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The skill sets of genetic counselors are strongly utilized in industry, as evidenced by 20% of genetic counselors reporting employment within industry in 2016. In addition, industry genetic counselors are expanding their roles, taking on new responsibilities, and creating new opportunities. These advances have impacted the profession as a whole including, but not limited to, genetic counseling training curricula, a shift back to genetic counseling directly to patients, and a growing influence of genetic counselors on industry test offerings. Industry genetic counselors and training programs are working together to address the challenges and opportunities presented by workforce changes and novel interpretations of how genetic counselors' core competencies can be utilized. Counseling of patients by industry genetic counselors has become more commonplace and addresses a need for alternate service delivery models. Industry genetic counselors often provide significant contributions to test development, education, marketing, and interpretation. Beyond these broad examples, individual industry genetic counselors have created unique niches for themselves, using their genetic counseling training combined with unique opportunities offered through industry, as illustrated by genetic counselors' various roles and responsibilities highlighted here.
Assuntos
Conselheiros , Aconselhamento Genético , Testes Genéticos , Genética Médica/organização & administração , Pesquisa Biomédica , Biotecnologia , Biologia Computacional , Conselheiros/educação , Indústria Farmacêutica , Humanos , Medicina de Precisão , Diagnóstico Pré-Natal , Sequenciamento do ExomaRESUMO
De novo germline mutations in GNB1 have been associated with a neurodevelopmental phenotype. To date, 28 patients with variants classified as pathogenic have been reported. We add 18 patients with de novo mutations to this cohort, including a patient with mosaicism for a GNB1 mutation who presented with a milder phenotype. Consistent with previous reports, developmental delay in these patients was moderate to severe, and more than half of the patients were non-ambulatory and nonverbal. The most observed substitution affects the p.Ile80 residue encoded in exon 6, with 28% of patients carrying a variant at this residue. Dystonia and growth delay were observed more frequently in patients carrying variants in this residue, suggesting a potential genotype-phenotype correlation. In the new cohort of 18 patients, 50% of males had genitourinary anomalies and 61% of patients had gastrointestinal anomalies, suggesting a possible association of these findings with variants in GNB1. In addition, cutaneous mastocytosis, reported once before in a patient with a GNB1 variant, was observed in three additional patients, providing further evidence for an association to GNB1. We will review clinical and molecular data of these new cases and all previously reported cases to further define the phenotype and establish possible genotype-phenotype correlations.
Assuntos
Subunidades beta da Proteína de Ligação ao GTP/genética , Estudos de Associação Genética , Mutação/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Epilepsia/genética , Feminino , Subunidades beta da Proteína de Ligação ao GTP/química , Humanos , Masculino , Sistema Nervoso/crescimento & desenvolvimento , Fenótipo , Gravidez , Estrutura Terciária de ProteínaRESUMO
The DNA damage inducible SOS response in bacteria serves to increase survival of the species at the cost of mutagenesis. The SOS response first initiates error-free repair followed by error-prone repair. Here, we have employed a multi-omics approach to elucidate the temporal coordination of the SOS response. Escherichia coli was grown in batch cultivation in bioreactors to ensure highly controlled conditions, and a low dose of the antibiotic ciprofloxacin was used to activate the SOS response while avoiding extensive cell death. Our results show that expression of genes involved in error-free and error-prone repair were both induced shortly after DNA damage, thus, challenging the established perception that the expression of error-prone repair genes is delayed. By combining transcriptomics and a sub-proteomics approach termed signalomics, we found that the temporal segregation of error-free and error-prone repair is primarily regulated after transcription, supporting the current literature. Furthermore, the heterology index (i.e., the binding affinity of LexA to the SOS box) was correlated to the maximum increase in gene expression and not to the time of induction of SOS genes. Finally, quantification of metabolites revealed increasing pyrimidine pools as a late feature of the SOS response. Our results elucidate how the SOS response is coordinated, showing a rapid transcriptional response and temporal regulation of mutagenesis on the protein and metabolite levels.
