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1.
Neurobiol Dis ; 130: 104516, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31229688

RESUMO

Spinocerebellar ataxia 42 (SCA42) is a neurodegenerative disorder recently shown to be caused by c.5144G > A (p.Arg1715His) mutation in CACNA1G, which encodes the T-type voltage-gated calcium channel CaV3.1. Here, we describe a large Japanese family with SCA42. Postmortem pathological examination revealed severe cerebellar degeneration with prominent Purkinje cell loss without ubiquitin accumulation in an SCA42 patient. To determine whether this mutation causes ataxic symptoms and neurodegeneration, we generated knock-in mice harboring c.5168G > A (p.Arg1723His) mutation in Cacna1g, corresponding to the mutation identified in the SCA42 family. Both heterozygous and homozygous mutants developed an ataxic phenotype from the age of 11-20 weeks and showed Purkinje cell loss at 50 weeks old. Degenerative change of Purkinje cells and atrophic thinning of the molecular layer were conspicuous in homozygous knock-in mice. Electrophysiological analysis of Purkinje cells using acute cerebellar slices from young mice showed that the point mutation altered the voltage dependence of CaV3.1 channel activation and reduced the rebound action potentials after hyperpolarization, although it did not significantly affect the basic properties of synaptic transmission onto Purkinje cells. Finally, we revealed that the resonance of membrane potential of neurons in the inferior olivary nucleus was decreased in knock-in mice, which indicates that p.Arg1723His CaV3.1 mutation affects climbing fiber signaling to Purkinje cells. Altogether, our study shows not only that a point mutation in CACNA1G causes an ataxic phenotype and Purkinje cell degeneration in a mouse model, but also that the electrophysiological abnormalities at an early stage of SCA42 precede Purkinje cell loss.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31105016

RESUMO

INTRODUCTION: Spinocerebellar ataxia (SCA) type 34, a form of autosomal dominantly inherited ataxia, has recently been associated with mutations in the ELOVL4 gene. However, a genetic study of the prevalence of SCA34 in an ataxia cohort has never been reported. METHODS: We performed a mutation screening of ELOVL4 in a cohort of 153 undiagnosed index ataxia patients, selected after excluding for common SCA types, in a series of 506 Japanese index ataxia patients. RESULTS: Heterozygous mutation c.698C > T (p.T233M) was detected in an index patient with multisystem neurodegeneration including ataxia and erythrokeratodermia skin lesions, an archetypal skin phenotype in SCA34. The patient's father also presented with ataxia but not skin lesions. Although this mutation has been recently reported in a single English-Canadian patient, the present study confirms its cosegregation with the ataxia phenotype in the Japanese kindred. Brain magnetic resonance imaging (MRI) of the patient and his father revealed marked pontine and cerebellar atrophy as well as the hot cross bun sign, that is common in cerebellar type of multiple system atrophy and was also described in SCA34 patients harboring two other mutations: p.L168F and p.W246G. CONCLUSION: This represents the first genetic study of the prevalence of SCA34 in an ataxia cohort and demonstrates its low prevalence (0.2%) in ataxia patients. The broad SCA34 clinical spectrum suggests variable multisystem neurodegeneration. Clinicians should be aware of this rare disease entity, particularly if erythrokeratodermia or the hot cross bun sign in MRI are present in undiagnosed degenerative ataxia patients.

3.
Eur Neurol ; 81(1-2): 13-18, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31013498

RESUMO

BACKGROUND: Caudate nucleus atrophy is a well-known neuroimaging feature of Huntington's disease (HD). Some researchers have reported a decrease in the volume of the striatum on magnetic resonance images (MRIs) even in the presymptomatic stage of the disease. Despite the many neuroimaging studies on HD, the optimal method for measuring the caudate nucleus area on MRIs and the most effective cutoff values for diagnosing HD remain unclear. OBJECTIVES AND METHODS: To define suitable imaging sequences and cutoff values for HD, we measured the area of the head of the caudate nucleus (HCN) in 11 patients with HD, 22 age- and sex-matched individuals without neurodegenerative disorders in the central nervous system, 22 sex-matched patients with Alzheimer's disease, 22 sex-matched patients with Parkinson's disease, and 7 patients with dentatorubral-pallidoluysian atrophy. RESULTS: On T2-weighted images (T2WIs), we found significantly reduced HCN area at the rostral level in individuals with HD relative to those of the individuals in the other groups. A significant inverse correlation (ρ = -0.61, p = 0.046) was observed between the HD duration and HCN area at the rostral slice level on T2WIs. The cutoff value for distinguishing patients with HD from healthy individuals and those with other neurodegenerative diseases was 85 mm2 at the rostral level on T2WIs (100% sensitivity and specificity). CONCLUSIONS: This cutoff value can be applied clinically to evaluate brain atrophy in HD. Our method is advantageous because it is simple and can be implemented easily in daily clinical practice.

