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1.
Hum Genet ; 139(2): 227-245, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31919630

RESUMO

Fragile X-related disorders are due to a dynamic mutation of the CGG repeat at the 5' UTR of the FMR1 gene, coding for the RNA-binding protein FMRP. As the CGG sequence expands from premutation (PM, 56-200 CGGs) to full mutation (> 200 CGGs), FMRP synthesis decreases until it is practically abolished in fragile X syndrome (FXS) patients, mainly due to FMR1 methylation. Cells from rare individuals with no intellectual disability and carriers of an unmethylated full mutation (UFM) produce slightly elevated levels of FMR1-mRNA and relatively low levels of FMRP, like in PM carriers. With the aim of clarifying how UFM cells differ from CTRL and FXS cells, a comparative proteomic approach was undertaken, from which emerged an overexpression of SOD2 in UFM cells, also confirmed in PM but not in FXS. The SOD2-mRNA bound to FMRP in UFM more than in the other cell types. The high SOD2 levels in UFM and PM cells correlated with lower levels of superoxide and reactive oxygen species (ROS), and with morphological anomalies and depolarization of the mitochondrial membrane detected through confocal microscopy. The same effect was observed in CTRL and FXS after treatment with MC2791, causing SOD2 overexpression. These mitochondrial phenotypes reverted after knock-down with siRNA against SOD2-mRNA and FMR1-mRNA in UFM and PM. Overall, these data suggest that in PM and UFM carriers, which have high levels of FMR1 transcription and may develop FXTAS, SOD2 overexpression helps to maintain low levels of both superoxide and ROS with signs of mitochondrial degradation.


Assuntos
Ataxia/patologia , Metilação de DNA , Proteína do X Frágil de Retardo Mental/metabolismo , Síndrome do Cromossomo X Frágil/patologia , Mitocôndrias/patologia , Proteínas Mitocondriais/metabolismo , Mutação , Proteoma/análise , Tremor/patologia , Ataxia/genética , Ataxia/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Fibroblastos/metabolismo , Fibroblastos/patologia , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , Humanos , Masculino , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , RNA Interferente Pequeno/genética , Superóxido Dismutase/antagonistas & inibidores , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Tremor/genética , Tremor/metabolismo
3.
Artigo em Inglês | MEDLINE | ID: mdl-31413903

RESUMO

Background: KIF1C (Kinesin Family Member 1C) variants have been associated with hereditary spastic paraplegia and spastic ataxia. Case report: We report fraternal twins presenting with cerebellar ataxia and dystonic tremor. Their brain MRI showed a hypomyelinating leukoencephalopathy. Whole exome sequencing identified a homozygous KIF1C variant in both patients. Discussion: KIF1C variants can manifest as a complex movement disorder with cerebellar ataxia and dystonic tremor. KIF1C variants may also cause a hypomyelinating leukoencephalopathy.


Assuntos
Ataxia Cerebelar/genética , Cinesina/genética , Mutação/genética , Tremor/genética , Adolescente , Ataxia Cerebelar/diagnóstico , Distonia/genética , Distúrbios Distônicos , Feminino , Humanos , Masculino , Paraplegia Espástica Hereditária/genética , Tremor/diagnóstico , Gêmeos Dizigóticos
4.
Nat Genet ; 51(8): 1222-1232, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31332380

RESUMO

Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.


Assuntos
Ataxia/genética , Encéfalo/patologia , Síndrome do Cromossomo X Frágil/genética , Marcadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Distrofias Musculares/genética , Doenças Neurodegenerativas/genética , Tremor/genética , Expansão das Repetições de Trinucleotídeos/genética , Adulto , Ataxia/patologia , Encéfalo/metabolismo , Estudos de Casos e Controles , Feminino , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/patologia , Estudo de Associação Genômica Ampla , Humanos , Corpos de Inclusão Intranuclear/genética , Corpos de Inclusão Intranuclear/patologia , Desequilíbrio de Ligação , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Masculino , Pessoa de Meia-Idade , Distrofias Musculares/patologia , Mutação , Doenças Neurodegenerativas/patologia , Neuroimagem/métodos , Linhagem , Tremor/patologia
5.
J Clin Neurosci ; 66: 269-270, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31178302

