scholarly journals Thrombocytopenia Caused By Compound Heterozygous Missense Mutations C.3946G>a in Vwf Gene and C.1825C>T in MYO5A Gene?

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4208-4208
Author(s):  
Rong-Fu Zhou ◽  
Wenjin Gao ◽  
Yueyi Xu
Keyword(s):  
Platelet Count ◽  
Conflicts Of Interest ◽  
Hepatitis Virus ◽  
Cell Metabolism ◽  
Coagulation Factor ◽  
Asian Population ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
History Of ◽  
Blood Routine

Abstract Objective: One patient with thrombocytopenia from childhood was examined to identify the cause of thrombocytopenia. Methods: The previous medical history of the patient was comprehensively reviewed, with blood routine examination , reticular platelet count, autoantibodies, hepatitis virus full set, thyroid function, plasma coagulation factor VIII activity, vWF activity and antigen testing, and NGS with peripheral blood to detect thrombosis and hemostatic related genes. Results: The female patient, 43 years old, was presented with thrombocytopenia for more than 40 years. She had no history of fever or bleeding with no significant menstrual volume increasing. His father had similar thrombocytopenia but died four years ago. On third June,2021, she had no skin bruises or enlarged spleen. Blood routine test showed wbc 7.4x10 9/l, HB 112g/l, Plt 47x10 9/l and reticular platelet count 1.85%. Hepatitis B surface antibody was 147.08mIU/ml. FVIII:C was 62.0% with vWF:A 17.4% and vWF:Ag 61.9%. NGS results suggested that there was a heterozygous c.3946G> A missense mutations in Exon28 of vWF gene (chr12:6128638) , resulting in p.Val1316Met. The variation is rare in the East Asian population and is shown in the human disease database to cause type 2B vWD, which causes increased platelet clearance due to variation in vWF molecule-platelet binding regions, clinically manifested as mild to moderate platelet reduction. there was also a heterozygous c.1825C>T missense mutation in Exon15 of MYO5A gene (chr15:52676447) , resulting in p.Arg609Cys. There are adverse effects on the structure / function of the MYH12 protein encoded by the MYO5A gene. The MYH12 protein is involved in cell metabolism and cytoskeletal activity, and this protein deficiency might also cause thrombocytopenia, which is clearly warranted to further investigation. Conclusions：compound heterozygous missense mutations c.3946G>A in vWF gene and c.1825C>T in MYO5A gene might caused thrombocytopenia in the patient. Disclosures No relevant conflicts of interest to declare.

scholarly journals Compound Heterozygous Nonsense Mutations Leading to Hereditary Deficiency of Coagulation Factor XI in a Chinese Pedigree

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5032-5032
Author(s):  
Qian Li ◽  
Hui Zeng ◽  
Yong Xu ◽  
Min Zhou ◽  
Bing Chen ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
Coagulation Factor ◽  
Compound Heterozygous ◽  
Sequencing Analysis ◽  
Factor Xi ◽  
Nonsense Mutations ◽  
Prolonged Aptt ◽  
Dna Sequencing Analysis

Abstract The objective is to identify the gene mutations responsible for the deficiency of factor XI (FXI) in a Chinese pedigree. The FXI activity was tested with clotting assay. The F11 gene was amplified by PCR with direct sequencing. ClustalX-2.1-win and three online bioinformatics softwares were used to study the conservatism and harm of the mutation. The proband was a 70-year-old male and had a prolonged APTT of 67.8s. The corrected APTT was 28.3s and he had reduced FXI: activity of 0.8%. His son and daughter had normal APTT of 26s and 27.3s and FXI:C of 72% and 75%, respectively. DNA sequencing analysis showed the proband carried a compound heterozygous g.841C>T and g.1556G>A mutation , resulting in Ser281Stop and Trp519Stop, respectively, which caused premature termination of transcription in the F11. His son had the heterozygous g.841C>T mutation of F11 and his daughter had the heterozygous g.1556G>A mutation of F11. The three bioinformatics softwares indicated that the mutation had affected the function of the protein. The two nonsense mutations had been reported previously in different patient, but this is the first time to be reported in the proband, which was responsible for the decrease of FXI: activity. Disclosures No relevant conflicts of interest to declare.