4.
Am J Hum Genet ; 104(5): 925-935, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982609

RESUMO

Colony stimulating factor 1 receptor (CSF1R) plays key roles in regulating development and function of the monocyte/macrophage lineage, including microglia and osteoclasts. Mono-allelic mutations of CSF1R are known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an adult-onset progressive neurodegenerative disorder. Here, we report seven affected individuals from three unrelated families who had bi-allelic CSF1R mutations. In addition to early-onset HDLS-like neurological disorders, they had brain malformations and skeletal dysplasia compatible to dysosteosclerosis (DOS) or Pyle disease. We identified five CSF1R mutations that were homozygous or compound heterozygous in these affected individuals. Two of them were deep intronic mutations resulting in abnormal inclusion of intron sequences in the mRNA. Compared with Csf1r-null mice, the skeletal and neural phenotypes of the affected individuals appeared milder and variable, suggesting that at least one of the mutations in each affected individual is hypomorphic. Our results characterized a unique human skeletal phenotype caused by CSF1R deficiency and implied that bi-allelic CSF1R mutations cause a spectrum of neurological and skeletal disorders, probably depending on the residual CSF1R function.

5.
Proc Natl Acad Sci U S A ; 115(28): 7428-7433, 2018 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-29941578

RESUMO

In performing skillful movement, humans use predictions from internal models formed by repetition learning. However, the computational organization of internal models in the brain remains unknown. Here, we demonstrate that a computational architecture employing a tandem configuration of forward and inverse internal models enables efficient motor learning in the cerebellum. The model predicted learning adaptations observed in hand-reaching experiments in humans wearing a prism lens and explained the kinetic components of these behavioral adaptations. The tandem system also predicted a form of subliminal motor learning that was experimentally validated after training intentional misses of hand targets. Patients with cerebellar degeneration disease showed behavioral impairments consistent with tandemly arranged internal models. These findings validate computational tandemization of internal models in motor control and its potential uses in more complex forms of learning and cognition.


Assuntos
Cerebelo/patologia , Aprendizagem/fisiologia , Modelos Neurológicos , Atividade Motora/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Mãos/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade
6.
J Neurol Sci ; 387: 187-195, 2018 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-29571861

RESUMO

Cerebellar ataxias (CAs) are heterogeneous conditions often require differential diagnosis. This study aimed to establish a diagnostic decision tree for differentiating CAs based on pontine MRI findings. Two-hundred and two consecutive ataxia patients were clinically classified into 4 groups: (1) spinocerebellar ataxia (SCA) with brainstem involvement (SCA-BSI), (2) Pure cerebellar SCA, (3) cerebellar dominant multiple system atrophy (MSA-c), and (4) Other CA. Signal intensity in pons was graded into 3 types: hot cross bun sign (HCBS), pontine midline linear T2-hyperintensity (PMH), or normal. The distance ratio of pontine base to tegmentum, named "BT-ratio", was measured. The presence of HCBS indicated either MSA-c with a specificity of 97.7%, or SCA2. When PMH was observed, a BT-ratio above 3.54 strongly indicated SCA-BSI, namely Machado-Joseph disease, SCA1, or dentatorubral-pallidoluysian atrophy, whereas a BT-ratio below 3.54 indicated MSA-c or SCA2. When the signal intensity was normal, a BT-ratio above 3.52 indicated SCA-BSI, whereas a BT-ratio below 3.52 suggested Pure cerebellar SCA or Other CA with pure cerebellar type. The decision tree was confirmed useful in a different 30 CA patients. We propose that differential diagnosis of CAs can be supported by combining pontine MRI signal intensity changes and BT-ratio.

