scholarly journals Adult Onset Spinocerebellar Ataxia in a Canadian Movement Disorders Clinic

2005 ◽  
Vol 32 (4) ◽  
pp. 450-458 ◽  
Author(s):  
Scott Kraft ◽  
Sarah Furtado ◽  
Ranjit Ranawaya ◽  
Jillian Parboosingh ◽  
Stacey Bleoo ◽  
...  
Keyword(s):  
Family History ◽  
Movement Disorders ◽  
Autosomal Recessive ◽  
Fragile X ◽  
Positive Family History ◽  
Friedreich Ataxia ◽  
Genetic Diagnosis ◽  
Common Mutation ◽  
Adult Onset ◽  
Spinocerebellar Ataxias

ABSTRACT:Background:The spinocerebellar ataxias (SCAs) are a genetically and clinically heterogeneous group of neurodegenerative disorders. Relative frequencies vary within different ethnic groups and geographical locations.Objectives:1) To determine the frequencies of hereditary and sporadic adult onset SCAs in the Movement Disorders population; 2) to assess if the fragile X mental retardation gene 1 (FMR1) premutation is found in this population.Methods:A retrospective chart review of individuals with a diagnosis of adult onset SCA was carried out. Testing for SCA types 1, 2, 3, 6, 7, and 8, Dentatorubral-pallidoluysian atrophy (DRPLA), Friedreich ataxia and the FMR1 expansion was performed.Results:A total of 69 patients in 60 families were identified. Twenty-one (35%) of the families displayed autosomal dominant and two (3.3%) showed autosomal recessive (AR) pattern of inheritance. A positive but undefined family history was noted in nine (15%). The disorder appeared sporadic in 26 patients (43.3%). In the AD families, the most common mutation was SCA3 (23.8%) followed by SCA2 (14.3%) and SCA6 (14.3%). The SCA1 and SCA8 were each identified in 4.8%. FA was found in a pseudodominant pedigree, and one autosomal recessive pedigree. One sporadic patient had a positive test (SCA3).Dentatorubral-pallidoluysian atrophy and FMR1 testing was negative.Conclusion:A positive family history was present in 53.3% of our adult onset SCA patients. A specific genetic diagnosis could be given in 61.9% of dominant pedigrees with SCA3 being the most common mutation, followed by SCA2 and SCA6. The yield in sporadic cases was low. The fragile X premutation was not found to be responsible for SCA.

scholarly journals Ataxias with Autosomal, X-Chromosomal or Maternal Inheritance

2009 ◽  
Vol 36 (4) ◽  
pp. 409-428 ◽  
Author(s):  
Josef Finsterer
Keyword(s):  
Ataxia Telangiectasia ◽  
Large Scale ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Late Onset ◽  
Fragile X ◽  
Axonal Neuropathy ◽  
Friedreich Ataxia ◽  
Point Mutations ◽  
Spinocerebellar Ataxias

Heredoataxias are a group of genetic disorders with a cerebellar syndrome as the leading clinical manifestation. The current classification distinguishes heredoataxias according to the trait of inheritance into autosomal dominant, autosomal recessive, X-linked, and maternally inherited heredoataxias. The autosomal dominant heredoataxias are separated into spinocerebellar ataxias (SCA1-8, 10-15, 17-23, 25-30, and dentato-rubro-pallido-luysian atrophy), episodic ataxias (EA1-7), and autosomal dominant mitochondrial heredoataxias (Leigh syndrome, MIRAS, ADOAD, and AD-CPEO). The autosomal recessive ataxias are separated into Friedreich ataxia, ataxia due to vitamin E deficiency, ataxia due to Abeta-lipoproteinemia, Refsum disease, late-onset Tay-Sachs disease, cerebrotendineous xanthomatosis, spinocerebellar ataxia with axonal neuropathy, ataxia telangiectasia, ataxia telangiectasia-like disorder, ataxia with oculomotor apraxia 1 and 2, spastic ataxia of Charlevoix-Saguenay, Cayman ataxia, Marinesco-Sjögren syndrome, and autosomal recessive mitochondrial ataxias (AR-CPEO, SANDO, SCAE, AHS, IOSCA, MEMSA, LBSL CoQ-deficiency, PDC-deficiency). Only two of the heredoataxias, fragile X/tremor/ataxia syndrome, and XLSA/A are transmitted via an X-linked trait. Maternally inherited heredoataxias are due to point mutations in genes encoding for tRNAs, rRNAs, respiratory chain subunits or single large scale deletions/duplications of the mitochondrial DNA and include MELAS, MERRF, KSS, PS, MILS, NARP, and non-syndromic mitochondrial disorders. Treatment of heredoataxias is symptomatic and supportive and may have a beneficial effect in single patients.**Please see page 424 for abbreviation list.

