X-linked adrenomyeloneuropathy associated with 14 novel ALD-gene mutations: no correlation between type of mutation and age of onset

1999 ◽  
Vol 105 (1-2) ◽  
pp. 116-119 ◽  
Author(s):  
M. Wichers ◽  
W. Köhler ◽  
W. Brennemann ◽  
V. Boese ◽  
P. Sokolowski ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Gene Mutations ◽  
Ald Gene

X-linked adrenomyeloneuropathy associated with 14 novel ALD-gene mutations: no correlation between type of mutation and age of onset

1999 ◽  
Vol 105 (1-2) ◽  
pp. 116-119 ◽  
Author(s):  
M. Wichers ◽  
W. Köhler ◽  
W. Brennemann ◽  
V. Boese ◽  
P. Sokolowski ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Gene Mutations ◽  
Ald Gene

scholarly journals The Clinical Spectrum of Young Onset Dementia Points to Its Stochastic Origins

2021 ◽  
pp. 1-17
Author(s):  
Peter K. Panegyres
Keyword(s):  
Small Vessel Disease ◽  
Age Of Onset ◽  
Gene Mutations ◽  
Lewy Body Disease ◽  
Corticobasal Degeneration ◽  
Young Onset ◽  
Clinical Presentations ◽  
Eeg Data ◽  
Common Causes ◽  
Young Onset Dementia

Background: Dementia is a major global health problem and the search for improved therapies is ongoing. The study of young onset dementia (YOD)—with onset prior to 65 years—represents a challenge owing to the variety of clinical presentations, pathology, and gene mutations. The advantage of the investigation of YOD is the lack of comorbidities that complicate the clinical picture in older adults. Here we explore the origins of YOD. Objective: To define the clinical diversity of YOD in terms of its demography, range of presentations, neurological examination findings, comorbidities, medical history, cognitive findings, imaging abnormalities both structural and functional, electroencephagraphic (EEG) data, neuropathology, and genetics. Methods: A prospective 20-year study of 240 community-based patients referred to specialty neurology clinics established to elucidate the nature of YOD. Results: Alzheimer’s disease (AD; n = 139) and behavioral variant frontotemporal (bvFTD; n = 58) were the most common causes with a mean age of onset of 56.5 years for AD (±1 SD 5.45) and 57.1 years for bvFTD (±1 SD 5.66). Neuropathology showed a variety of diagnoses from multiple sclerosis, Lewy body disease, FTD-MND, TDP-43 proteinopathy, adult-onset leukoencephalopathy with axonal steroids and pigmented glia, corticobasal degeneration, unexplained small vessel disease, and autoimmune T-cell encephalitis. Non-amnestic forms of AD and alternative forms of FTD were discovered. Mutations were only found in 11 subjects (11/240 = 4.6%). APOE genotyping was not divergent between the two populations. Conclusion: There are multiple kinds of YOD, and most are sporadic. These observations point to their stochastic origins.

Unusual Segregation of APP Mutations in Monogenic Alzheimer Disease

2019 ◽  
Vol 19 (2) ◽  
pp. 96-100
Author(s):  
Gioia Mastromoro ◽  
Stefano Gambardella ◽  
Enrica Marchionni ◽  
Rosa Campopiano ◽  
Alice Traversa ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Autosomal Dominant ◽  
Age Of Onset ◽  
Gene Mutations ◽  
Missense Variant ◽  
The Other ◽  
Dominant Trait ◽  
Homozygous State ◽  
Severe Clinical Picture ◽  
App Gene

APP gene mutations causing Alzheimer disease (AD) segregate in an autosomal dominant pattern. We report on a 40-year-old woman with a severe cognitive decline starting at 36 years, while her affected relatives presented symptoms onset in the 6th decade. The proband carried an APP missense variant in homozygous state (NM_000484.4: c.2032G>A; NP_000475.1: p.Asp678Asn; rs63750064) and showed a more severe clinical picture than the other AD relatives, as regards the age of onset and the rate of disease progression. This mutation behaves as a semi-dominant trait. The very rare chance of studying APP mutations in the homozygous state demonstrates they are not always dominant and other segregation models are possible.

