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1.
Hum Mutat ; 34(2): 296-300, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23086778

RESUMO

Kohlschütter-Tönz syndrome (KTS) is a rare autosomal recessive disorder characterized by amelogenesis imperfecta, psychomotor delay or regression and seizures starting early in childhood. KTS was established as a distinct clinical entity after the first report by Kohlschütter in 1974, and to date, only a total of 20 pedigrees have been reported. The genetic etiology of KTS remained elusive until recently when mutations in ROGDI were independently identified in three unrelated families and in five likely related Druze families. Herein, we report a clinical and genetic study of 10 KTS families. By using a combination of whole exome sequencing, linkage analysis, and Sanger sequencing, we identify novel homozygous or compound heterozygous ROGDI mutations in five families, all presenting with a typical KTS phenotype. The other families, mostly presenting with additional atypical features, were negative for ROGDI mutations, suggesting genetic heterogeneity of atypical forms of the disease.


Assuntos
Amelogênese Imperfeita/genética , Demência/genética , Epilepsia/genética , Heterogeneidade Genética , Proteínas de Membrana/genética , Proteínas Nucleares/genética , Pré-Escolar , Exoma , Feminino , Deleção de Genes , Ligação Genética , Humanos , Lactente , Masculino , Mutação , Linhagem , Fenótipo , Análise de Sequência de DNA
2.
Cerebellum ; 12(4): 596-9, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23436002

RESUMO

Ataxia-telangiectasia-like disorder (ATLD) due to mutations in the MRE11 gene is a very rare autosomal recessive disease, described so far in only 20 patients. Little is known about the onset of the first symptoms or the clinical course of the disease. The present report contributes to the diagnosis of ATLD and its prognosis at onset. We report 30 years of clinical and ophthalmic observations and the results of quantitative magnetic resonance (MR), MR spectroscopy (proton magnetic resonance spectroscopic imaging) and neuropsychological assessment in the first Italian siblings identified with ATLD. Although the disease had early onset and the clinical picture was initially severe, suggesting ataxia-telangiectasia, neurological impairment, ocular motor apraxia and neuropsychological tests showed very slow deterioration in adult age. The patients developed eye and head motor strategies to compensate ocular motor apraxia. MR measurements and MR spectroscopy disclosed widespread neuronal and axonal involvement. ATLD should be considered in patients with ocular apraxia and ataxia in infancy. The long follow-up provided insights into clinical outcome, with functional neuroimaging studies shedding light on the pathogenetic mechanisms of this rare disease.


Assuntos
Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/genética , Irmãos , Adulto , Feminino , Seguimentos , Humanos , Itália , Masculino , Pessoa de Meia-Idade
3.
Ann Neurol ; 68(5): 611-8, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20853438

RESUMO

OBJECTIVE: Neurodegeneration with brain iron accumulation (NBIA) represents a distinctive phenotype of neurodegenerative disease for which several causative genes have been identified. The spectrum of neurologic disease associated with mutations in NBIA genes is broad, with phenotypes that range from infantile neurodegeneration and death in childhood to adult-onset parkinsonism-dystonia. Here we report the discovery of a novel gene that leads to a distinct form of NBIA. METHODS: Using autozygosity mapping and candidate gene sequencing, we identified mutations in the fatty acid hydroxylase gene FA2H, newly implicating abnormalities of ceramide metabolism in the pathogenesis of NBIA. RESULTS: Neuroimaging demonstrated T2 hypointensity in the globus pallidus, confluent T2 white matter hyperintensities, and profound pontocerebellar atrophy in affected members of two families. Phenotypically, affected family members exhibited spastic quadriparesis, ataxia, and dystonia with onset in childhood and episodic neurological decline. Analogous to what has been reported previously for PLA2G6, the phenotypic spectrum of FA2H mutations is diverse based on our findings and those of prior investigators, because FA2H mutations have been identified in both a form of hereditary spastic paraplegia (SPG35) and a progressive familial leukodystrophy. INTERPRETATION: These findings link white matter degeneration and NBIA for the first time and implicate new signaling pathways in the genesis of NBIA.