P0051NOVEL AND KNOWN MUTATIONS IDENTIFIED BY CLINICAL EXOME SEQUENCING FOR THE DIAGNOSIS OF POLYCYSTIC KIDNEY DISEASE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Tiziana Vaisitti ◽  
Monica Sorbini ◽  
Martina Callegari ◽  
Silvia Kalantari ◽  
Valeria Bracciamà ◽  
...  
Keyword(s):  
Family History ◽  
Exome Sequencing ◽  
Autosomal Recessive ◽  
Positive Family History ◽  
Genetic Diagnosis ◽  
Clinical Suspicion ◽  
University Hospital ◽  
Missense Mutations ◽  
Variants Of Unknown Significance ◽  
Clinical Exome Sequencing

Abstract Background and Aims Autosomal dominant PKD determines formation of multiple cysts predominantly in the kidneys and usually becomes symptomatic during adulthood and can lead to renal failure. In contrast, in autosomal recessive PKD cysts occur in both the kidneys and the liver and usually presents an earlier onset. Obtaining genetic diagnosis is important to confirm clinical diagnosis and is required before treating with vasopressin 2 receptor blockers, which are the only drugs known to slow down the disease. Furthermore, in the case of kidney transplant from a living family member it is essential to exclude the presence of the mutation in the donor. We used clinical exome sequencing to provide genetic diagnosis to a cohort of patients with a clinical suspicion of PKD. Method 175 patients were referred to the Immunogenetics and Transplant Biology Service of the Turin University Hospital through a network of nephrology centers operating in the Piedmont region. Some patients were referred following genetic counseling. All patients signed an informed consent and the referring physicians provided relevant clinical data. DNA from eligible patients was extracted, checked for integrity, quantified and used for library preparation. A clinical exome sequencing (CES) kit by Illumina was used, allowing the analysis of 6,700 clinically relevant genes. Results Out of the 175 recruited patients eligible for CES, 38 (21.7%) had a clinical suspicion or diagnosis of PKD, with 50% of them presenting family history. The majority of the cohort was represented by male subjects (60.5%) and included both children (34.2%) and adults. The analytical approach was based on initial analysis of genes responsible for PKD (PKD1, PKD2 and PKHD1). If no mutation could be identified, analysis was then extended to a panel of 99 genes responsible for ciliopathies. This approach led to the identification of causative variants in 33/38 (86.8%) of the PKD cohort, while no variant could be identified in 5/38 patients. In 5/33 (15.2%) patients, mutations were inconclusive as found in heterozygosity in genes known to have an autosomal recessive mode of inheritance, while 27/33 (81.8%) were in line with the initial clinical suspicion/diagnosis. Of these, the majority was represented by missense mutations (12), followed by frameshift and nonsense mutations (6 each) and 3 splicing variants. As expected, the majority of mutations were found in PKD1 17/27 (63%), PKD2 3/27 (11.1%) and PKHD1 2/27 (7.4%). In these two latter patients, variants were found as compound heterozygosity. We also found mutations in other genes known to cause cysts, including TSC2 and CPT2. Of note, in 7 patients carrying PKD1 mutations, we found a second variant in PKD1 or PKHD1. Interestingly, when looking at patients characterized by kidney failure but lacking a clinical suspicion at recruitment or diagnosed with other phenotypes (66/175), we found variants in PKD1 and in PKD2 in 11 patients (9 and 2, respectively). Of all identified variants in PKD1, PKD2 and PKHD1 genes, 17.6% were annotated as pathogenic (C5), 41.2% were likely pathogenic (C4) and 41.2% were variants of unknown significance (C3). 19 variants in these genes were not previously reported. All the variants found in genes responsible for PKD were validated and confirmed by Sanger sequencing. Family segregation studies are ongoing. Finally, it is worth mentioning that in a portion of cases (5/38) with clinical and phenotypic features of PKD, supported also by a positive family history, we could not detect mutations in causative genes. These results may be explained by the presence of intronic variants, in line with data reported in literature. Conclusion These results demonstrate that CES may be applied to PKD patients to identify causative variants during their routine diagnostic flow. Furthermore, CES may be a useful tool to detect mutations in PKD-related genes in patients with undiagnosed diseases, considering its rapidly decreasing costs.