Epidemiological and Genetic Analysis of Sideroblastic Anemia — Multicenter Study In Japan

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4225-4225
Author(s):  
Rie Ohba ◽  
Kazumichi Furuyama ◽  
Shigeru Tsuchiya ◽  
Atsushi Manabe ◽  
Etsuro Ito ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Genetic Analysis ◽  
Conflicts Of Interest ◽  
Age Of Onset ◽  
Gene Mutations ◽  
Clinical Information ◽  
Refractory Anemia ◽  
Sideroblastic Anemia ◽  
Ring Sideroblasts ◽  
Amino Acid Mutations

Abstract Abstract 4225 Introduction: Sideroblastic anemia is characterized by anemia with the emergence of ring sideroblasts in the bone marrow. There are two forms of sideroblastic anemia. One is an inherited sideroblastic anemia, and another is an acquired sideroblastic anemia. Because sideroblastic anemia is a rare disease, there are few comprehensive studies of sideroblastic anemia, including clinical and genetic information. In the present study, we have performed national-wide survey of sideroblastic anemia in Japan to investigate the epidemiology and pathogenesis of the disease. Method: This study consists of three-step surveys. First, the patients of sideroblastic anemia were searched by simple questionnaire to hematological department of hospitals in all areas in Japan (first investigation). Next, detailed clinical information of sideroblastic anemia patients were collected (second investigation). Survey items were age of onset, gender, family history, hematology, bone marrow and biochemical findings. Then, genetic analyses of patients who were suspected inherited sideroblastic anemia were performed (third investigation). For the genetic analysis, mutations of ALAS2, ABC7, GLRX5, SLC25A38, which are known to be responsible genes for inherited sideroblastic anemia, were examined. Result: At the first investigation, sideroblastic anemia patients were surveyed in the 1086 institutions of Japan. There were 14 cases of confirmed or suspected cases of inherited sideroblastic anemia and 285 cases of suspected or confirmed cases of acquired sideroblastic anemia. These patients were subjects of second investigation. As of August 9, data of 99 patients have been collected. In these cases there are 7 cases of confirmed inherited sideroblastic anemia, 7 cases of suspected inherited sideroblastic anemia, 28 cases of refractory anemia with ring sideroblasts (MDS-RARS) and 57 cases of refractory cytopenia with multilineage dysplasia with ring sideroblasts (MDS-RCMD-RS). Median age of onset was 70.5 years old in MDS-RCMD-RS cases, whereas that of cases in inherited sideroblastic anemia was 14 years old. Hemoglobin level in inherited sideroblastic anemia and RCMD-RS was 6.7g/dl and 8.3g/dl. MCV was 64.7 fl, 105.1 fl in inherited sideroblastic anemia and RCMD-RS. There was thus significant different between MCV level in inherited sideroblastic anemia and RCMD-RS. Chromosomal abnormality of +8 and idic (X) (q13), associated with ABC7 gene, were detected in 7 and 2 of 25 RCMD-RS patients, respectively. At the moment, 4 confirmed and 4 suspected patients of inherited sideroblastic anemia proceeded to third investigation. As a result, mutations of ALAS2, which is the first enzyme of heme biosynthesis in erythroid cells, have been identified in 6 out of 8 patients. The amino acid mutations were detected in exon 5 (R170C, R170L), exon 9 (R411C, R452C), and exon 11 (V562A). For patients without mutations in ALAS2 gene, mutations of other genes related to inherited sideroblastic anemia have been analyzed; however, no mutations are identified so far. Conclusion: The results showed that RCMD-RS is most common in sideroblastic anemia, and XLSA is most frequent type of inherited sideroblastic anemia. However, there are significant number of suspected cases of inherited sideroblastic anemia. The genetic analysis of these cases, including RARS without chromosomal anomaly, is currently in progress. This research has been supported by Grant-in-Aid for Scientific Research from Ministry of Health, Labour and Welfare of Japan. Disclosures: No relevant conflicts of interest to declare.

