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1.
BMC Neurol ; 24(1): 154, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38714961

RESUMO

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by CGG repeat expansion of FMR1 gene. Both FXTAS and neuronal intranuclear inclusion disease (NIID) belong to polyglycine diseases and present similar clinical, radiological, and pathological features, making it difficult to distinguish these diseases. Reversible encephalitis-like attacks are often observed in NIID. It is unclear whether they are presented in FXTAS and can be used for differential diagnosis of NIID and FXTAS. CASE PRESENTATION: A 63-year-old Chinese male with late-onset gait disturbance, cognitive decline, and reversible attacks of fever, consciousness impairment, dizziness, vomiting, and urinary incontinence underwent neurological assessment and examinations, including laboratory tests, electroencephalogram test, imaging, skin biopsy, and genetic test. Brain MRI showed T2 hyperintensities in middle cerebellar peduncle and cerebrum, in addition to cerebellar atrophy and DWI hyperintensities along the corticomedullary junction. Lesions in the brainstem were observed. Skin biopsy showed p62-positive intranuclear inclusions. The possibilities of hypoglycemia, lactic acidosis, epileptic seizures, and cerebrovascular attacks were excluded. Genetic analysis revealed CGG repeat expansion in FMR1 gene, and the number of repeats was 111. The patient was finally diagnosed as FXTAS. He received supportive treatment as well as symptomatic treatment during hospitalization. His encephalitic symptoms were completely relieved within one week. CONCLUSIONS: This is a detailed report of a case of FXTAS with reversible encephalitis-like episodes. This report provides new information for the possible and rare features of FXTAS, highlighting that encephalitis-like episodes are common in polyglycine diseases and unable to be used for differential diagnosis.


Assuntos
Ataxia , Encefalite , Síndrome do Cromossomo X Frágil , Tremor , Humanos , Masculino , Pessoa de Meia-Idade , Tremor/diagnóstico , Tremor/genética , Tremor/etiologia , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/diagnóstico , Síndrome do Cromossomo X Frágil/complicações , Ataxia/diagnóstico , Ataxia/genética , Encefalite/diagnóstico , Encefalite/complicações , Encefalite/genética , Encefalite/patologia , Proteína do X Frágil da Deficiência Intelectual/genética , Diagnóstico Diferencial , Corpos de Inclusão Intranuclear/patologia , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/complicações
2.
Artigo em Inglês | MEDLINE | ID: mdl-38737299

RESUMO

Background: Tremor disorders have various genetic causes. Case report: A 60-year-old female with a family history of tremor presented a combined tremor syndrome, transient episodes of loss of contact and speech disturbances, as well as distal painful symptoms. Genetic screening revealed a novel heterozygous missense variant in the KCNQ2 gene. Discussion: The KCNQ2 protein regulates action potential firing, and mutations in its gene are associated with epilepsy and neuropathic pain. The identified variant, although of uncertain significance, may disrupt KCNQ2 function and also play a role in tremor pathogenesis. This case highlights the importance of genetic screening in combined tremor disorders.


Assuntos
Canal de Potássio KCNQ2 , Mutação de Sentido Incorreto , Tremor , Humanos , Feminino , Canal de Potássio KCNQ2/genética , Pessoa de Meia-Idade , Tremor/genética , Tremor/fisiopatologia
3.
Sensors (Basel) ; 24(8)2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38676203

