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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(1): 21-24, 2020 Jan 10.
Artigo em Chinês | MEDLINE | ID: mdl-31922589

RESUMO

OBJECTIVE: To identify potential variant in a child diagnosed as infantile neuroaxonal dystrophy. METHODS: Genomic DNA was extracted from peripheral blood samples from the patient and his parents and subjected to next generation sequencing. Suspected variant was verified by PCR and Sanger sequencing. Pathogenicity of the mutation was predicted by using bioinformatic software including SIFT and PolyPhen-2. RESULTS: The child was found to carry compound heterozygous variations c.668C>A (p.Pro223Gln) and c.2266C>T (p.Gln756Ter) of the PLA2G6 gene, which were respectively inherited from his father and mother. c.2266C>T has changed codon 756 (glutamine) into a stop codon, resulting premature termination of peptide chain synthesis. c.2266C>T has not been reported previously and was predicted to be harmful. CONCLUSION: The compound variants of c.668C>A (p.Pro223Gln) and c.2266C>T (p.Gln756Ter) of the PLA2G6 gene probably underlies the disease in the child. Above finding has enriched the variant spectrum of the PLA2G6 gene.


Assuntos
Fosfolipases A2 do Grupo VI , Distrofias Neuroaxonais , Criança , Fosfolipases A2 do Grupo VI/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Distrofias Neuroaxonais/genética
2.
Genes (Basel) ; 11(1)2020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31936863

RESUMO

Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM) is an inherited neurodegenerative disorder of unknown etiology. Clinical signs of neurological deficits develop within the first year of life in vitamin E (vitE) deficient horses. A genome-wide association study (GWAS) was carried out using 670,000 SNP markers in 27 case and 42 control Quarter Horses. Two markers, encompassing a 2.5 Mb region on ECA7, were associated with the phenotype (p = 2.05 × 10-7 and 4.72 × 10-6). Within this region, caytaxin (ATCAY) was identified as a candidate gene due to its known role in Cayman Ataxia and ataxic/dystonic phenotypes in mouse models. Whole-genome sequence data in four eNAD/EDM and five unaffected horses identified 199 associated variants within the ECA7 region. MassARRAY® genotyping was performed on these variants within the GWAS population. The three variants within ATCAY were not concordant with the disease phenotype. No difference in expression or alternative splicing was identified using qRT-PCR in brainstem across the ATCAY transcript. Atcayji-hes mice were then used to conduct functional analysis in a second animal model. Histologic lesions were not identified in the central nervous system of Atcayji-hes mice. Additionally, supplementation of homozygous Atcayji-hes mice with 600 IU/day of dl-α-tocopheryl acetate (vitE) during gestation, lactation, and adulthood did not improve the phenotype. ATCAY has therefore been excluded as a candidate gene for eNAD/EDM.


Assuntos
Cavalos/genética , Distrofias Neuroaxonais/genética , Animais , Modelos Animais de Doenças , Feminino , Estudo de Associação Genômica Ampla , Homozigoto , Doenças dos Cavalos/genética , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Distrofias Neuroaxonais/veterinária , Fenótipo , Vitamina E , Deficiência de Vitamina E
3.
Artigo em Inglês | MEDLINE | ID: mdl-31489256

RESUMO

Background: Specific phenomenology and pattern of involvement in movement disorders point toward a probable clinical diagnosis. For example, forehead chorea usually suggests Huntington's disease; feeding dystonia suggests neuroacanthocytosis and risus sardonicus is commonly seen in Wilson's disease. Dystonic opisthotonus has been described as a characteristic feature of neurodegeneration with brain iron accumulation (NBIA) related to PANK2 and PLA2G6 mutations. Case report: We describe two additional patients in their 30s with severe extensor truncal dystonia causing opisthotonic posturing in whom evaluation revealed the diagnosis of NBIA confirmed by genetic testing. Discussion: Dystonic opisthotonus may be more common in NBIA than it is reported and its presence especially in a young patient should alert the neurologists to a possibility of probable NBIA.