Asparagine-Linked Glycosylation at the NH2-Terminus Does Not Influence Secretion or Function of Coagulation Factors V and VIII

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2220-2220
Author(s):  
Sundar Rajan Selvaraj ◽  
Steven W Pipe
Keyword(s):  
Mammalian Cell ◽  
Cho Cells ◽  
Mammalian Cells ◽  
Conflicts Of Interest ◽  
Coagulation Factor ◽  
Missense Mutations ◽  
Mammalian Cell Lines ◽  
Er Chaperone ◽  
Chaperone Interactions ◽  
And Function

Abstract Abstract 2220 The commercial production of recombinant factor VIII (rFVIII) is 2 to 3 orders of magnitude lower than that of comparably sized proteins in heterologous mammalian cell expression systems. One of the major contributing factors to its very low expression levels is protein misfolding and chaperone mediated retention in the endoplasmic reticulum (ER). Glucose regulated protein 78, also known as BiP, a central player in ER homeostasis, plays an important role in retention of FVIII in the ER. The secretion of Factor V (FV), a coagulation factor homologue of FVIII, is much more efficient (∼10- to 15-fold higher) in mammalian cells. Although the proteins share an identical domain structure, with close to 40% homology in their A and C domains, unlike with FVIII, BiP does not bind to and retain FV in the ER. Successful bioengineering strategies to improve the secretion of FVIII have been rationally informed by detailed study of ER chaperone interactions. A previous report indicated that the presence of multiple asparagine (N)-linked glycans within the first 50 amino acid residues of the NH2-terminus of some glycoproteins steers the nascent polypeptide away from BiP and towards the calnexin-calreticulin lectin protein folding machinery, resulting in more efficient folding and secretion of the protein (Molinari & Helenius, Science 2000). We hypothesized that the lack of BiP binding and the more efficient secretion of FV over FVIII could be the result of the presence of two N-linked glycans at positions 23 and 27 in FV, whereas FVIII has a single N-linked glycan at position 41. We investigated the role of N-linked glycans at the NH2-termini in the secretion and function of FV and FVIII. Single and double glycosylation mutants of FV were created by replacing Asn residues with Gln residues at positions 23 and 27. Similarly, Asn at position 41 of FVIII was mutated to Gln. The mutants were transiently transfected in COS-1 and CHO cells and their secretion and function were analyzed and compared to that of the respective wild type (WT) proteins. Antigen and activity assays revealed that the secretion and function of single and double glycosylation mutants of FV were no different from the WT protein indicating that the two N-linked glycans at the NH2–terminus did not contribute to the secretion or function of FV. Similarly, the FVIII glycosylation mutant did not display a significant reduction in secretion or function. We next tested if increasing the density of N-linked glycosylation at the NH2–terminus of FVIII might help improve folding and secretion. Two additional N-linked glycosylation sequons were introduced at positions 17 and 47 of FVIII by mutating M17N and K47N. Single and double glycosylation mutants were analyzed by transfections in COS-1 and CHO cells and compared to the WT protein. While the M17N glycosylation mutant was quite similar to the WT protein, the K47N mutant displayed a significant reduction in secretion. However, K47 is located adjacent to K48, a residue which has been shown to be the site of known hemophilia A missense mutations. The secretion of the M17N/K47N double mutant was reduced even further to almost half of the WT protein in cell media. We conclude that, unlike some other glycoprotein-ER chaperone interactions, early N-linked oligosaccharides at the NH2–termini of FV and FVIII do not contribute significantly to the secretion and function of either protein. Previous structural comparisons between FV and FVIII have revealed that a stretch of hydrophobic amino acids within the FVIII A1 domain may contribute to BiP interaction and a targeted point mutation (F309S) improved secretion of FVIII up to 3-fold (Swaroop et al, J Biol Chem 1997). Additional structure and function comparative studies between FV and FVIII may identify new targets for bioengineering strategies with an aim to further enhance the expression of rFVIII in mammalian cell lines. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Frequent germline mutations of HAVCR2 in sporadic subcutaneous panniculitis-like T-cell lymphoma

2019 ◽  
Vol 3 (4) ◽  
pp. 588-595 ◽  
Author(s):  
Chantana Polprasert ◽  
Yasuhide Takeuchi ◽  
Nobuyuki Kakiuchi ◽  
Kenichi Yoshida ◽  
Thamathorn Assanasen ◽  
...  
Keyword(s):  
T Cell ◽  
Somatic Mutations ◽  
Cell Lymphoma ◽  
Germline Mutations ◽  
T Cell Lymphoma ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Whole Exome ◽  
History Of ◽  
Underlying Diseases

