RESUMO
Spinocerebellar ataxia 42 (SCA42) is a neurodegenerative disorder recently shown to be caused by c.5144Gâ¯>â¯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.5168Gâ¯>â¯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 11-20â¯weeks and showed Purkinje cell loss at 50â¯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.
Assuntos
Canais de Cálcio Tipo T/metabolismo , Cerebelo/metabolismo , Fenótipo , Células de Purkinje/metabolismo , Ataxias Espinocerebelares/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Canais de Cálcio Tipo T/genética , Cerebelo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Células de Purkinje/patologia , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologiaRESUMO
Recently, an increasing number of NOTCH3 mutations have been described to cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Here, we report 2 CADASIL patients from a Japanese family, who were found to possess a novel NOTCH3 mutation. The proband only had chronic headache, and her mother had previously suffered a minor stroke. Although the patients' clinical symptoms were mild, their distinctive magnetic resonance imaging (MRI) features suggested CADASIL. Genetic analysis revealed that both patients had a novel heterozygous NOTCH3 mutation (p.Cys478Tyr) leading to stereotypical cysteine loss. The present finding suggests that genetic testing for NOTCH3 mutations in patients with distinctive MRI features, even if the symptoms are as mild as chronic headache, should help to broaden the mutational and clinical spectrum of CADASIL.
Assuntos
CADASIL/genética , Mutação , Receptores Notch/genética , Idoso , CADASIL/complicações , CADASIL/diagnóstico , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Transtornos da Cefaleia/diagnóstico , Transtornos da Cefaleia/genética , Heterozigoto , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Linhagem , Fenótipo , Valor Preditivo dos Testes , Receptor Notch3 , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/genéticaRESUMO
Nonhuman primates (NHPs), which are closely related to humans, are useful in biomedical research, and an increasing number of NHP disease models have been reported using gene editing. However, many disease-related genes cause perinatal death when manipulated homozygously by gene editing. In addition, NHP resources, which are limited, should be efficiently used. Here, to address these issues, we developed a method of introducing heterozygous genetic modifications into common marmosets by combining Platinum transcription activator-like effector nuclease (TALEN) and a gene-editing strategy in oocytes. We succeeded in introducing the heterozygous exon 9 deletion mutation in the presenilin 1 gene, which causes familial Alzheimer's disease in humans, using this technology. As a result, we obtained animals with the expected genotypes and confirmed several Alzheimer's disease-related biochemical changes. This study suggests that highly efficient heterozygosity-oriented gene editing is possible using TALEN and oocytes and is an effective method for producing genetically modified animals.
Assuntos
Callithrix , Éxons , Edição de Genes , Heterozigoto , Presenilina-1 , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição , Animais , Callithrix/genética , Edição de Genes/métodos , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição/genética , Presenilina-1/genética , Feminino , Modelos Animais de Doenças , Doença de Alzheimer/genética , Animais Geneticamente Modificados/genética , Oócitos/metabolismoRESUMO
Limited mouth opening is a characteristic of masticatory muscle tendon-aponeurosis hyperplasia (MMTAH). Although genetic involvement is suspected where familial onset is frequently observed, the genetic background of MMTAH is yet to be elucidated. In this study, we conducted whole genome sequencing of 10 patients with MMTAH and their family members when available. We also conducted RNA sequencing of normal temporal tendon (as disease region) and Achilles tendon (as control region) from commercially available pig samples. We identified 51 genes that had rare variants in patients with MMTAH and were highly expressed in the temporal tendons of pigs. Among the 51 genes, 37 genes have not been reported to be causative for human genetic diseases so far. As an implication of genetic involvement in the pathogenesis of MMTAH, 21 of these 37 genes were identified in two independent families. In particular, PCDH1 and BAIAP3 were identified in one affected individual in a family and consistently segregated in unrelated family, indicating they could be candidate causative genes of MMTAH. Our findings will help elucidate the genetic landscape of MMTAH and provide insights into future possibilities for tendon regeneration treatment.
