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1.
BMC Med Genet ; 19(1): 193, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30400883

RESUMO

BACKGROUND: X-linked creatine transporter deficiency (OMIM#300036,CRTR-D) is characterized by cerebral creatine deficiency, intellectual disabilities, severe speech impairment, seizures and behavioral problems. Mutations in the creatine transporter gene SLC6A8, a member of the solute-carrier family 6 mapped to Xq28, have been reported to cause the creatine transporter deficiency. CASE PRESENTATION: The proband presented at 5 yrs. 1 month of age with delays in intellectual and development, seizures and behavioral problems. A novel missense mutation, c.1181C > A (p.Thr394Lys), in the SLC6A8 gene (NM_005629.3) was detected via targeted exome sequencing, and then validated by Sanger sequencing. Multiple in silico variant effect analysis methods, including SIFT, PolyPhen2, PROVEAN, and Mutation Taster predicted that this variant was likely damaging or diseasing-causing. This hemizygous variation was also identified in the affected brother with the same clinical condition and inherited from the heterozygous carrier mother. The diagnosis was suggested by increased urinary creatine/creatinine (Cr:Crn) ratio and markedly reduced creatine content peak by brain proton magnetic resonance spectroscopy (MRS). The proband's mother became pregnant with a 3rd sibling, in whom the Sanger sequencing result of c.1181C > A was negative. CONCLUSION: The novel mutation c.1181C > A in the SLC6A8 gene reported in a Chinese family has expanded the mutation spectrum of CRTR-D. The combination of powerful new technologies such as targeted exome sequencing with thorough systematic clinical evaluation of patients will improve the diagnostic yield, and assist in genetic counselling and prenatal diagnosis for suspected genetic disorders.


Assuntos
Encefalopatias Metabólicas Congênitas/genética , Creatina/deficiência , Deficiência Intelectual/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Convulsões/genética , Povo Asiático , Sequência de Bases , Encefalopatias Metabólicas Congênitas/etnologia , Encefalopatias Metabólicas Congênitas/fisiopatologia , Encefalopatias Metabólicas Congênitas/urina , Pré-Escolar , Cromossomos Humanos Par 10/química , Creatina/genética , Creatina/urina , Creatinina/urina , Análise Mutacional de DNA , Exoma , Expressão Gênica , Humanos , Deficiência Intelectual/etnologia , Deficiência Intelectual/fisiopatologia , Deficiência Intelectual/urina , Herança Materna , Deficiência Intelectual Ligada ao Cromossomo X/etnologia , Deficiência Intelectual Ligada ao Cromossomo X/fisiopatologia , Deficiência Intelectual Ligada ao Cromossomo X/urina , Linhagem , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/urina , Convulsões/etnologia , Convulsões/fisiopatologia , Convulsões/urina , Irmãos
2.
Genet Med ; 19(2): 256-263, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28055022

RESUMO

Disclaimer: These ACMG Standards and Guidelines are intended as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these standards and guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of others that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, clinical laboratory geneticists should apply their professional judgment to the specific circumstances presented by the patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these Standards and Guidelines. They also are advised to take notice of the date any particular guideline was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Cerebral creatine deficiency syndromes are neurometabolic conditions characterized by intellectual disability, seizures, speech delay, and behavioral abnormalities. Several laboratory methods are available for preliminary and confirmatory diagnosis of these conditions, including measurement of creatine and related metabolites in biofluids using liquid chromatography-tandem mass spectrometry or gas chromatography-mass spectrometry, enzyme activity assays in cultured cells, and DNA sequence analysis. These guidelines are intended to standardize these procedures to help optimize the diagnosis of creatine deficiency syndromes. While biochemical methods are emphasized, considerations for confirmatory molecular testing are also discussed, along with variables that influence test results and interpretation.Genet Med 19 2, 256-263.


