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1.
Nat Commun ; 11(1): 6164, 2020 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-33268780

RESUMO

Familial hemiplegic migraine is an episodic neurological disorder characterized by transient sensory and motor symptoms and signs. Mutations of the ion pump α2-Na/K ATPase cause familial hemiplegic migraine, but the mechanisms by which α2-Na/K ATPase mutations lead to the migraine phenotype remain incompletely understood. Here, we show that mice in which α2-Na/K ATPase is conditionally deleted in astrocytes display episodic paralysis. Functional neuroimaging reveals that conditional α2-Na/K ATPase knockout triggers spontaneous cortical spreading depression events that are associated with EEG low voltage activity events, which correlate with transient motor impairment in these mice. Transcriptomic and metabolomic analyses show that α2-Na/K ATPase loss alters metabolic gene expression with consequent serine and glycine elevation in the brain. A serine- and glycine-free diet rescues the transient motor impairment in conditional α2-Na/K ATPase knockout mice. Together, our findings define a metabolic mechanism regulated by astrocytic α2-Na/K ATPase that triggers episodic motor paralysis in mice.


Assuntos
Astrócitos/metabolismo , Ataxia/genética , Metaboloma/genética , Enxaqueca com Aura/genética , ATPase Trocadora de Sódio-Potássio/genética , Transcriptoma , Animais , Astrócitos/patologia , Ataxia/metabolismo , Ataxia/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Eletroencefalografia , Feminino , Neuroimagem Funcional , Glicina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Enxaqueca com Aura/metabolismo , Enxaqueca com Aura/patologia , Teste de Desempenho do Rota-Rod , Serina/metabolismo , ATPase Trocadora de Sódio-Potássio/deficiência
2.
Zhonghua Er Ke Za Zhi ; 58(11): 928-932, 2020 Nov 02.
Artigo em Chinês | MEDLINE | ID: mdl-33120466

RESUMO

Objective: To explore the clinical characteristics and gene variation of primary coenzyme Q10 deficiency-7 (COQ10D7) in children. Methods: Clinical data and genetic tests results of a COQ10D7 child caused by coenzyme Q4 (COQ4) gene variation at the First Affiliated Hospital of Xiamen University in March 2020 were collected and analyzed. A literature search with "primary coenzyme Q10 deficiency" or "COQ4 gene" as the keyword was conducted at Wanfang database, China national knowledge infrastructure(CNKI), PubMed, online Mendelian inheritance in man(OMIM), ClinVar database (up to April 2020), the clinical characteristics and gene variation of children with primary COQ10D7 were summarized. Results: A 5-month-old boy was diagnosed as "epilepsy" because of intermittent epileptic seizures in three months. He had feeding difficulties, growth retardation, hypotonia of limbs and increased lactic acid. His whole exon gene testing suggested a homozygous variation of COQ4 gene (c.370G>A). One article in Chinese and 9 articles in English were found, which made up the complete case data of 33 patients (including our case). There were 12 missense variations, 2 frameshift variations, 1 splicing variation, 1 nonsense variation and 1 deletion variation, among these variations c. 370G>A was found only in children in southern China.The age of onset was mostly in the neonatal period (22 cases). Among all patients, 20 cases had presented neonatal respiratory distress or respiratory insufficiency, 21 cases had seizures, 20 cases had hypertrophic cardiomyopathy, and 26 cases had elevated serum lactic acid or lactic acidosis. Brain dysplasia, brain atrophy, basal ganglia and other lesions were observed on brain magnetic resonance imaging in 28 cases. Most of them had a poor prognosis with a mortality rate of 20/33. The age of death ranged from 4 hours to 42 months old. Conclusions: The main clinical phenotypes of primary COQ10D7 are neonatal respiratory distress or respiratory insufficiency, epilepsy, myocardial hypertrophy and lactic acid elevation. Primary COQ10D7 is caused by homozygous or compound heterozygous variation in the COQ4 gene, and c.370G>A may be the hotspot variation in children in southern China.


