scholarly journals PRRT2 Gene Analysis of Paroxysmal Kinesigenic Dyskinesia (PKD) in Thai Children

2021 ◽  
Author(s):  
Pantaree Laosuebsakulthai ◽  
Surachai Likasitwattanakul ◽  
Theerapong Pho-iam ◽  
Wanna Thongnoppakhun ◽  
Mongkol Chanvanichtrakool
Keyword(s):  
Hot Spot ◽  
Transmembrane Protein ◽  
Complete Response ◽  
Gene Analysis ◽  
Detection Rates ◽  
Mutation Status ◽  
Familial Cases ◽  
Paroxysmal Kinesigenic Dyskinesia ◽  
Siriraj Hospital ◽  
Sporadic Cases

Objective: To examine the frequency of the proline-rich transmembrane protein-2 (PRRT2) gene mutation in Thai patients with paroxysmal kinesigenic dyskinesia (PKD). Material and Methods: A retrospective study of children aged 0-18 years with a diagnosis of PKD at Siriraj Hospital. The genetic analyses of the PRRT2 gene were done by bidirectional Sanger sequencing.Results: Twelve patients with PKD were included. The known PRRT2 mutation, c.649dupC (p.Arg217Profs*8), was identified in three of the patients (25.0%), one of the nine sporadic cases (11.1%) and two of the three familial cases (66.6%), all from different families. PKD had a complete response to carbamazepine treatment regardless of PRRT2 mutation status. Conclusion: Our study provided the new details of the clinical phenotypes and PRRT2 gene analysis findings for Thai PKD. PRRT2 mutations were identified in our Thai PKD patients with increased detection rates in the familial PKD cases. The c.649dupC (p.Arg217Profs*8) was also found to be a hot-spot mutation in our Thai PKD patients. Furthermore, this study demonstrates the importance of PRRT2 gene analysis in order to properly diagnose and treat these patients.

scholarly journals De novo mutations in SOD1 are a cause of ALS

2021 ◽  
pp. jnnp-2021-327520
Author(s):  
Kathrin Müller ◽  
Ki-Wook Oh ◽  
Angelica Nordin ◽  
Sudhan Panthi ◽  
Seung Hyun Kim ◽  
...  
Keyword(s):  
De Novo ◽  
Hot Spot ◽  
De Novo Mutations ◽  
Embryonal Development ◽  
Familial Cases ◽  
Sporadic Als ◽  
Potential Benefits ◽  
Sporadic Cases ◽  
Als Patients ◽  
Lateral Sclerosis

ObjectiveThe only identified cause of amyotrophic lateral sclerosis (ALS) are mutations in a number of genes found in familial cases but also in sporadic cases. De novo mutations occurring in a parental gonadal cell, in the zygote or postzygotic during embryonal development can result in an apparently sporadic/isolated case of ALS later in life. We searched for de novo mutations in SOD1 as a cause of ALS.MethodsWe analysed peripheral-blood exome, genome and Sanger sequencing to identify deleterious mutations in SOD1 in 4000 ALS patients from Germany, South Korea and Sweden. Parental kinship was confirmed using highly polymorphic microsatellite markers across the genome. Medical genealogical and clinical data were reviewed and compared with the literature.ResultsWe identified four sporadic ALS cases with de novo mutations in SOD1. They aggregate in hot-spot codons earlier found mutated in familial cases. Their phenotypes match closely what has earlier been reported in familial cases with pathogenic mutations in SOD1. We also encountered familial cases where de novo mutational events in recent generations may have been involved.ConclusionsDe novo mutations are a cause of sporadic ALS and may also be underpinning smaller families with few affected ALS cases. It was not possible to ascertain if the origin of the de novo mutations was parental germline, zygotic or postzygotic during embryonal development. All ALS patients should be offered genetic counselling and genetic screening, the challenges of variant interpretation do not outweigh the potential benefits including earlier confirmed diagnosis and possible bespoken therapy.

Immune Checkpoint Inhibitors: Basics and Challenges

2019 ◽  
Vol 26 (17) ◽  
pp. 3009-3025 ◽  
Author(s):  
Bin Li ◽  
Ho Lam Chan ◽  
Pingping Chen
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Complete Response ◽  
Modern World ◽  
Basic Principles ◽  
Mutation Status ◽  
Anti Cancer ◽  
Cancer Types ◽  
Shed Light

Cancer is one of the most deadly diseases in the modern world. The last decade has witnessed dramatic advances in cancer treatment through immunotherapy. One extremely promising means to achieve anti-cancer immunity is to block the immune checkpoint pathways – mechanisms adopted by cancer cells to disguise themselves as regular components of the human body. Many review articles have described a variety of agents that are currently under extensive clinical evaluation. However, while checkpoint blockade is universally effective against a broad spectrum of cancer types and is mostly unrestricted by the mutation status of certain genes, only a minority of patients achieve a complete response. In this review, we summarize the basic principles of immune checkpoint inhibitors in both antibody and smallmolecule forms and also discuss potential mechanisms of resistance, which may shed light on further investigation to achieve higher clinical efficacy for these inhibitors.