Assuntos
Amidinotransferases/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/genética , Encefalopatias Metabólicas Congênitas/genética , Creatina/deficiência , Creatina/metabolismo , Guanidinoacetato N-Metiltransferase/deficiência , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Transtornos dos Movimentos/congênito , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Proteínas Repressoras/genética , Distúrbios da Fala/genética , Amidinotransferases/sangue , Amidinotransferases/líquido cefalorraquidiano , Amidinotransferases/genética , Amidinotransferases/urina , Erros Inatos do Metabolismo dos Aminoácidos/sangue , Erros Inatos do Metabolismo dos Aminoácidos/líquido cefalorraquidiano , Erros Inatos do Metabolismo dos Aminoácidos/urina , Encefalopatias Metabólicas Congênitas/sangue , Encefalopatias Metabólicas Congênitas/líquido cefalorraquidiano , Encefalopatias Metabólicas Congênitas/urina , Técnicas de Laboratório Clínico/métodos , Creatina/sangue , Creatina/líquido cefalorraquidiano , Creatina/genética , Creatina/urina , Deficiências do Desenvolvimento/sangue , Deficiências do Desenvolvimento/líquido cefalorraquidiano , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/urina , Testes Genéticos/normas , Genética Médica/normas , Genômica , Guanidinoacetato N-Metiltransferase/sangue , Guanidinoacetato N-Metiltransferase/líquido cefalorraquidiano , Guanidinoacetato N-Metiltransferase/genética , Guanidinoacetato N-Metiltransferase/urina , Guias como Assunto , Humanos , Deficiência Intelectual/sangue , Deficiência Intelectual/líquido cefalorraquidiano , Deficiência Intelectual/urina , Transtornos do Desenvolvimento da Linguagem/sangue , Transtornos do Desenvolvimento da Linguagem/líquido cefalorraquidiano , Transtornos do Desenvolvimento da Linguagem/urina , Deficiência Intelectual Ligada ao Cromossomo X/sangue , Deficiência Intelectual Ligada ao Cromossomo X/líquido cefalorraquidiano , Deficiência Intelectual Ligada ao Cromossomo X/urina , Transtornos dos Movimentos/sangue , Transtornos dos Movimentos/líquido cefalorraquidiano , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/urina , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/sangue , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/líquido cefalorraquidiano , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/urina , Proteínas Repressoras/sangue , Proteínas Repressoras/líquido cefalorraquidiano , Proteínas Repressoras/urina , Distúrbios da Fala/sangue , Distúrbios da Fala/líquido cefalorraquidiano
3.
J Dev Behav Pediatr ; 37(4): 322-6, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27096572

RESUMO

OBJECTIVE: Creatine transporter deficiency (CTD) is an X-linked, neurometabolic disorder associated with intellectual disability that is characterized by brain creatine (Cr) deficiency and caused by mutations in SLC6A8, the Cr transporter 1 protein gene. CTD is identified by elevated urine creatine/creatinine (Cr/Crn) ratio or reduced Cr peak on brain magnetic resonance spectroscopy; the diagnosis is confirmed by decreased Cr uptake in cultured fibroblasts, and/or identification of a mutation in the SLC6A8 gene. Prevalence studies suggest this disorder may be underdiagnosed. We sought to identify cases from a well-characterized cohort of children diagnosed with neurodevelopmental disorders. METHOD: Urine screening for CTD was performed on a cohort of 46 males with autism spectrum disorder (ASD) and 9 males with a history of non-ASD developmental delay (DD) classified with intellectual disability. RESULTS: We identified 1 patient with CTD in the cohort based on abnormal urine Cr/Crn, and confirmed the diagnosis by the identification of a novel frameshift mutation in the SLC6A8 gene. This patient presented without ASD but with intellectual disability, and was characterized by a nonspecific phenotype of early language delay and DD that persisted into moderate-to-severe intellectual disability, consistent with previous descriptions of CTD. CONCLUSION: Identification of patients with CTD is possible by measuring urine Cr and Crn levels and the current case adds to the growing literature of neurocognitive deficits associated with the disorder that affect cognition, language and behavior in childhood.


Assuntos
Transtorno do Espectro Autista/urina , Encefalopatias Metabólicas Congênitas/fisiopatologia , Encefalopatias Metabólicas Congênitas/urina , Creatina/deficiência , Deficiências do Desenvolvimento/urina , Deficiência Intelectual/urina , Proteínas de Membrana Transportadoras/urina , Deficiência Intelectual Ligada ao Cromossomo X/fisiopatologia , Deficiência Intelectual Ligada ao Cromossomo X/urina , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Criança , Creatina/urina , Humanos , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/urina
4.
Brain Dev ; 36(7): 630-3, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24045174

RESUMO

Creatine transporter deficiency (CTD) is an example of X-linked intellectual disability syndromes, caused by mutations in SLC6A8 on Xq28. Although this is the second most frequent genetic cause of intellectual disabilities in Europe or America after Fragile X syndrome, information on the morbidity of this disease is limited in Japan. Using the HPLC screening method we have established recently, we examined samples of urine of 105 patients (73 males and 32 females) with developmental disabilities at our medical center. And we have found a family with three ID boys with a novel missense mutation in SLC6A8. This is the second report of a Japanese family case of CTD. A systematic diagnostic system of this syndrome should be established in Japan to enable us to estimate its frequency and treatment.