Assuntos
Ataxia , Doenças Mitocondriais , Debilidade Muscular , Ubiquinona/deficiência , Ataxia/diagnóstico , Ataxia/genética , Criança , China , Humanos , Lactente , Masculino , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Debilidade Muscular/diagnóstico , Debilidade Muscular/genética , Mutação , Ubiquinona/genética
3.
Nat Commun ; 11(1): 5267, 2020 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-33077711

RESUMO

Peroxisomes perform beta-oxidation of branched and very-long chain fatty acids, which leads to the formation of reactive oxygen species (ROS) within the peroxisomal lumen. Peroxisomes are therefore prone to ROS-mediated damages. Here, using light to specifically and acutely induce ROS formation within the peroxisomal lumen, we find that cells individually remove ROS-stressed peroxisomes through ubiquitin-dependent pexophagy. Heat shock protein 70 s mediates the translocation of the ubiquitin E3 ligase Stub1 (STIP1 Homology and U-Box Containing Protein 1) onto oxidatively-stressed peroxisomes to promote their selective ubiquitination and autophagic degradation. Artificially targeting Stub1 to healthy peroxisomes is sufficient to trigger pexophagy, suggesting a key role Stub1 plays in regulating peroxisome quality. We further determine that Stub1 mutants found in Ataxia patients are defective in pexophagy induction. Dysfunctional peroxisomal quality control may therefore contribute to the development of Ataxia.


Assuntos
Proteínas de Choque Térmico HSC70/metabolismo , Estresse Oxidativo , Peroxissomos/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Ataxia/genética , Ataxia/metabolismo , Ataxia/fisiopatologia , Transporte Biológico , Linhagem Celular , Proteínas de Choque Térmico HSC70/genética , Humanos , Macroautofagia , Peroxissomos/genética , Espécies Reativas de Oxigênio/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
4.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 2845-2848, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018599

RESUMO

FRM1 premutation carriers exhibit various subtle deficits in balance and stability, prior to the development of the movement disorder Fragile X Associated Tremor/Ataxia Syndrome (FXTAS). Force plate posturography has increasingly been combined with the temporal sensitive imaging methods such as EEG to offer insight into the neural mechanisms which govern postural control. This study investigated cortical theta power during continuous balance and its relationship to balance performance in Fragile X premutation carriers. Eight premutation carriers and 6 controls stood on a force platform under altered sensory and cognitive conditions while postural sway and high-density EEG data were simultaneously recorded. Carriers exhibited greater sway area when sensory input was reduced (p=0.01) and cognitive load was increased (p=0.01), as well as significantly reduced frontal theta power compared to the Control Group. The relationship between theta power and postural control seen in the control group may indicate an increase in error detection caused by reduced visual input and greater discrepancies between expected and actual balance state. While the lower theta power in frontal regions of carriers may indicate a disruption in neural networks underpinning postural control. Such results provide new insight into the neural correlates of balance control in Fragile X premutation carriers.


Assuntos
Síndrome do Cromossomo X Frágil , Equilíbrio Postural , Ataxia/genética , Proteína do X Frágil de Retardo Mental , Síndrome do Cromossomo X Frágil/genética , Humanos , Tremor/genética
5.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 2909-2912, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018615

RESUMO

Fragile X-associated Tremor/Ataxia Syndrome is a genetic neurodegenerative disorder affecting carriers of the FMR1 premutation. Not all carriers develop the condition and the age of onset is somewhat variable. A greater understanding of disease progression would be beneficial. Eight carriers and five controls matched by age, sex, and dominant hand volunteered to perform a sway task on a force platform while EEG was simultaneously recorded. Sway parameters were extracted from the movement data at important timepoints throughout their sway cycles and matched to their EEG activity. Distributed source analysis was applied. While there initially appeared to be differences in neural activity between the two groups in the anterior lobe, the right posterior lobe, the right superior parietal lobule and the right parietal lobe, these differences did not survive correction for multiple comparisons.


Assuntos
Proteína do X Frágil de Retardo Mental , Síndrome do Cromossomo X Frágil , Ataxia/genética , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Heterozigoto , Humanos , Tremor/genética
6.
Nat Commun ; 11(1): 5168, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33057011

RESUMO

The potassium ion (K+) channel plays a fundamental role in controlling K+ permeation across the cell membrane and regulating cellular excitabilities. Mutations in the transmembrane pore reportedly affect the gating transitions of K+ channels, and are associated with the onset of neural disorders. However, due to the lack of structural and dynamic insights into the functions of K+ channels, the structural mechanism by which these mutations cause K+ channel dysfunctions remains elusive. Here, we used nuclear magnetic resonance spectroscopy to investigate the structural mechanism underlying the decreased K+-permeation caused by disease-related mutations, using the prokaryotic K+ channel KcsA. We demonstrated that the conformational equilibrium in the transmembrane region is shifted toward the non-conductive state with the closed intracellular K+-gate in the disease-related mutant. We also demonstrated that this equilibrium shift is attributable to the additional steric contacts in the open-conductive structure, which are evoked by the increased side-chain bulkiness of the residues lining the transmembrane helix. Our results suggest that the alteration in the conformational equilibrium of the intracellular K+-gate is one of the fundamental mechanisms underlying the dysfunctions of K+ channels caused by disease-related mutations.


