical courses that can occur in patients with Von Willebrand disease and the different approaches to management.

A novel mutation in the PEX12 gene causing a peroxisomal biogenesis disorder

2015 ◽  
Vol 42 (9) ◽  
pp. 1359-1363
Author(s):  
Jana Konkoľová ◽  
Robert Petrovič ◽  
Ján Chandoga ◽  
Edita Halasová ◽  
Petra Jungová ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Peroxisomal Biogenesis ◽  
Peroxisomal Biogenesis Disorder

Assessment of HbF QTLs Affecting Disease Severity and Genetic Analysis in Patients Homozygous for Codon 8 (–AA) β0-Thalassemia Mutation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2690-2690
Author(s):  
Zhihua Jiang ◽  
Shengwen Huang ◽  
Hong Yuan Luo ◽  
Nejat Akar ◽  
A.Nazli Basak ◽  
...  
Keyword(s):  
Disease Severity ◽  
Intergenic Region ◽  
Globin Gene ◽  
Thalassemia Major ◽  
Disease Phenotype ◽  
Severe Phenotype ◽  
Mild Phenotype ◽  
Mild Disease ◽  
Minor Alleles ◽  
Thalassemia Mutation

Abstract In β-thalassemia major, an inherited disorder caused by homozygosity or compound heterozygosity for β-thalassemia mutations, most patients are severely anemic and require chronic RBC transfusions. Elevated levels of HbF can ameliorate the disease severity and 3 major HbF quantitative trait loci (QTL) on chr 11p, 6q (the HBS1L-MYB intergenic polymorphism) and 2p (BCL11A) are associated with HbF levels in all populations studied. We studied Iraqi-American non-identical twins with markedly elevated HbF who are homozygous for codon 8 (–AA) β0-thalassemia mutation, but are clinically well and transfusion independent. MLPA analysis of the β-globin gene cluster did not show any hereditary persistence of fetal hemoglobin deletions or γ-globin gene quadruplication. Sequencing HBG2 and HBG1 promoters excluded other γ-globin gene promoter non-deletional HPFH mutations. We characterized 12 Turkish and Iraqi patients who are homozygous for codon 8 (–AA) frame-shift β-thalassemia mutation. Among this group, three patients from two Turkish families have a mild disease phenotype, six patients from four Turkish families have a severe phenotype, and three Iraqi patients from three families have a severe phenotype. To assess the contribution of 3 major HbF QTLs to disease severity, we genotyped polymorphisms in these QTL in all 14 patients (Table). Homozygosity for rs7482144 minor alleles (the -158 5' HBG2 Xmn1 C-T SNP) in the HBB gene cluster is present in 13 of 14 patients with the exception being one patient with a severe phenotype. No distinct pattern for the BCL11A sentinel SNP rs766432 minor allele is found between mild and severely affected patients. Homozygosity for rs9399137 minor alleles marking the HBS1L-MYB intergenic region is present in two patients with a mild phenotype, while heterozygosity for minor alleles and homozygosity for major alleles are present in both mild and severe patients. Although the Iraqi-American twins first studied have the most minor alleles (5 of 6 possible minor alleles), the other three patients with mild phenotype have 4, 3 and 2 minor alleles, respectively. Strikingly, one patient with mild phenotype is only homozygous for the rs7482144 minor alleles. Patients with severe phenotypes have 2 to 4 QTL minor alleles. Neither individual QTL genotypes nor the number of QTL minor alleles can distinguish the mild phenotype and severe phenotype in patients with β-thalassemia major of Iraqi and Turkish origin suggesting that other factors contribute to the mild phenotype and high HbF levels in these patients. The entire 14.7 kb intergenic region of between HBG1 and HBD of one twin was sequenced and revealed 19 known SNPs and 4 novel SNPs. The potential roles of these SNPs in regulating γ-globin gene expression are under investigation. We are also investigating whether there are any other potential cis- or trans-acting factors that contribute to mild disease phenotype in these patients using genome-wide SNP arrays, whole genome sequencing and whole exome sequencing. By studying these unusual cases we hope to provide new understanding and insights for elevated HbF production in β-hemoglobinopathies. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Cellular Hydration and Oxidation As Phenotype Modifiers in Sickle Cell Anemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2446-2446
Author(s):  
Mary A Risinger ◽  
Neha Dagaonkar ◽  
Georgios E Christakopoulos ◽  
Jie Liu ◽  
Katie Giger Seu ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Research Funding ◽  
Hydration Status ◽  
Ros Generation ◽  
Severe Phenotype ◽  
Mild Phenotype ◽  
Blood Samples ◽  
Nucleotide Mutation ◽  
Significant Difference