Abstract Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of peripheral T-cell lymphoma affecting younger patients and associated with hemophagocytic lymphohistiocytosis. To clarify the molecular pathogenesis of SPTCL, we analyzed paired tumor and germline DNAs from 13 patients by whole-exome sequencing. All cases were Asians and were phenotypically sporadic with no family history of SPTCL. Consistent with a recent report, germline mutations in HAVCR2, encoding T-cell immunoglobulin mucin 3 (TIM3), were identified in 11 of 13 (85%) cases. All mutated cases were primary SPTCL, whereas the 2 cases without mutation were secondary SPTCL associated with underlying diseases, including viral infection and autoimmune disease. Ten patients harbored homozygous p.Y82C mutations, and 1 showed compound heterozygous mutations (p.Y82C and p.T101I). Both missense mutations altered highly conserved residues located in the extracellular immunoglobulin variable–like domain. According to the Genome Aggregation Database of >138 500 general individuals, both mutations were documented with minor allele frequencies < 0.007, indicating remarkable enrichment of these HAVCR2 alleles in SPTCL. SPTCL cells also harbored somatic mutations (6.2 per patient) that are frequently identified in genes associated with epigenetic regulation and signal transduction. In conclusion, individuals harboring biallelic HAVCR2 (TIM3) germline mutations were highly susceptible to sporadic SPTCL, which was also associated with clonal somatic mutations.

Identification of a Novel Coagulation Factor X Compound Heterozygous Mutation Associated with Differential Initiating Clotting Pathway Function.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1129-1129
Author(s):  
Amanda L Vanden Hoek ◽  
Kimberley Talbot ◽  
Isis Carter ◽  
Linda Vickars ◽  
Cedric John Carter ◽  
...  
Keyword(s):  
Western Blot ◽  
Conflicts Of Interest ◽  
Coagulation Factor ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Severe Bleeding ◽  
Compound Heterozygous ◽  
Bleeding Diathesis ◽  
Intrinsic Pathway ◽  
Extrinsic Pathway

Abstract Abstract 1129 Introduction: Factor × (FX) deficiency is a rare form of haemophilia characterized by a decrease in circulating FX antigen and/or activity levels, which can result in a variable bleeding diathesis. In heterozygous patients, bleeding may be absent or mild while homozygous and doubly heterozygous patients have phenotypes that are often associated with moderate or severe bleeding. Patient History: In this study, a propositus now aged 75 with a moderate bleeding diathesis is described. Neither parent had a history of bleeding. The patient was originally diagnosed as FX-deficient based on clinical measurements of coagulation factors. With prostate surgery, he had unexpected bleeding, that could not be explained surgically, requiring large volumes of plasma and red cell concentrates. Other surgical challenges, including dental extractions, were not complicated by bleeding but were preceded by plasma infusion. Methods: Plasma FX antigen levels were assayed by western blot using FX-specific monoclonal antibodies. To follow activity, prothrombin time and activated partial thromboplastin time clotting tests were used to evaluate the extrinsic and intrinsic initiating branches of coagulation, respectively. The entire F10 gene (8 exons and flanking intronic sequences) was amplified using PCR and sequenced to identify mutations. Results: DNA sequence analysis identified two mutations, which were presumably on different alleles based on a lack of parental bleeding. The first was a previously reported mutation that disrupts the splice site between exons 1 and 2 (IVS1 +1 G>A) and was hypothesized to lead to premature degradation of FX mRNA transcripts (Wang WB et al, Haemophilia 2005). This explains a 50% loss of antigen in our heterozygous patient. The second was a novel mutation at nucleotide 28145 (C>T) which results in an Arg386 to Cys (Arg386Cys) substitution in the serine protease domain of FX. Quantification of plasma FX antigen by western blot analysis revealed 15% of normal, which correlated precisely with 15% extrinsic pathway activity. However, intrinsic pathway clotting activity was only 5% of normal. The fragmentation of FX antigen in plasma after initiation of coagulation was followed over time. When initiated through the extrinsic pathway, the patient's FX fragmentation profile was identical to normal plasma. However, when clotting was triggered through the intrinsic pathway, activation to FXa and appearance of other fragments was notably slower. This further confirms that the patient's novel FX defect predominantly affects the intrinsic pathway while maintaining normal function in the extrinsic pathway. Conclusions: Here we describe a compound heterozygous FX deficiency. The first mutation has been reported once before (IVS1 +1 G>A) and accounts for 50% loss of FX antigen. The second FX mutation we identified is novel and may result in alternate disulfide bond formation; in particular at the nearby sole covalent link between the heavy and light chains of FX. This may explain the 35% further reduction in FX plasma antigen to 15% for this patient. Interestingly, the differential effect of Arg386Cys on the extrinsic and intrinsic coagulation pathways suggests that Arg386 may be involved in the substrate recognition by the intrinsic FIXa/FVIIIa Xase complex. As this Xase functions to amplify coagulation, Arg386Cys may be predicted to most affect hemostasis under severe conditions such as surgery. Production of recombinant FX containing this mutation is currently underway. Disclosures: No relevant conflicts of interest to declare.

Hematology Guided Correction of Coagulation Defects Using ROTEM Assays in Cirrhosis Can Reduce the Use of Fresh Frozen Plasma Prior to Invasive Procedures

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2341-2341
Author(s):  
Charles S Greenberg ◽  
Caroline Dupre Vaughn ◽  
Joseph Meserve ◽  
Adrian Reuben ◽  
Ming Yeong Lim ◽  
...  
Keyword(s):  
Platelet Count ◽  
Conflicts Of Interest ◽  
Coagulation Factor ◽  
Early Time ◽  
Fresh Frozen Plasma ◽  
Clotting Factor ◽  
Invasive Procedures ◽  
Fibrin Gel ◽  
Fresh Frozen ◽  
Frozen Plasma

Abstract Fresh frozen plasma is often prescribed for correction of the INR prior to invasive procedures in patients with cirrhosis. The coagulopathy associated with cirrhosis is attributed to abnormalities in platelets, fibrinogen levels and coagulation factor levels. There are conflicting opinions regarding the need to correct any abnormality prior to invasive procedures. The purpose of this study was to develop a ROTEM-based algorithm to support hemostasis in patients with cirrhosis having an invasive procedure. ROTEM represents an FDA approved instrument that provides a series of assays to monitor the initiation, propagation and stabilization of fibrin. We conducted preliminary studies using ROTEM assays in cirrhosis and found that the ROTEM assays are sensitive to changes in platelet count( < 80K), clotting factor levels (<30%) and fibrinogen levels (< 150mg%), making it a suitable assay to guide factor replacement in cirrhosis. To validate the utility of ROTEM assays, we incorporated ROTEM testing into our standard work-up of coagulopathy in liver disease. We performed routine PT, aPTT, fibrinogen, clotting factor levels (Factors V and VII) and hematocrit in parallel to ROTEM assays. We initially studied 50 stable patients from hepatology clinic with cirrhosis that had a median meld score of 16, PT INR of 1.8 and platelet count of 77K. We found that 25% of patients had normal ROTEM assays despite an abnormal set of screening coagulation assays. Furthermore, the time to initiate a clot (CT) was sensitive to low factor levels. The EXTEM was more sensitive than the INTEM CT (10% abnormal vs 5%). The INTEM clot formation time (CFT) was more sensitive to platelet count than the EXTEM CFT and became abnormal with platelets <85K. This prelimnary study validated the sensitivity and speficicty of the ROTEM assays in cirrhosis. The CFT represents an early time point in forming a fibrin gel and correlates with the rapid formation of thrombin. Fibrin must form rapidly to be effective. This led us to utilize a single clinician to guide the transfusion management of cases with cirrhosis prior to invasive procedures using The ROTEM algorithm. 44 pts with cirrhosis were treated ; they had 99 procedures performed (47 High-Moderate risk: biopsy, TIPS) and 52 low risk procedures (paracentesis, PICC line). The average INR was 2.2. No patient was denied treatment, nor was any attempt made to rely solely on the ROTEM assay to decide on plasma, cryo or platelet transfusion. Prolongation of CT > 5 sec normal range was used to infuse 2 units FFP; prolongation of CFT was used to infuse platelets and FIBTEM less than 9 was used to infuse cryo. 41U of FFP were transfused (0.4 U FFP per case), 16 Units cryo and 16 units of platelets (0.16 transfusion per case). The previous institutional use based on correcting INR for 99 cases was 297 U FFP, realizing a cost savings of 86%. No bleeding or other adverse events related to the transfusions were reported. When a second clinician reviewed blood product selection based on ROTEM values alone, there was agreement regarding use of FFP, cryo and platelets in 84% of the transfusion orders. ROTEM testing alone could be used to manage these cases without correcting the INR and is the subject of future studies.. The ROTEM assay became available for use by the hepatology and ICU services and no hematology consult was required for testing. This allowed clinical services to use ROTEM assays as part of their patient management in cirrhosis. We audited the use of ROTEM and did not detect any widely consistent use of ROTEM parameters to guide treatment. The average use of FFP in these cases was 5-fold higher than our protocol. In conclusion, we have developed a ROTEM-based algorithm for managing the coagulopathy of cirrhotic patients prior to invasive procedures. This ROTEM guided approach reduces the use of FFP and avoids complications caused by attempts to use FFP to the INR, which is not always feasible and potentially dangerous. Fututre studies are planned to address the optimum ROTEM assays and specific assay values for recommending use of FFP. cryo and platelets. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Molecular Genetic Analysis of Coagulation Factor XI (FXI) Deficiency in Two Chinese Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5033-5033
Author(s):  
Rong-Fu Zhou ◽  
Qian Li ◽  
Min Zhou
Keyword(s):  
Genetic Analysis ◽  
Conflicts Of Interest ◽  
Coagulation Factor ◽  
Chinese Patients ◽  
Compound Heterozygous ◽  
Factor Xi ◽  
Factor Xi Deficiency ◽  
Software Analysis ◽  
Prolonged Aptt ◽  
Compound Heterozygous Mutations