Assuntos
Distonia/etiologia , Distúrbios do Metabolismo do Ferro/complicações , Distrofias Neuroaxonais/complicações , Postura/fisiologia , Adulto , Distonia/fisiopatologia , Humanos , Distúrbios do Metabolismo do Ferro/diagnóstico , Distúrbios do Metabolismo do Ferro/genética , Masculino , Músculo Esquelético/fisiopatologia , Distrofias Neuroaxonais/diagnóstico , Distrofias Neuroaxonais/genética , Tronco/fisiopatologia
4.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(9): 851-855, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31506141

RESUMO

Infantile neuroaxonal dystrophy (INAD) is a rare neurodegenerative disease. Two boys aged 3 years and 4 years and 2 months respectively, were admitted to the hospital due to delayed mental and motor development. There were no abnormalities at birth, and both children had low muscle strength and tension on admission. One child was not able to stand alone and had impaired vision. Electromyography showed neurogenic damage, and head MRI revealed cerebellar atrophy. High-throughput sequencing revealed compound heterozygous mutations in the PLA2G6 gene in the two children. The mutations (IVS11-1G>T and c.1984C>G) in one child were new mutations, and immunohistochemistry showed a reduction in the protein expression of PLAG6 in the muscular tissue of this child. INAD has the main clinical manifestations of psychomotor developmental regression and cerebellar atrophy. High-throughput sequencing can help with clinical diagnosis.


Assuntos
Fosfolipases A2 do Grupo VI/genética , Distrofias Neuroaxonais , Doenças Neurodegenerativas , Pré-Escolar , Humanos , Imagem por Ressonância Magnética , Masculino , Mutação , Distrofias Neuroaxonais/genética , Doenças Neurodegenerativas/genética
5.
Genes (Basel) ; 10(9)2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491999

RESUMO

Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM) is a neurologic disease that has been reported in young horses from a wide range of breeds. The disease is inherited and associated with vitamin E deficiency during the first two years of life, resulting in bilateral symmetric ataxia. A missense mutation (chr3:71,917,591 C > T) within adhesion G protein-coupled receptor L3 (ADGRL3) was recently associated with risk for EDM in the Caspian breed. In order to confirm these findings, genotyping of this missense mutation, along with the three other associated single nucleotide polymorphisms (SNPs) in the genomic region, was carried out on 31 postmortem-confirmed eNAD/EDM cases and 43 clinically phenotyped controls from various breeds. No significant association was found between eNAD/EDM confirmed cases and genotype at any of the four identified SNPs (P > 0.05), including the nonsynonymous variant (EquCab2.0 chr3:71,917,591; allelic P = 0.85). These findings suggest that the four SNPs, including the missense variant in the ADGRL3 region, are not associated with risk for eNAD/EDM across multiple breeds of horses.


Assuntos
Doenças dos Cavalos/genética , Cavalos/genética , Distrofias Neuroaxonais/genética , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas-G/genética , Receptores de Peptídeos/genética , Animais , Mutação de Sentido Incorreto , Distrofias Neuroaxonais/veterinária
6.
Biomed Pharmacother ; 118: 109068, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31404774

RESUMO

NBIA (Neurodegeneration with brain iron accumulation) is a group of inherited neurologic disorders characterized by marked genetic heterogeneity, in which iron atypical accumulates in basal ganglia resulting in brain magnetic resonance imaging changes, histopathological abnormalities, and neuropsychiatric clinical symptoms. With the rapid development of high-throughput sequencing technologies, ten candidate genes have been identified, including PANK2, PLA2G6, C19orf12, WDR45, FA2H, ATP13A2, FTL, CP, C2orf37, and COASY. They are involved in seemingly unrelated cellular pathways, such as iron homeostasis (FTL, CP), lipid metabolism (PLA2G6, C19orf12, FA2H), Coenzyme A synthesis (PANK2, COASY), and autophagy (WDR45, ATP13A2). In particular, PANK2, COASY, PLA2G6, and C19orf12 are located on mitochondria, which associate with certain subtypes of NBIA showing mitochondria dysregulation. However, the relationships among those four genes are still unclear. Therefore, this review is specifically focused on dysregulation of mitochondria in NBIA and afore-mentioned four genes, with summaries of both pathological and clinical findings.


Assuntos
Fosfolipases A2 do Grupo VI/genética , Distúrbios do Metabolismo do Ferro/genética , Mitocôndrias/patologia , Proteínas Mitocondriais/genética , