Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 122
Filtrar
1.
Lancet Neurol ; 19(9): 738-747, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32822634

RESUMO

BACKGROUND: Spinocerebellar ataxias (SCAs) are autosomal dominant neurodegenerative diseases. Our aim was to study the conversion to manifest ataxia among apparently healthy carriers of mutations associated with the most common SCAs (SCA1, SCA2, SCA3, and SCA6), and the sensitivity of clinical and functional measures to detect change in these individuals. METHODS: In this prospective, longitudinal, observational cohort study, based at 14 referral centres in seven European countries, we enrolled children or siblings of patients with SCA1, SCA2, SCA3, or SCA6. Eligible individuals were those without ataxia, defined by a score on the Scale for the Assessment and Rating of Ataxia (SARA) of less than 3; participants had to be aged 18-50 years for children or siblings of patients with SCA1, SCA2, or SCA3, and 35-70 years for children or siblings of patients with SCA6. Study visits took place at recruitment and after 2, 4, and 6 years (plus or minus 3 months). We did genetic testing to identify mutation carriers, with results concealed to the participant and clinical investigator. We assessed patients with clinical scales, questionnaires of patient-reported outcome measures, a rating of the examiner's confidence of presence of ataxia, and performance-based coordination tests. Conversion to ataxia was defined by an SARA score of 3 or higher. We analysed the association of factors at baseline with conversion to ataxia and the evolution of outcome parameters on temporal scales (time from inclusion and time to predicted age at ataxia onset) in the context of mutation status and conversion status. This study is registered with ClinicalTrials.gov, NCT01037777. FINDINGS: Between Sept 13, 2008, and Oct 28, 2015, 302 participants were enrolled. We analysed data for 252 participants with at least one follow-up visit. 83 (33%) participants were from families affected by SCA1, 99 (39%) by SCA2, 46 (18%) by SCA3, and 24 (10%) by SCA6. In participants who carried SCA mutations, 26 (52%) of 50 SCA1 carriers, 22 (59%) of 37 SCA2 carriers, 11 (42%) of 26 SCA3 carriers, and two (13%) of 15 SCA6 carriers converted to ataxia. One (3%) of 33 SCA1 non-carriers and one (2%) of 62 SCA2 non-carriers converted to ataxia. Owing to the small number of people who met our criteria for ataxia, subsequent analyses could not be done in carriers of the SCA6 mutation. Baseline factors associated with conversion were age (hazard ratio 1·13 [95% CI 1·03-1·24]; p=0·011), CAG repeat length (1·25 [1·11-1·41]; p=0·0002), and ataxia confidence rating (1·72 [1·23-2·41]; p=0·0015) for SCA1; age (1·08 [1·02-1·14]; p=0·0077) and CAG repeat length (1·65 [1·27-2·13]; p=0·0001) for SCA2; and age (1·27 [1·09-1·50]; p=0·0031), confidence rating (2·60 [1·23-5·47]; p=0·012), and double vision (14·83 [2·15-102·44]; p=0·0063) for SCA3. From the time of inclusion, the SARA scores of SCA1, SCA2, and SCA3 mutation carriers increased, whereas they remained stable in non-carriers. On a timescale defined by the predicted time of ataxia onset, SARA progression in SCA1, SCA2, and SCA3 mutation carriers was non-linear, with marginal progression before ataxia and increasing progression after ataxia onset. INTERPRETATION: Our study provides quantitative data on the conversion of non-ataxic SCA1, SCA2, and SCA3 mutation carriers to manifest ataxia. Our data could prove useful for the design of preventive trials aimed at delaying the onset of ataxia by aiding sample size calculations and stratification of study participants. FUNDING: European Research Area Network for Research Programmes on Rare Diseases, Polish Ministry of Science and Higher Education, Italian Ministry of Health, European Community's Seventh Framework Programme.