7.
Intern Med ; 57(11): 1651-1654, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29434122

RESUMO

A 58-year-old man consulted our hospital due to a 2-year history of dysarthria and a 1-month history of blepharospasm. In addition to the ataxic dysarthria and blepharospasm, a neurological examination demonstrated slight ataxia of the trunk and lower limbs. Brain MRI demonstrated atrophy of the upper portion of the cerebellar vermis. Gene analysis established a diagnosis of spinocerebellar ataxia type 31 (SCA31). Single photon emission computed tomography (SPECT) with the three-dimensional stereotaxic ROI template (3DSRT) software program demonstrated hyperperfusion in the lenticular nucleus and thalamus. Although the association between SCA31 and blepharospasm in our patient remains unclear, we considered that this combination might be more than coincidental.


Assuntos
Blefarospasmo/etiologia , Ataxia Cerebelar/etiologia , Proteínas do Tecido Nervoso/genética , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/diagnóstico , Atrofia , Tronco Encefálico/patologia , Testes Genéticos , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Ataxias Espinocerebelares/genética , Tomografia Computadorizada de Emissão de Fóton Único
8.
J Neurol Sci ; 382: 87-90, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-29111027

RESUMO

Spinocerebellar ataxia type 8 (SCA8), an autosomal dominant neurodegenerative disorder showing slowly progressive cerebellar ataxia, is caused by a tri-nucleotide CTG repeat expansion (CTGexp) in the SCA8 gene. As the CTGexp is not fully penetrant, the significance of screening CTGexp in ataxia subjects remains obscure. We tested SCA8 CTGexp in a cohort of 797 ataxia subjects, and if present, its sequence configuration was analyzed. CTGexp was found in 16 alleles from 14 individuals, 2 of which was homozygous for CTGexp. Nucleotide sequencing disclosed 3 types of CTGexp sequence configurations: uninterrupted CTGexp, tri-nucleotide CTA interruption and CCG interruption. The 2 individuals with homozygous expansions were both sporadic cases with clinical features compatible with SCA8, supporting gene dosage effect. Seven out of 14 CTGexp-positive subjects were also carriers of other SCA expansions [Machado-Joseph disease (n=1), SCA6 (n=3) and SCA31 (n=3)], whereas 7 others were not complicated with such major SCAs. Ages of onset in subjects with pure CTGexp tended to be earlier than those with interrupted CTGexp among the 7 subjects not complicated by major SCAs, suggesting that pure CTGexp have stronger pathogenic effect than interrupted CTGexps. The present study underscores importance of disclosing sequence configuration when testing SCA8.


Assuntos
RNA Longo não Codificante/genética , Degenerações Espinocerebelares/genética , Expansão das Repetições de Trinucleotídeos , Adolescente , Adulto , Idade de Início , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Coortes , Humanos , Japão , Pessoa de Meia-Idade , Prevalência , Degenerações Espinocerebelares/epidemiologia
10.
Neuron ; 94(1): 108-124.e7, 2017 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-28343865

RESUMO

Microsatellite expansion disorders are pathologically characterized by RNA foci formation and repeat-associated non-AUG (RAN) translation. However, their underlying pathomechanisms and regulation of RAN translation remain unknown. We report that expression of expanded UGGAA (UGGAAexp) repeats, responsible for spinocerebellar ataxia type 31 (SCA31) in Drosophila, causes neurodegeneration accompanied by accumulation of UGGAAexp RNA foci and translation of repeat-associated pentapeptide repeat (PPR) proteins, consistent with observations in SCA31 patient brains. We revealed that motor-neuron disease (MND)-linked RNA-binding proteins (RBPs), TDP-43, FUS, and hnRNPA2B1, bind to and induce structural alteration of UGGAAexp. These RBPs suppress UGGAAexp-mediated toxicity in Drosophila by functioning as RNA chaperones for proper UGGAAexp folding and regulation of PPR translation. Furthermore, nontoxic short UGGAA repeat RNA suppressed mutated RBP aggregation and toxicity in MND Drosophila models. Thus, functional crosstalk of the RNA/RBP network regulates their own quality and balance, suggesting convergence of pathomechanisms in microsatellite expansion disorders and RBP proteinopathies.