RESUMO
The past few decades have been plagued by an increasing number of infections caused by antibiotic resistant bacteria. To mitigate the rise in untreatable infections, we need new antibiotics with novel targets and drug combinations that reduce resistance development. The novel ß-clamp targeting antimicrobial peptide BTP-001 was recently shown to have a strong additive effect in combination with the halogenated pyrrolopyrimidine JK-274. In this study, the molecular basis for this effect was examined by a comprehensive proteomic and metabolomic study of the individual and combined effects on Staphylococcus aureus. We found that JK-274 reduced activation of several TCA cycle enzymes, likely via increasing the cellular nitric oxide stress, and BTP-001 induced oxidative stress in addition to inhibiting replication, translation, and DNA repair processes. Analysis indicated that several proteins linked to stress were only activated in the combination and not in the single treatments. These results suggest that the strong additive effect is due to the activation of multiple stress responses that can only be triggered by the combined effect of the individual mechanisms. Importantly, the combination dose required to eradicate S. aureus was well tolerated and did not affect cell viability of immortalized human keratinocyte cells, suggesting a species-specific response. Our findings demonstrate the potential of JK-274 and BTP-001 as antibiotic drug candidates and warrant further studies.
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An informed choice about health-related direct-to-consumer genetic testing (DTCGT) requires knowledge of potential benefits, risks, and limitations. To understand the information that potential consumers of DTCGT services are exposed to on company websites, we conducted a content analysis of 23 health-related DTCGT websites. Results revealed that benefit statements outweighed risk and limitation statements 6 to 1. The most frequently described benefits were: 1) disease prevention, 2) consumer education, 3) personalized medical recommendations, and 4) the ability to make health decisions. Thirty-five percent of websites also presented at least one risk of testing. Seventy-eight percent of websites mentioned at least one limitation of testing. Based on this information, potential consumers might get an inaccurate picture of genetic testing which could impact their ability to make an informed decision. Practices that enhance the presentation of balanced information on DTCGT company websites should be encouraged.
Assuntos
Comportamento de Escolha , Participação da Comunidade , Testes Genéticos , Consentimento Livre e Esclarecido , Internet , HumanosRESUMO
Currently, there is a world-wide rise in antibiotic resistance causing burdens to individuals and public healthcare systems. At the same time drug development is lagging behind. Therefore, finding new ways of treating bacterial infections either by identifying new agents or combinations of drugs is of utmost importance. Additionally, if combination therapy is based on agents with different modes of action, resistance is less likely to develop. The synthesis of 21 fused pyrimidines and a structure-activity relationship study identified two 6-aryl-7H-pyrrolo [2,3-d] pyrimidin-4-amines with potent activity towards Staphylococcus aureus. The MIC-value was found to be highly dependent on a bromo or iodo substitution in the 4-benzylamine group and a hydroxyl in the meta or para position of the 6-aryl unit. The most active bromo and iodo derivatives had MIC of 8 mg/L. Interestingly, the most potent compounds experienced a four-fold lower MIC-value when they were combined with the antimicrobial peptide betatide giving MIC of 1-2 mg/L. The front runner bromo derivative also has a low activity towards 50 human kinases, including thymidylate monophosphate kinase, a putative antibacterial target.
RESUMO
BACKGROUND: ATP8A2 mutations have recently been described in several patients with severe, early-onset hypotonia and cognitive impairment. The aim of our study was to characterize the clinical phenotype of patients with ATP8A2 mutations. METHODS: An observational study was conducted at multiple diagnostic centres. Clinical data is presented from 9 unreported and 2 previously reported patients with ATP8A2 mutations. We compare their features with 3 additional patients that have been previously reported in the medical literature. RESULTS: Eleven patients with biallelic ATP8A2 mutations were identified, with a mean age of 9.4 years (range 2.5-28 years). All patients with ATP8A2 mutations (100%) demonstrated developmental delay, severe hypotonia and movement disorders, specifically chorea or choreoathetosis (100%), dystonia (27%) and facial dyskinesia (18%). Optic atrophy was observed in 78% of patients for whom funduscopic examination was performed. Symptom onset in all (100%) was noted before 6 months of age, with 70% having symptoms noted at birth. Feeding difficulties were common (91%) although most patients were able to tolerate pureed or thickened feeds, and 3 patients required gastrostomy tube insertion. MRI of the brain was normal in 50% of the patients. A smaller proportion was noted to have mild cortical atrophy (30%), delayed myelination (20%) and/or hypoplastic optic nerves (20%). Functional studies were performed on differentiated induced pluripotent cells from one child, which confirmed a decrease in ATP8A2 expression compared to control cells. CONCLUSIONS: ATP8A2 gene mutations have emerged as the cause of a novel neurological phenotype characterized by global developmental delays, severe hypotonia and hyperkinetic movement disorders, the latter being an important distinguishing feature. Optic atrophy is common and may only become apparent in the first few years of life, necessitating repeat ophthalmologic evaluation in older children. Early recognition of the cardinal features of this condition will facilitate diagnosis of this complex neurologic disorder.