Abstract Although Sickle Cell Anemia (SCA) is caused by a single nucleotide mutation in the beta globin gene, there is broad phenotypic variability in affected individuals. It would be highly advantageous to be able to predict which SCA patients are most likely to suffer severe complications and which are likely to benefit from specific treatments. Since two of the major pathologic mechanisms in SCA are erythrocyte dehydration and chronic inflammation, alterations in the expression and/or function of proteins affecting these processes may be responsible for heterogeneity in SCA phenotype. We have developed a 23-gene Next-Generation sequencing panel to identify variants in genes involved in erythrocyte hydration and in reactive oxygen species (ROS) generation and reduction in patients with SCA. We have collected blood samples from an initial cohort of 18 SCA patients with severe phenotype, defined by history of stroke or abnormal transcranial Doppler velocities, and 13 SCA patients with mild phenotype for DNA preparation and for specialized testing to evaluate erythrocyte hydration status and ROS generation. Advia Automated Cell Counter results provided the clearest indications of erythrocyte dehydration in patient blood samples. The ability to examine reticulocyte parameters made it possible to evaluate hydration regardless of the frequency of transfusion. Reticulocyte CHCM, MCV, and percent hyperdense cells were significantly different between the two groups and indicative of a greater degree of dehydration in the severe phenotype group. Osmoscans (using a LoRRca ektacytometer) demonstrated a highly significant left shift indicative of erythrocyte dehydration in both mild and severe groups relative to controls (O min and O hyper values significantly decreased). Both phenotypic groups also demonstrated a significantly lower EI max in relation to controls, indicating decreased deformability of sickle erythrocytes. Deformability scans revealed significant increases in SS ½ and decreases in EI max in both groups in relation to the controls. There were significant differences between mild and severe phenotype groups in osmoscan O min and O hyper values and in deformability assay SS ½ and EI max values. The severe group had values closer to the normal values, most likely due to the contribution of transfused blood in the severe phenotype group. There were no significant differences between the mild and severe SCA phenotype groups in intracellular cation levels (K+ and Na+) measured by flame emission spectroscopy, although both groups had significantly higher intracellular Na+ compared to normal controls. Erythrocyte ROS detection was performed using a flow cytometry DCFDA assay. Both mild and severe phenotype groups demonstrated a highly significant increase in ROS compared to controls. However there was not a significant difference in erythrocyte ROS between the mild and severe phenotype groups. DNA from patient blood samples has been sequenced using the Haloplex target enrichment system and Illumina high-throughput sequencing. We analyzed 23 genes that are likely candidates to be involved in erythrocyte hydration (ABCB6, ABCG5, ABCG8, AQP1, AQP3, ATP2B4, KCNN4, PIEZO1, RHAG, SLC9A1, SLC12A4, SLC12A6, SLC12A7, SLC2A1, SLC4A1, STOM, TRPC6, XK) or in ROS production or reduction (G6PD, NOX1, CYBB, NOX4, NOX5). At least 19 variants classified as possibly damaging have been detected in 10 of the genes. Future study will be directed toward exploring the phenotypic implications of identified variants. Results of this study should further our understanding of the pathogenesis of SCD and help identify biomarkers of disease severity which may ultimately help guide clinical management for individual patients. They may also suggest novel targets for development of new therapies for SCD based on the modulation of erythrocyte hydration and inflammation. Disclosures Quinn: Amgen: Research Funding; Eli Lilly: Research Funding; Silver Lake Research Corporation: Consultancy. Joiner:Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Simultaneous Testing for 6 Lysosomal Storage Disorders and X-Adrenoleukodystrophy in Dried Blood Spots by Tandem Mass Spectrometry

2016 ◽  
Vol 62 (9) ◽  
pp. 1248-1254 ◽  
Author(s):  
Silvia Tortorelli ◽  
Coleman T Turgeon ◽  
Dimitar K Gavrilov ◽  
Devin Oglesbee ◽  
Kimiyo M Raymond ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Tandem Mass Spectrometry ◽  
Fabry Disease ◽  
Flow Injection ◽  
Lysosomal Storage Disorders ◽  
Tandem Mass ◽  
Lysosomal Storage ◽  
Peroxisomal Biogenesis ◽  
Peroxisomal Biogenesis Disorder ◽  
Storage Disorders

Abstract BACKGROUND Newborn screening for lysosomal storage disorders (LSD) has revealed that late-onset variants of these conditions are unexpectedly frequent and therefore may evade diagnosis. We developed an efficient and cost-effective multiplex assay to diagnose six LSDs and several peroxisomal disorders in patients presenting with diverse phenotypes at any age. METHODS Three 3-mm dried blood spot (DBS) punches were placed into individual microtiter plates. One disc was treated with a cocktail containing acid sphingomyelinase-specific substrate and internal standard (IS). To the second DBS we added a cocktail containing substrate and IS for β-glucosidase, acid α-glucosidase, α-galactosidase A, galactocerebrosidase, and α-L-iduronidase. The third DBS was extracted with methanol containing d4-C26 lysophosphatidylcholine as IS and stored until the enzyme plates were combined and purified by liquid–liquid and solid-phase extraction. The extracts were evaporated, reconstituted with the extract from the lysophosphatidylcholine plate, and analyzed by flow injection tandem mass spectrometry. RESULTS Reference intervals were determined by analysis of 550 samples from healthy controls. DBS from confirmed patients with 1 of the 6 LSDs (n = 33), X-adrenoleukodystrophy (n = 9), or a peroxisomal biogenesis disorder (n = 5), as well as carriers for Fabry disease (n = 17) and X-adrenoleukodystrophy (n = 5), were analyzed for assay validation. Prospective clinical testing of 578 samples revealed 25 patients affected with 1 of the detectable conditions. CONCLUSIONS Our flow injection tandem mass spectrometry approach is amenable to high-throughput population screening for Hurler disease, Gaucher disease, Niemann–Pick A/B disease, Pompe disease, Krabbe disease, Fabry disease, X-adrenoleukodystrophy, and peroxisomal biogenesis disorder in DBS.

Absence of biochemical evidence at an early age delays diagnosis in a patient with a clinically severe peroxisomal biogenesis disorder

2016 ◽  
Vol 20 (2) ◽  
pp. 331-335 ◽  
Author(s):  
Natalia Lüsebrink ◽  
Luciana Porto ◽  
Hans R. Waterham ◽  
Sacha Ferdinandusse ◽  
Hendrik Rosewich ◽  
...  
Keyword(s):  
Early Age ◽  
Biochemical Evidence ◽  
Peroxisomal Biogenesis ◽  
Peroxisomal Biogenesis Disorder
Sign in / Sign up

Export Citation Format

Share Document