Assuntos
Proteínas de Ligação a DNA/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Repetições de Microssatélites/genética , Doença dos Neurônios Motores/genética , Dobramento de RNA/genética , Proteína FUS de Ligação a RNA/genética , Ataxias Espinocerebelares/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Animais Geneticamente Modificados , Expansão das Repetições de DNA , Proteínas de Drosophila/genética , Drosophila melanogaster , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Chaperonas Moleculares/genética , Células PC12 , Biossíntese de Proteínas/genética , Proteínas de Ligação a RNA/genética , Ratos
12.
J Neurol Sci ; 373: 321-328, 2017 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-28131213

RESUMO

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant neurodegenerative disorder. However, it remains unclear whether SCA6 shows a gene dosage effect, defined by earlier age-of-onset in homozygotes than heterozygotes. Herein, we retrospectively analyzed four homozygous SCA6 subjects from our single institution cohort of 120 SCA6 subjects. We also performed a neuropathological investigation into an SCA6 individual with compound heterozygous expansions. In the 116 heterozygotes, there was an inverse correlation of age-of-onset with the number of CAG repeats in the expanded allele, and with the total number of CAG repeats, in both normal and expanded alleles. The age-of-onset in the four homozygotes was within the 95% confidence interval of the age-of-onset versus the repeat-lengths correlations determined in the 116 heterozygotes. Nevertheless, all homozygotes had earlier onset than their parents, and showed rapid disease progression. Neuropathology revealed neuronal loss, as well as α1A-calcium channel protein aggregates in Purkinje cells, a few α1A-calcium channel protein aggregates in the neocortex and basal ganglia, and neuronal loss in Clarke's column and the globus pallidus not seen in heterozygotes. These data suggest a mild clinical and neuropathological gene dosage effect in SCA6 subjects.

14.
J Neurol ; 263(11): 2179-2187, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27502082

RESUMO

Imaging of type 1 metabotropic glutamate receptor (mGluR1) has recently become possible using positron emission tomography (PET). We aimed to examine the relationship between mGluR1 and cerebellar ataxia. Families with spinocerebellar ataxia type 19/22 (SCA19/22) and SCA6, six patients with sporadic SCA, and 26 healthy subjects underwent PET using an mGluR1 radiotracer. Volumes-of-interest were placed on the anterior and posterior lobes and vermis. The binding potential (BPND) was calculated to estimate mGluR1 availability. A partial volume correction was applied to the BPND values. The Scale for the Assessment and Rating of Ataxia (SARA) score were measured. In each patient with SCA19/22 and SCA6, the anterior lobe showed the highest decrease rates in the BPND values, compared with healthy subjects. In the families with SCA19/22 and SCA6, the disease durations and SARA scores were shorter and lower, respectively, in the offspring, compared with the parents. However, the offspring paradoxically showed lower BPND values, especially in the anterior lobe, compared with the parents. The patients with sporadic SCA showed significantly lower BPND values in all subregions than healthy subjects. The BPND values significantly correlated with the SARA scores in all participants. In conclusion, these results showed a decrease in mGluR1 availability in patients with hereditary and sporadic SCA, a correlation between mGluR1 availability and degree of cerebellar ataxia, and paradoxical findings in two families. These results suggest the potential use of mGluR1 imaging as a specific biomarker of cerebellar ataxia.


Assuntos
Ataxia Cerebelar/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Ataxia Cerebelar/diagnóstico por imagem , Ataxia Cerebelar/genética , Saúde da Família , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tecido Parenquimatoso/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Degenerações Espinocerebelares/genética
15.
PLoS One ; 10(12): e0143518, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26637123

RESUMO

Oxidative stress has a ubiquitous role in neurodegenerative diseases and oxidative damage in specific regions of the brain is associated with selective neurodegeneration. We previously reported that Alzheimer disease (AD) model mice showed decreased insulin-degrading enzyme (IDE) levels in the cerebrum and accelerated phenotypic features of AD when crossbred with alpha-tocopherol transfer protein knockout (Ttpa-/-) mice. To further investigate the role of chronic oxidative stress in AD pathophysiology, we performed DNA microarray analysis using young and aged wild-type mice and aged Ttpa-/- mice. Among the genes whose expression changed dramatically was Phospholipase A2 group 3 (Pla2g3); Pla2g3 was identified because of its expression profile of cerebral specific up-regulation by chronic oxidative stress in silico and in aged Ttpa-/- mice. Immunohistochemical studies also demonstrated that human astrocytic Pla2g3 expression was significantly increased in human AD brains compared with control brains. Moreover, transfection of HEK293 cells with human Pla2g3 decreased endogenous IDE expression in a dose-dependent manner. Our findings show a key role of Pla2g3 on the reduction of IDE, and suggest that cerebrum specific increase of Pla2g3 is involved in the initiation and/or progression of AD.