Abstract Objective: To investigate the molecular pathogenesis of two coagulation factor XI (FXI) deficiency patients. Methods: The diagnosis was validated by coagulant assays: APTT and correct test, PT, INR and coagulation factors activities. Coagulation factor activity were tested with clotting assay. The patients' DNA were extracted and all exons and flanking sequences of FXI gene were amplified using PCR. After purified, the products were sent for sequencing directly, the mutations were detected by comparing with wild sequences and analyzed using some bioinformatics software. Results: The two patients were diagnosed as coagulation factor XI deficiency due to prolonged APTT and low activities of coagulation factor FXI. The results of APTT, FXI:C was 88.1s, 1.1% and 107.1s, 3.8% , respectively. Genetic analysis found that compound heterozygous mutations g.1251-1G > A and g.1271delT in the first patient and the sequencing results of TA plasmid clones showed that the two mutations were located on different single strands of chromosomes. Double heterozygous mutations g.1070A >G and g.1446C > G were detected in the second patient, resulting in Lys357Arg and Cys482Stop. Software analysis indicated the mutations probably brought amino acid sequence changed, protein features affected and splice site changed. Conclusion: Compound heterozygous mutations g.1251-1G > A, g.1271delT and g.1070A > G , g.1446C > G had been identified in two coagulation factor XI deficiency patients, which might be the cause of their prolonged APTT and low FXI:C. To the best of our knowledge, the four mutations are reported for the first time in the literature. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Novel G6PC3 Mutations in patients with Congenital Neutropenia: Case reports and Review of the Literature

2021 ◽  
Vol 21 ◽  
Author(s):  
Seyed Farzad Maroufi ◽  
Zoha Shaka ◽  
Helia Mojtabavi ◽  
Mona Sadeghalvad ◽  
Elham Rayzan ◽  
...  
Keyword(s):  
Heart Defects ◽  
Case Reports ◽  
Severe Neutropenia ◽  
Prior History ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
First Case ◽  
History Of

