RESUMO
This study aims to give an overview of the number of prenatal tests for Huntington's disease (HD), test results, and pregnancy outcomes in the Netherlands between 1998 and 2008 and to compare them with available data from the period 1987 to 1997. A total of 126 couples underwent prenatal diagnosis (PND) on 216 foetuses: 185 (86%) direct tests and 31 (14%) exclusion tests. In 9% of direct tests the risk for the foetus was 25%. Four at-risk parents (4%) carried intermediate alleles. Ninety-one foetuses had CAG expansions ≥36% or 50% risk haplotypes: 75 (82%) were terminated for HD, 12 (13%) were carried to term; four pregnancies were miscarried, terminated for other reasons or lost to follow-up. Unaffected pregnancies (122 foetuses) resulted in the birth of 112 children. The estimated uptake of PND was 22% of CAG expansion carriers (≥36 repeats) at reproductive age. PND was used by two new subgroups: carriers of intermediate alleles and 50% at-risk persons opting for a direct prenatal test of the foetus. A significant number of HD expansion or 50% risk pregnancies were continued. Speculations were made on causative factors contributing to these continuations. Further research on these couples' motives is needed.
Assuntos
Testes Genéticos , Doença de Huntington/diagnóstico , Doença de Huntington/genética , Diagnóstico Pré-Natal , Adulto , Feminino , Aconselhamento Genético , Haplótipos , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Gravidez , Resultado da Gravidez , Estudos Retrospectivos , Risco , Expansão das Repetições de TrinucleotídeosRESUMO
BACKGROUND: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype--genotype correlation has been lacking. METHODS: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). RESULTS AND CONCLUSIONS: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.
Assuntos
Encefalopatias Metabólicas Congênitas/genética , Creatina/deficiência , Creatina/metabolismo , Deficiência Intelectual Ligada ao Cromossomo X/genética , Proteínas do Tecido Nervoso/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Adulto , Criança , Creatina/genética , Genes Ligados ao Cromossomo X , Testes Genéticos , Genótipo , Humanos , Masculino , Fenótipo , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Estudos RetrospectivosRESUMO
BACKGROUND: Frontotemporal dementia (FTD) is the second most common type of presenile dementia and can be distinguished into various clinical variants. The identification of MAPT and GRN defects and the discovery of the TDP-43 protein in FTD have led to the classification of pathologic and genetic subtypes. In addition to these genetic subtypes, there exist familial forms of FTD with unknown genetic defects. METHODS: We investigated the frequency, demographic, and clinical data of patients with FTD with a positive family history in our prospective cohort of 364 patients. Genetic analysis of genes associated with FTD was performed on all patients with a positive family history. Immunohistochemical studies were carried out with a panel of antibodies (tau, ubiquitin, TDP-43) in brains collected at autopsy. RESULTS: In the total cohort of 364 patients, 27% had a positive family history suggestive for an autosomal mode of inheritance, including MAPT (11%) and GRN (6%) mutations. We identified a new Gln300X GRN mutation in a patient with a sporadic FTD. The mean age at onset in GRN patients (61.8 +/- 9.9 years) was higher than MAPT patients (52.4 +/- 5.9 years). In the remaining 10% of patients with suggestive autosomal dominant inheritance, the genetic defect has yet to be identified. Neuropathologically, this group can be distinguished into familial FTLD+MND and familial FTLD-U with hippocampal sclerosis. CONCLUSION: Future genetic studies need to identify genetic defects in at least two distinct familial forms of frontotemporal dementia (FTD) with unknown genetic defects: frontotemporal lobe degeneration with ubiquitin-positive inclusions with hippocampal sclerosis and frontotemporal lobe degeneration with motor neuron disease.
