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1.
Am J Med Genet A ; 185(10): 2922-2928, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34075706

RESUMO

While genetics evaluation is increasingly utilized in adult neurology patients, its usage and efficacy are not well characterized. Here, we report our experience with 1461 consecutive patients evaluated in an adult neurogenetics clinic at a large academic medical center between January 2015 and March 2020. Of the 1461 patients evaluated, 1215 patients were referred for the purposes of identifying a genetic diagnosis for an undiagnosed condition, 90.5% of whom underwent genetic testing. The modalities of genetic testing utilized varied across referral diagnostic categories, including a range of utilization of whole exome sequencing (WES) as an initial test in 13.9% of neuromuscular patients to 52.9% in white matter disorder patients. The usage of WES increased over time, from 7.7% of initial testing in 2015 to a peak of 27.3% in 2019. Overall, genetic testing yielded a causal genetic diagnosis in 30.7% of patients. This yield was higher in certain referring diagnosis categories, such as neuromuscular (39.0%) and epilepsy (29.8%). Our study demonstrates that evaluation at an adult neurogenetics referral center can yield diagnoses in a substantial fraction of patients. Additional research will be needed to determine optimal genetic testing strategies and cost effectiveness of adult neurogenetics evaluation.


Assuntos
Testes Genéticos/tendências , Doenças do Sistema Nervoso/diagnóstico , Adulto , Análise Custo-Benefício , Testes Diagnósticos de Rotina/tendências , Exoma/genética , Feminino , Humanos , Masculino , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologia , Sequenciamento do Exoma
3.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361012

RESUMO

Loss-of-function mutations in the KV4.3 channel-encoding KCND3 gene are linked to neurodegenerative cerebellar ataxia. Patients suffering from neurodegeneration associated with iron deposition may also present with cerebellar ataxia. The mechanism underlying brain iron accumulation remains unclear. Here, we aim to ascertain the potential pathogenic role of KCND3 variant in iron accumulation-related cerebellar ataxia. We presented a patient with slowly progressive cerebellar ataxia, parkinsonism, cognitive impairment, and iron accumulation in the basal ganglia and the cerebellum. Whole exome sequencing analyses identified in the patient a heterozygous KCND3 c.1256G>A (p.R419H) variant predicted to be disease-causing by multiple bioinformatic analyses. In vitro biochemical and immunofluorescence examinations revealed that, compared to the human KV4.3 wild-type channel, the p.R419H variant exhibited normal protein abundance and subcellular localization pattern. Electrophysiological investigation, however, demonstrated that the KV4.3 p.R419H variant was associated with a dominant increase in potassium current amplitudes, as well as notable changes in voltage-dependent gating properties leading to enhanced potassium window current. These observations indicate that, in direct contrast with the loss-of-function KCND3 mutations previously reported in cerebellar ataxia patients, we identified a rare gain-of-function KCND3 variant that may expand the clinical and molecular spectra of neurodegenerative cerebellar disorders associated with brain iron accumulation.


Assuntos
Disfunção Cognitiva/genética , Mutação com Ganho de Função , Ferro/metabolismo , Transtornos Parkinsonianos/genética , Canais de Potássio Shal/genética , Ataxias Espinocerebelares/genética , Potenciais de Ação , Idoso , Encéfalo/metabolismo , Disfunção Cognitiva/patologia , Células HEK293 , Humanos , Masculino , Transtornos Parkinsonianos/patologia , Domínios Proteicos , Canais de Potássio Shal/química , Canais de Potássio Shal/metabolismo , Ataxias Espinocerebelares/patologia
4.
Hum Mutat ; 39(11): 1476-1484, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30311377

RESUMO

The field of epilepsy genetics is advancing rapidly and epilepsy is emerging as a frequent indication for diagnostic genetic testing. Within the larger ClinGen framework, the ClinGen Epilepsy Gene Curation Expert Panel is tasked with connecting two increasingly separate fields: the domain of traditional clinical epileptology, with its own established language and classification criteria, and the rapidly evolving area of diagnostic genetic testing that adheres to formal criteria for gene and variant curation. We identify critical components unique to the epilepsy gene curation effort, including: (a) precise phenotype definitions within existing disease and phenotype ontologies; (b) consideration of when epilepsy should be curated as a distinct disease entity; (c) strategies for gene selection; and (d) emerging rules for evaluating functional models for seizure disorders. Given that de novo variants play a prominent role in many of the epilepsies, sufficient genetic evidence is often awarded early in the curation process. Therefore, the emphasis of gene curation is frequently shifted toward an iterative precuration process to better capture phenotypic associations. We demonstrate that within the spectrum of neurodevelopmental disorders, gene curation for epilepsy-associated genes is feasible and suggest epilepsy-specific conventions, laying the groundwork for a curation process of all major epilepsy-associated genes.