Evidence of linkage in MSH6-associated region exclusive to high-risk African-American families with prostate cancer.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 180-180
Author(s):  
Elisa M. Ledet ◽  
Oliver Sartor ◽  
Rayford Walter ◽  
Joan Bailey-Wilson ◽  
Diptasri Mandal
Keyword(s):  
Prostate Cancer ◽  
African American ◽  
High Risk ◽  
Age Of Onset ◽  
Gene Mutations ◽  
Therapeutic Implications ◽  
Linkage Analyses ◽  
Msh6 Gene ◽  
Hereditary Nonpolyposis ◽  
Repair Genes

180 Background: The significance of germline variants and their implications for prostate cancer (PCa) patients has gained prominence. Mismatch repair (MMR) genes such as MSH6 and MSH2, along with DNA repair genes, may be more important in PCa than previously appreciated. In the present study, we compared linkage results between African American (AA) and Caucasian (CA) PCa families with multiple affected family members. Methods: Study subjects were from 15 large, high-risk, clinically homogenous AA families and 4 CA families from Southern Louisiana. All families had at least ≥ 3 members with family member diagnosed with PCa. Genotyping for linkage analyses was done using Illumina Infinium II SNP HumanLinkage-12 panel. 6,068 SNPs were released for linkage analyses. Parametric linkage analyses were performed using Merlin software, version 1.1.2. An HLOD score > 1.86 was considered suggestive of linkage. Results: A total of 129 individuals from 15 AA families were genotyped including 45 affected men, 44 unaffected men, and 40 women. The average age at diagnosis was 61; 8 of 15 families had more than 4 affected individuals. 50 CA individuals from similar families were genotyped including 12 affected men, 26 presently unaffected men, and 12 women. For CA families, the average age of onset was 66, with at least 5 affected individuals in each family. In AAs, we identified a peak of suggestive linkage at chromosome 2p16 (HLOD = 1.97). Similarly, in CA families, the strongest linkage signal was observed on chromosome 2q14.1 with an HLOD score of 1.94. At the2 q14 linkage region, there was no linkage in AA PCa families (HLOD = 0.0004). Similarly, on 2p16, there was no linkage in the CA cohort (HLOD = 0). Conclusions: The MSH6 gene is located in 2p16 region. MMR gene mutations have been shown to have evidence of microsatellite instability in PCa as well as hereditary nonpolyposis colorectal cancer. MSH6 gene may represent a genetic variant contributing to risk of PCa in high risk AA families. This potentially has therapeutic implications for use of PD1 inhibitors in this population.

scholarly journals A CASE OF RARE INHERITED RESTRICTIVE CARDIOMYOPATHY CAUSED BY A NOVEL MUTATION IN MYH7 GENE

2021 ◽  
Vol 9 (09) ◽  
pp. 780-786
Author(s):  
Aya Belkhadir ◽  
◽  
Kamal Marzouki ◽  
Mohamed Aoudad ◽  
Amale Tazi Mezalek ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Novel Mutation ◽  
Phenotypic Variability ◽  
Phenotypic Expression ◽  
Gene Mutations ◽  
Restrictive Cardiomyopathy ◽  
Incomplete Penetrance ◽  
Patients At Risk ◽  
History Of ◽  
Pace Maker

Introduction: Inherited restrictive cardiomyopathy (RCM) is a rare cause of RCM associated with cytoskeletal and sarcoma gene mutations. We describe a case of inherited RCM due to MYH7s genetic mutation.Case description: A 66 year-old-woman was admitted for acute global heart failure. She had a family history of RCM with a mutation of MYH7 gene: sons sudden death at 30, one of her daughters who is 40 and grandson who is 1. The transthoracic cardiac ultrasound (TTE) showed a bi-atrial dilation, a non-dilated left ventricle (LV) non-hypertrophied. Genetic investigation found the same pathogenic missense mutation (c. 1477A>G in heterozygous state) in our patient and her daughter who has a non-obstructive hypertrophy cardiomyopathy (HCM).A few weeks later, our patient had a syncope on complete atrioventricular block. A triple chamber pace maker was installed. Discussion: Familial RCMs mutations are characterized by high allelic, genetic and phenotypic variability, with autosomal dominant inheritance and variable penetrance. This mutation is rarely found in RCM, it is usually reported in HCM (OMIM 160760). Genetic screening should be considered to identify patients at risk in families with suspected familial transmission. MYH7 mutations seem to be associated with severe phenotypes, earlier age of onset and more pejorative evolution than other mutations. Conclusion:The evaluation of familial RCM requires an understanding of its variable phenotypic expression and incomplete penetrance. RCM and HCM may coexist in the same family. Genetic testing for hereditary RCM should be considered when secondary causes have been excluded.