scholarly journals Clinical, epidemiological and autoimmune associations in childhood vitiligo in Qatar

2020 ◽  
Vol 6 (2) ◽  
pp. 151
Author(s):  
Haya Al Mannai ◽  
Mohamed Allam ◽  
Hassan Riad
Keyword(s):  
Family History ◽  
Autoimmune Diseases ◽  
Age Of Onset ◽  
Positive Family History ◽  
Thyroid Peroxidase ◽  
Base Line ◽  
Adult Onset ◽  
Prognostic Features ◽  
History Of ◽  
The Mean

<p class="abstract"><strong>Background:</strong> Childhood vitiligo although clinically similar to adult onset vitiligo but it has distinct clinical, epidemiological and prognostic features compared to adult onset vitiligo.</p><p class="abstract"><strong>Methods:</strong> This is a retrospective study that was carried out on 85 pediatric patients up to age of 18 years old with the diagnosis of vitiligo, where the clinical and epidemiological data  including clinical type of vitiligo, family history of autoimmune diseases like thyroid disorders and diabetes mellitus and laboratory results including anti-thyroid peroxidase antibodies (anti-TPO antibodies), anti-parietal cell antibodies, antinuclear antibodies (ANA), Vitamin D and Vitamin B12 were retrieved from the files of these patients.<strong></strong></p><p class="abstract"><strong>Results:</strong> The mean age of the children affected by vitiligo was 10.4 years, the mean age of onset of vitiligo was 5.4 years, 54 (63.5%) percent were girls and 31 (36.5%) were boys. A positive family history of vitiligo was found in 44.7% of the participants, family history of DM was found in 64.7% of patients and family history of thyroid disease was found in 32.9% of the participants. The prevalence of thyroid autoimmunity was found to be in 22.4% of total participants.</p><p class="abstract"><strong>Conclusions:</strong> Childhood vitiligo has distinct clinical features, more common family history for autoimmune diseases and thyroid autoantibodies rather than overt clinical diseases, which raise the necessity to perform a routine initial immunological and thyroid screening in children with vitiligo and to repeat them at annual bases if there were abnormal values at base line or strong family history.</p>

HEREDITARY AND ENVIRONMENTAL FACTORS IN THE PATHOGENESIS OF RHEUMATIC FEVER

PEDIATRICS ◽  
1957 ◽  
Vol 19 (5) ◽  
pp. 908-915
Author(s):  
Eugene F. Diamond
Keyword(s):  
Family History ◽  
Rheumatic Fever ◽  
Autosomal Recessive ◽  
Positive Family History ◽  
Recessive Gene ◽  
Environmental Groups ◽  
Environmental Group ◽  
The Family ◽  
History Of ◽  
Unfavorable Environmental Factor

A study of cases of rheumatic fever admitted to La Rabida Sanitarium over a 5-year period was carried out to evaluate heredity and environment as etiologic factors in rheumatic disease. The incidence of rheumatic fever was shown to be higher in families where one or both parents were known to have a positive family history of rheumatic fever. The incidence of rheumatic fever was compared in environmental groups. A totally unfavorable environment was shown to increase the incidence of rheumatic fever. No single unfavorable environmental factor changed the incidence of rheumatic fever. The incidence of rheumatic fever in each environmental group was higher when there was a positive family history for rheumatic fever, indicating an hereditary factor in the family incidence of rheumatic fever. Analysis of the various mating types in the families with a positive rheumatic trait was carried out. Agreement with a simple autosomal recessive gene inheritance was obtained in families where both parents had a definite family history, but no agreement was obtained in cases where only one parent gave a positive family history.