RESUMO

FXTAS is a neurodegenerative disorder occurring in some Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene premutation carriers (PMCs) and is characterized by cerebellar ataxia, tremor, and cognitive deficits that negatively impact balance and gait and increase fall risk. Dual-tasking (DT) cognitive-motor paradigms and challenging balance conditions may have the capacity to reveal markers of FXTAS onset. Our objectives were to determine the impact of dual-tasking and sensory and stance manipulation on balance in FXTAS and potentially detect subtle postural sway deficits in FMR1 PMCs who are asymptomatic for signs of FXTAS on clinical exam. Participants with FXTAS, PMCs without FXTAS, and controls underwent balance testing using an inertial sensor system. Stance, vision, surface stability, and cognitive demand were manipulated in 30 s trials. FXTAS participants had significantly greater total sway area, jerk, and RMS sway than controls under almost all balance conditions but were most impaired in those requiring vestibular control. PMCs without FXTAS had significantly greater RMS sway compared with controls in the feet apart, firm, single task conditions both with eyes open and closed (EC) and the feet together, firm, EC, DT condition. Postural sway deficits in the RMS postural sway variability domain in asymptomatic PMCs might represent prodromal signs of FXTAS. This information may be useful in providing sensitive biomarkers of FXTAS onset and as quantitative balance measures in future interventional trials and longitudinal natural history studies.


Assuntos
Ataxia , Síndrome do Cromossomo X Frágil , Equilíbrio Postural , Tremor , Humanos , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Tremor/genética , Tremor/fisiopatologia , Equilíbrio Postural/fisiologia , Masculino , Pessoa de Meia-Idade , Feminino , Ataxia/genética , Ataxia/fisiopatologia , Idoso , Biomarcadores , Proteína do X Frágil da Deficiência Intelectual/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Adulto , Sintomas Prodrômicos
4.
Exp Neurol ; 376: 114772, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38599366

RESUMO

Animals on Earth need to hold postures and execute a series of movements under gravity and atmospheric pressure. VAChT-Cre is a transgenic Cre driver mouse line that expresses Cre recombinase selectively in motor neurons of S-type (slow-twitch fatigue-resistant) and FR-type (fast-twitch fatigue-resistant). Sequential motor unit recruitment is a fundamental principle for fine and smooth locomotion; smaller-diameter motor neurons (S-type, FR-type) first contract low-intensity oxidative type I and type IIa muscle fibers, and thereafter larger-diameter motor neurons (FInt-type, FF-type) are recruited to contract high-intensity glycolytic type IIx and type IIb muscle fibers. To selectively eliminate S- and FR-type motor neurons, VAChT-Cre mice were crossbred with NSE-DTA mice in which the cytotoxic diphtheria toxin A fragment (DTA) was expressed in Cre-expressing neurons. The VAChT-Cre;NSE-DTA mice were born normally but progressively manifested various characteristics, including body weight loss, kyphosis, kinetic and postural tremor, and muscular atrophy. The progressive kinetic and postural tremor was remarkable from around 20 weeks of age and aggravated. Muscular atrophy was apparent in slow muscles, but not in fast muscles. The increase in motor unit number estimation was detected by electromyography, reflecting compensatory re-innervation by remaining FInt- and FF-type motor neurons to the orphaned slow muscle fibers. The muscle fibers gradually manifested fast/slow hybrid phenotypes, and the remaining FInt-and FF-type motor neurons gradually disappeared. These results suggest selective ablation of S- and FR-type motor neurons induces progressive muscle fiber-type transition, exhaustion of remaining FInt- and FF-type motor neurons, and late-onset kinetic and postural tremor in mice.


Assuntos
Camundongos Transgênicos , Neurônios Motores , Tremor , Animais , Neurônios Motores/patologia , Neurônios Motores/fisiologia , Camundongos , Tremor/genética , Tremor/fisiopatologia , Fibras Musculares de Contração Lenta/patologia , Fibras Musculares de Contração Rápida/patologia , Doenças Musculares/fisiopatologia , Doenças Musculares/patologia , Doenças Musculares/etiologia , Fadiga Muscular/fisiologia , Postura/fisiologia , Animais Recém-Nascidos , Modelos Animais de Doenças
5.
Mol Biol Rep ; 51(1): 480, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38578387