scholarly journals Alternating Hemiplegia of Childhood: Genotype–Phenotype Correlations in a Cohort of 39 Italian Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Ramona Cordani ◽  
Michela Stagnaro ◽  
Livia Pisciotta ◽  
Francesco Danilo Tiziano ◽  
Maria Grazia Calevo ◽  
...  
Keyword(s):  
Movement Disorders ◽  
Language Impairment ◽  
Age Of Onset ◽  
Muscle Tone ◽  
Demographic Data ◽  
Gene Mutations ◽  
Clinical Registry ◽  
Alternating Hemiplegia Of Childhood ◽  
Severe Intellectual Disability ◽  
Neurological Features

Alternating hemiplegia of childhood is a rare neurological disease characterized by paroxysmal movement disorders and chronic neurological disturbances, with onset before 18 months of age. Mutations in the ATP1A3 gene have been identified in up to 80% of patients. Thirty-nine patients [20 females, 19 males, mean age 25.32 years (7.52–49.34)] have been recruited through the Italian Biobank and Clinical Registry for Alternating Hemiplegia of Childhood. Demographic data, genotype, paroxysmal movement disorders, chronic neurological features, and response to flunarizine have been analyzed. ATP1A3 gene mutations have been detected in 92.3% of patients. Patients have been divided into three groups—p.Asp801Asn mutation patients (26%), p.Glu815Lys cases (23%), and patients with other ATP1A3 mutations—and statistically compared. The Italian cohort has a higher percentage of ATP1A3 gene mutation than reported in literature (92.3%). Our data confirm a more severe phenotype in patients with p.Glu815Lys mutation, with an earlier age of onset of plegic (p = 0.02 in the correlation with other mutations) and tonic attacks. P.Glu815Lys patients most frequently present altered muscle tone, inability to walk (p = 0.01 comparing p.Glu815Lys and p.Asp801Asn mutations), epilepsy, and a more severe grade of dystonia (p < 0.05 comparing p.Glu815Lys and p.Asp801Asn mutations). They have moderate/severe intellectual disability and severe language impairment (p < 0.05). Interestingly, flunarizine seems to be more efficacious in patients with p.Glu815Lys mutation than p.Asp801Asn. In conclusion, our research suggests a genotype–phenotype correlation and provides information on this disorder's features, clinical course, and treatment.

Familial hypophosphatemic rickets caused by a PHEX gene mutation accompanied by a NPR2 missense mutation

2020 ◽  
Vol 33 (2) ◽  
pp. 305-311
Author(s):  
Yongting Zhao ◽  
Fan Yang ◽  
Lihong Wang ◽  
Hui Che
Keyword(s):  
Gene Mutation ◽  
Age Of Onset ◽  
Gene Mutations ◽  
Hereditary Disease ◽  
Hypophosphatemic Rickets ◽  
Chinese Patients ◽  
Chinese Family ◽  
Dihydroxyvitamin D ◽  
Phex Gene ◽  
Urinary Phosphorus Excretion

AbstractBackgroundFamilial hypophosphatemic rickets, which is usually acknowledged as X-linked hypophosphatemic rickets (XLH), is a rare hereditary disease. XLH caused by mutations in the PHEX gene often manifests as growth retardation, skeletal deformities, osteodynia and dental dysplasia. NPR2 mutations are reported to cause disproportionate short stature. Our study was designed to identify the gene mutations of three patients in one family.Case descriptionA 40-year-old Chinese male visited the hospital for continuous osteodynia and presented with bilateral leg bowing, absent teeth and a progressive limp. The age of onset was approximately 2 years old. His 63-year-old mother and 42-year-old brother both shared identical symptoms with him. The laboratory tests were consistent with XLH, which showed decreased levels of blood phosphorus and 1,25-dihydroxyvitamin D3 as well as increased urinary phosphorus excretion. Mutation analysis revealed that the proband as well as his mother and his brother all had a PHEX mutation in exon 14 (c.1543C > T), and the proband also had a NPR2 mutation in exon 21 (c.3058C > T).ConclusionsWe report the familial hypophosphatemic rickets of three patients in a Chinese family caused by a PHEX gene mutation in exon 14 (c.1543C > T), which had never been reported in Chinese patients. We first report an XLH case together with a NPR2 mutation that had never been reported before.