Assuntos
Epilepsia/genética , Testes Genéticos , Humanos , Mutação/genética , Fenótipo
5.
Neurogenetics ; 19(2): 105-110, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29589152

RESUMO

To determine the diagnostic yield of different genetic test modalities in adult patients with neurological disorders, we evaluated all adult patients seen for genetic diagnostic evaluation in the outpatient neurology practice at the University of Pennsylvania between January 2016 and April 2017 as part of the newly created Penn Neurogenetics Program. Subjects were identified through our electronic medical system as those evaluated by the Program's single clinical genetic counselor in that period. A total of 377 patients were evaluated by the Penn Neurogenetics Program in different settings and genetic testing recommended. Of those, 182 (48%) were seen in subspecialty clinic setting and 195 (52%) in a General Neurogenetics Clinic. Genetic testing was completed in over 80% of patients in whom it was recommended. The diagnostic yield was 32% across disease groups. Stratified by testing modality, the yield was highest with directed testing (50%) and array comparative genomic hybridization (45%), followed by gene panels and exome testing (25% each). In conclusion, genetic testing can be successfully requested in clinic in a large majority of adult patients. Age is not a limiting factor for a genetic diagnostic evaluation and the yield of clinical testing across phenotypes (almost 30%) is consistent with previous phenotype-focused or research-based studies. These results should inform the development of specific guidelines for clinical testing and serve as evidence to improve reimbursement by insurance payers.


Assuntos
Testes Genéticos/métodos , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Testes Genéticos/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
8.
PLoS Genet ; 7(7): e1002114, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21750680

RESUMO

Ophthalmo-acromelic syndrome (OAS), also known as Waardenburg Anophthalmia syndrome, is defined by the combination of eye malformations, most commonly bilateral anophthalmia, with post-axial oligosyndactyly. Homozygosity mapping and subsequent targeted mutation analysis of a locus on 14q24.2 identified homozygous mutations in SMOC1 (SPARC-related modular calcium binding 1) in eight unrelated families. Four of these mutations are nonsense, two frame-shift, and two missense. The missense mutations are both in the second Thyroglobulin Type-1 (Tg1) domain of the protein. The orthologous gene in the mouse, Smoc1, shows site- and stage-specific expression during eye, limb, craniofacial, and somite development. We also report a targeted pre-conditional gene-trap mutation of Smoc1 (Smoc1(tm1a)) that reduces mRNA to ∼10% of wild-type levels. This gene-trap results in highly penetrant hindlimb post-axial oligosyndactyly in homozygous mutant animals (Smoc1(tm1a/tm1a)). Eye malformations, most commonly coloboma, and cleft palate occur in a significant proportion of Smoc1(tm1a/tm1a) embryos and pups. Thus partial loss of Smoc-1 results in a convincing phenocopy of the human disease. SMOC-1 is one of the two mammalian paralogs of Drosophila Pentagone, an inhibitor of decapentaplegic. The orthologous gene in Xenopus laevis, Smoc-1, also functions as a Bone Morphogenic Protein (BMP) antagonist in early embryogenesis. Loss of BMP antagonism during mammalian development provides a plausible explanation for both the limb and eye phenotype in humans and mice.


Assuntos
Anoftalmia/genética , Proteína Morfogenética Óssea 1/antagonistas & inibidores , Mutação , Osteonectina , Síndrome de Waardenburg/genética , Animais , Proteína Morfogenética Óssea 1/genética , Coloboma/genética , Análise Mutacional de DNA , Extremidades/crescimento & desenvolvimento , Olho/crescimento & desenvolvimento , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Osteonectina/genética , Osteonectina/metabolismo , Linhagem , Sindactilia/genética , Xenopus laevis
9.
Neurol Clin Pract ; 14(4): e200303, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38855716

RESUMO

Background: Qalsody (tofersen), an intrathecal therapy (IT) antisense oligonucleotide (ASO), was granted accelerated approval by the Food and Drug Administration for the treatment of SOD1-mediated amyotrophic lateral sclerosis (ALS) on April 25, 2023. Academic centers need to be prepared for expedited drug delivery. The purpose of this model was to predict the number of SOD1-ALS patients whom we expect to see at our center at the time of Qalsody approval and to use it to extrapolate to a model for a hypothetical sporadic IT ALS therapy. Recent Findings: We predicted that 6 symptomatic and 14 presymptomatic SOD1 patients would come to our center, whereas a sporadic therapy would generate 108 patients, creating excess office visits, lumbar punctures, and genetic counseling visits. Implications for Practice: As new therapies for neurologic diseases come to market, preparing for increased office volume and complex drug delivery are essential for optimal care.