RESUMO

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder associated with dysfunction of movement, memory, and the peripheral nervous system. We report an 82 years old male who presented with tremors and difficulty with balance that started at 65 years of age. His motor examination revealed decreased strength in left lower extremity. Tremors were seen in both the upper limbs at rest that worsened with movement. Bilateral lower extremities showed absent vibration and proprioception sensations, absent reflexes and upgoing toes. Electrodiagnostic studies revealed sensory predominant axonal sensory-motor peripheral polyneuropathy. Brain MRI revealed microvascular ischemic changes. The cervical and lumbar MRI showed diffuse degenerative changes. Genetic test for heritable causes of ataxia revealed a premutation in Fragile X gene (84 CGG repeats), confirming the diagnosis of FXTAS. On further genetic testing three out of his four daughters also tested positive for the FMR1 premutation. In appropriate clinical setting, Fragile X-associated tremor/ataxia syndrome (FXTAS) should be considered in every middle aged/elderly patient who presented with slowly progressive ataxia, tremor and peripheral polyneuropathy without any history of cognitive or neurological disabilities in childhood.


Assuntos
Ataxia/diagnóstico , Ataxia/genética , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/diagnóstico , Síndrome do Cromossomo X Frágil/genética , Tremor/diagnóstico , Tremor/genética , Idoso de 80 Anos ou mais , Testes Genéticos/métodos , Humanos , Masculino
6.
Pract Neurol ; 19(3): 196-207, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31048364

RESUMO

Progressive ataxia in adults can be difficult to diagnose, owing to its heterogeneity and the rarity of individual causes. Many patients remain undiagnosed ('idiopathic' ataxia). This paper provides suggested diagnostic pathways for the general neurologist, based on Ataxia UK's guidelines for professionals. MR brain scanning can provide diagnostic clues, as well as identify 'structural' causes such as tumours and multiple sclerosis. Advances in molecular genetics, including the wider and cheaper availability of 'next-generation sequencing', have enabled clinicians to identify many more cases with a genetic cause. Finally, autoimmunity is probably an under-recognised cause of progressive ataxia: as well as patients with antigliadin antibodies there are smaller numbers with various antibodies, including some associated with cancer. There are a few treatable ataxias, but also symptomatic treatments to help people with the spectrum of complications that might accompany progressive ataxias. Multidisciplinary team involvement and allied health professionals' input are critical to excellent patient care, including in the palliative phase. We can no longer justify a nihilistic approach to the management of ataxia.


Assuntos
Ataxia/diagnóstico , Ataxia/terapia , Degenerações Espinocerebelares/genética , Adulto , Ataxia/complicações , Encéfalo/metabolismo , Encéfalo/patologia , Testes Genéticos , Humanos , Mutação/genética , Degenerações Espinocerebelares/complicações , Tremor/genética
7.
Ann Neurol ; 85(5): 681-690, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30854718

RESUMO

OBJECTIVE: Degenerative cerebellar ataxias (DCAs) affect up to 1 in 5,000 people worldwide, leading to incoordination, tremor, and falls. Loss of Purkinje cells, nearly universal across DCAs, dysregulates the dentatothalamocortical network. To address the paucity of treatment strategies, we developed an electrical stimulation-based therapy for DCAs targeting the dorsal dentate nucleus. METHODS: We tested this therapeutic strategy in the Wistar Furth shaker rat model of Purkinje cell loss resulting in tremor and ataxia. We implanted shaker rats with stimulating electrodes targeted to the dorsal dentate nucleus and tested a spectrum of frequencies ranging from 4 to 180 Hz. RESULTS: Stimulation at 30 Hz most effectively reduced motor symptoms. Stimulation frequencies >100 Hz, commonly used for parkinsonism and essential tremor, worsened incoordination, and frequencies within the tremor physiologic range may worsen tremor. INTERPRETATION: Low-frequency deep cerebellar stimulation may provide a novel strategy for treating motor symptoms of degenerative cerebellar ataxias. Ann Neurol 2019;85:681-690.