RESUMO

Fragile X syndrome (FXS) is a genetic disorder characterized by mutation in the FMR1 gene, leading to the absence or reduced levels of fragile X Messenger Ribonucleoprotein 1 (FMRP). This results in neurodevelopmental deficits, including autistic spectrum conditions. On the other hand, Fragile X-associated tremor/ataxia syndrome (FXTAS) is a distinct disorder caused by the premutation in the FMR1 gene. FXTAS is associated with elevated levels of FMR1 mRNA, leading to neurodegenerative manifestations such as tremors and ataxia.Mounting evidence suggests a link between both syndromes and mitochondrial dysfunction (MDF). In this minireview, we critically examine the intricate relationship between FXS, FXTAS, and MDF, focusing on potential therapeutic avenues to counteract or mitigate their adverse effects. Specifically, we explore the role of mitochondrial cofactors and antioxidants, with a particular emphasis on alpha-lipoic acid (ALA), carnitine (CARN) and Coenzyme Q10 (CoQ10). Findings from this review will contribute to a deeper understanding of these disorders and foster novel therapeutic strategies to enhance patient outcomes.


Assuntos
Síndrome do Cromossomo X Frágil , Doenças Mitocondriais , Humanos , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/genética , Tremor/tratamento farmacológico , Tremor/genética , Antioxidantes/uso terapêutico , Ataxia/tratamento farmacológico , Ataxia/genética , Proteína do X Frágil da Deficiência Intelectual/genética
6.
Neurology ; 102(8): e209296, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38507676

RESUMO

A 35-year-old woman with a progressive, bilateral upper limb tremor, personality change, behavioral disturbance, and primary ovarian insufficiency was found to have AARS2-related leukodystrophy. She had congenital nystagmus which evolved to head titubation by age 8 years and then developed an upper limb tremor in her mid-teens. These symptoms stabilized during her 20s, but soon after this presentation at age 35 years, neurologic and behavioral disturbances progressed rapidly over a 12-month period requiring transition to an assisted living facility with care support (4 visits/day) and assistance for all activities of daily living. MRI of the brain demonstrated confluent white matter changes predominantly involving the frontal lobes consistent with a leukodystrophy. All other investigations were unremarkable. Nongenetic causes of a leukodystrophy including sexually transmitted diseases and recreational drug use were excluded. Family history was negative for similar symptoms. Gene panel testing identified compound heterozygous pathogenic AARS2 mutations. This case highlights the importance of MRI brain imaging in progressive tremor syndromes, the utility of gene panels in simultaneous testing of multiple disorders with overlapping phenotypes, and the need for awareness of comorbid endocrinological disorders in many of the genetic leukodystrophies, whose identification may aid in clinical diagnosis.


Assuntos
Doenças Desmielinizantes , Leucoencefalopatias , Doenças Neurodegenerativas , Humanos , Feminino , Adolescente , Adulto , Criança , Tremor/genética , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Atividades Cotidianas , Mutação , Encéfalo/diagnóstico por imagem , Encéfalo/patologia
7.
Artigo em Inglês | MEDLINE | ID: mdl-38550904

RESUMO

Background: Evaluating tremor severity is a critical component of diagnosing and clinically managing patients with essential tremor (ET). We examined the comparability of tremor severity ratings derived from two frequently used tremor rating scales: the Washington Heights-Inwood Genetic Study of Essential Tremor (WHIGET) rating scale and the Tremor Research Group Essential Tremor Rating Scale (TETRAS). Methods: A trained assistant administered and videotaped a neurological examination, including eight items assessing upper limb action tremor (arms outstretched, arms in the wingbeat position, finger-nose-finger maneuver, and drawing of Archimedes spirals). An experienced movement disorders neurologist reviewed the videos and assigned WHIGET and TETRAS ratings. We calculated associations between TETRAS and WHIGET ratings using Spearman rank order correlations. Subsequently, we collapsed these ratings into four tremor severity categories (absent, mild, moderate, severe) and then two broader tremor severity categories (absent/mild, moderate/severe). We calculated weighted Kappa coefficients to assess agreement between category assignments based on the TETRAS and the WHIGET. Results: Spearman's r' s were significant for all items (p's ≤ 0.001, mean r = 0.89). Weighted Kappa's revealed substantial to near perfect agreement for all eight items (mean k = 0.86, range = 0.64 to 1.00). Conclusion: Analyses revealed substantial strength of association and substantial to near perfect agreement between items rated with the WHIGET and TETRAS scales. These data indicated that ratings provided by each scale are highly comparable.