Assuntos
Progressão da Doença , Mutação/genética , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética , Adulto , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Adulto Jovem
5.
J Neurosci ; 40(8): 1722-1731, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-31941666

RESUMO

Regulating muscle force and timing are fundamental for accurate motor performance. In spinocerebellar ataxia type 6 (SCA6), there is evidence that individuals have greater force dysmetria but display better temporal accuracy during fast goal directed contractions. Here, we test whether greater temporal accuracy occurs in all individuals with SCA6, and can be explained by lesser temporal variability. Further we examine whether it is linked to disease severity and specific degenerative changes in the cerebellum. Nineteen human participants with SCA6 (13 woman) and 18 healthy controls performed fast goal-directed ankle dorsiflexion contractions aiming at a spatiotemporal target. We quantified the endpoint control of these contractions, gray matter (GM) integrity of the cerebellum, and disease severity using the International Cooperative Ataxia Rating Scale (ICARS). SCA6 individuals exhibited lower temporal endpoint error and variability than the healthy controls (p = 0.008). Statistically, SCA6 clustered into two distinct groups for temporal variability. A group with low temporal variability ranging from 10 to 19% (SCA6a) and a group with temporal variability similar to healthy controls (SCA6b; 19-40%).SCA6a exhibited greater disease severity than SCA6b, as assessed with ICARS (p < 0.001). Lower temporal variability, which was not associated with disease duration (R 2 = 0.1, p > 0.2), did correlate with both greater ICARS (R 2 = 0.3) and reduced GM volume in cerebellar lobule VI (R 2 = 0.35). Other cerebellar lobules did not relate to temporal variability. We provide new evidence that a subset of SCA6 with greater loss of GM in cerebellum lobule VI exhibit temporal invariance and more severe ataxia than other SCA6 individuals.SIGNIFICANCE STATEMENT Variability is an inherent feature of voluntary movement, and traditionally more variability in the targeted output infers impaired performance. For example, cerebellar patients present exacerbated temporal variability during multijoint movements, which is thought to contribute to their motor deficits. In the current work, we show that in a subgroup of spinocerebellar ataxia type 6 individuals, temporal variability is lower than that of healthy controls when performing single-joint fast-goal directed movements. This invariance related to exacerbated atrophy of lobule VI of the cerebellum and exacerbated disease severity. The relation between invariance and disease severity suggests that pathological motor variability can manifest not only as an exacerbation but also as a reduction relative to healthy controls.


Assuntos
Cerebelo/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Ataxias Espinocerebelares/diagnóstico por imagem , Idoso , Atrofia/diagnóstico por imagem , Atrofia/patologia , Cerebelo/patologia , Feminino , Substância Cinzenta/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Ataxias Espinocerebelares/patologia
6.
J Hum Genet ; 65(4): 363-369, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31907387

RESUMO

Spinocerebellar ataxia (SCA) is a genetically heterogeneous disease characterized by cerebellar ataxia. Many causative genes have been identified to date, the most common etiology being the abnormal expansion of repeat sequences, and the mutation of ion channel genes also play an important role in the development of SCA. Some of them encode calcium and potassium channels. However, due to limited reports about potassium genes in SCA, we screened 192 Japanese individuals with dominantly inherited SCA who had no abnormal repeat expansions of causative genes for potassium channel mutations (KCNC3 for SCA13 and KCND3 for SCA19/SCA22) by target sequencing. As a result, two variants were identified from two patients: c.1973G>A, p.R658Q and c.1018G>A, p.V340M for KCNC3, and no pathogenic variant was identified for KCND3. The newly identified p.V340M exists in the extracellular domain, and p.R658Q exists in the intracellular domain on the C-terminal side, although most of the reported KCNC3 mutations are present at the transmembrane site. Adult-onset and slowly progressive cerebellar ataxia are the main clinical features of SCA13 and SCA19 caused by potassium channel mutations, which was similar in our cases. SCA13 caused by KCNC3 mutations may present with deep sensory loss and cognitive impairment in addition to cerebellar ataxia. In this study, mild deep sensory loss was observed in one case. SCA caused by potassium channel gene mutations is extremely rare, and more cases should be accumulated in the future to elucidate its pathogenesis due to channel dysfunction.