Assuntos
Encefalopatias Metabólicas Congênitas/diagnóstico , Encefalopatias Metabólicas Congênitas/genética , Creatina/deficiência , Deficiências do Desenvolvimento/genética , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Deficiência Intelectual Ligada ao Cromossomo X/genética , Proteínas do Tecido Nervoso/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Povo Asiático , Encefalopatias Metabólicas Congênitas/complicações , Encefalopatias Metabólicas Congênitas/urina , Criança , Creatina/genética , Creatina/urina , Deficiências do Desenvolvimento/complicações , Humanos , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/complicações , Deficiência Intelectual Ligada ao Cromossomo X/urina , Mutação de Sentido Incorreto , Linhagem , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/urina
5.
Amino Acids ; 43(2): 993-7, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22080216

RESUMO

Cerebral creatine deficiency syndromes (CCDS) are caused by genetic defects in L-arginine:glycine amidinotransferase, guanidinoacetate methyltransferase or creatine transporter 1. CCDS are characterized by abnormal concentrations of urinary creatine (CR), guanidinoacetic acid (GA), or creatinine (CN). In this study, we describe a simple HPLC method to determine the concentrations of CR, GA, and CN using a weak-acid ion chromatography column with a UV detector without any derivatization. CR, GA, and CN were separated clearly with the retention times (mean ± SD, n = 3) of 5.54 ± 0.0035 min for CR, 6.41 ± 0.0079 min for GA, and 13.53 ± 0.046 min for CN. This new method should provide a simple screening test for the diagnosis of CCDS.


Assuntos
Encefalopatias Metabólicas Congênitas/diagnóstico , Encefalopatias Metabólicas Congênitas/urina , Creatina/urina , Creatinina/urina , Glicina/análogos & derivados , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Deficiência Intelectual Ligada ao Cromossomo X/urina , Cromatografia Líquida de Alta Pressão , Cromatografia por Troca Iônica , Creatina/deficiência , Creatina/isolamento & purificação , Creatinina/isolamento & purificação , Glicina/isolamento & purificação , Glicina/urina , Humanos , Masculino , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/urina , Transferases/deficiência
6.
Am J Med Genet A ; 155A(10): 2446-52, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21910234

RESUMO

Creatine deficiency syndrome due to mutations in X-linked SLC6A8 gene results in nonspecific intellectual disability (ID). Diagnosis cannot be established on clinical grounds and is often based on the assessment of brain creatine levels by magnetic resonance spectroscopy (MRS). Considering high costs of MRS and necessity of sedation, this technique cannot be used as a first level-screening test. Likewise, gene test analysis is time consuming and not easily accessible to all laboratories. In this article feasibility of urine analysis (creatine/creatinine (Cr/Crn) ratio) performed by nuclear magnetic resonance (NMR) as a first level-screening test is explored. Before running a systematic selection of cases a preliminary study for further molecular analysis is shown. NMR urine spectra (n = 1,347) of male patients with an ID without a clinically recognizable syndrome were measured. On the basis of abnormal Cr/Crn ratio, three patients with the highest values were selected for molecular analysis. A confirmatory second urine test was positive in two patients and diagnosis was further confirmed by a decreased brain creatine level and by SLC6A8 gene analysis. A de novo mutation was identified in one. Another patient inherited a novel mutation from the mother who also has a mild ID. A repeat urine test was negative in the third patient and accordingly creatine level in the brain and SLC6A8 gene analysis both gave a normal result. We conclude that Cr/Crn ratio measured by NMR for male patients represents a rapid and useful first level screening test preceding molecular analysis.