Assuntos
Ataxia Cerebelar/terapia , Cerebelo/fisiologia , Estimulação Encefálica Profunda/métodos , Eletrodos Implantados , Tremor/terapia , Animais , Ataxia Cerebelar/genética , Ataxia Cerebelar/fisiopatologia , Estimulação Encefálica Profunda/instrumentação , Células de Purkinje/fisiologia , Ratos , Ratos Transgênicos , Ratos Wistar , Tremor/genética , Tremor/fisiopatologia
8.
Methods Mol Biol ; 1942: 173-189, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30900185

RESUMO

Individuals carrying an FMR1 expansion between 55 and 200 CGG repeats, are at risk of developing the Fragile X-associated tremor/ataxia syndrome (FXTAS), a late onset neurodegenerative disorder characterized by cerebellar gait ataxia, intentional tremor, neuropathy, parkinsonism, cognitive decline, and psychological disorders, such as anxiety and depression. In addition, brain atrophy, white matter disease, and hyperintensities of the middle cerebellar peduncles can also be present. The neuropathological distinct feature of FXTAS is represented by the presence of eosinophilic intranuclear inclusions in neurons and astrocytes throughout the brain and in other tissues. In this chapter, protocols for available diagnostic tools, in both humans and mice, the clinical features and the basic molecular mechanisms leading to FXTAS and the animal models proposed to study this disorder are discussed.


Assuntos
Ataxia/diagnóstico , Encéfalo/patologia , Modelos Animais de Doenças , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/diagnóstico , Mutação , Tremor/diagnóstico , Animais , Ataxia/genética , Encéfalo/metabolismo , Feminino , Síndrome do Cromossomo X Frágil/genética , Humanos , Corpos de Inclusão Intranuclear , Masculino , Camundongos , Tremor/genética , Repetições de Trinucleotídeos
10.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1379-1388, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30771487

RESUMO

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disorder caused by an expansion of 55 to 200 CGG repeats (premutation) in FMR1. These CGG repeats are Repeat Associated non-ATG (RAN) translated into a small and pathogenic protein, FMRpolyG. The cellular and molecular mechanisms of FMRpolyG toxicity are unclear. Various mitochondrial dysfunctions have been observed in FXTAS patients and animal models. However, the causes of these mitochondrial alterations are not well understood. In the current study, we investigated interaction of FMRpolyG with mitochondria and its role in modulating mitochondrial functions. Beside nuclear inclusions, FMRpolyG also formed small cytosolic aggregates that interact with mitochondria both in cell and mouse model of FXTAS. Importantly, expression of FMRpolyG reduces ATP levels, mitochondrial transmembrane potential, mitochondrial supercomplexes assemblies and activities and expression of mitochondrial DNA encoded transcripts in cell and animal model of FXTAS, as well as in FXTAS patient brain tissues. Overall, these results suggest that FMRpolyG alters mitochondrial functions, bioenergetics and initiates cell death. The further study in this direction will help to establish the role of mitochondria in FXTAS conditions.


Assuntos
Ataxia/genética , Complexo de Proteínas da Cadeia de Transporte de Elétrons/genética , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Mitocôndrias/genética , RNA Mensageiro/genética , Tremor/genética , Expansão das Repetições de Trinucleotídeos , Trifosfato de Adenosina/biossíntese , Idoso , Idoso de 80 Anos ou mais , Animais , Ataxia/metabolismo , Ataxia/patologia , Linhagem Celular Tumoral , Cerebelo/metabolismo , Cerebelo/patologia , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Modelos Animais de Doenças , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Metabolismo Energético/genética , Proteína do X Frágil de Retardo Mental/química , Proteína do X Frágil de Retardo Mental/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Síndrome do Cromossomo X Frágil/patologia , Expressão Gênica , Células HEK293 , Humanos , Potencial da Membrana Mitocondrial/genética , Camundongos , Camundongos Transgênicos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neurônios/metabolismo , Neurônios/patologia , Agregados Proteicos/genética , RNA Mensageiro/metabolismo , Tremor/metabolismo , Tremor/patologia
12.
Neuropediatrics ; 49(6): 373-378, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30114719