Assuntos
Encéfalo/metabolismo , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos Heredodegenerativos do Sistema Nervoso/metabolismo , Ferro/metabolismo , Oxigenases de Função Mista/genética , Adolescente , Adulto , Encéfalo/patologia , Criança , Mapeamento Cromossômico/métodos , Diagnóstico por Imagem/métodos , Feminino , Transtornos Heredodegenerativos do Sistema Nervoso/patologia , Humanos , Masculino , Mutação , Linhagem
4.
Hum Mutat ; 30(3): E500-19, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19105190

RESUMO

Autosomal recessive spastic paraplegia with thinning of corpus callosum (ARHSP-TCC) is a complex form of HSP initially described in Japan but subsequently reported to have a worldwide distribution with a particular high frequency in multiple families from the Mediterranean basin. We recently showed that ARHSP-TCC is commonly associated with mutations in SPG11/KIAA1840 on chromosome 15q. We have now screened a collection of new patients mainly originating from Italy and Brazil, in order to further ascertain the spectrum of mutations in SPG11, enlarge the ethnic origin of SPG11 patients, determine the relative frequency at the level of single Countries (i.e., Italy), and establish whether there is one or more common mutation. In 25 index cases we identified 32 mutations; 22 are novel, including 9 nonsense, 3 small deletions, 4 insertions, 1 in/del, 1 small duplication, 1 missense, 2 splice-site, and for the first time a large genomic rearrangement. This brings the total number of SPG11 mutated patients in the SPATAX collection to 111 cases in 44 families and in 17 isolated cases, from 16 Countries, all assessed using homogeneous clinical criteria. While expanding the spectrum of mutations in SPG11, this larger series also corroborated the notion that even within apparently homogeneous population a molecular diagnosis cannot be achieved without full gene sequencing.


Assuntos
Agenesia do Corpo Caloso , Deleção de Genes , Mutação , Proteínas/genética , Paraplegia Espástica Hereditária/genética , Adolescente , Adulto , Argélia , Sequência de Bases , Brasil , Análise Mutacional de DNA , Saúde da Família , Feminino , Frequência do Gene , Genes Recessivos , Testes Genéticos , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Marrocos , Linhagem , Portugal , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/etnologia , Adulto Jovem
5.
J Neurol Sci ; 260(1-2): 265-6, 2007 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-17509615

RESUMO

We report the clinical and therapeutic approach of a case of 'dystonia gravidarum'. The patient came to our observation with neck and bilateral feet dystonia, appearing after the onset of pregnancy. She was treated with clonazepam, 0.5 mg three times a day, during the pregnancy. After delivery of a healthy full-term child by caesarean section, she was completely able to turn her neck to either side.


Assuntos
Distonia/tratamento farmacológico , Distonia/fisiopatologia , Músculo Esquelético/fisiopatologia , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/fisiopatologia , Adulto , Anticonvulsivantes/uso terapêutico , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/fisiopatologia , Clonazepam/uso terapêutico , Distonia/etiologia , Feminino , Pé/inervação , Pé/fisiopatologia , Humanos , Hipotireoidismo/complicações , Hipotireoidismo/fisiopatologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/inervação , Pescoço/inervação , Pescoço/fisiopatologia , Gravidez , Prognóstico , Resultado do Tratamento , Tremor/complicações , Tremor/fisiopatologia
6.
Orphanet J Rare Dis ; 10: 22, 2015 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-25888393