Assuntos
Tremor Essencial , Tremor , Humanos , Tremor/diagnóstico , Tremor/genética , Tremor Essencial/diagnóstico , Washington , Exame Neurológico , Extremidade Superior
9.
Genes (Basel) ; 15(2)2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38397227

RESUMO

While the manifestations of many inherited retinal disorders are limited to loss of vision, others are part of a syndrome that affects multiple tissues, particularly the nervous system. Most syndromic retinal disorders are thought to be recessively inherited. Two dogs out of a litter of Cirneco dell' Etna dogs, both males, showed signs of retinal degeneration, along with tremors and signs described as either atypical seizures or paroxysmal dyskinesias, while the other two male littermates were normal. We named this oculo-neurological syndrome CONS (Cirneco oculo-neurological syndrome), and undertook homozygosity mapping and whole-genome sequencing to determine its potential genetic etiology. Notably, we detected a 1-bp deletion in chromosome 6 that was predicted to cause a frameshift and premature stop codon within the canine AMPD2 gene, which encodes adenosine monophosphate deaminase, an enzyme that converts adenosine 5'-monophosphate (AMP) to inosine 5'-monophosphate (IMP). Genotyping of the available Cirneco population suggested perfect segregation between cases and controls for the variant. Moreover, this variant was absent in canine genomic databases comprised of thousands of unaffected dogs. The AMPD2 genetic variant we identified in dogs presents with retinal manifestations, adding to the spectrum of neurological manifestations associated with AMPD2 variants in humans.


Assuntos
AMP Desaminase , Degeneração Retiniana , Tremor , Animais , Cães , Masculino , AMP Desaminase/genética , Mutação da Fase de Leitura , Retina , Degeneração Retiniana/genética , Degeneração Retiniana/veterinária , Tremor/genética , Tremor/veterinária , Sequenciamento Completo do Genoma
10.
J Neurol Sci ; 457: 122864, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38185014

RESUMO

Congenital myopathy with tremor (MYOTREM) is a recently described disorder characterized by mild myopathy and a postural and intention tremor present since early infancy. MYOTREM is associated with pathogenic variants in MYBPC1 which encodes slow myosin-binding protein C, a sarcomere protein with regulatory and structural roles. Here, we describe a family with three generations of variably affected members exhibiting a novel variant in MYBPC1 (c.656 T > C, p.Leu219Pro). Among the unique features of affected family members is the persistence of tremor in sleep. We also present the first muscle magnetic resonance images for this disorder, and report muscle atrophy and fatty infiltration.


Assuntos
Doenças Musculares , Tremor , Humanos , Família , Mutação/genética , Tremor/diagnóstico por imagem , Tremor/genética
11.
Ann Neurol ; 95(3): 558-575, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38069470