Assuntos
Proteínas de Bactérias/metabolismo , Ativação do Canal Iônico/genética , Canais de Potássio/metabolismo , Potássio/metabolismo , Alanina/genética , Ataxia/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/isolamento & purificação , Epilepsia/genética , Humanos , Síndrome do QT Longo/genética , Espectroscopia de Ressonância Magnética , Simulação de Dinâmica Molecular , Mutação de Sentido Incorreto , Canais de Potássio/genética , Canais de Potássio/isolamento & purificação , Conformação Proteica em alfa-Hélice/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Streptomyces lividans , Valina/genética
7.
Neurology ; 95(19): e2675-e2682, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-32887777

RESUMO

OBJECTIVE: To determine genotype-phenotype correlation in succinic semialdehyde dehydrogenase (SSADH) deficiency. METHODS: ALDH5A1 variants were studied with phenotype correlation in the SSADH natural history study. Assignment of gene variant pathogenicity was based on in silico testing and in vitro enzyme activity after site-directed mutagenesis and expression in HEK293 cells. Phenotypic scoring used a Clinical Severity Score (CSS) designed for the natural history study. RESULTS: Twenty-four patients were enrolled (10 male, 14 female, median age 8.2 years). There were 24 ALDH5A1 variants, including 7 novel pathogenic variants: 2 missense, 3 splice site, and 2 frameshift. Four previously reported variants were identified in >5% of unrelated families. There was a correlation with age and presence (p = 0.003) and severity (p = 0.002) of epilepsy and with obsessive-compulsive disorder (OCD) (p = 0.016). The median IQ score was 53 (Q25-Q75, 49-61). There was no overall correlation between the gene variants and the CSS, although a novel missense variant was associated with the mildest phenotype by CSS in the only patient with a normal IQ, whereas a previously reported variant was consistently associated with the most severe phenotype. CONCLUSIONS: Seven novel pathogenic and one previously unpublished benign ALDH5A1 variants were detected. There is an age-dependent association with worsening of epilepsy and presence of OCD in SSADH deficiency. Overall, there does not appear to be a correlation between genotype and phenotypic severity in this cohort of 24 patients. We did find a suspected correlation between a novel pathogenic missense variant and high functionality, and a previously reported pathogenic missense variant and maximal severity.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Deficiências do Desenvolvimento/genética , Succinato-Semialdeído Desidrogenase/deficiência , Adolescente , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Ataxia/genética , Ataxia/fisiopatologia , Criança , Simulação por Computador , Deficiências do Desenvolvimento/fisiopatologia , Eletroencefalografia , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Mutação da Fase de Leitura , Estudos de Associação Genética , Células HEK293 , Heterozigoto , Homozigoto , Humanos , Técnicas In Vitro , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Masculino , Hipotonia Muscular/genética , Hipotonia Muscular/fisiopatologia , Mutagênese Sítio-Dirigida , Mutação de Sentido Incorreto , Transtorno Obsessivo-Compulsivo/genética , Transtorno Obsessivo-Compulsivo/fisiopatologia , Sítios de Splice de RNA , Índice de Gravidade de Doença , Succinato-Semialdeído Desidrogenase/genética
8.
Biochim Biophys Acta Mol Basis Dis ; 1866(12): 165918, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800941

RESUMO

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disorder caused by an expansion of 55-200 CGG repeats at 5UTR of FMR1 gene, known as premutation. The main clinical and neuropathological features of FXTAS include progressive intention tremor, gait ataxia, neuronal cell loss and presence of ubiquitin-positive intranuclear inclusions in neurons and astrocytes. Various mitochondrial dysfunctions are reported in in vitro/vivo models of FXTAS; however, the molecular mechanisms underlying such mitochondrial dysfunctions are unclear. CGG expansions are pathogenic through distinct mechanisms involving RNA gain of function, impaired DNA damage repair and FMRpolyG toxicity. Here, we have systematically reviewed the reports of mitochondrial dysfunctions under premutation condition. We have also focused on potential emerging mechanisms to understand mitochondrial associated pathology in FXTAS. This review highlights the important role of mitochondria in FXTAS and other related disorders; and suggests focus of future studies on mitochondrial dysfunction along with other prevailing mechanisms to alleviate neurodegeneration.