Assuntos
Demência/classificação , Demência/genética , Adulto , Idade de Início , Idoso , Demência/fisiopatologia , Complexos Endossomais de Distribuição Requeridos para Transporte , Feminino , Lobo Frontal/patologia , Humanos , Padrões de Herança , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas do Tecido Nervoso/genética , Testes Neuropsicológicos , Linhagem , Progranulinas , Estudos Prospectivos , Lobo Temporal/patologia , Proteínas tau/genéticaRESUMO
Cerebellar ataxias represent a heterogeneous group of neurodegenerative disorders. Two main categories are distinguished: hereditary and sporadic ataxias. Sporadic ataxias may be symptomatic or idiopathic. The clinical classification of hereditary ataxias is nowadays being replaced by an expanding genotype-based classification. A large spectrum of degenerative and metabolic disorders may also present with ataxia early or late in the course of disease. We present a diagnostic algorithm for the adult patient presenting with subacute cerebellar ataxia, based on family history and straightforward clinical characteristics of the patient. Along with the algorithm, an overview of the autosomal dominant, autosomal recessive, X-linked, mitochondrial, symptomatic and idiopathic subtypes of cerebellar ataxia is presented. An appropriate diagnosis is of utmost importance to such considerations as prognosis, genetic counselling and possible therapeutic implications.
Assuntos
Algoritmos , Técnicas e Procedimentos Diagnósticos , Testes Genéticos/métodos , Padrões de Herança/genética , Degenerações Espinocerebelares/classificação , Degenerações Espinocerebelares/diagnóstico , Encéfalo/patologia , Humanos , Imageamento por Ressonância Magnética , Degenerações Espinocerebelares/genéticaRESUMO
OBJECTIVE: To assess the prevalence, nature, and associated phenotypes of PINK1 gene mutations in a large series of patients with early-onset (<50 years) parkinsonism. METHODS: The authors studied 134 patients (116 sporadic and 18 familial; 77% Italian) and 90 Italian controls. The whole PINK1 coding region was sequenced from genomic DNA; cDNA was analyzed in selected cases. RESULTS: Homozygous pathogenic mutations were identified in 4 of 90 Italian sporadic cases, including the novel Gln456Stop mutation; single heterozygous truncating or missense mutations were found in another 4 Italian sporadic cases, including two novel mutations, Pro196Leu and Gln456Stop. Pathogenic mutations were not identified in the familial cases. Novel (Gln115Leu) and known polymorphisms were identified with similar frequency in cases and controls. In cases carrying single heterozygous mutation, cDNA analysis detected no additional mutations, and revealed a major pathogenic effect at mRNA level for the mutant C1366T/Gln456Stop allele. All patients with homozygous mutations had very early disease onset, slow progression, and excellent response to l-dopa, including, in some, symmetric onset, dystonia at onset, and sleep benefit, resembling parkin-related disease. Phenotype in patients with single heterozygous mutation was similar, but onset was later. CONCLUSIONS: PINK1 homozygous mutations are a relevant cause of disease among Italian sporadic patients with early-onset parkinsonism. The role of mutations found in single heterozygous state is difficult to interpret. Our study suggests that, at least in some patients, these mutations are disease causing, in combination with additional, still unknown factors.