Assuntos
Envelhecimento/genética , Doença de Alzheimer/genética , Cérebro/metabolismo , Fosfolipases A2 do Grupo III/genética , Insulisina/genética , Doença de Alzheimer/metabolismo , Animais , Proteínas de Transporte/genética , Células Cultivadas , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Técnicas de Inativação de Genes , Fosfolipases A2 do Grupo III/metabolismo , Células HEK293 , Humanos , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Especificidade de Órgãos , Estresse Oxidativo , Regulação para Cima
16.
Hum Mol Genet ; 24(17): 4780-91, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26034136

RESUMO

Spinocerebellar ataxia type 6 (SCA6) is dominantly inherited neurodegenerative disease, caused by an expansion of CAG repeat encoding a polyglutamine (PolyQ) tract in the Cav2.1 voltage-gated calcium channel. Its key pathological features include selective degeneration of the cerebellar Purkinje cells (PCs), a common target for PolyQ-induced toxicity in various SCAs. Mutant Cav2.1 confers toxicity primarily through a toxic gain-of-function mechanism; however, its molecular basis remains elusive. Here, we studied the cerebellar gene expression patterns of young Sca6-MPI(118Q/118Q) knockin (KI) mice, which expressed mutant Cav2.1 from an endogenous locus and recapitulated many phenotypic features of human SCA6. Transcriptional signatures in the MPI(118Q/118Q) mice were distinct from those in the Sca1(154Q/2Q) mice, a faithful SCA1 KI mouse model. Temporal expression profiles of the candidate genes revealed that the up-regulation of genes associated with microglial activation was initiated before PC degeneration and was augmented as the disease progressed. Histological analysis of the MPI(118Q/118Q) cerebellum showed the predominance of M1-like pro-inflammatory microglia and it was concomitant with elevated expression levels of tumor necrosis factor, interleukin-6, Toll-like receptor (TLR) 2 and 7. Genetic ablation of MyD88, a major adaptor protein conveying TLR signaling, altered expression patterns of M1/M2 microglial phenotypic markers in the MPI(118Q/118Q) cerebellum. More importantly, it ameliorated PC loss and partially rescued motor impairments in the early disease phase. These results suggest that early neuroinflammatory response may play an important role in the pathogenesis of SCA6 and its modulation could pave the way for slowing the disease progression during the early stage of the disease.


Assuntos
Deleção de Genes , Fator 88 de Diferenciação Mieloide/genética , Células de Purkinje/metabolismo , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologia , Animais , Biomarcadores , Cerebelo/metabolismo , Cerebelo/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Camundongos , Microglia/metabolismo , Atividade Motora , Fator 88 de Diferenciação Mieloide/deficiência , RNA Mensageiro/genética
18.
J Neurol Sci ; 355(1-2): 202-5, 2015 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-26055313

RESUMO

OBJECTIVE: Imaging of metabotropic glutamate receptor type 1 (mGluR1), localized exclusively in the cerebellar Purkinje cells and related to cerebellar function, has recently become possible using positron emission tomography (PET). We report the initial mGluR1 imaging in a 74-year-old woman with spinocerebellar ataxia type 6 (SCA6). METHODS: The patient and 9 age-matched healthy controls underwent PET scanning with a mGluR1 radiotracer, N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl] -4-(11)C-methoxy-N-methylbenzamide. Volumes-of-interest were placed on the anterior and posterior lobes, vermis, and flocculus. Binding potential (BPND) was calculated to estimate mGluR1 availability using the simplified reference tissue model. A partial volume correction was applied to the BPND values. Additionally, the volume of the whole cerebellum was measured using MRI. RESULTS: The corrected BPND values of the cerebellar subregions and the volume of the whole cerebellum in the patient were 51.0% to 68.3% and 72.6%, respectively, of the controls. Thus, the magnitude of reduced BPND values was relatively larger than the magnitude of cerebellar atrophy in the patient. CONCLUSION: These findings suggest that the measurement of mGluR1 availability is more sensitive than morphological measurements by MRI to detect reduced cerebellar function. Thus, imaging of mGluR1, probably reflecting the number and distribution of Purkinje cells, can be a specific and sensitive marker for estimation of cerebellar function.