Background: Severe congenital neutropenia (SCN4) caused by mutations in glucose-6-phosphatase catalytic subunit 3 (G6PC3) is characterized by recurrent infections due to severe neutropenia, and it may be accompanied by other extra-hematopoietic manifestations; including structural heart defects, urogenital abnormalities, prominent superficial venous markings, growth retention, and inflammatory bowel diseases with rare incidence. The homozygous or compound heterozygous mutations of G6PC3 are responsible for most cases of autosomal recessive SCN4. Herein, we present two cases of SCN4 affected by novel mutations in the G6PC3, in addition to a summarized list of variants in G6PC3 gene that are reported as pathogenic and related to the SCN4 phenotype. Case presentation: Herein we present two cases of SCN4; the first case was a three-months old boy with severe neutropenia and prior history of hospitalization due to umbilical separation, umbilical herniation, omphalitis, and pyelonephritis; and the second case was an eight-year-old with a history of neutropenia, recurrent and severe episodes of intractable diarrhea, refractory rectovaginal and rectoperineal fistula, congenital inguinal hernia, and ASD type 2. Whole exome sequencing was performed for both cases and revealed two novel homozygous missense mutations in G6PC3 that were predicted to be deleterious; c.337G>A, p. Gly113Arg in the first case and c.479C>T; P. Ser160Leu in the second case. To our knowledge, both of these two mutations has not been reported in the G6PDC3 gene. Conclusions: In patients with severe neutropenia with varying extra hematopoietic syndrome, mutation of G6PC3 should be suspected after ruling out other mutations related to neutropenia. This study pointed toward novel G6PC3 mutations, that should be considered in order to diagnose patients with severe congenital neutropenia.

NEW FINDINGS From the FRENCH COHORT of MYH9-RELATED DISORDERS: PHENOTYPE PECULIARITIES and GENOTYPE NOVELTIES on Behalf of the National French Reference Center on Inherited Platelet Disorders (CRPP)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1155-1155
Author(s):  
Béatrice Saposnik ◽  
Sylvie Binard ◽  
Alan T. Nurden ◽  
Paquita Nurden ◽  
Nicole Schlegel
Keyword(s):  
Splice Site ◽  
Conflicts Of Interest ◽  
Family Members ◽  
Initial Result ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Tail Domain ◽  
Giant Platelets ◽  
New Findings ◽  
Platelet Disorders

Abstract Abstract 1155 MYH9-Related Diseases (RD) are inherited platelet disorders combining thrombocytopenia and giant platelets with various associations of leukocyte inclusions, deafness, nephritis and cataracts. Mutations in the MYH9 gene, that encodes the nonmuscle myosin heavy chain IIA (NMMHC-IIA), are the hallmark of these disorders. Our cohort includes a total of 161 subjects (90 women, 71 men): 76 propositi (37 isolated, 39 family index cases) with MYH9 mutations and 85 family members (45 women, 40 men) belonging to the 39 unrelated families. The cases with an identified mutation were classified according to the location of the mutation either in the motor domain (MD patients (P): “MDP”) or in the tail domain (TD patients (P): “TDP”) of NMMHC-IIA. MYH9 mutations were found in a total of 109 subjects: the 76 propositi (45 women, 31 men) and 33/85 (38.8%) family members (19 women, 14 men, from 22 families). Among the 41 different mutations detected, the majority were missense mutations (33 = 80.5%) and new (25 = 61%). Two substitutions in intron 39 were discovered for the first time: 1 in the donor splice site (corresponding to a classical MYH9-RD phenotype) and the other in position minus 3 of the acceptor splice site (moderate thrombocytopenia only without giant platelets). A total of 15 different exons were identified as having mutations, 4 exons remained unaffected. Mutations were more frequently found in exons 1, 16, 26, 30, 38 and 40, as already published. The majority of patients (102 = 93.6%) were heterozygous for one mutation but 7 patients (6.4%) were compound heterozygous for 2 mutations. Significant differences between MDP and TDP were found for bleeding symptoms (65% of MDP, 33% of TDP, p=0.0037), nephropathy (31.5% of MDP, 11.6% of TDP, p=0.015), age (years, mean) at onset for nephropathy (21 for MDP, 48 for TDP, p=0.0003), deafness (54% of MDP, 23.7% of TDP, p=0.0025), and association bleeding/extra-hematological symptoms (68.2% of MDP, 27.7% of TDP, p=0.01). Patients with bleeding had a lower platelet count than non-bleeders (mean= 42G/L versus 62G/L, p=0.0024) but there were no significant differences in the percentage of giant platelets. ITP (splenectomy for 7) was the initial misdiagnosis for 29/69 (42%), (51.7% of MDP, 35% of TDP, p= 0.165). Cataracts occurred in 4 patients only. Altogether these results showed that the clinical phenotype of MYH9-RD was more severe for MDP than TDP. New mutations were discovered and were widespread along the exons and in some cases two mutations were identified in the same patient. The sequencing of the full gene and all exons-introns boundaries should be mandatory for each patient whatever the initial result. Disclosures: No relevant conflicts of interest to declare.