Assuntos
Ataxia/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Mitocôndrias/metabolismo , Tremor/metabolismo , Animais , Ataxia/genética , Síndrome do Cromossomo X Frágil/genética , Humanos , Mitocôndrias/genética , Tremor/genética
10.
Sci Rep ; 10(1): 11099, 2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632326

RESUMO

Fragile X associated tremor/ataxia syndrome (FXTAS) is a late adult-onset neurodegenerative disorder that affects movement and cognition in male and female carriers of a premutation allele of 55-200 CGG repeats in the Fragile X mental retardation (FMR1) gene. It is currently unknown if and when an individual carrier of a premutation allele will develop FXTAS, as clinical assessment fails to identify carriers at risk before significant neurological symptoms are evident. The primary objective of this study was to investigate the alternative splicing landscape at the FMR1 locus in conjunction with brain measures in male individuals with a premutation allele enrolled in a very first longitudinal study, compared to age-matched healthy male controls, with the purpose of identifying biomarkers for early diagnosis, disease prediction and, a progression of FXTAS. Our findings indicate that increased expression of FMR1 mRNA isoforms, including Iso4/4b, Iso10/10b, as well as of the ASFMR1 mRNAs Iso131bp, are present in premutation carriers as compared to non-carrier healthy controls. More specifically, we observed a higher expression of Iso4/4b and Iso10/10b, which encode for truncated proteins, only in those premutation carriers who developed symptoms of FXTAS over time as compared to non-carrier healthy controls, suggesting a potential role in the development of the disorder. In addition, we found a significant association of these molecular changes with various measurements of brain morphology, including the middle cerebellar peduncle (MCP), superior cerebellar peduncle (SCP), pons, and midbrain, indicating their potential contribution to the pathogenesis of FXTAS. Interestingly, the high expression levels of Iso4/4b observed both at visit 1 and visit 2 and found to be associated with a decrease in mean MCP width only in those individuals who developed FXTAS over time, suggests their role as potential biomarkers for early diagnosis of FXTAS.


Assuntos
Ataxia/diagnóstico , Biomarcadores/análise , Encéfalo/metabolismo , Proteína do X Frágil de Retardo Mental/genética , Proteína do X Frágil de Retardo Mental/metabolismo , Síndrome do Cromossomo X Frágil/diagnóstico , Tremor/diagnóstico , Expansão das Repetições de Trinucleotídeos , Adulto , Idoso , Ataxia/genética , Ataxia/metabolismo , Estudos de Casos e Controles , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Isoformas de Proteínas , Tremor/genética , Tremor/metabolismo
12.
Adv Genet ; 105: 95-136, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32560791

RESUMO

The Fragile Mental Retardation 1 gene (FMR1), at Xq27.3, encodes the fragile mental retardation protein (FMRP), and displays in its 5'-untranslated region a series of polymorphic CGG triplet repeats that may undergo dynamic mutation. Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability among men, and is most frequently due to FMR1 full mutation and consequent transcription repression. FMR1 premutations may associate with at least two other clinical conditions, named fragile X-associated primary ovarian insufficiency (FXPOI) and tremor and ataxia syndrome (FXTAS). While FXPOI and FXTAS appear to be mediated by FMR1 mRNA accumulation, relative reduction of FMRP, and triplet repeat translation, FXS is due to the lack of the RNA-binding protein FMRP. Besides its function as mRNA translation repressor in neuronal and stem/progenitor cells, RNA editing roles have been assigned to FMRP. In this review, we provide a brief description of FMR1 transcribed microsatellite and associated clinical disorders, and discuss FMRP molecular roles in ribonucleoprotein complex assembly and trafficking, as well as aspects of RNA homeostasis affected in FXS cells.