RESUMO

OBJECTIVE: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset progressive genetic neurodegenerative disorder that occurs in FMR1 premutation carriers. The temporal, spatial, and cell-type specific patterns of neurodegeneration in the FXTAS brain remain incompletely characterized. Intranuclear inclusion bodies are the neuropathological hallmark of FXTAS, which are largest and occur most frequently in astrocytes, glial cells that maintain brain homeostasis. Here, we characterized neuropathological alterations in astrocytes in multiple regions of the FXTAS brain. METHODS: Striatal and cerebellar sections from FXTAS cases (n = 12) and controls (n = 12) were stained for the astrocyte markers glial fibrillary acidic protein (GFAP) and aldehyde dehydrogenase 1L1 (ALDH1L1) using immunohistochemistry. Reactive astrogliosis severity, the prevalence of GFAP+ fragments, and astrocyte density were scored. Double label immunofluorescence was utilized to detect co-localization of GFAP and cleaved caspase-3. RESULTS: FXTAS cases showed widespread reactive gliosis in both grey and white matter. GFAP staining also revealed remarkably severe astrocyte pathology in FXTAS white matter - characterized by a significant and visible reduction in astrocyte density (-38.7% in striatum and - 32.2% in cerebellum) and the widespread presence of GFAP+ fragments reminiscent of apoptotic bodies. White matter specific reductions in astrocyte density were confirmed with ALDH1L1 staining. GFAP+ astrocytes and fragments in white matter were positive for cleaved caspase-3, suggesting that apoptosis-mediated degeneration is responsible for reduced astrocyte counts. INTERPRETATION: We have established that FXTAS neuropathology includes robust degeneration of astrocytes, which is specific to white matter. Because astrocytes are essential for maintaining homeostasis within the central nervous system, a loss of astrocytes likely further exacerbates neuropathological progression of other cell types in the FXTAS brain. ANN NEUROL 2024;95:558-575.


Assuntos
Síndrome do Cromossomo X Frágil , Substância Branca , Humanos , Astrócitos/metabolismo , Tremor/genética , Gliose/patologia , Caspase 3/metabolismo , Substância Branca/patologia , Síndrome do Cromossomo X Frágil/diagnóstico , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , Ataxia/genética , Proteína do X Frágil da Deficiência Intelectual/genética
12.
Ann Clin Transl Neurol ; 11(2): 414-423, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38059543

RESUMO

OBJECTIVES: To investigate and characterize epileptic seizures and electrophysiological features of familial cortical myoclonic tremor with epilepsy (FCMTE) type 1 patients in a large Chinese cohort. METHODS: We systematically evaluated 125 FCMTEtype 1 patients carrying the pentanucleotide (TTTCA) repeat expansion in the SAMD12 gene in China. RESULTS: Among the 28 probands, epileptic seizures (96.4%, 27/28) were the most common reason for an initial clinic visit. Ninety-seven (77.6%, 97/125) patients had experienced seizures. The seizures onset age was 36.5 ± 9.0 years, which was 6.9 years later than cortical tremors. The seizures were largely rare (<1/year, 58.8%) and occasional (1-6/year, 37.1%). Prolonged prodromes were reported in 57.7% (56/97). Thirty-one patients (24.8%, 31/125) reported photosensitivity history, and 79.5% (31/39) had a photoparoxysmal response. Interictal epileptiform discharges (IEDs) were recorded in 69.1% (56/81) of patients. Thirty-three patients showed generalized IEDs and 72.7% (24/33) were occipitally dominant, while 23 patients presented with focal IEDs with 65.2% (15/23) taking place over the occipital lobe. Overnight EEG of FCMTE patients displayed paradoxical sleep-wake fluctuation, with a higher average IED index of 0.82 ± 0.88/min during wakefulness and a lower IED index of 0.04 ± 0.06/min during non-rapid eye movement sleep stages I-II. INTERPRETATION: FCMTE type 1 has a benign course of epilepsy and distinct clinical and electrophysiological features. In addition to a positive family history and cortical myoclonus tremor, the seizure prodromes, specific seizure triggers, photosensitivity, distribution of IEDs, and unique fluctuations during sleep-wake cycle are cues for proper genetic testing and an early diagnosis of FCMTE.