RESUMO
Spinocerebellar ataxia type 34 (SCA34) is an autosomal dominant inherited ataxia due to mutations in ELOVL4, which encodes one of the very long-chain fatty acid elongases. SCA38, another spinocerebellar ataxia, is caused by mutations in ELOVL5, a gene encoding another elongase. However, there have been no previous studies describing the neuropathology of either SCA34 or 38. This report describes the neuropathological findings of an 83-year-old man with SCA34 carrying a pathological ELOVL4 mutation (NM_022726, c.736T>G, p.W246G). Macroscopic findings include atrophies in the pontine base, cerebellum, and cerebral cortices. Microscopically, marked neuronal and pontocerebellar fiber loss was observed in the pontine base. In addition, in the pontine base, accumulation of CD68-positive macrophages laden with periodic acid-Schiff (PAS)-positive material was observed. Many vacuolar lesions were found in the white matter of the cerebral hemispheres and, to a lesser extent, in the brainstem and spinal cord white matter. Immunohistological examination and ultrastructural observations with an electron microscope suggest that these vacuolar lesions are remnants of degenerated oligodendrocytes. Electron microscopy also revealed myelin sheath destruction. Unexpectedly, aggregation of the four-repeat tau was observed in a spatial pattern reminiscent of progressive supranuclear palsy. The tau lesions included glial fibrillary tangles resembling tuft-shaped astrocytes and neurofibrillary tangles and pretangles. This is the first report to illustrate that a heterozygous missense mutation in ELOVL4 leads to neuronal loss accompanied by macrophages laden with PAS-positive material in the pontine base and oligodendroglial degeneration leading to widespread vacuoles in the white matter in SCA34.
Assuntos
Encéfalo/patologia , Degeneração Neural/patologia , Oligodendroglia/patologia , Ataxias Espinocerebelares/patologia , Substância Branca/patologia , Idoso de 80 Anos ou mais , Proteínas do Olho/genética , Humanos , Masculino , Proteínas de Membrana/genética , Mutação de Sentido Incorreto , Degeneração Neural/genética , Ataxias Espinocerebelares/genética , Vacúolos/patologiaRESUMO
Aggressive therapy-resistant and refractory acute myeloid leukemia (AML) has an extremely poor outcome. By analyzing a large number of genetically complex and diverse, primary high-risk poor-outcome human AML samples, we identified specific pathways of therapeutic vulnerability. Through drug screens followed by extensive in vivo validation and genomic analyses, we found inhibition of cytosolic and mitochondrial anti-apoptotic proteins XIAP, BCL2 and MCL1, and a key regulator of mitosis, AURKB, as a vulnerability hub based on patient-specific genetic aberrations and transcriptional signatures. Combinatorial therapeutic inhibition of XIAP with an additional patient-specific vulnerability eliminated established AML in vivo in patient-derived xenografts (PDXs) bearing diverse genetic aberrations, with no signs of recurrence during off-treatment follow-up. By integrating genomic profiling and drug-sensitivity testing, this work provides a platform for a precision-medicine approach for treating aggressive AML with high unmet need.
Assuntos
Leucemia Mieloide Aguda , Proteínas Proto-Oncogênicas c-bcl-2 , Apoptose/genética , Proteínas Reguladoras de Apoptose/uso terapêutico , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genéticaRESUMO
Progressive multifocal leukoencephalopathy (PML) is caused by John Cunningham (JC) virus in immunocompromized patients such as those with human immunodeficiency virus (HIV) infection, hematological malignancy, autoimmune disorder, and immunodeficiency disorder as well as those undergoing chemotherapy or immunosuppressive therapy. No effective treatments have been established for PML, which commonly causes severe neurological sequelae. We describe the first case of PML in a patient without HIV infection who exhibited remarkable improvement following acute pyelonephritis with Escherichia coli bacteremia.