Assuntos
Disfunção Cognitiva/genética , Mutação , Canais de Potássio/genética , Ataxias Espinocerebelares/genética , Adulto , Grupo com Ancestrais do Continente Asiático , Disfunção Cognitiva/diagnóstico por imagem , Feminino , Testes Genéticos , Humanos , Japão , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Ataxias Espinocerebelares/diagnóstico por imagem
7.
Cerebellum ; 19(1): 161-163, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31721007

RESUMO

Spinocerebellar ataxia type 5 (SCA-5) is a predominantly slowly progressive adult onset ataxia. We describe a child with a presentation of ataxic cerebral palsy (CP) and developmental delay at 6 months of age. Genetic testing confirmed a c.812C>T p.(Thr271Ile) mutation within the SPTBN2 gene. Seven previous cases of infantile onset SCA-5 are reported in the literature, four of which had a CP presentation. Early onset of SCA-5 presents with ataxic CP and is a rare cause of cerebral palsy.


Assuntos
Ataxia/complicações , Ataxia/diagnóstico por imagem , Paralisia Cerebral/complicações , Paralisia Cerebral/diagnóstico por imagem , Doenças Genéticas Inatas/complicações , Doenças Genéticas Inatas/diagnóstico por imagem , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxia/genética , Paralisia Cerebral/genética , Doenças Genéticas Inatas/genética , Humanos , Lactente , Masculino , Ataxias Espinocerebelares/genética
8.
Neurol Sci ; 41(1): 155-160, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31485862

RESUMO

BACKGROUND: Spinal cerebellar ataxia 11 (SCA11) is a rare disease, characterized by progressive cerebellar ataxia, abnormal eye sign. Four families have been reported in the past. We report on China's first family with spinocerebellar ataxia 11. METHODS: A careful investigation of the clinical manifestations, brain imaging, and exome and Sanger sequencing were utilized to identify pathogenic genetic variants in a three-generation pedigree that includes 5 affected individuals. RESULTS: The proband and affected members began to develop cerebellar ataxia, dysarthria, nystagmus, and strabismus at approximately age 40 for no apparent reason. The lifespan of patients in the family is shortened. Brain MRIs showed cerebellar atrophy and slight atrophy of the bulbar medulla. Electromyography showed extensive neurogenic damage. Sensory evoked potentials of lower limbs showed damage to the spinal-brainstem-cortical conduction pathway. Genetic analysis revealed a novel point mutation (c.3290T>C) in the TTBK2 gene encoding tau-microtubule kinase 2, which led to an amino acid exchange (p.Val1097Ala). The missense mutation segregated with the phenotype. The mutation has a very low mutation rate in the population, the variant amino acids are highly conserved among species, and protein function damage prediction at the mutation site is detrimental and is highly likely to cause protein damage. The pathogenicity prediction of the mutation site shows that it is likely to cause disease. This variation is consistent with the diagnosis of SCA11. CONCLUSION: The first SCA11-affected family in China was characterized by gait instability, movement disorders and dysarthria with obvious cerebellar atrophy. The pathogenic allele was a c.3290T>C mutation in the TTBK2 gene.