Assuntos
Ataxia/genética , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Homeostase/genética , Insuficiência Ovariana Primária/genética , RNA/metabolismo , Ribonucleoproteínas/genética , Tremor/genética , Ataxia/metabolismo , Núcleo Celular/genética , Núcleo Celular/metabolismo , Citoplasma/genética , Citoplasma/metabolismo , Feminino , Proteína do X Frágil de Retardo Mental/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Humanos , Masculino , Mutação , Insuficiência Ovariana Primária/metabolismo , RNA/genética , Edição de RNA , Ribonucleoproteínas/metabolismo , Tremor/metabolismo
13.
Hum Genet ; 139(12): 1531-1539, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32533363

RESUMO

The fragile X premutation is defined by the expansion of the CGG trinucleotide repeat at the 5' UTR of the FMR1 gene to between 55 and 200 repeats, while repeat tracks longer than 200 are defined as full mutations. Men carrying a premutation are at increased risk for fragile X-associated tremor/ataxia syndrome (FXTAS); those with > 200 repeats have fragile X syndrome, a common genetic form of intellectual disabilities. In our study, we tested the hypothesis that men carrying a fragile X premutation or full mutation are "biologically older", as suggested by the associated age-related disorder in the presence of the fragile X premutation or the altered cellular pathology that affects both the fragile X premutation and full mutation carriers. Thus, we predicted that both groups would have shorter telomeres than men carrying the normal size repeat allele. Using linear regression models, we found that, on average, premutation carriers had shorter telomeres compared with non-carriers (n = 69 vs n = 36; p = 0.02) and that there was no difference in telomere length between full mutation carriers and non-carriers (n = 37 vs n = 29; p > 0.10). Among premutation carriers only, we also asked whether telomere length was shorter among men with vs without symptoms of FXTAS (n = 28 vs n = 38 and n = 27 vs n = 41, depending on criteria) and found no evidence for a difference (p > 0.10). Previous studies have shown that the premutation is transcribed whereas the full mutation is not, and the expanded repeat track in FMR1 transcript is thought to lead to the risk for premutation-associated disorders. Thus, our data suggest that the observed premutation-only telomere shortening may be a consequence of the toxic effect of the premutation transcript and suggest that premutation carriers are "biologically older" than men carrying the normal size allele in the same age group.


Assuntos
Ataxia/genética , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Telômero/genética , Tremor/genética , Regiões 5' não Traduzidas/genética , Adulto , Idoso , Alelos , Ataxia/patologia , Síndrome do Cromossomo X Frágil/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Telômero/patologia , Telômero/ultraestrutura , Homeostase do Telômero/genética , Tremor/patologia , Expansão das Repetições de Trinucleotídeos/genética , Adulto Jovem
14.
Eur J Med Genet ; 63(7): 103941, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32407885

RESUMO

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a recently described autosomal dominant syndrome of developmental delay, cortical vision loss with optic nerve atrophy, epilepsy, and autism spectrum disorder. Due to its many overlapping features with congenital disorders of glycosylation (CDG), the differential diagnosis between these disorders may be difficult and relies on molecular genetic testing. We report on a 31-year-old female initially diagnosed with ALG6-CDG based on glycosylation abnormalities on transferrin isoelectrofocusing and targeted genetic testing, and later diagnosed with BBSOAS by whole-exome sequencing (WES). Functional studies on cultured fibroblasts including Western blotting and RT-qPCR, as well as mass spectrometry of glycosylated transferrin and MALDI-TOF glycan analysis in serum, demonstrated normal glycosylation in this patient. In this report, we extend the phenotype of BBSOAS with ataxia and protein-losing enteropathy. This case is illustrative of the utility of whole exome sequencing in the diagnostic odyssey, and the potential pitfalls of relying on focused genetic testing results for diagnosis of conditions with complex overlapping phenotypes.


Assuntos
Defeitos Congênitos da Glicosilação/genética , Glucosiltransferases/genética , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Atrofias Ópticas Hereditárias/genética , Fenótipo , Adulto , Ataxia/genética , Transtorno do Espectro Autista/genética , Epilepsia/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Testes Genéticos , Glicosilação , Humanos , Deficiência Intelectual/diagnóstico , Mutação , Atrofias Ópticas Hereditárias/diagnóstico , Atrofia Óptica/diagnóstico , Atrofia Óptica/genética , Sequenciamento Completo do Exoma
15.
BMC Neurol ; 20(1): 145, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32312236