Assuntos
Hospedeiro Imunocomprometido , Leucoencefalopatia Multifocal Progressiva/imunologia , Pielonefrite/complicações , Adulto , Anemia Hemolítica Autoimune/complicações , Bacteriemia/complicações , Feminino , Humanos , Neoplasias Pulmonares/complicações , Linfoma de Zona Marginal Tipo Células B/complicaçõesRESUMO
Olivary hypertrophy (OH) is the secondary degeneration of the inferior olivary nucleus (ION). It is observed one month after the onset of a primary lesion within the dento-rubro-olivary pathway and is usually associated with oculopalatal tremors. Here, we report two unique cases with rare autoimmune diseases leading to OH development with progressive cerebellar ataxia, both of which improved with steroid treatment. The first patient was a 59-year-old man with slowly progressive dysarthria and ataxic gait without palatal tremor. Anti-N-methyl-d-aspartate (NMDA) receptor antibody was positive in the CSF, supporting a diagnosis of anti-NMDA receptor encephalitis. The second patient was a 56-year-old man who developed dysarthria, ataxia, gait disturbance, and palatal tremor. He was diagnosed with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), based on presence of a punctate contrast-enhancing lesion in the middle cerebellar peduncle, pons, and cerebellum on magnetic resonance imaging (MRI). Brain MRI in both patients demonstrated high signal intensity regions in the bilateral IONs. Semi-quantitative volume analysis of MRI revealed significant reduction in ION volume after steroid treatment and accordingly cerebellar ataxia was improved in both cases. Clinical and radiological features of the two cases were unique, indicating potential novel etiologies in the pathophysiology of OH associated with cerebellar ataxia.
Assuntos
Glucocorticoides/uso terapêutico , Núcleo Olivar/efeitos dos fármacos , Núcleo Olivar/diagnóstico por imagem , Prednisolona/uso terapêutico , Glucocorticoides/farmacologia , Humanos , Hipertrofia/diagnóstico por imagem , Hipertrofia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prednisolona/farmacologiaRESUMO
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.698Câ¯>â¯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.
Assuntos
Ataxia , Proteínas do Olho/genética , Proteínas de Membrana/genética , Dermatopatias Genéticas , Ataxias Espinocerebelares , Adulto , Ataxia/diagnóstico , Ataxia/epidemiologia , Ataxia/genética , Ataxia/patologia , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Linhagem , Prevalência , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/epidemiologia , Dermatopatias Genéticas/genética , Dermatopatias Genéticas/patologia , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/epidemiologia , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologiaRESUMO
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 , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares , Ataxias Espinocerebelares/genética , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
RATIONALE: OSAM is a rare ventriculoperitoneal (VP) shunt complication where cervical spinal cord compression by epidural venous plexus engorgement is caused by cerebrospinal fluid (CSF) overdrainage. Symmetrically indented deformity of the upper cervical spinal cord and surrounding epidural venous engorgement are characteristic radiological findings. Both of them are typically detected on magnetic resonance imaging (MRI) and enhanced computed tomography (CT). PATIENT CONCERNS: The 77-year-old man who underwent the placement of a VP shunt without an antisiphon device to treat post-subarachnoid hemorrhage (SAH) hydrocephalus presented with progressive quadriplegia 10 years postoperatively. DIAGNOSIS: MRI revealed a symmetrically indented spinal cord from the craniocervical junction (CCJ) to the C2 level and enhanced CT showed the epidural venous engorgement, which were characteristic radiological findings of overshunting-associated myelopathy (OSAM). However, MRI atypically failed to detect the engorged epidural vein and showed no compressive lesion around the spinal cord. INTERVENTION: In order to reveal how the cervical spinal cord was deformed and compressed by engorged epidural vein, CT myelography was performed. OUTCOMES: CT myelography proved that the epidural vein dynamically engorged and compressed the cervical spinal cord immediately after rotation and extension of the neck. LESSONS: CT myelography combined with neck rotation and extension revealed the dynamic change of the epidural venous engorgement, and is useful for evaluation and diagnosis of OSAM especially when epidural venous engorgement was not detectable on MRI.