Association of apolipoprotein E and myeloperoxidase genotypes to clinical course of familial and sporadic multiple sclerosis

2004 ◽  
Vol 10 (3) ◽  
pp. 266-271 ◽  
Author(s):  
B Zakrzewska-Pniewska ◽  
M Styczynska ◽  
A Podlecka ◽  
R Samocka ◽  
B Peplonska ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Apolipoprotein E ◽  
Brain Atrophy ◽  
Genetic Factors ◽  
Clinical Course ◽  
Progression Rate ◽  
Disease Course ◽  
Familial Cases ◽  
Sporadic Cases ◽  
The Relationship

The importance of apolipoprotein E (ApoE) and myeloperoxidase (MPO) genotypes in the clinical characteristics of multiple sclerosis (MS) has been recently emphasized. In a large group of Polish patients we have tested the hypothesis that polymorphism in ApoE and MPO genes may influence the course of the disease. G enotypes were determined in 117 MS patients (74 females and 43 males; 99 sporadic and 18 familial cases) with mean EDSS of 3.6, mean age of 44.1 years, mean duration of the disease 12.8 years and mean onset of MS at 31.2 years, and in 100 healthy controls. The relationship between ApoE and MPO genes’ polymorphism and the MS activity as well as the defect of remyelination (diffuse demyelination) and brain atrophy on MRI were analysed. The ApoE o4 allele was not related to the disease course or the ApoE o2 to the intensity of demyelination on MRI. The genotype MPO G/G was found in all familial MS and in 57% (56/99) of sporadic cases. This genotype was also related to more pronounced brain atrophy on MRI. The MPO G/G subpopulation was characterized by a significantly higher proportion of patients with secondary progressive MS (PB- 0.05) and by a higher value of EDSS. A ccording to our results the MPO G allele is frequently found (in 96% of cases) among Polish patients with MS. More severe nervous tissue damage in the MPO G/G form can be explained by the mechanism of accelerated oxidative stress. It seems that MPO G/G genotype may be one of the genetic factors influencing the progression rate of disability in MS patients.

scholarly journals VH gene analysis of hairy cell leukemia reveals a homogeneous mutation status and suggests its marginal zone B-cell origin

Leukemia ◽  
2004 ◽  
Vol 18 (10) ◽  
pp. 1729-1732 ◽  
Author(s):  
V Vanhentenrijk ◽  
A Tierens ◽  
I Wlodarska ◽  
G Verhoef ◽  
C D Wolf-Peeters
Keyword(s):  
B Cell ◽  
Hairy Cell Leukemia ◽  
Marginal Zone ◽  
Gene Analysis ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Mutation Status ◽  
Vh Gene

Townes-Brocks syndrome: twenty novelSALL1 mutations in sporadic and familial cases and refinement of theSALL1 hot spot region

2007 ◽  
Vol 28 (2) ◽  
pp. 204-205 ◽  
Author(s):  
Elke M. Botzenhart ◽  
Gabriella Bartalini ◽  
Edward Blair ◽  
Angela F. Brady ◽  
Frances Elmslie ◽  
...  
Keyword(s):  
Hot Spot ◽  
Familial Cases

Clinical features of familial juvenile cases of moyamoya disease: analysis of patients treated in a single institute over a 28-year period

2013 ◽  
Vol 12 (2) ◽  
pp. 175-180 ◽  
Author(s):  
Maki Mukawa ◽  
Tadashi Nariai ◽  
Yoshiharu Matsushima ◽  
Kikuo Ohno
Keyword(s):  
Clinical Features ◽  
Moyamoya Disease ◽  
Mr Angiography ◽  
Posterior Cerebral Artery ◽  
Clinical Course ◽  
Intelligence Scale ◽  
Familial Cases ◽  
Sporadic Cases ◽  
Tokyo Medical ◽  
Disease Analysis