Assuntos
Epilepsias Mioclônicas , Epilepsia , Humanos , Adulto , Pessoa de Meia-Idade , Tremor/genética , Epilepsias Mioclônicas/genética , Convulsões
13.
Cells ; 12(24)2023 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-38132093

RESUMO

Fragile X (FMR1) premutation is a common mutation that affects about 1 in 200 females and 1 in 450 males and can lead to the development of fragile-X-associated tremor/ataxia syndrome (FXTAS). Although there is no targeted, proven treatment for FXTAS, research suggests that sulforaphane, an antioxidant present in cruciferous vegetables, can enhance mitochondrial function and maintain redox balance in the dermal fibroblasts of individuals with FXTAS, potentially leading to improved cognitive function. In a 24-week open-label trial involving 15 adults aged 60-88 with FXTAS, 11 participants successfully completed the study, demonstrating the safety and tolerability of sulforaphane. Clinical outcomes and biomarkers were measured to elucidate the effects of sulforaphane. While there were nominal improvements in multiple clinical measures, they were not significantly different after correction for multiple comparisons. PBMC energetic measures showed that the level of citrate synthase was higher after sulforaphane treatment, resulting in lower ATP production. The ratio of complex I to complex II showed positive correlations with the MoCA and BDS scores. Several mitochondrial biomarkers showed increased activity and quantity and were correlated with clinical improvements.


Assuntos
Leucócitos Mononucleares , Tremor , Adulto , Masculino , Feminino , Humanos , Tremor/tratamento farmacológico , Tremor/genética , Tremor/complicações , Proteína do X Frágil da Deficiência Intelectual/genética , Ataxia/tratamento farmacológico , Ataxia/genética , Biomarcadores
14.
Int J Mol Sci ; 24(24)2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38139097

RESUMO

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that affects older premutation carriers (55-200 CGG repeats) of the fragile X gene. Despite the high prevalence of the FXTAS disorder, neuropathology studies of individuals affected by FXTAS are limited. We performed hematoxylin and eosin (H&E) staining in the hippocampus of 26 FXTAS cases and analyzed the tissue microscopically. The major neuropathological characteristics were white matter disease, intranuclear inclusions in neurons and astrocytes, and neuron loss. Astrocytes contained more and larger inclusions than neurons. There was a negative correlation between age of death and CGG repeat length in cases over the age of 60. The number of astroglial inclusions (CA3 and dentate gyrus) and the number of CA3 neuronal inclusions increased with elevated CGG repeat length. In the two cases with a CGG repeat size less than 65, FXTAS intranuclear inclusions were not present in the hippocampus, while in the two cases with less than 70 (65-70) CGG repeat expansion, neurons and astrocytes with inclusions were occasionally identified in the CA1 sub-region. These findings add hippocampus neuropathology to the previously reported changes in other areas of the brain in FXTAS patients, with implications for understanding FXTAS pathogenesis.


Assuntos
Síndrome do Cromossomo X Frágil , Tremor , Humanos , Tremor/genética , Substância Cinzenta/metabolismo , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/patologia , Ataxia/genética , Hipocampo/metabolismo , Expansão das Repetições de Trinucleotídeos
15.
Stem Cell Res ; 73: 103236, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37890330

RESUMO

FCMTE1 is an autosomal dominant inherited neurodegenerative disorder characterized by myoclonic tremors and epilepsy. The cause of FCMTE1 is an abnormal (TTTCA)n insertion in intron 4 of SAMD12 gene. Fibroblasts obtained from a FCMTE1 patient were successfully transformed into induced pluripotent stem cells (iPSCs) (ZJUi013-A) using the Sendai virus. Our approach provided a resource for further pathogenesis study and drug screening of FCMTE1.


Assuntos
Epilepsia , Células-Tronco Pluripotentes Induzidas , Humanos , Tremor/genética , Linhagem
16.
Cells ; 12(19)2023 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-37830578