Assuntos
Adenosina Trifosfatases/genética , Disfunção Cognitiva/genética , Hipotonia Muscular/genética , Mutação/genética , Atrofia Óptica/genética , Proteínas de Transferência de Fosfolipídeos/genética , Encéfalo/patologia , Disfunção Cognitiva/etiologia , Humanos , Imageamento por Ressonância Magnética , Hipotonia Muscular/etiologia , Atrofia Óptica/etiologia , Sequenciamento do ExomaRESUMO
The spinocerebellar ataxias (SCAs) are progressive neurodegenerative disorders linked to more than 20 genetic loci. Most often, these diseases are caused by expansion of triplet repeats encoding polyglutamine (polyQ) tracts. The phenotype is variable and can cause a disease that overlaps clinically with Parkinson's disease (PD). l-Dopa-responsive parkinsonism with minimal cerebellar deficits has been described in SCA2 and SCA3. In order to define if mutation at these loci is a common cause of clinically defined parkinsonism we typed the SCA-2 and SCA-3 repeats for expansion in a series of 280 patients diagnosed with PD or parkinsonism. We identified one pathogenic expansion in SCA-2 in a North American family with autosomal dominant parkinsonism.
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Proteínas do Tecido Nervoso/genética , Doença de Parkinson/genética , Adolescente , Idoso , Idoso de 80 Anos ou mais , Ataxina-3 , Ataxinas , DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares , Doença de Parkinson/fisiopatologia , Linhagem , Sequências Repetitivas de Ácido Nucleico/genética , Proteínas Repressoras , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tremor/fisiopatologiaRESUMO
Restless Legs Syndrome is characterized by the irresistible, often indescribable unpleasant urge to move the limbs while resting. It has an estimated prevalence of approximately 29.3 % in US private practice. Restless Legs Syndrome often has a familial component; whether the familial and non-familial forms differ in terms of clinical features has previously been investigated, with the only significant factor emerging as younger age at onset in familial cases. Our study further explores a possible underlying difference between familial and sporadic forms of RLS by comparing familial RLS with sporadic RLS in terms of demographic and clinical features including subject gender, age of onset, and severity measures based an the IRLSSG severity scale. Both gender and family history are significant predictors of onset age in an overall model and also significant when analyzed independently. Participants who reported more severe RLS symptoms were significantly younger in age and progressed more rapidly. Two variables from the IRLSSG severity scale were significantly associated with age of onset when tested independently: discomfort and the urge to move the limb for relief. Our analysis supports the prevailing hypothesis that RLS is divided into earlier onset disease with a clear genetic component and later onset disease with unclear etiology, and that one or more endophenotypes might exist within the disorder which could further characterize these subjects for future genetic studies.
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Saúde da Família , Síndrome das Pernas Inquietas/diagnóstico , Síndrome das Pernas Inquietas/epidemiologia , Caracteres Sexuais , Idade de Início , Análise de Variância , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , PrevalênciaRESUMO
Lewy body disease includes clinically and pathologically defined disorders in which Lewy bodies occur in the nervous system. In recent years, the molecular features of these disorders have been emerging. Several genetic loci have been identified in association with familial Lewy body disease; however, the genetic risks underlying most cases of familial Lewy body disease remain to be discovered. The fact that Lewy bodies stain strongly with antibodies to asynuclein and that mutations in the alpha-synuclein gene lead to syndromes in which parkinsonism and dementia occur gives us important clues regarding the biologic processes leading to disease. Pursuit of additional mendelian causes of familial Lewy body disease and study of the factors contributing to the complex phenotypes associated with Lewy body disorders will elucidate underlying disease pathways and, thus, possible targets for therapeutic intervention.
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Encéfalo/patologia , Corpos de Lewy/patologia , Doença por Corpos de Lewy/genética , Doenças Neurodegenerativas/genética , Idoso , Cromossomos Humanos Par 4 , Predisposição Genética para Doença , Humanos , Doença por Corpos de Lewy/etnologia , Doença por Corpos de Lewy/patologia , Mutação , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/genética , Sinucleínas , alfa-SinucleínaRESUMO
We administered a culturally corrected University of Pennsylvania Smell Identification Test (ccUPSIT) consisting of 25 odor items to 20 patients with 'Lubag' or X-linked dystonia-parkinsonism and 20 control subjects matched by sex, age, educational background, smoking history, and geographical origin. The mean ccUPSIT score of Lubag patients (18 +/- 3.19) was statistically lower (P = 0.003) than controls (20.5 +/- 3.02). The smell scores did not correlate with phenotype, severity of dystonia, or duration of disease. Nine of 20 Lubag patients (45%) had ccUPSIT scores below the mean, with the lowest score being 11. This pilot study suggests that olfactory dysfunction may occur in Lubag patients.