Assuntos
Mielografia/métodos , Compressão da Medula Espinal/etiologia , Doenças da Medula Espinal/complicações , Tomografia Computadorizada por Raios X/métodos , Derivação Ventriculoperitoneal/efeitos adversos , Idoso , Medula Cervical/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Compressão da Medula Espinal/diagnóstico por imagem , Doenças da Medula Espinal/diagnóstico por imagemRESUMO
Myasthenia gravis (MG), a neuromuscular junction autoimmune disease, sometimes complicates second malignancies; however, T-cell lymphoproliferative disorders have rarely been reported. A 55-year-old man, who received oral tacrolimus and prednisolone for MG for 16 years after thymectomy, presented with left abdominal pain, lymphadenopathy, and splenomegaly. A lymph node biopsy revealed peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). This is the first report of oral tacrolimus leading to a T-cell lymphoproliferative disorder in patient without a history of transplantation. Physicians should be aware of the possibility of rare T-cell lymphoproliferative disorders, such as PTCL-NOS, occurring as complications in MG patients on immunosuppressive regimens after thymectomy.
Assuntos
Imunossupressores/efeitos adversos , Linfoma de Células T Periférico/induzido quimicamente , Linfoma de Células T Periférico/diagnóstico , Miastenia Gravis/tratamento farmacológico , Tacrolimo/efeitos adversos , Timectomia , Terapia Combinada , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/complicações , Miastenia Gravis/cirurgia , Tacrolimo/uso terapêuticoRESUMO
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.
Assuntos
Ataxia Cerebelar/diagnóstico por imagem , Árvores de Decisões , Imageamento por Ressonância Magnética , Ponte/efeitos dos fármacos , Adulto , Idoso , Ataxia Cerebelar/classificação , Cerebelo/diagnóstico por imagem , Estudos de Coortes , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Curva ROCRESUMO
Progressive encephalomyelitis with rigidity and myoclonus (PERM) is an autoimmune disorder involving the brainstem and spinal cord and is sometimes associated with thymoma. We encountered a 75-year-old woman with typical PERM features, glycine receptor antibody, and thymoma. Her neurologic symptoms improved after thymectomy, but she unexpectedly developed anasarca with massive pleural effusions and hypoalbuminemia and finally succumbed to death. The autopsy showed edema and mononuclear infiltration in the pleura but no neuropathological findings typical of PERM. Effective treatment of PERM can reverse the neuropathological signs of encephalomyelitis. The autoimmune nature of anasarca is possible but not proven.
Assuntos
Doenças Autoimunes/complicações , Edema/etiologia , Encefalomielite/complicações , Rigidez Muscular/complicações , Mioclonia/complicações , Timectomia/efeitos adversos , Timoma/complicações , Timoma/cirurgia , Neoplasias do Timo/complicações , Neoplasias do Timo/cirurgia , Idoso , Autoanticorpos/sangue , Doenças Autoimunes/cirurgia , Autopsia , Edema/imunologia , Encefalomielite/cirurgia , Evolução Fatal , Feminino , Humanos , Rigidez Muscular/cirurgia , Mioclonia/cirurgia , Derrame Pleural/etiologia , Derrame Pleural/imunologia , Complicações Pós-Operatórias , Receptores de Glicina/imunologia , Albumina Sérica/análiseRESUMO
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 , Povo Asiático/genética , Estudos de Coortes , Humanos , Japão , Pessoa de Meia-Idade , Prevalência , Degenerações Espinocerebelares/epidemiologiaRESUMO
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 , LinhagemRESUMO