10.
Biology (Basel) ; 13(2)2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38392311

RESUMO

Advances in gene-specific therapeutics for patients with neuromuscular disorders (NMDs) have brought increased attention to the importance of genetic diagnosis. Genetic testing practices vary among adult neuromuscular clinics, with multi-gene panel testing currently being the most common approach; follow-up testing using broad-based methods, such as exome or genome sequencing, is less consistently offered. Here, we use five case examples to illustrate the unique ability of broad-based testing to improve diagnostic yield, resulting in identification of SORD-neuropathy, HADHB-related disease, ATXN2-ALS, MECP2 related progressive gait decline and spasticity, and DNMT1-related cerebellar ataxia, deafness, narcolepsy, and hereditary sensory neuropathy type 1E. We describe in each case the technological advantages that enabled identification of the causal gene, and the resultant clinical and personal implications for the patient, demonstrating the importance of offering exome or genome sequencing to adults with NMDs.

11.
J Neurol ; 271(2): 733-747, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37891417

RESUMO

The role of genetic testing in neurologic clinical practice has increased dramatically in recent years, driven by research on genetic causes of neurologic disease and increased availability of genetic sequencing technology. Genetic testing is now indicated for adults with a wide range of common neurologic conditions. The potential clinical impacts of a genetic diagnosis are also rapidly expanding, with a growing list of gene-specific treatments and clinical trials, in addition to important implications for prognosis, surveillance, family planning, and diagnostic closure. The goals of this review are to provide practical guidance for clinicians about the role of genetics in their practice and to provide the neuroscience research community with a broad survey of current progress in this field. We aim to answer three questions for the neurologist in practice: Which of my patients need genetic testing? What testing should I order? And how will genetic testing help my patient? We focus on common neurologic disorders and presentations to the neurology clinic. For each condition, we review the most current guidelines and evidence regarding indications for genetic testing, expected diagnostic yield, and recommended testing approach. We also focus on clinical impacts of genetic diagnoses, highlighting a number of gene-specific therapies recently approved for clinical use, and a rapidly expanding landscape of gene-specific clinical trials, many using novel nucleotide-based therapeutic modalities like antisense oligonucleotides and gene transfer. We anticipate that more widespread use of genetic testing will help advance therapeutic development and improve the care, and outcomes, of patients with neurologic conditions.


Assuntos
Doenças do Sistema Nervoso , Neurociências , Adulto , Humanos , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/terapia , Testes Genéticos , Neurologistas , Instituições de Assistência Ambulatorial
12.
Hum Genet ; 130(4): 495-504, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21340693

RESUMO

BMP4 loss-of-function mutations and deletions have been shown to be associated with ocular, digital, and brain anomalies, but due to the paucity of these reports, the full phenotypic spectrum of human BMP4 mutations is not clear. We screened 133 patients with a variety of ocular disorders for BMP4 coding region mutations or genomic deletions. BMP4 deletions were detected in two patients: a patient affected with SHORT syndrome and a patient with anterior segment anomalies along with craniofacial dysmorphism and cognitive impairment. In addition to this, three intragenic BMP4 mutations were identified. A patient with anophthalmia, microphthalmia with sclerocornea, right-sided diaphragmatic hernia, and hydrocephalus was found to have a c.592C >T (p.R198X) nonsense mutation in BMP4. A frameshift mutation, c.171dupC (p.E58RfsX17), was identified in two half-siblings with anophthalmia/microphthalmia, discordant developmental delay/postaxial polydactyly, and poor growth as well as their unaffected mother; one affected sibling carried an additional BMP4 mutation in the second allele, c.362A > G (p.H121R). This is the first report indicating a role for BMP4 in SHORT syndrome, Axenfeld-Rieger malformation, growth delay, macrocephaly, and diaphragmatic hernia. These results significantly expand the number of reported loss-of-function mutations, further support the critical role of BMP4 in ocular development, and provide additional evidence of variable expression/non-penetrance of BMP4 mutations.