Assuntos
Proteínas Serina-Treonina Quinases/genética , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética , Adulto , China , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Linhagem
9.
Sci Rep ; 9(1): 17329, 2019 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-31758059

RESUMO

Clinically differentiating multiple system atrophy cerebellar (MSA-C) phenotype and spinocerebellar ataxias (SCAs) is challenging especially in the early stage. We assessed diagnostic value of brain magnetic resonance imaging (MRI) in differentiating MSA-C and SCAs based at different disease stages (<3, 3-7, and >7 years of disease duration). Overall, 186 patients with probable MSA-C and 117 with genetically confirmed SCAs were included. Hot cross bun (HCB) signs and middle cerebellar peduncle (MCP) hyperintensities were exclusively prevalent in MSA-C compared to SCAs at <3 years (HCB, 44.6% versus 0.9%; MCP hyperintensities, 38.3% versus 0.9%, respectively). Sensitivity, specificity, and positive predictive value (PPV) for HCB signs to differentiate MSA-C from SCAs were 45%, 99%, and 99% and those for MCP hyperintensities were 68%, 99%, and 99%, respectively; considering both HCB signs and MCP hyperintensities, specificity and PPV were 100%. However, the differential value of MRI signs decreased over time. MCP widths were smaller and showed more significant decrease in MSA-C than in SCAs. In conclusion, pontine and MCP changes were exclusively prominent in early stage MSA-C rather than in SCAs. Therefore, we should consider disease duration when interpreting pontine and MCP changes in brain MRIs, which will help better differentiate MSA-C and SCAs.


Assuntos
Cerebelo/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Ataxias Espinocerebelares/diagnóstico por imagem , Adulto , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Sensibilidade e Especificidade
10.
Brain ; 142(12): 3791-3805, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31747689

RESUMO

Our cerebellum has been proposed to generate prediction signals that may help us plan and execute our motor programmes. However, to what extent our cerebellum is also actively involved in perceiving the action of others remains to be elucidated. Using functional MRI, we show here that observing goal-directed hand actions of others bilaterally recruits lobules VI, VIIb and VIIIa in the cerebellar hemispheres. Moreover, whereas healthy subjects (n = 31) were found to be able to discriminate subtle differences in the kinematics of observed limb movements of others, patients suffering from spinocerebellar ataxia type 6 (SCA6; n = 21) were severely impaired in performing such tasks. Our data suggest that the human cerebellum is actively involved in perceiving the kinematics of the hand actions of others and that SCA6 patients' deficits include a difficulty in perceiving the actions of other individuals. This finding alerts us to the fact that cerebellar disorders can alter social cognition.


Assuntos
Cerebelo/fisiopatologia , Percepção de Movimento/fisiologia , Ataxias Espinocerebelares/fisiopatologia , Mapeamento Encefálico , Cerebelo/diagnóstico por imagem , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Desempenho Psicomotor/fisiologia , Ataxias Espinocerebelares/diagnóstico por imagem
11.
Stereotact Funct Neurosurg ; 97(4): 241-243, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31743916

RESUMO

The beneficial effect of thalamic deep brain stimulation (DBS) on action tremor has been reported in a few cases of spinocerebellar ataxia (SCA); however, several factors should be taken into account regarding the indication for DBS in advanced cases. We performed DBS of the ventral intermediate nucleus (Vim) of the thalamus for treatment of coarse action tremor in a patient with SCA2 (spinocerebellar ataxia type 2) in the wheelchair-bound stage. Although improvement of the tremor of the proximal part was incomplete, the patient regained substantial parts of daily functioning. The effect lasted for more than 6 years, and the suppression of tremor significantly contributed to maintaining the level of the patient's expression into the bedridden stage. Vim DBS can be a treatment option for tremor in SCA patients, even in the advanced stage, as long as the tremor is depriving the patient of behavioral expression. As residual proximal tremor may hamper functional recovery, DBS of other targets or multi-targets should be further explored to attain a better outcome.