Rituximab May Be a Useful Option in Children with Severe Chronic Immunthrombocytopenia (ITP)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4692-4692
Author(s):  
Susan Halimeh ◽  
Erdmuth Schubert ◽  
George Paulus ◽  
Hannelore Rott ◽  
Michael Schaefers ◽  
...  
Keyword(s):  
Platelet Count ◽  
Conflicts Of Interest ◽  
Clinical Results ◽  
Sudden Onset ◽  
Subsequent Treatment ◽  
Time Intervals ◽  
Time Period ◽  
Heavily Pretreated ◽  
History Of

Abstract Abstract 4692 This otherwise healthy 12-year-old girl presented in March, 2011 with a history of severe ITP that had been diagnosed in November, 2007. Since then, she had suffered from recurrent bruises, petechiae, epistaxis, persistent bleending after tooth-loss and during menstruation (menarche: April, 2010), and subsequent iron-deficiency. Severe headache of sudden onset turned out to be caused by intracranial hemorrhage (ICH) in December, 2009, and in September, 2010, respectively. CT-scans in September 2010 revealed 2 additional ICH which had occured without symptomps. Fortunately, she recovered without sequelae from these complications. The initial and the subsequent treatment consisted of immunoglobulie (IG) and prednisone (IV or orally) given in various doses and for various time-intervals, always followed by a rise in platelet count for short periods of time, and a subsequent decline, when the drugs were withdrawn. Both ICH occured in phases of watchful waiting, while platelet count were below 1000. Splenectomy was offered and repeatedly denied by the patient and her parents. After the second ICH (Sept 2010) the patient received continuous weekly IG as prophylaxis of further ICH. Serious side-effects of prednisone in this patient (Cushing’s habitus, abdominal striae, insomnia and secondary depression) led to withdrawal of this drug. Since February 2011, the efficacy of IG was decreasing significantly, and the patient was referred to hematological practice for further treatment. We obtained the patient’s and her parents’ informed consent for a trial of 4 weekly doses rituximab (375mg/ square meter body surface after premedication with an antihistamine and 50mg prednisone). The infusions were given over a time-period of 5 weeks (May – June 2011) and were well tolerated. Platelet counts began to rise significantly after the 2. course and have remained above 200 000 since the beginning of July, 2011 without any other medication. Through the long-term course in this patient yet has to be followed, we feel that Rituximab (though not licensed for ITP in Germany) has been a useful option in this heavily pretreated patient. Because of good clinical results from US trials, like cases confirm previous reports of B.U. Mueller and C.M. Benett (Pediatr. Blood Cancer 2009; 52:259 and Blood 2006; 107:2639) we are now able to perform this treatment. Disclosures: No relevant conflicts of interest to declare.

Anti-Myelin Oligodendrocyte Glycoprotein Encephalomyelitis and Extensive Longitudinal Transverse Myelitis Associated with Compound Heterozygous NLRP3 Missense Mutations in a Young Child

2020 ◽  
Author(s):  
Deirdre O'Sullivan ◽  
Michael Moore ◽  
Susan Byrne ◽  
Andreas O. Reiff ◽  
Susanna Felsenstein
Keyword(s):  
Young Child ◽  
Genetic Basis ◽  
Transverse Myelitis ◽  
Acute Disseminated Encephalomyelitis ◽  
Myelin Oligodendrocyte Glycoprotein ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Childhood Onset

AbstractAcute disseminated encephalomyelitis in association with extensive longitudinal transverse myelitis is reported in a young child with positive anti-myelin oligodendrocyte glycoprotein (MOG) antibody with heterozygous NLRP3 missense mutations; p.(Arg488Lys) and p.(Ser159Ile). This case may well present an exceptional coincidence, but may describe a yet unrecognized feature of the spectrum of childhood onset cryopyrinopathies that contribute to the understanding of the genetic basis for anti-MOG antibody positive encephalomyelitis. Based on this observation, a larger scale study investigating the role of NLRP3 and other inflammasomes in this entity would provide important pathophysiological insights and potentially novel avenues for treatment.

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