Assuntos
Predisposição Genética para Doença/genética , Mutação/genética , Doença de Parkinson/genética , Proteínas Quinases/genética , Adolescente , Adulto , Idade de Início , Criança , Análise Mutacional de DNA , DNA Complementar/análise , DNA Complementar/genética , Feminino , Frequência do Gene , Testes Genéticos , Genoma/genética , Genótipo , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Doença de Parkinson/epidemiologia , Doença de Parkinson/fisiopatologia , Fenótipo , Polimorfismo Genético/genética , Homologia de Sequência de AminoácidosAssuntos
Cromossomos Humanos Par 11 , Ataxias Espinocerebelares/genética , Idade de Início , Criança , Mapeamento Cromossômico , Progressão da Doença , Feminino , Humanos , Escore Lod , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Linhagem , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/epidemiologiaRESUMO
BACKGROUND: International prevalence estimates of autosomal dominant cerebellar ataxias (ADCA) vary from 0.3 to 2.0 per 100,000. The prevalence of ADCA in the Netherlands is unknown. Fifteen genetic loci have been identified (SCA-1-8, SCA-10-14, SCA-16, and SCA-17) and nine of the corresponding genes have been cloned. In SCA-1, SCA2, SCA3, SCA6, SCA7, SCA-12 and SCA-17 the mutation has been shown to be an expanded CAG repeat. Previously, the length of the CAG repeat was found to account for 50 to 80% of variance in age at onset. Because of heterogeneity in encoded proteins, different pathophysiologic mechanisms leading to neurodegeneration could be involved. The relationship between CAG repeat length and age at onset would then differ accordingly. METHOD: Based on the results of SCA mutation analysis in the three DNA diagnostic laboratories that serve the entire Dutch population, the authors surveyed the number of families and affected individuals per SCA gene, as well as individual repeat length and age at onset. Regression analysis was applied to study the relationship between CAG repeat length and age at onset per SCA gene. The slopes of the different regression curves were compared. RESULTS: On November 1, 2000, mutations were found in 145 ADCA families and 391 affected individuals were identified. The authors extrapolated a minimal prevalence of 3.0 per 100,000 (range 2.8 to 3.8/100,000). SCA3 was the most frequent mutation. CAG repeat length contributed to 52 to 76% of age at onset variance. Regression curve slopes for SCA-1, SCA2, SCA3, and SCA7 did not differ significantly. CONCLUSIONS: The estimated minimal prevalence of ADCA in the Netherlands is 3.0 per 100,000 inhabitants. Except for SCA6, the relationship between age at onset and CAG repeat expansion does not differ significantly between SCA-1, SCA2, SCA3, and SCA7 patient groups in our population, indicating that these SCA subtypes share similar mechanisms of polyglutamine-induced neurotoxicity, despite heterogeneity in gene products.
Assuntos
Ataxias Espinocerebelares/epidemiologia , Ataxias Espinocerebelares/genética , Adulto , Idade de Início , Humanos , Pessoa de Meia-Idade , Mutação , Países Baixos/epidemiologia , Prevalência , Análise de Regressão , Ataxias Espinocerebelares/fisiopatologia , Expansão das Repetições de TrinucleotídeosRESUMO
Huntington's disease (HD) is a late onset, incurable, autosomal dominantly-inherited, progressive neuropsychiatric disease, characterised by chorea, changes in personality, mood and behaviour, and dementia. Huntington's disease is a clinical diagnosis. The advent of DNA diagnosis has made predictive, prenatal and preimplantation testing possible for at-risk persons or asymptomatic carriers. The prevalence is estimated to be 3-10/100,000 among individuals of European descent; HD is less common in other ethnic groups. Huntington's disease is caused by an expanded trinucleotide CAG repeat in the HD gene on chromosome 4. The gene encodes for the protein huntingtin, with an as yet unknown function. The mutated huntingtin has an elongated stretch of glutamines which leads to a gain of function such as overactivity, excitotoxicity, or to interactions with other proteins.