p25α/tubulin polymerization promoting protein (TPPP) is an oligodendroglial protein that plays crucial roles including myelination, and the stabilization of microtubules. In multiple system atrophy (MSA), TPPP is suggested to relocate from the myelin sheath to the oligodendroglial cell body, before the formation of glial cytoplasmic inclusions (GCIs), the pathologic hallmark of MSA. However, much is left unknown about the re-distribution of TPPP in MSA. We generated new antibodies against the N- and C-terminus of TPPP, and analyzed control and MSA brains, including the brain of a familial MSA patient carrying homozygous mutations in the coenzyme Q2 gene (COQ2). In control brain tissues, TPPP was localized not only in the cytoplasmic component of the oligodendroglia including perinuclear cytoplasm and peripheral processes in the white matter, but also in the nucleus of a fraction (62.4%) of oligodendroglial cells. Immunoelectron microscopic analysis showed TPPP in the nucleus and mitochondrial membrane of normal oligodendroglia, while western blot also supported its nuclear and mitochondrial existence. In MSA, the prevalence of nuclear TPPP was 48.6% in the oligodendroglia lacking GCIs, whereas it was further decreased to 19.6% in the oligodendroglia with phosphorylated α-synuclein (pα-syn)-positive GCIs, both showing a significant decrease compared to controls (62.4%). In contrast, TPPP accumulated in the perinuclear cytoplasm where mitochondrial membrane (TOM20 and cytochrome C) and fission (DRP1) proteins were often immunoreactive. We conclude that in MSA-oligodendroglia, TPPP is reduced, not only in the peripheral cytoplasm, but also in the nucleus and relocated to the perinuclear cytoplasm.
Assuntos
Encéfalo/metabolismo , Atrofia de Múltiplos Sistemas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Oligodendroglia/metabolismo , Animais , Anticorpos , Núcleo Celular/química , Núcleo Celular/metabolismo , Citoplasma/química , Citoplasma/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Atrofia de Múltiplos Sistemas/genética , Mutação , Proteínas do Tecido Nervoso/imunologia , Oligodendroglia/ultraestrutura , Fosforilação , Ubiquinona/genéticaAssuntos
Dopaminérgicos/uso terapêutico , Levodopa/uso terapêutico , Doença de Machado-Joseph/complicações , Tremor/complicações , Tremor/tratamento farmacológico , Adulto , Eletromiografia , Humanos , Doença de Machado-Joseph/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada de Emissão de Fóton Único , Tremor/diagnóstico por imagem , Gravação em VídeoRESUMO
The human α1A voltage-dependent calcium channel (Cav2.1) is a pore-forming essential subunit embedded in the plasma membrane. Its cytoplasmic carboxyl(C)-tail contains a small poly-glutamine (Q) tract, whose length is normally 4â¼19 Q, but when expanded up to 20â¼33Q, the tract causes an autosomal-dominant neurodegenerative disorder, spinocerebellar ataxia type 6 (SCA6). A recent study has shown that a 75-kDa C-terminal fragment (CTF) containing the polyQ tract remains soluble in normal brains, but becomes insoluble mainly in the cytoplasm with additional localization to the nuclei of human SCA6 Purkinje cells. However, the mechanism by which the CTF aggregation leads to neurodegeneration is completely elusive, particularly whether the CTF exerts more toxicity in the nucleus or in the cytoplasm. We tagged recombinant (r)CTF with either nuclear-localization or nuclear-export signal, created doxycyclin-inducible rat pheochromocytoma (PC12) cell lines, and found that the CTF is more toxic in the cytoplasm than in the nucleus, the observations being more obvious with Q28 (disease range) than with Q13 (normal-length). Surprisingly, the CTF aggregates co-localized both with cAMP response element-binding protein (CREB) and phosphorylated-CREB (p-CREB) in the cytoplasm, and Western blot analysis showed that the quantity of CREB and p-CREB were both decreased in the nucleus when the rCTF formed aggregates in the cytoplasm. In human brains, polyQ aggregates also co-localized with CREB in the cytoplasm of SCA6 Purkinje cells, but not in other conditions. Collectively, the cytoplasmic Cav2.1-CTF aggregates are sufficient to cause cell death, and one of the pathogenic mechanisms may be abnormal CREB trafficking in the cytoplasm and reduced CREB and p-CREB levels in the nuclei.