RESUMO

BACKGROUND: Twenty-five patients with Niemann Pick disease type C (age range: 7 months to 44 years) were enrolled in an Italian independent multicenter trial and treated with miglustat for periods from 48 to 96 months. METHODS: Based on the age at onset of neurological manifestations patients' phenotypes were classified as: adult (n = 6), juvenile (n = 9), late infantile (n = 6), early infantile (n = 2). Two patients had an exclusively visceral phenotype. We clinically evaluated patients' neurological involvement, giving a score of severity ranging from 0 (best) to 3 (worst) for gait abnormalities, dystonia, dysmetria, dysarthria, and developmental delay/cognitive impairment, and from 0 to 4 for dysphagia. We calculated a mean composite severity score transforming the original scores proportionally to range from 0 to 1 to summarize the clinical picture of patients and monitor their clinical course. RESULTS: We compared the results after 24 months of treatment in 23 patients showing neurological manifestations. Stabilization or improvement of all parameters was observed in the majority of patients. With the exception of developmental delay/cognitive impairment, these results persisted after 48-96 months in 41 - 55% of the patients (dystonia: 55%, dysarthria: 50%, gait abnormalities: 43%, dysmetria: 41%, respectively). After 24 months of therapy the majority of the evaluable patients (n = 20), demonstrated a stabilization or improvement in the ability to swallow four substances of different consistency (water: 65%, purée: 58%, little pasta: 60%, biscuit: 55%). These results persisted after 48-96 months in 40-50% of patients, with the exception of water swallowing. Stabilization or improvement of the composite severity score was detected in the majority (57%) of 7 patients who were treated early (within 3.5 years from onset) and rarely in patients who received treatment later. CONCLUSIONS: The results of this study suggest that miglustat treatment can improve or stabilize neurological manifestations, at least for a period of time; the severity of clinical conditions at the beginning of treatment can influence the rate of disease progression. This conclusion applies particularly to patients with juvenile or adult onset of the disease. TRIAL REGISTRATION: EudraCT number 2006-005842-35.


Assuntos
1-Desoxinojirimicina/análogos & derivados , Inibidores Enzimáticos/uso terapêutico , Doença de Niemann-Pick Tipo C/tratamento farmacológico , 1-Desoxinojirimicina/administração & dosagem , 1-Desoxinojirimicina/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Esquema de Medicação , Inibidores Enzimáticos/administração & dosagem , Feminino , Humanos , Lactente , Itália/epidemiologia , Masculino , Doença de Niemann-Pick Tipo C/epidemiologia , Adulto Jovem
7.
J Neurol Sci ; 221(1-2): 105-8, 2004 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-15178223

RESUMO

We report the case of a 51-year-old woman with anosmia and chronic sensory ataxic neuropathy. Olfactory tests suggested neurosensory anosmia. Immunocytochemical analysis showed serum antibodies against dorsal root ganglion (DRG) cells and olfactory neurons, in the absence of other known causes of anosmia and sensory neuropathy. Clinical and laboratory data suggested a slow autoimmune process affecting dorsal root ganglion and olfactory cells.


Assuntos
Anticorpos/sangue , Gânglios Espinais/imunologia , Transtornos do Olfato/imunologia , Nervo Olfatório/imunologia , Polirradiculoneuropatia/imunologia , Ataxia/imunologia , Feminino , Humanos , Pessoa de Meia-Idade , Fibras Nervosas Mielinizadas/patologia , Transtornos do Olfato/complicações , Polirradiculoneuropatia/complicações , Nervo Sural/patologia
8.
Hum Mol Genet ; 13(18): 2155-63, 2004 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-15269180