Object The authors compared the clinical features between familial and sporadic cases of moyamoya disease (MMD) by retrospectively analyzing data on patients with MMD registered in the database of Tokyo Medical and Dental University over a period of 28 years. Methods In total, 383 patients with hospital records at Tokyo Medical and Dental University from 1980 to 2007 were registered into the database. The data on all of these patients were retrospectively reviewed to clarify the occurrence of familial cases. Clinical features of child or adolescent patients (< 20 years of age) with MMD were compared between familial and sporadic cases in a subgroup of patients who were registered after 1995, initially diagnosed using MR angiography, and assessed using an intelligence scale. Results Familial occurrence was observed in 59 patients (15.4%) in 40 pedigrees. The clinical features of juvenile patients were analyzed in 124 patients, 22 (17.7%) of whom had familial histories. In comparison with the sporadic cases, patients with familial histories were significantly younger at onset (4.7 vs 6.6 years old), had significantly more cortical infarction (59.1% vs 25.5%), and had significantly more stenoocclusive lesions in the posterior cerebral artery (45.4% vs 24.5%). The rate of patients with intellectual disturbance (intelligence quotient < 75) was significantly larger in the familial cases (47.4%) than in the sporadic cases (17.8%). Conclusions This survey of the clinical features of familial MMD suggests that patients with familial MMD had a more serious clinical course in childhood than the sporadic MMD cases.

scholarly journals Clinical features of patients with paroxysmal kinesigenic dyskinesia, mutation screening of PRRT2 and the effects of morning draughts of oxcarbazepine

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Gang Pan ◽  
Linmei Zhang ◽  
Shuizhen Zhou
Keyword(s):  
Clinical Features ◽  
Transmembrane Protein ◽  
Mutation Screening ◽  
Venous Blood ◽  
Gene Mutations ◽  
Paroxysmal Kinesigenic Dyskinesia ◽  
Starting Dose ◽  
Dyskinetic Movement ◽  
Effective Doses ◽  
Polymerase Chain

Abstract Background The objective of this study was to summarize clinical features and PRRT2 mutations of paediatric paroxysmal kinesigenic dyskinesia (PKD) patients and observe the tolerability and effects of morning draughts of oxcarbazepine. Methods Twenty patients diagnosed with PKD at Children’s Hospital of Fudan University between January 2011 and December 2015 were enrolled. These patients’ medical records were reviewed. Peripheral venous blood was obtained from all enrolled patients, and polymerase chain reaction (PCR) and Sanger sequencing were used to sequence proline-rich transmembrane protein 2 (PRRT2) gene mutations. Clinical features of PKD patients with and without PRRT2 mutations were compared. All enrolled patients were treated with morning draughts of oxcarbazepine (OXC). The starting dose was 5 mg/kg·d, and the dose was increased by 5 mg/kg·d each week until attacks stopped. Effective doses and adverse effects were recorded. Results For all enrolled patients, dyskinesia was triggered by sudden movement. Dyskinetic movement usually involved the limbs and was bilateral; the majority of enrolled patients exhibited both dystonia and choreoathetosis. We identified PRRT2 mutations in 5 patients, including 4 familial patients and 1 sporadic patient. All 20 patients took low doses of OXC (5–20 mg/kg·d) as draughts in the morning, and dyskinesia attacks stopped in 19 patients. Conclusions Paediatric PKD patients have various phenotypes. PRRT2 mutations are common in familial cases. OXC taken as morning draughts can be a treatment option for paediatric PKD patients.

Bone Marrow Angiogenesis in Chronic Lymphocytic Leukemia: Relationship to Classical and Modern Prognostic Factors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4943-4943
Author(s):  
Lukas Smolej ◽  
Pavel Zak ◽  
Petra Benesova ◽  
David Belada ◽  
Monika Hrudkova ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Prognostic Factors ◽  
Microvessel Density ◽  
Clinical Course ◽  
Hot Spot ◽  
Lymphocytic Leukemia ◽  
Control Group ◽  
Mutation Status ◽  
Genetic Abnormalities