Assuntos
Proteína Morfogenética Óssea 4/genética , Olho/embriologia , Olho/metabolismo , Transtornos do Crescimento/genética , Hipercalcemia/genética , Doenças Metabólicas/genética , Mutação/genética , Nefrocalcinose/genética , Sequência de Aminoácidos , Criança , Pré-Escolar , Aberrações Cromossômicas , Olho/patologia , Feminino , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Linhagem , Homologia de Sequência de Aminoácidos
13.
Genet Med ; 13(5): 437-42, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21285886

RESUMO

PURPOSE: The goal of our study was to determine whether genomic copy number abnormalities (deletions and duplications) affecting genes involved in eye development contributed to the etiology of anophthalmia, microphthalmia, and coloboma. METHODS: The affected individuals were evaluated for the presence of deletions and duplications in genomic DNA by a very high-resolution array comparative genomic hybridization. RESULTS: Array analysis of 32 patients detected one case with a deletion encompassing the renal-coloboma syndrome associated gene PAX2. Nonpolymorphic copy number changes were also observed at several candidate chromosomal regions, including 6p12.3, 8q23.1q23.2, 13q31.3, 15q11.2q13.1, 16p13.13, and 20q13.13. CONCLUSIONS: This study identified the first patient with the typical phenotype of the renal-coloboma syndrome caused by a submicroscopic deletion of the coding region of the PAX2 gene. The finding suggests that PAX2 deletion testing should be performed in addition to gene sequencing as a part of molecular evaluation for the renal-coloboma syndrome. Array comparative genomic hybridization testing of 32 affected individuals showed that genomic deletions and duplications are not a common cause of nonsyndromic anophthalmia, microphthalmia, or coloboma but undoubtedly contribute to the etiology of these eye anomalies. Therefore, array comparative genomic hybridization testing represents an important and valuable addition to candidate gene sequencing in research and diagnostics of ocular birth defects.


Assuntos
Hibridização Genômica Comparativa , Anormalidades do Olho/genética , Deleção Cromossômica , Duplicação Cromossômica/genética , Variações do Número de Cópias de DNA/genética , Deleção de Genes , Humanos , Fator de Transcrição PAX2/genética
14.
Curr Opin Ophthalmol ; 22(5): 309-13, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21825993

RESUMO

PURPOSE OF REVIEW: To summarize recent breakthroughs regarding the genes known to play a role in normal ocular development in humans and to elucidate the role mutations in these genes play in anophthalmia and microphthalmia. RECENT FINDINGS: The main themes discussed within this article are the various documented genetic advances in identifying the various causes of anophthalmia and microphthalmia. In addition, the complex interplay of these genes during critical embryonic development will be addressed. SUMMARY: The recent identification of many eye development genes has changed the ability to identify a cause of anophthalmia and microphthalmia in many individuals. Syndrome identification and the availability of genetic testing underscores the desirability of evaluation by a geneticist for all individuals with anophthalmia and microphthalmia in order to provide appropriate management, long-term guidance, and genetic counseling.


Assuntos
Anoftalmia/genética , Microftalmia/genética , Fatores de Transcrição/genética , Anoftalmia/embriologia , Anoftalmia/etiologia , Análise Mutacional de DNA , Proteínas do Olho/genética , Feminino , Fatores de Transcrição Forkhead/genética , Proteínas de Homeodomínio/genética , Humanos , Microftalmia/embriologia , Microftalmia/etiologia , Mutação/genética , Fatores de Transcrição Otx/genética , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/genética , Gravidez , Proteínas Repressoras/genética , Fatores de Transcrição SOXB1/genética , Fator de Crescimento Transformador beta/genética
15.
Am J Med Genet A ; 152A(12): 3120-3, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21082658

RESUMO

Anophthalmia and microphthalmia are etiologically and clinically heterogeneous. We present a 13-year-old boy with microphthalmia and multiple anomalies who was evaluated as part of our research into the etiology of microphthalmia. His clinical features included left microphthalmia, persistent hyperplastic primary vitreous and posterior coloboma, right posterior pole coloboma, pectus excavatum, mild hypotonia, mild delays in speech and motor development, and an anxiety disorder with social difficulties. Investigations with a chromosome microarray revealed a de novo deletion of chromosome 16p11.2 of approximately 882 kb in size. Deletions of this region of chromosome 16p11.2 are a newly delineated microdeletion syndrome, but this is the first report of microphthalmia and coloboma associated with monosomy for 16p11.2, and emphasizes the clinical variability that can be present with this deletion. This report contributes to the growing knowledge regarding this microdeletion and suggests that rare copy number changes may be a cause of microphthalmia and other eye anomalies.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 16 , Coloboma/genética , Microftalmia/genética , Anormalidades Múltiplas/genética , Anoftalmia/genética , Criança , Quebra Cromossômica , Hibridização Genômica Comparativa , Análise Citogenética , Humanos , Masculino , Análise em Microsséries , Monossomia/genética , Análise de Sequência com Séries de Oligonucleotídeos , Doenças do Nervo Óptico/genética
16.
Case Rep Neurol Med ; 2020: 7219514, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32908740