RESUMO

Hypomorphic mutations of the MRE11 gene are the hallmark of the radiosensitive ataxia-telangiectasia-like disorder (ATLD). Here, we describe a new family with two affected siblings, ATLD5 and ATLD6, now aged 37 and 36, respectively. They presented with late onset cerebellar degeneration slowly progressing until puberty and absence of telangiectasias, and were cancer-free. Both patients were wild-type for ATM and NBS1, but compound heterozygotes for MRE11 gene mutations [1422C-->A, T481K; 1714C-->T, R571X]. The 1422C-->A allele was inherited from the mother, whereas the 1714C-->T, allele paternally inherited, was apparently null as a result of nonsense-mediated mRNA decay (NMD). Interestingly, the 1714C-->T mutation is the same as previously identified in an unrelated English ATLD family (probands ATLD3 and ATLD4), suggesting an important role for NMD in saving potentially lethal mutations. Lymphoblastoid cell lines (LCLs) derived from ATLD5 and ATLD6 were normal for ATM, but defective for Mre11, Rad50 and Nbs1 (the MRN complex) protein expression. Their response to gamma-radiation was abnormal, as evidenced by the enhanced radiosensitivity, attenuated autophosphorylation of ATM-S1981 and phosphorylation of the ATM targets p53-S15 and Smc1-S966, failure to form Mre11 nuclear foci and defective G1 checkpoint arrest. The fibroblasts, but not LCLs, from ATLD5 and ATLD6 showed an impaired ATM-dependent Chk2 phosphorylation. These findings further underscore the interconnection between ATM activity and MRN function, which rationalizes the clinical similarity between ataxia-telangiectasia (A-T) and ATLD.


Assuntos
Ataxia Telangiectasia/genética , Ataxia Telangiectasia/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Mutação/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adulto , Alelos , Ataxia Telangiectasia/etnologia , Proteínas Mutadas de Ataxia Telangiectasia , Ciclo Celular/genética , Núcleo Celular/imunologia , Núcleo Celular/metabolismo , Células Cultivadas , Quinase do Ponto de Checagem 2 , Análise Mutacional de DNA , Proteínas de Ligação a DNA/análise , Feminino , Fibroblastos/imunologia , Fibroblastos/metabolismo , Heterozigoto , Humanos , Itália , Linfócitos/efeitos da radiação , Proteína Homóloga a MRE11 , Masculino , Proteínas Nucleares/metabolismo , Fosforilação
9.
J Lipid Res ; 43(11): 1908-19, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12401890

RESUMO

We analyzed Niemann-Pick type C disease 1 (NPC1) gene in 12 patients with Niemann-Pick type C disease by sequencing both cDNA obtained from fibroblasts and genomic DNA. All the patients were compound heterozygotes. We found 15 mutations, eight of which previously unreported. The comparison of cDNA and genomic DNA revealed discrepancies in some subjects. In two unrelated patients carrying the same mutations (P474L and nt 2972del2) only one mutant allele (P474L), was expressed in fibroblasts. The mRNA corresponding to the other allele was not detected even in cells incubated with cycloheximide. The promoter variants (-1026T/G and -1186T/C or -238 C/G), found to be in linkage with 2972del2 allele do not explain the lack of expression of this allele, as they were also found in control subjects. In another patient, (N1156S/Q922X) the N1156S allele was expressed in fibroblasts while the expression of the other allele was hardly detectable. In a fourth patient cDNA analysis revealed a point mutation in exon 20 (P1007A) and a 56 nt deletion in exon 22 leading to a frameshift and a premature stop codon. The first mutation was confirmed in genomic DNA; the second turned out to be a T-->G transversion in exon 22, predicted to cause a missense mutation (V1141G). In fact, this transversion generates a donor splice site in exon 22, which causes an abnormal pre-mRNA splicing leading to a partial deletion of this exon. In some NPC patients, therefore, the comparison between cDNA and genomic DNA may reveal an unexpected expression of some mutant alleles of NPC1 gene.


Assuntos
Alelos , Proteínas de Transporte/genética , Regulação da Expressão Gênica/genética , Glicoproteínas de Membrana/genética , Mutação/genética , Doenças de Niemann-Pick/genética , Adolescente , Adulto , Idade de Início , Sequência de Aminoácidos , Sequência de Bases , Proteínas de Transporte/química , Criança , Pré-Escolar , DNA Complementar/genética , Éxons/genética , Feminino , Fibroblastos , Testes Genéticos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Glicoproteínas de Membrana/química , Dados de Sequência Molecular , Proteína C1 de Niemann-Pick , Polimorfismo Genético/genética , Sítios de Splice de RNA/genética
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