Assuntos
Cromossomos Humanos Par 4/genética , Doença de Huntington/genética , Mutação/genética , Expansão das Repetições de Trinucleotídeos , Sequência de Bases , Análise Mutacional de DNA , Diagnóstico Diferencial , Europa (Continente)/epidemiologia , Testes Genéticos/psicologia , Humanos , Proteína Huntingtina , Doença de Huntington/diagnóstico , Doença de Huntington/epidemiologia , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genéticaRESUMO
OBJECTIVES: Until recently a definite diagnosis of Huntington's disease could be made by a combination of clinical findings, a positive family history, and pathological confirmation. Prevalence data are based on these criteria. After finding the gene and its pathogenic mutation direct diagnostic confirmation became available. The aim of this study was to determine to what extent the direct assessment of CAG repeat length has allowed the diagnoses of additional patients, with atypical psychiatric or neurological disease, or those without a family history, that could otherwise not be diagnosed using traditional criteria. PATIENTS AND METHODS: From all 191 referred patients suspected of having Huntington's disease between July 1993 and January 1996 CAG repeat length was determined and the family history was reviewed in the Leiden roster. After a retrospective search the patients were subdivided in positive, negative, suspect, and unknown family histories. Patients with an expanded repeat (>35) were finally diagnosed as having Huntington's disease. The family history was compared with the repeat length and the clinical features. RESULTS: Clinical information was obtained for 172 patients. Of these, 126 patients had an expanded repeat, 77 had a positive, eight a negative, 40 a suspect, and one an unknown family history. Of the 44 patients with a normal repeat length four had a positive family history. Of the two patients with an intermediate repeat (between 30-36 repeats), one with a negative family history received a clinical diagnosis of Gilles de la Tourette's syndrome. The other had an unknown family history. CONCLUSION: Despite verification of the family history through the Leiden roster, many more patients and families could be diagnosed with the new approach than would have been possible with the traditional criteria. Because prevalence studies have been based on this type of information, the data suggest an underestimation of the prevalence of Huntington's disease in the community of 14%.
Assuntos
DNA/genética , Testes Genéticos , Doença de Huntington/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Doença de Huntington/diagnóstico , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Síndrome de Tourette/diagnóstico , Síndrome de Tourette/genética , Repetições de Trinucleotídeos/genéticaRESUMO
Little is known about the mechanism of CGG instability and the time frame of instability early in embryonic development in the fragile X syndrome. Discordant monozygotic twin brothers with the fragile X syndrome could give us insight into the time frame of the instability. We describe monochorionic diamniotic twin brothers with the fragile X syndrome who had different CGG repeats and different mental capacities, whereas the normal mother had a premutation. The more retarded brother had a full mutation in all his cells and no FMR-1 protein expression in lymphocytes, whereas the less retarded brother had 50%/50% mosaicism for a premutation and full mutation and FMR-1 protein expression in 26% of his lymphocytes. The differences in repeat size could have arisen either before or after the time of splitting. The time of splitting in this type of twin is around day 6-7. Given the high percentage of mosaicism, we hypothesise that the instability started before the time of splitting at day 6-7.
Assuntos
Síndrome do Cromossomo X Frágil/genética , Proteínas do Tecido Nervoso/genética , Proteínas de Ligação a RNA , Repetições de Trinucleotídeos , Gêmeos Monozigóticos/genética , Pré-Escolar , Metilação de DNA , Feminino , Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil/metabolismo , Síndrome do Cromossomo X Frágil/psicologia , Humanos , Masculino , Mutagênese , Proteínas do Tecido Nervoso/metabolismo , LinhagemRESUMO
Microscopically detectable deletions and X;autosome translocations have previously facilitated the construction of a high-resolution interval map of the Xq21 region. Here, we have generated three yeast artificial chromosome contigs spanning approximately 7 megabases of the Xq13.3-q21.31 region. In addition, a novel deletion associated with choroideremia and mental retardation was identified and mapped in detail. The proximal deletion endpoint was positioned between the loci DXS995 and DXS232, which enabled us to confirm the critical region for a locus involved in mental retardation. The distal deletion endpoint is situated in the Xq21.33 band, which allowed us to refine the order of several markers in this region.
Assuntos
Coroideremia/genética , Deleção Cromossômica , Cromossomos Artificiais de Levedura , Deficiência Intelectual/genética , Cromossomo X , Sequência de Bases , Mapeamento Cromossômico , Clonagem Molecular , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos , Linhagem , Translocação GenéticaRESUMO
Another possible sporadic case of the Ohdo blepharophimosis syndrome is described and compared with the seven patients previously reported. It can be considered a distinctive syndrome showing blepharophimosis, ptosis, dental hypoplasia, mental retardation and deafness. This case helps to define the spectrum of the phenotypic anomalies.