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Distonia/diagnóstico , Distonia/genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Olfato/genética , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Odorantes , Projetos PilotoRESUMO
Spinocerebellar ataxia (SCA) 17 is a dominant, progressive, neurodegenerative disorder. The disease is caused by a triplet repeat expansion mutation within TATA-binding protein (TBP). Ataxia, dementia, parkinsonism and dystonia are common features. We have previously shown in several pedigrees that SCA-2 and SCA-3 can cause both parkinsonism and typical Parkinson's disease in the absence of prominent ataxia; a finding which has been confirmed by others. Given these previous findings and the description of parkinsonism as a common feature of SCA-17 we examined this locus in a series of probands from families with 2 or more members affected with parkinsonism (n=51) and a group of sporadic parkinsonism patients (n=59). We did not find any repeat sizes in the pathogenic range. The repeats we observed ranged from 29 to 41 (mean 36.8; median 37). We conclude that SCA-17 repeat expansion mutations are not a common cause of familial parkinsonism.
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Transtornos Parkinsonianos/genética , Proteína de Ligação a TATA-Box/genética , Expansão das Repetições de Trinucleotídeos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Frequência do Gene , Humanos , Pessoa de Meia-Idade , Transtornos Parkinsonianos/etnologia , Linhagem , Reação em Cadeia da PolimeraseRESUMO
Primary hyperhidrosis is a neurogenic disorder of unknown cause characterized by excessive sweating in the palmar surface of the hands, armpits, groin and feet. In the course of a therapeutic trial for primary hyperhidrosis, 62 % of patients reported a positive family history. Examination of these pedigrees demonstrated a sibling recurrence risk of lambdas = 29-48 and an offspring recurrence risk of lambdao = 41-68 indicating that hyperhidrosis can be an inherited condition. The pattern of inheritance suggests an autosomal dominant mode of transmission with incomplete disease penetrance.
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Hiperidrose/genética , Feminino , Genes Dominantes , Mãos , Humanos , Masculino , LinhagemRESUMO
Parkinson's disease patients frequently have symptoms and signs of autonomic nervous dysfunction that are the source of considerable disability. Recent studies have revealed that most patients with Parkinson's disease, and all with Parkinson's disease-associated orthostatic hypotension, have a loss of cardiac sympathetic innervation. Familial Parkinson's disease, caused by mutation of the gene encoding alpha-synuclein, also features orthostatic hypotension, sympathetic neurocirculatory failure and cardiac sympathetic denervation. We have recently described a whole-gene triplication of alpha-synuclein causing Lewy body parkinsonism in a large, well characterized family called the 'Iowa kindred'. Here we report the results of cardiac PET scanning using the sympathoneural imaging agent, 6-[18F]fluorodopamine in affected and unaffected members of this kindred. Four family members were studied, two with parkinsonism, one clinically normal and one with benign essential tremor alone. Both affected members had obvious loss of cardiac sympathetic innervation; the unaffected member had normal innervation, as did the member with isolated essential tremor. The results indicate that, in this family, where disease is caused by overexpression of normal alpha-synuclein, cardiac sympathetic denervation cosegregates with parkinsonism. Post-mortem studies have demonstrated synuclein-positive Lewy body formation in the brains of individuals with parkinsonism who were also in the family described here and who also carry this triplication. These results indicate that both parkinsonism and cardiac sympathetic denervation can result from an excess of normal synuclein.
Assuntos
Dopamina/análogos & derivados , Coração/inervação , Mutação , Proteínas do Tecido Nervoso/genética , Doença de Parkinson/genética , Idoso , Doenças do Sistema Nervoso Autônomo/diagnóstico por imagem , Doenças do Sistema Nervoso Autônomo/genética , Humanos , Hipotensão Ortostática/genética , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Linhagem , Sinucleínas , Tomografia Computadorizada de Emissão , Manobra de Valsalva , alfa-SinucleínaRESUMO
Paroxysmal exercise-induced dystonia can occur with Parkinson's disease (PD), and in rare cases, this can also be the presenting symptom. We report on 2 second cousins (no known consanguinity) who presented with paroxysmal exercise-induced dystonia who later developed clinical features of PD. Although autosomal recessive inheritance was suggested, and the dystonic features further suggest parkin as a possible cause, sequencing for parkin mutations was negative and this family may represent a genetic variant of PD. Further genotype-phenotype studies in this and similar families may give clues to pre-symptomatic symptoms in PD and may reflect a particular phenotype of interest for genetics studies in the future.