Assuntos
Encefalopatias Metabólicas Congênitas/diagnóstico , Creatina/urina , Espectroscopia de Ressonância Magnética , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Proteínas do Tecido Nervoso/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Encéfalo/metabolismo , Encefalopatias Metabólicas Congênitas/urina , Creatina/deficiência , Creatina/metabolismo , Humanos , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/urina , Mutação/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/urina , Reação em Cadeia da Polimerase
7.
Autism Res ; 3(5): 268-72, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20589913

RESUMO

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that presents in the first three years of life. Currently, diagnosis of ASD is based on its behavioural manifestations, as laboratory diagnostic tests do not exist. Creatine deficiency syndrome (CDS) is one form of inborn error of metabolism where affected individuals have similar clinical features to individuals with ASD. Abnormal urinary creatine (CR) and guanidinoacetate (GAA) levels have been reported as biomarkers of CDS. We hypothesized that screening for abnormal levels of urinary CR and GAA in children with ASD may assist in identifying a subgroup of ASD individuals who can be managed with dietary interventions. Morning urine samples were collected from children with and without autism and analyzed for CR and GAA levels. Results showed there was no statistically significant difference in urinary CR:creatinine and GAA:creatinine between the children with ASD and sibling or unrelated controls. In conclusion, routine screening for abnormal urinary CR and GAA could be considered in ASD diagnostic protocols; however, individuals positive for CDS are likely to be rare in an ASD cohort.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/urina , Programas de Rastreamento/métodos , Biomarcadores/urina , Encefalopatias Metabólicas Congênitas/complicações , Encefalopatias Metabólicas Congênitas/diagnóstico , Encefalopatias Metabólicas Congênitas/urina , Criança , Transtornos Globais do Desenvolvimento Infantil/etiologia , Cromatografia Líquida de Alta Pressão/métodos , Creatina/deficiência , Creatina/urina , Feminino , Glicina/análogos & derivados , Glicina/urina , Humanos , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/complicações , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Deficiência Intelectual Ligada ao Cromossomo X/urina , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/urina , Síndrome , Espectrometria de Massas em Tandem/métodos
8.
J Inherit Metab Dis ; 33 Suppl 3: S5-11, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24137762

RESUMO

The urinary creatine:creatinine (Cr:Crn) ratio was measured in males from 49 families with a family history compatible with X-linked mental retardation (XLMR) in order to estimate the prevalence of SLC6A8 deficiency in Estonia. We identified 11 boys from 9 families with an increased urinary Cr:Crn ratio (18%). In three related boys, a hemizygous missense mutation (c.1271G>A; p.Gly424Asp) was identified. Their mother was heterozygous for the same mutation. Although many missense mutations have been described, the p.Gly424Asp mutation has not been previously reported. The clinical expression varied widely among affected males of this family. Patients 1 and 3 had relatively mild clinical expression (mild mental retardation (MR) and attention deficit disorder), but patient 2 had all typical clinical signs of SLC6A8 defect such as moderate MR, autistic features, expressive dysphasia and epilepsy. Among our patients, we saw significant problems in speech and language development combined with attention and behavioural difficulties. The number of false-positive biochemical results with increased urinary Cr:Crn ratio was higher (18%) in our study than in previous reports (1.8­10%). We therefore suggest that repeated biochemical testing should be performed before DNA sequencing analysis. Our study suggests that 2% (95% confidence limits: 0.05­11.1%) of this Estonian XLMR panel are due to mutations in the SLC6A8, which is similar to the prevalence reported in other populations. We therefore conclude that creatine transporter deficiency is a relatively common genetic disorder in males with sporadic or familiar MR and diagnostic screening of them should always include screening for SLC6A8 deficiency.


Assuntos
Encefalopatias Metabólicas Congênitas/diagnóstico , Creatina/deficiência , Análise Mutacional de DNA , Testes Genéticos/métodos , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Adolescente , Adulto , Biomarcadores/urina , Encefalopatias Metabólicas Congênitas/epidemiologia , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/psicologia , Encefalopatias Metabólicas Congênitas/urina , Criança , Creatina/genética , Creatina/urina , Creatinina/urina , Estônia/epidemiologia , Feminino , Predisposição Genética para Doença , Hereditariedade , Heterozigoto , Humanos , Inteligência/genética , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/epidemiologia , Deficiência Intelectual Ligada ao Cromossomo X/genética , Deficiência Intelectual Ligada ao Cromossomo X/psicologia , Deficiência Intelectual Ligada ao Cromossomo X/urina , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/deficiência , Linhagem , Pessoas com Deficiência Mental , Fenótipo , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/urina , Valor Preditivo dos Testes , Prevalência , Índice de Gravidade de Doença , Adulto Jovem
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