Assuntos
Estimulação Encefálica Profunda/métodos , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/terapia , Tremor/diagnóstico por imagem , Tremor/terapia , Núcleos Ventrais do Tálamo/diagnóstico por imagem , Feminino , Humanos , Pessoa de Meia-Idade , Ataxias Espinocerebelares/fisiopatologia , Fatores de Tempo , Tremor/fisiopatologia , Núcleos Ventrais do Tálamo/fisiopatologia
12.
Artigo em Inglês | MEDLINE | ID: mdl-31632837

RESUMO

Background: The spinocerebellar ataxias (SCAs) are a group of autosomal dominant degenerative diseases characterized by cerebellar ataxia. Classified according to gene discovery, specific features of the SCAs - clinical, laboratorial, and neuroradiological (NR) - can facilitate establishing the diagnosis. The purpose of this study was to review the particular NR abnormalities in the main SCAs. Methods: We conducted a literature search on this topic. Results: The main NR characteristics of brain imaging (magnetic resonance imaging or computerized tomography) in SCAs were: (1) pure cerebellar atrophy; (2) cerebellar atrophy with other findings (e.g., pontine, olivopontocerebellar, spinal, cortical, or subcortical atrophy; "hot cross bun sign", and demyelinating lesions); (3) selective cerebellar atrophy; (4) no cerebellar atrophy. Discussion: The main NR abnormalities in the commonest SCAs, are not pathognomonic of any specific genotype, but can be helpful in limiting the diagnostic options. We are progressing to a better understanding of the SCAs, not only genetically, but also pathologically; NR is helpful in the challenge of diagnosing the specific genotype of SCA.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Neuroimagem , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/patologia , Humanos
13.
J Neurol Sci ; 407: 116525, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31639532

RESUMO

We used quantitative susceptibility mapping (QSM) to assess the brain iron deposition in 28 patients with the cerebellar subtype of multiple system atrophy (MSA-C), nine patients with spinocerebellar ataxia type 6 (SCA6), and 23 healthy controls. Two reviewers independently measured the mean QSM values in brain structures including the putamen, globus pallidus, caudate nucleus, red nucleus, substantia nigra, and cerebellar dentate nucleus. A receiver operating characteristics (ROC) analysis was performed to assess the diagnostic usefulness of the QSM measurements. The QSM values in the substantia nigra were significantly higher in the MSA-C group compared to the HC group (p = .007). The QSM values in the cerebellar dentate nucleus were significantly higher in MSA-C than those in the SCA6 and HC groups (p < .001), and significantly lower in the SCA6 patients compared to the HCs (p = .027). The QSM values in the cerebellar dentate nucleus were correlated with disease duration in MSA-C, but inversely correlated with disease duration in SCA6. In the ROC analysis, the QSM values in the cerebellar dentate nucleus showed excellent accuracy for differentiating MSA-C from SCA6 (area under curve [AUC], 0.925), and good accuracy for differentiating MSA-C from healthy controls (AUC 0.834). QSM can identify increased susceptibility of the substantia nigra and cerebellar dentate nucleus in MSA-C patients. These results suggest that an increase in iron accumulation in the cerebellar dentate nucleus may be secondary to the neurodegeneration associated with MSA-C.


Assuntos
Encéfalo/diagnóstico por imagem , Ferro/metabolismo , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Ataxias Espinocerebelares/diagnóstico por imagem , Idoso , Encéfalo/metabolismo , Cerebelo/diagnóstico por imagem , Cerebelo/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/metabolismo , Ataxias Espinocerebelares/metabolismo
14.
Hum Brain Mapp ; 40(16): 4748-4758, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31365181

RESUMO

The cerebellum has been implicated in the feedforward control of speech production. However, the role of the cerebellum in the feedback control of speech production remains unclear. To address this question, the present event-related potential study examined the behavioral and neural correlates of auditory feedback control of vocal production in patients with spinocerebellar ataxia (SCA) and healthy controls. All participants were instructed to produce sustained vowels while hearing their voice unexpectedly pitch-shifted -200 or -500 cents. The behavioral results revealed significantly larger vocal compensations for pitch perturbations in patients with SCA relative to healthy controls. At the cortical level, patients with SCA exhibited significantly smaller cortical P2 responses that were source localized in the right superior temporal gyrus, primary auditory cortex, and supramarginal gyrus than healthy controls. These findings indicate that reduced brain activity in the right temporal and parietal regions are significant neural contributors to abnormal auditory-motor processing of vocal pitch regulation as a consequence of cerebellar degeneration, which may be related to disrupted reciprocal interactions between the cerebellum and cortical regions that support the top-down modulation of auditory-vocal integration. These differences in behavior and cortical activity between healthy controls and patients with SCA demonstrate that the cerebellum is not only essential for feedforward control but also plays a crucial role in the feedback-based control of speech production.