RESUMO

Some causes of spastic paraplegia are treatable and many are not. Diagnostic work-up to determine the etiology can be costly and invasive. Here we report the case of a man with slowly progressive spastic paraparesis. Using a multigene next-generation sequencing (NGS) panel, we identified a novel variant in the consensus splice site of the SPAST gene (exon 13, c.1536G>A, heterozygous), affecting codon 512 of the SPAST mRNA. The observed variant segregated with the disease in four tested family members. In this case, genetic confirmation obviated the need for additional testing such as MRI and lumbar puncture and helped the patient and his family understand his condition and prognosis. We conclude with a brief discussion of the SPG4/SPAST gene and the role of multigene panels in the diagnosis and management of hereditary spastic paraplegia.

17.
BMC Med Genet ; 10: 137, 2009 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-20003547

RESUMO

BACKGROUND: Anophthalmia and microphthalmia are etiologically and clinically heterogeneous. Lenz microphthalmia is a syndromic form that is typically inherited in an X-linked pattern, though the causative gene mutation is unknown. Townes-Brocks syndrome manifests thumb anomalies, imperforate anus, and ear anomalies. We present a 13-year-old boy with a syndromic microphthalmia phenotype and a clinical diagnosis of Lenz microphthalmia syndrome. CASE PRESENTATION: The patient was subjected to clinical and molecular evaluation, including array CGH analysis. The clinical features included left clinical anophthalmia, right microphthalmia, anteriorly placed anus with fistula, chordee, ventriculoseptal defect, patent ductus arteriosus, posteriorly rotated ears, hypotonia, growth retardation with delayed bone age, and mental retardation. The patient was found to have an approximately 5.6 Mb deletion of 16q11.2q12.1 by microarray based-comparative genomic hybridization, which includes the SALL1 gene, which causes Townes-Brocks syndrome. CONCLUSIONS: Deletions of 16q11.2q12.2 have been reported in several individuals, although those prior reports did not note microphthalmia or anophthalmia. This region includes SALL1, which causes Townes-Brocks syndrome. In retrospect, this child has a number of features that can be explained by the SALL1 deletion, although it is not clear if the microphthalmia is a rare feature of Townes-Brocks syndrome or caused by other mechanisms. These data suggest that rare copy number changes may be a cause of syndromic microphthalmia allowing a personalized genomic medicine approach to the care of patients with these aberrations.


Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 16 , Variações do Número de Cópias de DNA , Deleção de Genes , Estudos de Associação Genética , Microftalmia/genética , Adolescente , Anus Imperfurado/genética , Orelha Externa/anormalidades , Predisposição Genética para Doença , Humanos , Recém-Nascido , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Síndrome , Polegar/anormalidades
18.
J Huntingtons Dis ; 8(1): 79-85, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30689592

RESUMO

BACKGROUND: Advances in molecular therapeutic approaches in the last decade are translating into the design of non-traditional clinical trials. In order to improve their feasibility, it is important to understand the attitudes of potential participants towards these trials, their motivations to get involved and acceptance of risks. OBJECTIVE: We aimed to better understand the willingness of potential participants to participate in different molecular therapy trials for Huntington's disease (HD) based on their clinical and genetic status, trial design and goals of the treatment. METHODS: An anonymous survey was distributed through the Huntington's Disease Society of America (HDSA) on-line portal/website. Various hypothetical scenarios were presented followed by a survey consistent of Likert scale responses ascertaining willingness to participate, collecting demographic, clinical and genetic information. RESULTS: There were a total of 87 responses, including patients diagnosed with HD, pre-manifesting mutation carriers and asymptomatic participants at risk. The majority of participants indicated they were very likely or likely to participate in clinical trials independent of study design or goals of the therapy, with a more favorable view in premanifesting mutation carriers. However, more invasive procedures and trials including placebo were less favorably viewed across all diagnostic groups. CONCLUSIONS: In summary, most individuals in the HD community would consider participation in novel molecular therapy trials, but study design and goals could impact patient recruitment. This data can be used to inform the recruitment and consent process into clinical trials and to address common concerns by potential participants.