Assuntos
Encéfalo/diagnóstico por imagem , Receptores de Glutamato Metabotrópico/metabolismo , Ataxias Espinocerebelares/diagnóstico por imagem , Idoso , Benzamidas/farmacocinética , Radioisótopos de Carbono/farmacocinética , Estudos de Casos e Controles , Feminino , Humanos , Tomografia por Emissão de Pósitrons , Ligação Proteica/efeitos dos fármacos , Tiazóis/farmacocinética
19.
JAMA Neurol ; 72(7): 797-805, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26010696

RESUMO

IMPORTANCE: Although mutations in 26 causative genes have been identified in the spinocerebellar ataxias (SCAs), the causative genes in a substantial number of families with SCA remain unidentified. OBJECTIVE: To identify the causative gene of SCA in 2 Japanese families with distinct neurological symptoms and radiological presentations. DESIGN, SETTING, AND PARTICIPANTS: Clinical genetic study at a referral center of 11 members from 2 Japanese families, which started in 1997. MAIN OUTCOMES AND MEASURES: Results of neurological examinations and radiological evaluations. The causative mutation was identified using genome-wide linkage analysis and next-generation sequencing. RESULTS: Affected members (9 of 11 members [81.8%]) showed slowly progressive cerebellar ataxia (all 9 members [100%]), ocular movement disturbance (all 9 members [100%]), and pyramidal tract signs (8 of 9 members [88.9%]) with an age at onset between the second and sixth decades of life. Besides cerebellar and pontine atrophy, magnetic resonance imaging of the brain revealed the hot cross bun sign (4 of 6 members [66.7%]), pontine midline linear hyperintensity (2 of 6 members [33.3%]), or high intensity in the middle cerebellar peduncle (1 of 6 members [16.7%]), which are all reminiscent of multiple system atrophy in tested patients. Using linkage analysis combined with exome and whole-genome sequencing, we identified a novel heterozygous mutation in the ELOVL fatty acid elongase 4 (ELOVL4) gene (c.736T>G, p.W246G) in both families. Haplotype analysis indicated that it was unlikely that these 2 Japanese families shared a common ancestor. Although a missense mutation in ELOVL4 (c.504G>C, p.L168F) was recently reported to be associated with SCA with erythrokeratodermia variabilis (SCA34) in a French-Canadian family, signs of erythrokeratodermia variabilis were absent in our families. CONCLUSIONS AND RELEVANCE: Combined with the results of the family with SCA34 reported previously, this report confirms that mutations in ELOVL4 can cause dominantly inherited neurodegeneration severely affecting the cerebellum and brainstem. We should be aware that the presence of multiple system atrophy-like features on magnetic resonance imaging scans, together with cerebellar and brainstem atrophy, suggests SCA34, even when erythrokeratodermia variabilis is absent. The present study further broadened the spectrum of the clinical presentations of SCA34 associated with mutations in ELOVL4, which is involved in the biosynthesis of very long-chain fatty acids.


Assuntos
Ataxia/diagnóstico , Ataxia/genética , Proteínas do Olho/genética , Proteínas de Membrana/genética , Mutação/genética , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/genética , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/genética , Adulto , Sequência de Aminoácidos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem
20.
J Neurogenet ; 29(2-3): 80-4, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26004545

RESUMO

This study reports the first family in which spinocerebellar ataxia type 6 (SCA6) and spinocerebellar ataxia type 31 (SCA31) mutations were seen. An index patient first presented to our hospital due to gait and speech disturbances. Subsequent clinical investigation of this patient and her family members revealed consistent pure cerebellar ataxia transmitted in an autosomal-dominant manner. Genetic examination unexpectedly demonstrated that two of the five affected individuals had expansions of SCA6 and SCA31, while two others had SCA31 alone and the remaining had SCA6. Clinical manifestations were more severe in individuals with combined mutations relative to those with single mutation, suggesting that the SCA6 and SCA31 mutations have a cumulative pathogenic effect.


Assuntos
Encéfalo/patologia , Canais de Cálcio/genética , Ataxias Espinocerebelares/genética , Idoso , Feminino , Testes Genéticos , Humanos , Imagem por Ressonância Magnética , Masculino , Mutação , Linhagem , Ataxias Espinocerebelares/patologia
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