Assuntos
Cerebelo/fisiopatologia , Retroalimentação Sensorial , Fala , Ataxias Espinocerebelares/fisiopatologia , Estimulação Acústica , Adulto , Córtex Auditivo/diagnóstico por imagem , Córtex Auditivo/fisiopatologia , Mapeamento Encefálico , Cerebelo/diagnóstico por imagem , Eletroencefalografia , Potenciais Evocados , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Ataxias Espinocerebelares/diagnóstico por imagem , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/fisiopatologia , Voz , Adulto Jovem
15.
Parkinsonism Relat Disord ; 66: 182-188, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31445906

RESUMO

INTRODUCTION: Spinocerebellar ataxia type 10 (SCA10) is a hereditary neurodegenerative disorder caused by repeat expansions in the ATXN10 gene. Patients present with cerebellar ataxia frequently accompanied by seizures. Even though loss of cerebellar Purkinje neurons has been described, its brain degeneration pattern is unknown. Our aim was to characterize the gray and white matter degeneration patterns in SCA10 patients and the association with clinical features. METHODS: We enrolled 18 patients with molecular diagnosis of SCA10 and 18 healthy individuals matched for age and sex. All participants underwent brain MRI including high-resolution anatomical and diffusion images. Whole-brain Tract-Based Spatial Statistics (TBSS) and Voxel-Based Morphometry (VBM) were performed to identify white and grey matter degeneration respectively. A second analysis in the cerebellum identified the unbiased pattern of degeneration. Motor impairment was assessed using the SARA Scale. RESULTS: TBSS analysis in the patient group revealed white matter atrophy exclusively in the cerebellum. VBM analysis showed extensive grey matter degeneration in the cerebellum, brainstem, thalamus, and putamen. Significant associations between cerebellar degeneration and SARA scores were found. Additionally, degeneration in thalamic GM and WM in the cerebellar lobule VI were significantly associated with the presence of seizures. CONCLUSION: The results show that besides cerebellum and brainstem, brain degeneration in SCA10 includes predominantly the putamen and thalamus; involvement of the latter is strongly associated with seizures. Analysis of the unbiased degeneration pattern in the cerebellum suggests lobules VIIIb, IX, and X as the primary cerebellar targets of the disease, which expands to the anterior lobe in later stages.


Assuntos
Cerebelo/patologia , Substância Cinzenta/patologia , Putamen/patologia , Ataxias Espinocerebelares/patologia , Tálamo/patologia , Substância Branca/patologia , Adulto , Cerebelo/diagnóstico por imagem , Expansão das Repetições de DNA , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Linhagem , Putamen/diagnóstico por imagem , Ataxias Espinocerebelares/diagnóstico por imagem , Tálamo/diagnóstico por imagem , Substância Branca/diagnóstico por imagem
16.
Cerebellum ; 18(5): 972-975, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31410782

RESUMO

Spinocerebellar Ataxia 23 (SCAR23) is a newly described condition caused by mutations in TDP2 gene. To date, only four patients from two families have been reported, all carrying the same homozygous mutation. We describe a fifth patient, carrying a novel mutation in the same gene, thus confirming the role of TDP2 mutations in determining the disease and defining the main features SCAR23: pediatric onset ataxia and drug-resistant epilepsy and intellectual disability. We further show the clinical presentation which is associated with the neuroradiological evidence of progressive cerebellar atrophy, giving the evidence that SCAR23 can be classified as a degenerative condition.