RESUMO

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that appears in adult FMR1 premutation carriers. The neuropathological hallmark of FXTAS is an intranuclear inclusion in neurons and astrocytes. Nearly 200 different proteins have been identified in FXTAS inclusions, being the small ubiquitin-related modifier 2 (SUMO2), ubiquitin and p62 the most highly abundant. These proteins are components of the protein degradation machinery. This study aimed to characterize SUMO2/3 expression levels and autophagy process in human postmortem brain samples and skin fibroblast cultures from FXTAS patients. Results revealed that FXTAS postmortem brain samples are positive for SUMO2/3 conjugates and supported the idea that SUMO2/3 accumulation is involved in inclusion formation. Insights from RNA-sequencing data indicated that SUMOylation processes are significantly upregulated in FXTAS samples. In addition, the analysis of the autophagy flux showed the accumulation of p62 protein levels and autophagosomes in skin fibroblasts from FXTAS patients. Similarly, gene set analysis evidenced a significant downregulation in gene ontology terms related to autophagy in FXTAS samples. Overall, this study provides new evidence supporting the role of SUMOylation and autophagic processes in the pathogenic mechanisms underlying FXTAS.


Assuntos
Síndrome do Cromossomo X Frágil , Tremor , Adulto , Humanos , Tremor/genética , Tremor/metabolismo , Tremor/patologia , Ubiquitina/metabolismo , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/patologia , Ataxia/patologia , Autofagia , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo
17.
Artigo em Inglês | MEDLINE | ID: mdl-37746582

RESUMO

A 50-year-old male presented with a four-year history of gradually progressive rest tremor in the distal right lower limb and then spreading to the left lower limb in last 10-12 months. He developed right arm rest and action tremor two years later. Magnetic resonance imaging scans showed progressive frontotemporal and asymmetrical mesial temporal atrophy. Genetic testing revealed a heterozygous c.915+16C>T pathogenic variant in intron 9 of the MAPT gene. Presentation with rest tremor should not exclude frontotemporal dementia-parkinsonism due to a MAPT variant as a differential diagnosis though rest tremor is a rare presentation.


Assuntos
Demência Frontotemporal , Transtornos Parkinsonianos , Masculino , Humanos , Pessoa de Meia-Idade , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Tremor/diagnóstico por imagem , Tremor/genética , Proteínas tau/genética , Mutação/genética , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/genética
18.
Genes (Basel) ; 14(7)2023 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-37510285

RESUMO

BACKGROUND: Essential tremor (ET) is one of the more common movement disorders. Current diagnosis is solely based on clinical findings. ET appears to be inherited in an autosomal dominant pattern. Several loci on specific chromosomes have been studied by linkage analysis, but the causes of essential tremor are still unknown in many patients. Genetic studies described the association of several genes with familial ET. However, they were found only in distinct families, suggesting that some can be private pathogenic variants. AIM OF THE STUDY: to characterize the phenotype of an Italian family with ET and identify the genetic variant associated. METHODS: Clinical and genetic examinations were performed. Genetic testing was done with whole-exome sequencing (WES) using the Illumina platform. Bidirectional capillary Sanger sequencing was used to investigate the presence of variant in all affected members of the family. In silico prediction of pathogenicity was used to study the effect of gene variants on protein structure. RESULTS: The proband was a 15-year-old boy. The patient was the first of two children of a non-consanguineous couple. Family history was remarkable for tremor in the mother line. His mother suffered from bilateral upper extremity kinetic tremors (since she was 20 years old), anxiety, and depression. Other relatives referred bilateral upper extremity tremors. In the index case, WES analysis performed supposing a dominant mode of inheritance, identified a novel heterozygous missense variant in potassium calcium-activated channel subfamily N member 2 (KCNN2) (NM_021614.3: c.1145G>A, p.Gly382Asp). In the pedigree investigation, all carriers of the gene variant had ET and showed variable expressivity, the elder symptomatic relative showing cognitive impairment and hallucinations in the last decade, in addition to tremor since a young age. The amino acid residue #382 is located in a transmembrane region and in silico analysis suggested a causative role for the variant. Modelling of the mutant protein structure showed that the variant causes a clash in the protein structure. Therefore, the variant could cause a conformational change that alters the ability of the protein in the modulation of ion channels Conclusions: The KCNN2 gene variant identified could be associated with ET. The variant could modify a voltage-independent potassium channel activated by intracellular calcium.