Inherited Ataxias

2015 ◽  
Author(s):  
Susan Perlman
Keyword(s):  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Friedreich Ataxia ◽  
Spinocerebellar Ataxias ◽  
Recessive Ataxia ◽  
Internet Resources ◽  
Genetic Abnormalities ◽  
Repeat Expansions ◽  
The Common ◽  
Inherited Ataxias

The inherited ataxias are disorders that cause progressive imbalance as a result of pathology in the cerebellum and its various connecting pathways. Autosomal recessive ataxias include Friedreich ataxia, ataxia with isolated vitamin E deficiency, ataxia-telangiectasia, and autosomal recessive ataxia of Charlevoix-Saguenay, among others. A discussion of autosomal dominant ataxias covers spinocerebellar ataxias (SCA) types 1 through 14, dentatorubral pallidoluysian atrophy (DRPLA), and episodic ataxia (EA) syndromes. Clinical features, laboratory studies, differential diagnosis, and management of inherited ataxias are discussed. Tables describe both autosomal recessive ataxias and autosomal dominant ataxias (with known gene loci), childhood– or young adult–onset ataxias with ill-defined genetic abnormalities, phenotypic features that may indicate a specific genotype in the common autosomal dominant ataxias, and normal and expanded ranges of various repetitive nucleotide sequences in inherited ataxias. Figures include a diagrammatic representation of the type of repeat expansions associated with ataxias, aggregates of ataxin 3, a schematic of some of the proposed pathogenic mechanisms in the polyglutamine ataxias, and dystonia in a patient with SCA3. A sidebar offers selected Internet resources for information on ataxias. This chapter contains 64 references.

scholarly journals Genetic Diagnosis of Glaucoma

2020 ◽  
pp. 25-29
Author(s):  
Hany Mahmoud ◽  
Marwa S. Hashim
Keyword(s):  
Extracellular Matrix ◽  
Family History ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Disease Risk ◽  
Positive Family History ◽  
Genetic Diagnosis ◽  
Nerve Degeneration ◽  
Blood Collection

Purpose: Glaucoma, the most prevalent cause of irreversible blindness across the world, is progressive optic nerve degeneration and affection (neuropathy) caused by a mixture of both genetic and environmental factors [1]. The extracellular matrix (ECM) structure of the trabecular Meshwork TM has a major role in intraocular pressure IOP control.  Transforming growth factor beta (TGF-β) is a growth factor that plays major roles in cellular functions, including encouraging extracellular matrix synthesis and vascular angiogenesis. TGFβ2 treatment of TM cells alters ECM components [8] and induces ECM bonds. Aim of the Study: To study the relationship between family history and glaucoma according to genotype and genetic polymorphism. Methods: Blood collection and DNA extraction Genotyping: TGFB2 Rs99196 genotyping was done using TaqMan SNP genotyping Assay (ID C___8853564_10). StepOne real time PCR system (Applied Biosystem, Ca, USA) was used for amplifiction. Statistical Analysis: The sample size of the study group was calculated using a program at (www.openepi.com/SampleSize/ SSCC.htm). Results: Important genotype differences frequencies were detected between the positive family history and negative family history groups for the codominant, dominant, recessive and overdominant inheritance models. Conclusion: This study recommends that other polymorphisms of genes associated with glaucoma and the analysis of these gene products and their relationship with disease risk factors should be more studied.

scholarly journals Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism

2013 ◽  
Vol 168 (4) ◽  
pp. 557-564 ◽  
Author(s):  
Ritika R Kapoor ◽  
Sarah E Flanagan ◽  
Ved Bhushan Arya ◽  
Julian P Shield ◽  
Sian Ellard ◽  
...  
Keyword(s):  
Family History ◽  
Positive Family History ◽  
Genetic Diagnosis ◽  
Clinical Information ◽  
Congenital Hyperinsulinism ◽  
Molecular Characterisation ◽  
Heterogeneous Condition ◽  
Diffuse Disease ◽  
Molecular Aspects ◽  
Inherited Mutations