Assuntos
Proteínas de Ligação a DNA/genética , Epilepsia Resistente a Medicamentos/genética , Deficiência Intelectual/genética , Mutação/genética , Diester Fosfórico Hidrolases/genética , Ataxias Espinocerebelares/genética , Adolescente , Epilepsia Resistente a Medicamentos/complicações , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Feminino , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico por imagem , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/diagnóstico por imagem , Sequenciamento Completo do Exoma/métodos
17.
J Clin Neurosci ; 67: 139-144, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31182267

RESUMO

Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1; OMIM #607250), an exceedingly rare disorder having been documented in only a single family from Saudi Arabia, is the result of an unusual mutation in the tyrosyl DNA phosphodiesterase 1 gene (TDP1). We performed high-throughput sequencing (whole exome and ataxia gene panel) in two apparently unrelated Omani families segregating sensorimotor neuropathy and ataxia in an autosomal recessive fashion. Following validation by Sanger sequencing, all affected subjects (n = 4) were confirmed to carry the known SCAN1 pathogenic homozygous variant in the TDP1 gene, NM_001008744.1:c.1478A > G (p.His493Arg). In keeping with the initial description, our patients demonstrated progressive ataxia, cerebellar atrophy and disabling axonal sensori-motor neuropathy (n = 4), hypercholesterolemia (n = 2) and elevated serum alpha fetoprotein (n = 3). In addition, our patients also had mild cognitive deficits in multiple domains (n = 3), a feature not previously reported. Our findings independently revalidate the phenotype of TDP1 mutation and expand the clinical spectrum to include mild cognitive deficits. Haplotype sharing, as determined by DNA microarray (CytoScan HD), attests to a possible common founder mutation in the Arab population.


Assuntos
Ataxias Espinocerebelares/genética , Adolescente , Adulto , Exoma , Feminino , Humanos , Masculino , Mutação , Doenças do Sistema Nervoso Periférico/genética , Diester Fosfórico Hidrolases , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/psicologia , Adulto Jovem
18.
Intern Med ; 58(18): 2711-2714, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31178481

RESUMO

We herein report the successful management of a condition mimicking acquired laryngomalacia using conservative methods in an elderly man with a progressive neurological disorder. The patient developed stridor and was transferred to the intensive-care unit. Flexible laryngoscopy revealed a collapsed epiglottis during inspiration, as seen in acquired laryngomalacia, with mucinous material firmly adhered to the epiglottis. The stridor resolved after the removal of this material. Pathology revealed keratinized material, suggesting a collection of sputum or epithelial tissue. Thus, flexible laryngoscopy can differentiate the cause of airway obstruction and avoid unnecessary endotracheal intubation in patients with neurological disorders.


Assuntos
Transtornos de Deglutição/reabilitação , Epiglote , Corpos Estranhos/diagnóstico , Laringomalácia/diagnóstico , Ataxias Espinocerebelares/reabilitação , Idoso , Obstrução das Vias Respiratórias/etiologia , Transtornos de Deglutição/etiologia , Diagnóstico Diferencial , Corpos Estranhos/complicações , Humanos , Unidades de Terapia Intensiva , Laringoscopia , Masculino , Sons Respiratórios/etiologia , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/diagnóstico por imagem
19.
Cerebellum ; 18(4): 817-822, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31111429