RESUMO

Neonatal-onset movement disorders, especially in combination with seizures, are rare and often related to mitochondrial disorders. 3-methylglutaconic aciduria (3-MGA-uria) is a marker for mitochondrial dysfunction. In particular, consistently elevated urinary excretion of 3-methylglutaconic acid is the hallmark of a small but growing group of inborn errors of metabolism (IEM) due to defective phospholipid remodeling or mitochondrial membrane-associated disorders (mutations in TAZ, SERAC1, OPA3, CLPB, DNAJC19, TMEM70, TIMM50). Exome/genome sequencing is a powerful tool for the diagnosis of the clinically and genetically heterogeneous mitochondrial disorders. Here, we report 11 individuals, of whom 2 are previously unpublished, with biallelic variants in high temperature requirement protein A2 (HTRA2) encoding a mitochondria-localized serine protease. All individuals presented a recognizable phenotype with neonatal- or infantile-onset neurodegeneration and death within the first month of life. Hallmark features were central hypopnea/apnea leading to respiratory insufficiency, seizures, neutropenia, 3-MGA-uria, tonus dysregulation, and dysphagia. Tremor, jitteriness, dystonia, and/or clonus were also common. HTRA2 defect should be grouped under the IEM with 3-MGA-uria as discriminating feature. Clinical characteristics overlap with other disorders of this group suggesting a common underlying pathomechanism. Urinary organic acid analysis is a noninvasive and inexpensive test that can guide further genetic testing in children with suggestive clinical findings.


Assuntos
Deficiências do Desenvolvimento , Epilepsia , Serina Peptidase 2 de Requerimento de Alta Temperatura A/deficiência , Erros Inatos do Metabolismo , Doenças Mitocondriais , Transtornos dos Movimentos , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/genética , Distonia/diagnóstico , Distonia/etiologia , Distonia/genética , Epilepsia/diagnóstico , Epilepsia/etiologia , Epilepsia/genética , Evolução Fatal , Feminino , Humanos , Lactente , Recém-Nascido , Doenças do Recém-Nascido , Masculino , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Doenças Mitocondriais/complicações , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/etiologia , Transtornos dos Movimentos/genética , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/genética , Tremor/diagnóstico , Tremor/etiologia , Tremor/genética
13.
Epileptic Disord ; 20(4): 289-294, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30078772

RESUMO

SCN8A encephalopathy is a newly defined epileptic encephalopathy caused by de novo mutations of the SCN8A gene. We report herein a four-year-old boy presenting with severe non-epileptic abnormal movements, of possibly antenatal onset, progressively associated with pharmacoresistant epilepsy and regression, associated with a de novo heterozygous missense mutation of SCN8A. This case shows that paroxysmal non-epileptic episodes of severe tremor and hyperekplexia-like startles and a striking vegetative component can be the first early symptoms of severe SCN8A developmental and epileptic encephalopathy. Clinicians should be aware of these symptoms in order to avoid misdiagnosis and ensure early appropriate therapeutic management. [Published with video sequences on www.epilepticdisorders.com].


Assuntos
Encefalopatias , Epilepsia , Hiperecplexia , Doenças do Recém-Nascido , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Tremor , Encefalopatias/diagnóstico , Encefalopatias/genética , Encefalopatias/fisiopatologia , Pré-Escolar , Epilepsia/diagnóstico , Epilepsia/genética , Epilepsia/fisiopatologia , Humanos , Hiperecplexia/diagnóstico , Hiperecplexia/genética , Hiperecplexia/fisiopatologia , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/genética , Doenças do Recém-Nascido/fisiopatologia , Masculino , Tremor/diagnóstico , Tremor/genética , Tremor/fisiopatologia
14.
Clin Neurol Neurosurg ; 173: 173-175, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30149304

RESUMO

A 60-year-old man was admitted to our hospital. He had mild tremor in his four extremities when supine or sitting, which was markedly exacerbated when standing. We diagnosed him with Machado-Joseph disease according to the genetic test. His tremor improved with clonazepam, trihexyphenidyl, and a rotigotine patch.


Assuntos
Clonazepam/uso terapêutico , Doença de Machado-Joseph/tratamento farmacológico , Tremor/tratamento farmacológico , Triexifenidil/uso terapêutico , Eletromiografia/métodos , Humanos , Doença de Machado-Joseph/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Resultado do Tratamento , Tremor/genética
16.
J Genet ; 97(3): 665-677, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30027902