Assuntos
Anormalidades Múltiplas/fisiopatologia , Blefarofimose/fisiopatologia , Blefaroptose/fisiopatologia , Criança , Surdez/fisiopatologia , Humanos , Recém-Nascido , Deficiência Intelectual/fisiopatologia , Masculino , Síndrome , Anormalidades Dentárias/fisiopatologiaRESUMO
A patient is reported with the association of the oculo-auriculo-vertebral spectrum and situs inversus. Conditions with overlapping features and previously reported conditions associated with the oculo-auriculo-vertebral spectrum are reviewed. These conditions, as well as the reported association of the oculo-auriculo-vertebral spectrum and situs inversus can probably be seen as a part of the mesodermal malformation spectrum, due to an early abnormality in the development of the primitive streak or embryonic mesoderm.
Assuntos
Cardiopatias Congênitas/diagnóstico por imagem , Pulmão/anormalidades , Situs Inversus/diagnóstico por imagem , Coluna Vertebral/anormalidades , Vértebras Torácicas/anormalidades , Humanos , Lactente , Masculino , Radiografia , Coluna Vertebral/diagnóstico por imagem , Síndrome , Vértebras Torácicas/diagnóstico por imagemRESUMO
A girl with psychomotor retardation is described in whom the diagnosis phenylketonuria (PKU) was made at the age of 6.5 years. Previous investigations were not carried out as she was screened for PKU when she was a baby. Since the nationwide neonatal screening for PKU was started in 1974, 4 children have been detected with a false negative test result.
Assuntos
Deficiências do Desenvolvimento/etiologia , Fenilcetonúrias/sangue , Fenilcetonúrias/complicações , Doença Celíaca/diagnóstico , Criança , Diagnóstico Diferencial , Reações Falso-Negativas , Feminino , Humanos , Recém-Nascido , Programas de Rastreamento , Fenilcetonúrias/dietoterapiaRESUMO
Low birthweight as a symptom of the ectrodactyly ectodermal dysplasia clefting (EEC) syndrome is described before by Annerén. By presenting two patients (father and son) we give a brief review of the major and minor symptoms. We would like to add low birthweight as a minor symptom.
Assuntos
Anormalidades Múltiplas/diagnóstico , Fenda Labial/complicações , Fissura Palatina/complicações , Displasia Ectodérmica/complicações , Dedos/anormalidades , Dedos do Pé/anormalidades , Adulto , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Masculino , SíndromeRESUMO
The facial tumour described here is the first reported case of a large retinoblastoma detected early in pregnancy and adds another item to the differential diagnosis of facial tumours visualized by prenatal ultrasound examination. Ultrasound examination of the fetal eyes can be offered in cases of retinoblastomas where prenatal DNA diagnosis is otherwise impossible.
Assuntos
Neoplasias Oculares/diagnóstico por imagem , Retinoblastoma/diagnóstico por imagem , Ultrassonografia Pré-Natal , Adulto , Diagnóstico Diferencial , Neoplasias Oculares/patologia , Neoplasias Faciais/diagnóstico por imagem , Feminino , Humanos , Cariotipagem , Gravidez , Terceiro Trimestre da Gravidez , Retinoblastoma/patologia , Fatores de RiscoRESUMO
Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by widespread hamartosis. Preliminary evidence of linkage between the TSC locus and markers on chromosome 9q34 was established, but subsequently disputed. More recently, a putative TSC locus on chromosome 11 has been suggested and genetic heterogeneity seems likely. Here we describe an approach combining multipoint linkage analysis and heterogeneity tests that has enabled us to obtain significant evidence for locus heterogeneity after studying a relatively small number of families. Our results support a model with two different loci independently causing the disease. One locus (TSC1) maps in the vicinity of the Abelson oncogene at 9q34 and a second locus (TSC2) maps in the region of the anonymous DNA marker Lam L7 and the dopamine D2 receptor gene at 11q23.