Assuntos
Doença de Huntington/genética , Doença de Huntington/terapia , Terapia de Alvo Molecular , Adulto , Atitude , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Inquéritos e Questionários
19.
J Huntingtons Dis ; 8(4): 501-507, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31381522

RESUMO

BACKGROUND: Clinical care for Huntington's disease (HD) is often provided in experienced centers that provide multidisciplinary care. However, the value of these centers and their uptake by HD families remain unknown. OBJECTIVE: To describe the services provided by a new HD center, including estimates of capture of the population served. METHODS: Retrospective review of a HD Center launched in 2015, including quantitative and qualitative data on clinic visits, demographic and clinical data. RESULTS: We observed a rapid and ongoing growth on the annual number of clinic encounters, with high demand for in-clinic multidisciplinary care. Using census data and estimates of HD prevalence, we determined that we served about 20% of local patients with HD. Most HD patients received pharmacological treatment for psychiatric symptoms, and over half were treated for chorea. About 25% of new HD diagnoses were on patients without family history of HD. Finally, the demand for predictive testing in at risk individuals significantly increased following the press release reporting the successful completion of the Ionis-HTTRx (RG 6042) trial. CONCLUSIONS: This report indicates a high demand for multidisciplinary care by HD families, supporting its value, providing a snapshot of the organization and function of a single center. Furthermore, it demonstrates how dissemination of news related to research advances influence clinical behavior. Reporting similar information from other HD centers to would provide us with a more global view of the status of HD care across multiple geographical areas.


Assuntos
Necessidades e Demandas de Serviços de Saúde/estatística & dados numéricos , Hospitais Especializados , Doença de Huntington , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Ensaios Clínicos como Assunto , Humanos , Doença de Huntington/diagnóstico , Doença de Huntington/epidemiologia , Doença de Huntington/terapia , Estudos Retrospectivos
20.
Mol Vis ; 14: 583-92, 2008 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-18385794

RESUMO

PURPOSE: Mutations in the SOX2 and CHX10 genes have been reported in patients with anophthalmia and/or microphthalmia. In this study, we evaluated 34 anophthalmic/microphthalmic patient DNA samples (two sets of siblings included) for mutations and sequence variants in SOX2 and CHX10. METHODS: Conformational sensitive gel electrophoresis (CSGE) was used for the initial SOX2 and CHX10 screening of 34 affected individuals (two sets of siblings), five unaffected family members, and 80 healthy controls. Patient samples containing heteroduplexes were selected for sequence analysis. Base pair changes in SOX2 and CHX10 were confirmed by sequencing bidirectionally in patient samples. RESULTS: Two novel heterozygous mutations and two sequence variants (one known) in SOX2 were identified in this cohort. Mutation c.310 G>T (p. Glu104X), found in one patient, was in the region encoding the high mobility group (HMG) DNA-binding domain and resulted in a change from glutamic acid to a stop codon. The second mutation, noted in two affected siblings, was a single nucleotide deletion c.549delC (p. Pro184ArgfsX19) in the region encoding the activation domain, resulting in a frameshift and premature termination of the coding sequence. The shortened protein products may result in the loss of function. In addition, a novel nucleotide substitution c.*557G>A was identified in the 3'-untranslated region in one patient. The relationship between the nucleotide change and the protein function is indeterminate. A known single nucleotide polymorphism (c. *469 C>A, SNP rs11915160) was also detected in 2 of the 34 patients. Screening of CHX10 identified two synonymous sequence variants, c.471 C>T (p.Ser157Ser, rs35435463) and c.579 G>A (p. Gln193Gln, novel SNP), and one non-synonymous sequence variant, c.871 G>A (p. Asp291Asn, novel SNP). The non-synonymous polymorphism was also present in healthy controls, suggesting non-causality. CONCLUSIONS: These results support the role of SOX2 in ocular development. Loss of SOX2 function results in severe eye malformation. CHX10 was not implicated with microphthalmia/anophthalmia in our patient cohort.


Assuntos
Anoftalmia/genética , Proteínas de Ligação a DNA/genética , Variação Genética , Proteínas HMGB/genética , Proteínas de Homeodomínio/genética , Microftalmia/genética , Mutação , Fatores de Transcrição/genética , Adolescente , Criança , Estudos de Coortes , Feminino , Heterozigoto , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição SOXB1
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