BackgroundCongenital hyperinsulinism (CHI) is a clinically heterogeneous condition. Mutations in eight genes (ABCC8,KCNJ11,GLUD1,GCK,HADH,SLC16A1,HNF4AandHNF1A) are known to cause CHI.AimTo characterise the clinical and molecular aspects of a large cohort of patients with CHI.MethodologyThree hundred patients were recruited and clinical information was collected before genotyping.ABCC8andKCNJ11genes were analysed in all patients. Mutations inGLUD1,HADH,GCKandHNF4Agenes were sought in patients with diazoxide-responsive CHI with hyperammonaemia (GLUD1), raised 3-hydroxybutyrylcarnitine and/or consanguinity (HADH), positive family history (GCK) or when CHI was diagnosed within the first week of life (HNF4A).ResultsMutations were identified in 136/300 patients (45.3%). Mutations inABCC8/KCNJ11were the commonest genetic cause identified (n=109, 36.3%). Among diazoxide-unresponsive patients (n=105), mutations inABCC8/KCNJ11were identified in 92 (87.6%) patients, of whom 63 patients had recessively inherited mutations while four patients had dominantly inherited mutations. A paternal mutation in theABCC8/KCNJ11genes was identified in 23 diazoxide-unresponsive patients, of whom six had diffuse disease. Among the diazoxide-responsive patients (n=183), mutations were identified in 41 patients (22.4%). These include mutations inABCC8/KCNJ11(n=15),HNF4A(n=7),GLUD1(n=16) andHADH(n=3).ConclusionsA genetic diagnosis was made for 45.3% of patients in this large series. Mutations in theABCC8gene were the commonest identifiable cause. The vast majority of patients with diazoxide-responsive CHI (77.6%) had no identifiable mutations, suggesting other genetic and/or environmental mechanisms.

Abstract TMP94: Frequencies of Hereditary Cerebral Small Vessel Diseases Among Patients With Adult-Onset Leukoencephalopathy

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Masahiro Uemura ◽  
Hiroaki Nozaki ◽  
Naoko Sakai ◽  
Shouichirou Ando ◽  
Masato Kanazawa ◽  
...  
Keyword(s):  
White Matter ◽  
Family History ◽  
Small Vessel Disease ◽  
Age At Onset ◽  
Positive Family History ◽  
Small Vessel ◽  
Adult Onset ◽  
Genetic Tests ◽  
Neurological Signs ◽  
White Matter Disorders

Introduction: Recently, various causative genes have been identified in adult-onset white matter disorders. Some of these genes cause cerebral small vessel disease (CSVD). However, the frequency of genetic CSVD is unknown in the group of adult-onset white matter disorders (leukoencephalopathy). The purpose of this study is to clarify the frequency of genetic CSVD in adult-onset leukoencephalopathy patients and to examine their clinical features. Methods: One hundred patients in the Japanese cohort were included. All patients had neurological symptoms/signs and white matter lesions of grade 3/III classified by Fazekas grade on magnetic resonance imaging. Initially, genetic tests for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), high-temperature requirement A serine peptidase 1 (HTRA1)- related CSVD and retinovasculopathy with cerebral leukoencephalopathy (RVCL) were performed by Sanger method. For the remaining samples, we preformed whole exome sequencing. Patients were divided into groups according to the age at onset of neurological signs/symptoms and family history. Results: In 40 of 100 patients with leukoencephalopathy, we identified genetic mutations that cause CSVD: twenty-five patients with CADASIL,10 patients with HTRA1 -related CSVD, 3 patients with pseudoxanthoma elasticum (PXE), 1 patient with RVCL, and 1 patient with a mutation in COL4A1 . More than 85% patients have mutations in NOTCH3 or HTRA1 . In addition, we identified 3 patients with vanishing white matter disease, and 1 patient with X-linked adrenoleukodystrophy. The hereditary CSVDs other than CADASIL or HTRA1 -related CSVD were identified in the groups of age at onset ≤ 40 years-old irrespective of family history or age at onset ≤ 55 years-old with family history. Conclusions: The frequencies of genetic CSVDs were quite high among patients with leukoencephalopathy with neurological signs/symptoms. Although the genetic tests for CADASIL and HTRA1- related CSVD are sufficient for the most patients, we should consider the other genetic diseases especially for the patients with younger age onset of neurological signs/symptoms or positive family history.