RESUMO

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset, X-linked genetic, neurodegenerative disorder caused by a "premutation (PM)" in the fragile X mental retardation 1 (FMR1) gene. Here we report a case of FXTAS from mainland of China who presented with rare orthostatic tremor. A review of tremor of FXTAS in the literature is also included. CASE PRESENTATION: A 67-year-old right-handed farmer started with tremor of both legs 8 years ago which was present while standing but absent when sitting or lying and progressed with unsteady gait one and a half years ago. The brain MRI showed high intensity signal in the bilateral middle cerebellar peduncles (MCP) in T2-weighted and fluid-attenuated inversion recovery (FLAIR) images and gene test for premutation for FMR1 was positive with 101 CGG repeats. The patient met the the diagnosis of definite FXTAS. Clonazepam and topiramate were administered to control tremor. We reviewed the literature and identified 64 cases with detailed clinical and genetic information. Orthostatic tremor associated with FXTAS is very rare. We found 85.2% patients reported tremor,42.6% with intention tremor,36.1% with kinetic tremor,32.8% with rest tremor and 29.5% with posture tremor. 37.7% of patients who have tremor showed at least two types of tremor. There were 6 patients with isolated rest tremor. There was 2 patient with voice tremor and 6 with head tremor. We also found that 74.6% FXTAS patients had family history of FMR1 gene associated diseases including Fragile X syndrome (FXS), FXTAS or fragile X-associated primary ovarian insufficiency (FXPOI). CONCLUSIONS: Adding our data to the available literature suggests that orthostatic tremor could be a rare initial manifestation of FXTAS and the review will increasing our understanding the phenotype of tremor in FXTAS. Family history of FMR1 gene associated diseases might be an important clue to the diagnosis.


Assuntos
Ataxia , Síndrome do Cromossomo X Frágil , Tremor , Idoso , Anticonvulsivantes/uso terapêutico , Ataxia/diagnóstico , Ataxia/tratamento farmacológico , Ataxia/genética , Ataxia/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Clonazepam/uso terapêutico , Síndrome do Cromossomo X Frágil/diagnóstico , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Humanos , Imagem por Ressonância Magnética , Masculino , Topiramato/uso terapêutico , Tremor/diagnóstico , Tremor/tratamento farmacológico , Tremor/genética , Tremor/fisiopatologia
16.
BMC Neurol ; 20(1): 155, 2020 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-32336275

RESUMO

BACKGROUND: To investigate the genetic and environmental factors responsible for phenotype variability in a family carrying a novel CACNA1A missense mutation. Mutations in the CACNA1A gene were identified as responsible for at least three autosomal dominant disorders: FHM1 (Familial Hemiplegic Migraine), EA2 (Episodic Ataxia type 2), and SCA6 (Spinocerebellar Ataxia type 6). Overlapping clinical features within individuals of some families sharing the same CACNA1A mutation are not infrequent. Conversely, reports with distinct phenotypes within the same family associated with a common CACNA1A mutation are very rare. CASE PRESENTATION: A clinical, molecular, neuroradiological, neuropsychological, and neurophysiological study was carried out in proband and his carrier mother. The new heterozygous missense variant c.4262G > A (p.Arg1421Gln) in the CACNA1A gene was detected in the two affected family members. The proband showed a complex clinical presentation characterized by developmental delay, poor motor coordination, hemiplegic migraine attacks, behavioral dysregulation, and EEG abnormalities. The mother showed typical episodic ataxia attacks during infancy with no other comorbidities and mild cerebellar signs at present neurological evaluation. CONCLUSIONS: The proband and his mother exhibit two distinct clinical phenotypes. It can be hypothesized that other unknown modifying genes and/or environmental factors may cooperate to generate the wide intrafamilial variability.


Assuntos
Ataxia/genética , Canais de Cálcio/genética , Enxaqueca com Aura/genética , Nistagmo Patológico/genética , Criança , Família , Humanos , Masculino , Mutação de Sentido Incorreto , Fenótipo
18.
Int J Mol Sci ; 21(8)2020 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-32316562