Abstract Background: Angiogenesis is considered a potential prognostic factor in chronic lymphocytic leukemia (CLL). Elevated levels of various angiogenic factors have been identified in plasma or serum of CLL patients. However, results of studies assessing bone marrow neovascularization in CLL are controversial, in part due to different antibodies used for immunohistochemical identification of endothelial cells and different methods of assessing microvessel density (MVD). Moreover, there are insufficient data regarding relationship of bone marrow angiogenesis to other prognostic markers in CLL such as clinical stage, pattern of marrow infiltration, genetic abnormalities detected by fluorescent in situ hybridization (FISH), or mutation status of immunoglobulin heavy-chain variable-region genes (IgVH). Aims: To quantify MVD in bone marrow biopsies from CLL patients and control group and to assess its relationship to other prognostic factors. Methods: We analyzed bone marrow biopsy specimens from 22 untreated patients with CLL (16 males, 6 females, median age 62 years, range, 31–74). Control group consisted of 17 biopsies from individuals without evidence of malignant disease in bone marrow. Neovascularization was assessed using immunohistochemical staining of endothelial cells in bone marrow trephine biopsies with anti-CD34 monoclonal antibody. Microvessel density was assessed under light microscope equipped with image analysis software and calculated using hot spot method, i.e. identification of three loci with highest accumulation of microvessels under low (100x) magnification and counting microvessels in three high-power fields (400x magnification) per hot spot. MVD was expressed as mean number of microvessels per mm2. CLL cohort was further divided into subgroups according to clinical course (stable, n=11 vs. progressive, n=11), Rai stage (0, n=9 vs. I-IV, n=13), pattern of marrow infiltration (non-diffuse, n=11 vs. diffuse, n=11), genetic abnormalities (favourable, i.e. no abnormality or del13q14 as a sole aberration, n=10 vs. unfavourable, i.e. all other abnormalities, n=11), and IgVH mutation status (mutated, n=7 vs. unmutated, n=14). Results: MVD was significantly elevated in CLL group in comparison to controls (mean ± standard deviation [SD], 75.6 ± 50.6, 95% confidence interval [CI], 53.2–98.1/mm2 vs. 47.4 ± 21.8, 95% CI, 36.2–58.6/mm2, p=0.039). However, there were no significant MVD differences between CLL subgroups with regard to clinical course, pattern of marrow infiltration, Rai stage, FISH abnormalities or IgVH mutation status. Interestingly, when each subgroup was compared to controls, only patients with diffuse bone marrow infiltration (p=0.011), Rai stage I-IV (p=0.014) and mutated IgVH genes (p=0.019) had significantly increased MVD. Conclusions: This study shows that microvessel density is significantly elevated in CLL. However, this difference is maintained in three subgroups only: diffuse pattern of infiltration, mutated IgVH genes and Rai stage I-IV. We did not observe significant MVD differences between CLL subgroups with regard to classical or modern prognostic factors. Large prospective studies are necessary to confirm our results and elucidate the real clinical relevance of bone marrow angiogenesis in CLL.

Familial Chronic Myeloproliferative Neoplasms

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3078-3078
Author(s):  
Caterina Alati ◽  
Bruno Martino ◽  
Antonio Marino ◽  
Francesca Ronco ◽  
Manuela Priolo ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Biological Study ◽  
Consecutive Series ◽  
Inherited Disorders ◽  
Chronic Myeloproliferative Neoplasms ◽  
Familial Cases ◽  
Sporadic Cases

Abstract Abstract 3078 Chronic myeloproliferative neoplasms (CMNs) include Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF). So far limited studies of familial clusters of CMNs have been reported.Familial chronic myeloproliferative neoplasms are defined when in the same pedigree at least two relatives have CMNs. Familial CMNs should be distinguished from inherited disorders with Mendelian transmission, high penetrance and polyclonal haematopoiesis named ‘hereditary erythrocytosis' and ‘hereditary thrombocytosis'. Recently a 5- to 7-fold higher risk of MPN among first-degree relatives of patients with MPNs was reported. These findings support the limited studies suggesting a familial clustering in MPNs. The analysis of mutations of JAK2 and MPL may improve our ability to identify these conditions. In a consecutive series of patients observed in our Institution from January 2000 to June 2010, we found that among 460 patients with sporadic CMNs and 94 Ph1 positive chronic myeloid leukemia (CML), the prevalence of familial cases was 4%.With 22 pedigrees, 44 patients (8%) were identified with two relatives affected. Familial CMNs were 11 PV,14 ET,7 PMF, 5 CML respectively, while sporadic cases were 96 PV,204 ET,115 PMF and with other 45 CMNS not furtherly classified. As far as the distribution of the different CMNs within the familial cluster, We observed that only in 4 of 22 families (18%) all the affected relatives were diagnosed with the same disease (homogeneous pattern: PV one family and ET three families), whereas 14 families exhibited a mixed distribution among PV, ET and PMF. 8 families exhibited CMNs associated with other hematological disease such as chrocic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myelodisplastic syndrome (MDS). Among this, 6 families presented a first or second degree of relationship of first and second generation. In 10 cases the relatives were brothers, affected by familial CMNs with a prevalence of PV and TE clinical phenotype at diagnosis.According to JAK2 (V617F) mutational status, analyzed in 30 out of 44 patients, 19 patients showed a positivity pattern, while 18 families showed a heterogeneous pattern; they included both JAK2 (V617F) -positive and JAK2 (V617F)-negative patients. Among the 19 patients with JAK2 (V617F) positivity, the distribution of positivity according to the diagnosis was 100% of PV, 45% of ET and 55%of PMF; homozygosity was present only in PV cases. In our series, only two members of the same family were affected by familial CMNs. Finally it should be noted that in our series of familial cases clinical presentation, therapeutic approach and type and severity of complications were comparable to that of sporadic cases. In conclusion, the present study indicates the relevant possibility of familial CMNs, thus suggesting the opportunity of a detailed family history as part of the initial work-up of patients with CMDs; in addition it also suggests the usefulness of an accurate biological study. Disclosures: No relevant conflicts of interest to declare.

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