RESUMO

The inappropriate genetic expansion of various repetitive DNA sequences underlies over 20 distinct inherited diseases. The genetic context of these repeats in exons, introns and untranslated regions has played a major role in thinking about the mechanisms by which various repeat expansions might cause disease. Repeat expansions in exons are thought to give rise to expanded toxic protein repeats (i.e. polyQ). Repeat expansions in introns and UTRs (i.e. FXTAS) are thought to produce aberrant repeat-bearing RNAs that interact with and sequester a wide variety of essential proteins, resulting in cellular toxicity. However, a new phenomenon termed 'repeat-associated nonAUG dependent (RAN) translation' paints a new and unifying picture of how distinct repeat expansion-bearing RNAs might act as substrates for this noncanonical form of translation, leading to the production of a wide range of repeat sequence-specific-encoded toxic proteins. Here, we review how the model system Caenorhabditis elegans has been utilized to model many repeat disorders and discuss how RAN translation could be a previously unappreciated contributor to the toxicity associated with these different models.


Assuntos
Ataxia/genética , Ataxia/patologia , Caenorhabditis elegans/genética , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/patologia , Tremor/genética , Tremor/patologia , Expansão das Repetições de Trinucleotídeos/genética , Animais , Modelos Animais de Doenças , Humanos
17.
Brain ; 141(8): 2280-2288, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29939203

RESUMO

Familial cortical myoclonic tremor with epilepsy is an autosomal dominant neurodegenerative disease, characterized by cortical tremor and epileptic seizures. Although four subtypes (types 1-4) mapped on different chromosomes (8q24, 2p11.1-q12.2, 5p15.31-p15.1 and 3q26.32-3q28) have been reported, the causative gene has not yet been identified. Here, we report the genetic study in a cohort of 20 Chinese pedigrees with familial cortical myoclonic tremor with epilepsy. Linkage and haplotype analysis in 11 pedigrees revealed maximum two-point logarithm of the odds (LOD) scores from 1.64 to 3.77 (LOD scores in five pedigrees were >3.0) in chromosomal region 8q24 and narrowed the candidate region to an interval of 4.9 Mb. Using whole-genome sequencing, long-range polymerase chain reaction and repeat-primed polymerase chain reaction, we identified an intronic pentanucleotide (TTTCA)n insertion in the SAMD12 gene as the cause, which co-segregated with the disease among the 11 pedigrees mapped on 8q24 and additional seven unmapped pedigrees. Only two pedigrees did not contain the (TTTCA)n insertion. Repeat-primed polymerase chain reaction revealed that the sizes of (TTTCA)n insertion in all affected members were larger than 105 repeats. The same pentanucleotide insertion (ATTTCATTTC)58 has been reported to form RNA foci resulting in neurotoxicity in spinocerebellar ataxia type 37, which suggests the similar pathogenic process in familial cortical myoclonic tremor with epilepsy type 1.


Assuntos
Epilepsias Mioclônicas/genética , Repetições de Microssatélites/genética , Proteínas do Tecido Nervoso/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , China , Mapeamento Cromossômico , Epilepsias Mioclônicas/fisiopatologia , Epilepsia/genética , Grupos Étnicos/genética , Feminino , Ligação Genética , Haplótipos , Humanos , Íntrons/genética , Masculino , Pessoa de Meia-Idade , Mutagênese Insercional/genética , Proteínas do Tecido Nervoso/fisiologia , Doenças Neurodegenerativas/genética , Linhagem , Tremor/genética
18.
Harefuah ; 157(4): 241-244, 2018 Apr.
Artigo em Hebraico | MEDLINE | ID: mdl-29688643

RESUMO

INTRODUCTION: Fragile X Syndrome (FXS), the most common form of inherited mental retardation, is caused by a trinucleotide repeat expansion (CGG) in the 5'-untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene located at Xq27.3. Patients with fragile X -related mental retardation, carry the full mutation CGG-repeat expansions (>200 CGG repeats), which are generally accompanied by hypermethylation of the promoter region, with the consequent transcriptional silencing of the FMR1 gene and absence of the encoded FMR1 protein (FMRP). Expansion of the CGG triplet number above the normal range (n=5-54) towards the so-called premutation status (n=55-199) is associated with increased risk for Fragile X-Associated Premature Ovarian Insufficiency (FXPOI) in females and Fragile X-Associated Tremor/ Ataxia Syndrome (FXTAS) predominantly in males. In addition, premutation women carriers are at increased risk for learning disabilities, as well as psychologic, endocrine, autoimmune and metabolic disorders. The observation that premutation carriers, both males and females, have increased FMR1 transcript levels, led researchers to suggest a similar molecular pathogenesis in both FXPOI and FXTAS. Two models have been proposed as the culprits of FXTAS and FXPOI: The toxic RNA gain-of-function model and the Repeat Associated Non-AUG initiated (RAN) translation protein toxicity model. The Fragile X Multidisciplinary Center in Sheba Medical Center, at Tel Hashomer includes a team of geneticists, fertility specialists, endocrinologists, psychologists and neurologists who work together in order to provide early detection of FMR1 premutation carriers and offer FMR1 premutation carriers and their families adequate multidisciplinary medical consultation, follow-up and care.