scholarly journals Perforin-Mediated Cytotoxicity Is Critical for Surveillance of Spontaneous Lymphoma

2000 ◽  
Vol 192 (5) ◽  
pp. 755-760 ◽  
Author(s):  
Mark J. Smyth ◽  
Kevin Y.T. Thia ◽  
Shayna E.A. Street ◽  
Duncan MacGregor ◽  
Dale I. Godfrey ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Age Of Onset ◽  
Cancer Susceptibility ◽  
Immune Surveillance ◽  
Gene Mutations ◽  
P53 Gene ◽  
Tumor Rejection ◽  
Cytotoxic Lymphocytes ◽  
Immunocompetent Mice ◽  
Deficient Mice

Immune surveillance by cytotoxic lymphocytes against cancer has been postulated for decades, but direct evidence for the role of cytotoxic lymphocytes in protecting against spontaneous malignancy has been lacking. As the rejection of many experimental cancers by cytotoxic T lymphocytes and natural killer cells is dependent on the pore-forming protein perforin (pfp), we examined pfp-deficient mice for increased cancer susceptibility. Here we show that pfp-deficient mice have a high incidence of malignancy in distinct lymphoid cell lineages (T, B, NKT), indicating a specific requirement for pfp in protection against lymphomagenesis. The susceptibility to lymphoma was accentuated by simultaneous lack of expression of the p53 gene, mutations in which also commonly predispose to human malignancies, including lymphoma. In contrast, the incidence and age of onset of sarcoma was unaffected in p53-deficient mice. Pfp-deficient mice were at least 1,000-fold more susceptible to these lymphomas when transplanted, compared with immunocompetent mice in which tumor rejection was controlled by CD8+ T lymphocytes. This study is the first that implicates direct cytotoxicity by lymphocytes in regulating lymphomagenesis.

scholarly journals A review of multi-dimensional diagnosis of Alport syndrome in 22 children in Northeast China

2020 ◽  
Author(s):  
Li Zhang ◽  
Bai-chao Sun ◽  
Bing-gang Zhao ◽  
Qing-shan Ma
Keyword(s):  
Alport Syndrome ◽  
Age Of Onset ◽  
Pediatric Nephrology ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Basement Membranes ◽  
Economic Factors ◽  
Visual Problem ◽  
Risk Of Progression ◽  
Dimensional Diagnosis

Abstract Background Alport syndrome (AS) is progressive hereditary nephritis due to different gene mutations. Affected individuals usually develop hematuria during childhood with gradual deterioration of renal functions. We adopted multi-dimensional methods to diagnose Alport syndrome in order to decrease the misdiagnosis.Methods Twenty-two children were diagnosed and managed by the Department of Pediatric Nephrology of Jilin University First Hospital between January 2017 and January 2020 through multi-dimensional methods. Information collected included age of onset, age at diagnosis, clinical manifestations, family history (FH), renal pathology and their genotype. Results All patients presented with hematuria with various degrees of proteinuria in some patients. While three children suffered from hearing loss, none of the children in the cohort had any visual problem or renal failure. Besides five patients estimated as Stage 2, the remain seventeen cases were at Stage 0. Renal biopsy were obtained in eighteen patients and fourteen of them showed glomerular basement membranes (GBM)-specific abnormalities. Thirteen children had mutations of the collagen IV genes. Conclusion Combined with the importance of early diagnosis and economic factors, we adopted multi-dimensional methods to improve the diagnosis of Alport syndrome and estimate the risk of progression. We also reviewed the therapy progress.

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