The Epidemiology behind Pectus Excavatum: Clinical Study and Review of the Literature

2021 ◽  
Author(s):  
Konrad Reinshagen ◽  
Katja Kloth ◽  
Stefan Klohs ◽  
Jasmin Bhullar ◽  
Michael Boettcher ◽  
...  
Keyword(s):  
Family History ◽  
Chest Wall ◽  
Pectus Excavatum ◽  
Large Scale ◽  
Autosomal Recessive ◽  
Genetic Factors ◽  
Case Reports ◽  
Positive Family History ◽  
Review Of The Literature ◽  
Reduced Penetrance

Abstract Introduction Pectus excavatum (PE) is a funnel-shaped indentation of the sternum and is the most common deformity of the chest wall. It is associated with syndromic diseases but can occur as an isolated form. Familial occurrence is assumed in up to 40% of cases, but large-scale studies are lacking. Most of the data are obtained from case reports which postulate autosomal recessive, dominant with reduced penetrance, X-linked, and multifactorial patterns of inheritance. No monogenetic cause has been identified to date. This study was designed to provide basic information on the epidemiology, family history, and comorbidity for a large cohort of isolated PE and to show that there is an inheritance pattern for PE that indicates a genetic background. Materials and Methods A retrospective study was done using a paper-based questionnaire for all PE patients attending two specialized centers for chest wall deformities. Patients with isolated PE were included and asked to provide information on family history and comorbidities. Results Family history was available for 78 patients. A positive family history was found in 42 patients (54%) with a total of 53 affected family members. Conclusion The described family histories indicate an underlying genetic cause for PE. Identification of the genetic factors may contribute to characterize patients who are at risk of inheriting isolated PE.

scholarly journals Predictors of alcohol responsiveness in dystonia

Neurology ◽  
2018 ◽  
Vol 91 (21) ◽  
pp. e2020-e2026 ◽  
Author(s):  
Johanna Junker ◽  
Valerie Brandt ◽  
Brian D. Berman ◽  
Marie Vidailhet ◽  
Emmanuel Roze ◽  
...  
Keyword(s):  
Family History ◽  
Movement Disorders ◽  
Rating Scale ◽  
Age At Onset ◽  
Positive Family History ◽  
Self Report ◽  
Cross Sectional ◽  
Total N ◽  
Generalized Dystonia ◽  
History Of

ObjectiveTo determine predictors of alcohol responsiveness in a large cohort of patients with dystonia.MethodsA total of 2,159 participants with dystonia were prospectively enrolled in the cross-sectional Dystonia Coalition multicenter study. Patients with secondary, combined, or confirmed genetic dystonia (total n = 164) or unknown alcohol responsiveness (n = 737) were excluded. Patients answered a standardized questionnaire and were clinically examined using a standardized video protocol and the Burke-Fahn-Marsden Dystonia Rating Scale. Alcohol responsiveness was determined by patients' self-report.ResultsA total of 1,258 patients with isolated dystonia (mean age: 59.5 ± 12.2 years; 898 women) met the inclusion criteria; 369 patients (29.3%) reported improvement of dystonia after alcohol consumption. Alcohol responsiveness was not related to sex (p = 0.742), age (p = 0.715), or severity of dystonia (p = 0.623). Age at onset was lower in patients who responded to alcohol (p < 0.001). Alcohol responsiveness differed across dystonia subgroups (multifocal/generalized > segmental [p = 0.014]; cervical and laryngeal > cranial and limb [p < 0.001]) and was related to a positive family history of movement disorders (p = 0.001), and presence of tremor (p < 0.001).ConclusionThe association of alcohol responsiveness with a positive family history for movement disorders, generalized dystonia, and an earlier age at onset suggests that patients with dystonia who have an underlying genetic contribution may be more likely to respond beneficially to alcohol. The fact that dystonic tremor may respond to alcohol is in keeping with the observation that the intake of GABAergic drugs may have a beneficial effect in a proportion of patients.

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