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Distúrbios Distônicos/genética , Exercício Físico , Transtornos Parkinsonianos/genética , Idoso , Antiparkinsonianos/uso terapêutico , Carbidopa/uso terapêutico , Análise Mutacional de DNA , Progressão da Doença , Combinação de Medicamentos , Distúrbios Distônicos/diagnóstico , Distúrbios Distônicos/tratamento farmacológico , Feminino , Genótipo , Humanos , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Exame Neurológico/efeitos dos fármacos , Transtornos Parkinsonianos/diagnóstico , Fenótipo , Sêmen , Ubiquitina-Proteína Ligases/genética , Gravação de VideoteipeRESUMO
Some kindreds with familial parkinsonism exhibit genetic anticipation, suggesting possible involvement of trinucleotide repeat expansion. Recent reports have shown trinucleotide repeat expansions in the spinocerebellar ataxia 2 (SCA2) gene in patients with levodopa-responsive parkinsonism. We tested 136 unrelated patients with familial parkinsonism for SCA2 mutations. Two probands had borderline mutations; the rest were normal. (
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Antiparkinsonianos/uso terapêutico , Levodopa/uso terapêutico , Doença de Parkinson/genética , Transtornos Parkinsonianos/genética , Proteínas/genética , Adulto , Idoso , Alelos , Antecipação Genética/genética , Antiparkinsonianos/efeitos adversos , Ataxinas , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Levodopa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso , Exame Neurológico , Doença de Parkinson/diagnóstico , Doença de Parkinson/tratamento farmacológico , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/tratamento farmacológico , Linhagem , Fenótipo , Resultado do Tratamento , Repetições de TrinucleotídeosRESUMO
Spinocerebellar ataxia type 2 (SCA2) has been recognized recently as an uncommon cause of parkinsonism, an alternate presentation to the typical cerebellar disorder. This research review summarizes the existing literature on parkinsonism-predominant presentation SCA2 and presents new clinical cases of patients with this condition. Various phenotypes are noted in this subtype of SCA2, including parkinsonism indistinguishable from idiopathic Parkinson's disease (PD), parkinsonism plus ataxia, motor neuron disease, and postural tremor. In several kindreds with multiple affected family members, the SCA2 expansion segregated with disease; in addition, several single cases of parkinsonism with and without a family history are also described. The number of repeats in symptomatic patients ranged from 33 to 43. Interruption of the CAG repeat with CAA, CGG, or CCG was found in some individuals, possibly stabilizing the repeat structure and accounting for the relative stability of the repeat size across generations in some families; allele length is not necessarily indicative of trinucleotide repeat architecture. Positron emission tomography scanning in one family showed reduced fluorodopa uptake and normal to increased raclopride binding with a rostrocaudal gradient similar to that found in idiopathic PD. This review emphasizes the importance of testing for SCA2 in patients with parkinsonism and a family history of neurodegenerative disorders. Testing for SCA2 is also important in studies of inherited parkinsonism.
Assuntos
Transtornos Parkinsonianos/genética , Ataxias Espinocerebelares/genética , Antiparkinsonianos/uso terapêutico , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Encéfalo/patologia , Corpo Estriado/irrigação sanguínea , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina , Distonia/epidemiologia , Humanos , Levodopa/uso terapêutico , Imageamento por Ressonância Magnética , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/epidemiologia , Postura , Ataxias Espinocerebelares/tratamento farmacológico , Ataxias Espinocerebelares/epidemiologia , Tomografia Computadorizada de Emissão , Tomografia Computadorizada de Emissão de Fóton Único , Tremor/tratamento farmacológico , Tremor/epidemiologiaRESUMO
Mutations in DJ-1 have been linked to an autosomal recessive form of early-onset parkinsonism. To identify mutations causing Parkinson's disease (PD), we sequenced exons 1 through 7 of DJ-1 in 107 early-onset (age at diagnosis up to 50 years) PD subjects. One subject had a frameshift mutation in the first coding exon and an exon 7 splice mutation both predicted to result in a loss of functional protein. This subject was diagnosed with probable PD at age 24 years with asymmetric onset and an excellent response to levodopa therapy. Our observations suggest that sequence alterations in DJ-1 are a rare cause of early-onset PD.