RESUMO

While heterozygous mutations in the AFG3L2 gene have been linked to spinocerebellar ataxia 28 (SCA28), homozygous mutations in the same gene can cause spastic ataxia 5 (SPAX5). AFG3L2 encodes a mitochondrial ATP-dependent metalloprotease. We here report a SCA28 patient with biallelic AFG3L2 variants and his heterozygous mother. The patient and his mother underwent a detailed neurological examination and fibroblast lines were established. The effect of the two missense variants on mitochondria was assessed by form factor analysis and quantification of mitochondrial proteins (TOMM70, complex V). The 39-year-old index patient presented with a slowly progressive cerebellar gait disorder for 19 years, bilateral ptosis, and dysarthria. A cranial MRI showed mild cerebellar atrophy. He carried two compound-heterozygous, rare, missense variants (c.1847A>G [p.Y616C], c.2167G>A [p.V723M]) in AFG3L2, while his mother was heterozygous for the first change that had previously been described in SPAX5. Altered mitochondrial morphology and interconnectivity, together with reduced protein levels of TOMM70 and complex V (ATPase), suggest mitochondrial structural defects in the patient's fibroblasts. No significant abnormalities were found in his mother's fibroblast cultures albeit all measurements were slightly below the control level. We here present a SCA28 patient with compound-heterozygous AFG3L2 variants and demonstrate mitochondrial abnormalities in skin fibroblast cultures from this patient. Thus, AFG3L2 variants should be considered in both slowly progressive ataxias and phenotypes with clinical features reminiscent of mitochondrial disease. Of note, ptosis was present in both mutation carriers and may serve as a red flag in the diagnosis of SCA28.


Assuntos
Proteases Dependentes de ATP/genética , ATPases Associadas a Diversas Atividades Celulares/genética , Ataxias Espinocerebelares/congênito , Adulto , Atrofia , Progressão da Doença , Fibroblastos/patologia , Heterozigoto , Humanos , Imagem por Ressonância Magnética , Masculino , Mitocôndrias/patologia , Proteínas Mitocondriais/genética , Mutação/genética , Mutação de Sentido Incorreto/genética , Exame Neurológico , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/fisiopatologia
20.
Parkinsonism Relat Disord ; 65: 91-96, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31126790

RESUMO

INTRODUCTION: Spinocerebellar ataxia 48 has recently been described as an adult onset ataxia associated with a cerebellar cognitive affective syndrome, caused by a heterozygous mutation in the STUB1 gene. METHODS: We characterized the clinical and neuroimaging phenotype of eight patients from two autosomal dominant ataxia multigenerational Italian families, in whom we conducted whole exome sequencing, targeted multigene sequencing, and Sanger sequencing studies. RESULTS: We describe a complex syndrome characterized by ataxia and cognitive-psychiatric disorder in all cases, variably associated with chorea, parkinsonism, dystonia, urinary symptoms, and epilepsy. MRI showed a significant cerebellar atrophy, coupled to a T2-weighted hyperintensity affecting the dentate nuclei and extending to the middle cerebellar peduncles, whereas FDG-PET studies revealed glucose hypometabolism in cerebellum, striatum, and cerebral cortex. We identified two different novel STUB1 mutations segregating in the two families. One of the two mutations, p.(Gly33Ser), occurs in the TRP domain, whereas p.(Pro228Ser) is located in the ubiquitin ligase region. DISCUSSION: We emphasize the similarity of the described clinical picture with that of SCAR16, an autosomal recessive ataxia caused by biallelic mutations in the same gene, and of spinocerebellar ataxia type 17, which is considered the main Huntington's disease-like syndrome. The pathogenesis of the disease and the relationship between SCA48 and SCAR16 remain to be clarified.


Assuntos
Doenças dos Gânglios da Base/diagnóstico por imagem , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Mentais/diagnóstico por imagem , Ataxias Espinocerebelares/diagnóstico por imagem , Adulto , Idoso , Doenças dos Gânglios da Base/complicações , Doenças dos Gânglios da Base/genética , Transtornos Cognitivos/complicações , Transtornos Cognitivos/genética , Feminino , Humanos , Itália , Imagem por Ressonância Magnética/métodos , Masculino , Transtornos Mentais/complicações , Transtornos Mentais/genética , Pessoa de Meia-Idade , Linhagem , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/genética , Ubiquitina-Proteína Ligases/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...