Assuntos
Ataxia/genética , Síndrome do Cromossomo X Frágil/genética , Insuficiência Ovariana Primária/genética , Tremor/genética , Expansão das Repetições de Trinucleotídeos/genética , Portador Sadio , Feminino , Proteína do X Frágil de Retardo Mental/genética , Humanos , Masculino , Mutação
19.
Dev Period Med ; 22(1): 14-21, 2018.
Artigo em Polonês | MEDLINE | ID: mdl-29641417

RESUMO

Fragile X syndrome (FXS) is the second most common inherited cause of intellectual disability (ID), after Down syndrome. The severity of ID in FXS patients varies and depends mainly on the patient's sex. Besides intellectual disorders, additional symptoms, such as psychomotor delay, a specific behavioral phenotype, or emotional problems are present in FXS patients. In over 99% of the cases, the disease is caused by the presence of a dynamic mutation in the FMR1 gene localized on the X chromosome. Due to the expansion of CGG nucleotides (over 200 repeats), FMR1 gene expression is decreased and results in the significant reduction of the FMRP protein level. The CGG expansion to premutation range (55-200 CGG repeats) is equivalent to the FXS carrier status and may cause FMR1-dependent disorders - fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS). In contrast to FXS, clinical symptoms of these diseases occur later in adulthood. The aim of the article is to present the knowledge about the molecular background and epidemiology of fragile X syndrome and other FMR1-related disorders.


Assuntos
Ataxia/patologia , Expansão das Repetições de DNA , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/patologia , Regulação da Expressão Gênica , Insuficiência Ovariana Primária/patologia , Tremor/patologia , Ataxia/epidemiologia , Ataxia/genética , Ataxia/metabolismo , Feminino , Síndrome do Cromossomo X Frágil/epidemiologia , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , Humanos , Masculino , Mutação , Insuficiência Ovariana Primária/epidemiologia , Insuficiência Ovariana Primária/genética , Insuficiência Ovariana Primária/metabolismo , Tremor/epidemiologia , Tremor/genética , Tremor/metabolismo
20.
Dev Period Med ; 22(1): 22-32, 2018.
Artigo em Polonês | MEDLINE | ID: mdl-29641418

RESUMO

The presence of dynamic mutation in the FMR1 gene localized on the X chromosome (Xq28) is the major cause of Fragile X syndrome. As this syndrome is quite frequently diagnosed in patients with intellectual disability and autism spectrum disorders, the genetic testing of the FMR1 gene is a routine procedure performed in these patients. Molecular methods based on the PCR technique are used commonly, as they allow to identify normal (up to 54 CGG repeats, including grey zone alleles - 45-54 CGG repeats), premutation (55-200 CGG repeats) and full mutation (>200 CGG repeats) alleles.The article presents the basic methods used in the molecular diagnosis of Fragile X syndrome and other FMR1-related disorders. The following methods are presented: a screening test with GeneScan analysis, TP-PCR based tests and methods used for methylation analysis. Their pros and cons, as well as the resulting interpretation are discussed. Moreover, there is a presentation of the molecular diagnostic scheme following European Molecular Genetics Quality Network guidelines used in the Department of Medical Genetics.


Assuntos
Expansão das Repetições de DNA , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/diagnóstico , Ataxia/diagnóstico , Ataxia/genética , Feminino , Síndrome do Cromossomo X Frágil/genética , Humanos , Masculino , Mutação , Guias de Prática Clínica como Assunto , Insuficiência Ovariana Primária/diagnóstico , Insuficiência Ovariana Primária/genética , Tremor/diagnóstico , Tremor/genética
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