RESUMO

Mutations in the KCNA1 gene, which encodes voltage-gated Kv1.1 potassium channel α-subunits, cause a variety of human diseases, complicating simple genotype-phenotype correlations in patients. KCNA1 mutations are primarily associated with a rare neurological movement disorder known as episodic ataxia type 1 (EA1). However, some patients have EA1 in combination with epilepsy, whereas others have epilepsy alone. KCNA1 mutations can also cause hypomagnesemia and paroxysmal dyskinesia in rare cases. Why KCNA1 variants are associated with such phenotypic heterogeneity in patients is not yet understood. In this review, literature databases (PubMed) and public genetic archives (dbSNP and ClinVar) were mined for known pathogenic or likely pathogenic mutations in KCNA1 to examine whether patterns exist between mutation type and disease manifestation. Analyses of the 47 deleterious KCNA1 mutations that were identified revealed that epilepsy or seizure-related variants tend to cluster in the S1/S2 transmembrane domains and in the pore region of Kv1.1, whereas EA1-associated variants occur along the whole length of the protein. In addition, insights from animal models of KCNA1 channelopathy were considered, as well as the possible influence of genetic modifiers on disease expressivity and severity. Elucidation of the complex relationship between KCNA1 variants and disease will enable better diagnostic risk assessment and more personalized therapeutic strategies for KCNA1 channelopathy.


Assuntos
Ataxia/genética , Epilepsia/genética , Canal de Potássio Kv1.1/genética , Mutação , Animais , Comorbidade , Estudos de Associação Genética , Humanos , Canal de Potássio Kv1.1/química , Domínios Proteicos
19.
J Biol Chem ; 295(20): 7075-7095, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32277048

RESUMO

Genetic screening has identified numerous variants of the endosomal solute carrier family 9 member A6 (SLC9A6)/(Na+,K+)/H+ exchanger 6 (NHE6) gene that cause Christianson syndrome, a debilitating X-linked developmental disorder associated with a range of neurological, somatic, and behavioral symptoms. Many of these variants cause complete loss of NHE6 expression, but how subtler missense substitutions or nonsense mutations that partially truncate its C-terminal cytoplasmic regulatory domain impair NHE6 activity and endosomal function are poorly understood. Here, we describe the molecular and cellular consequences of six unique mutations located in the N-terminal cytoplasmic segment (A9S), the membrane ion translocation domain (L188P and G383D), and the C-terminal regulatory domain (E547*, R568Q, and W570*) of human NHE6 that purportedly cause disease. Using a heterologous NHE6-deficient cell expression system, we show that the biochemical, catalytic, and cellular properties of the A9S and R568Q variants were largely indistinguishable from those of the WT transporter, which obscured their disease significance. By contrast, the L188P, G383D, E547*, and W570* mutants exhibited variable deficiencies in biosynthetic post-translational maturation, membrane sorting, pH homeostasis in recycling endosomes, and cargo trafficking, and they also triggered apoptosis. These findings broaden our understanding of the molecular dysfunctions of distinct NHE6 variants associated with Christianson syndrome.


Assuntos
Ataxia , Endossomos , Epilepsia , Doenças Genéticas Ligadas ao Cromossomo X , Deficiência Intelectual , Microcefalia , Mutação de Sentido Incorreto , Transtornos da Motilidade Ocular , Trocadores de Sódio-Hidrogênio , Substituição de Aminoácidos , Animais , Ataxia/genética , Ataxia/metabolismo , Cricetinae , Endossomos/química , Endossomos/genética , Endossomos/metabolismo , Epilepsia/genética , Epilepsia/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Microcefalia/genética , Microcefalia/metabolismo , Transtornos da Motilidade Ocular/genética , Transtornos da Motilidade Ocular/metabolismo , Domínios Proteicos , Trocadores de Sódio-Hidrogênio/química , Trocadores de Sódio-Hidrogênio/genética , Trocadores de Sódio-Hidrogênio/metabolismo
20.
Lakartidningen ; 1172020 03 09.
Artigo em Sueco | MEDLINE | ID: mdl-32154899

RESUMO

Ataxias constitute a group of heterogeneous diseases with overlapping symptoms. The clinical investigation should primarily seek for treatable conditions such as neurometabolic disorders and autoimmune diseases. Rapid progression is often characteristic for paraneoplastic cerebellar degeneration, autoimmune diseases or multiple system atrophy (MSA). The rapid development of massive parallel DNA sequencing and its increased accessibility have enabled for improved diagnostic resolution of patients. A diagnosis based on the etiology is crucial for prognosis and treatment of ataxias. In hereditary forms, the identification of causative genetic factors is essential for family planning.


Assuntos
Ataxia , Doenças Autoimunes , Ataxia/genética , Ataxia/imunologia , Humanos , Análise de Sequência de DNA
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