Assuntos
Tremor Essencial , Feminino , Humanos , Tremor Essencial/genética , Tremor Essencial/patologia , Tremor/genética , Cálcio , Mutação de Sentido Incorreto , Testes Genéticos , Canais de Potássio Ativados por Cálcio de Condutância Baixa/genética
19.
Cells ; 12(12)2023 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-37371086

RESUMO

Familial adult myoclonus Epilepsy (FAME) is a non-coding repeat expansion disorder that has been reported under different acronyms and initially linked to four main loci: FAME1 (8q23.3-q24.1), FAME 2 (2p11.1-q12.1), FAME3 (5p15.31-p15.1), and FAME4 (3q26.32-3q28). To date, it is known that the genetic mechanism underlying FAME consists of the expansion of similar non-coding pentanucleotide repeats, TTTCA and TTTTA, in different genes. FAME is characterized by cortical tremor and myoclonus usually manifesting within the second decade of life, and infrequent seizures by the third or fourth decade. Cortical tremor is the core feature of FAME and is considered part of a spectrum of cortical myoclonus. Neurophysiological investigations as jerk-locked back averaging (JLBA) and corticomuscular coherence analysis, giant somatosensory evoked potentials (SEPs), and the presence of long-latency reflex I (or C reflex) at rest support cortical tremor as the result of the sensorimotor cortex hyperexcitability. Furthermore, the application of transcranial magnetic stimulation (TMS) protocols in FAME patients has recently shown that inhibitory circuits are also altered within the primary somatosensory cortex and the concomitant involvement of subcortical networks. Moreover, neuroimaging studies and postmortem autoptic studies indicate cerebellar alterations and abnormal functional connectivity between the cerebellum and cerebrum in FAME. Accordingly, the pathophysiological mechanism underlying FAME has been hypothesized to reside in decreased sensorimotor cortical inhibition through dysfunction of the cerebellar-thalamic-cortical loop, secondary to primary cerebellar pathology. In this context, the non-coding pentameric expansions have been proposed to cause cerebellar damage through an RNA-mediated toxicity mechanism. The elucidation of the underlying pathological mechanisms of FAME paves the way to novel therapeutic possibilities, such as RNA-targeting treatments, possibly applicable to other neurodegenerative non-coding disorders.


Assuntos
Epilepsias Mioclônicas , Mioclonia , Doenças Neurodegenerativas , Humanos , Adulto , Tremor/genética , Epilepsias Mioclônicas/genética , Reflexo
20.
Exp Brain Res ; 241(8): 1975-1987, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37347418

RESUMO

Women with the FMR1 premutation are susceptible to motor involvement related to atypical cerebellar function, including risk for developing fragile X tremor ataxia syndrome. Vocal quality analyses are sensitive to subtle differences in motor skills but have not yet been applied to the FMR1 premutation. This study examined whether women with the FMR1 premutation demonstrate differences in vocal quality, and whether such differences relate to FMR1 genetic, executive, motor, or health features of the FMR1 premutation. Participants included 35 women with the FMR1 premutation and 45 age-matched women without the FMR1 premutation who served as a comparison group. Three sustained /a/ vowels were analyzed for pitch (mean F0), variability of pitch (standard deviation of F0), and overall vocal quality (jitter, shimmer, and harmonics-to-noise ratio). Executive, motor, and health indices were obtained from direct and self-report measures and genetic samples were analyzed for FMR1 CGG repeat length and activation ratio. Women with the FMR1 premutation had a lower pitch, larger pitch variability, and poorer vocal quality than the comparison group. Working memory was related to harmonics-to-noise ratio and shimmer in women with the FMR1 premutation. Vocal quality abnormalities differentiated women with the FMR1 premutation from the comparison group and were evident even in the absence of other clinically evident motor deficits. This study supports vocal quality analyses as a tool that may prove useful in the detection of early signs of motor involvement in this population.


Assuntos
Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil , Humanos , Feminino , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Tremor/genética , Ataxia/genética , Memória de Curto Prazo/fisiologia
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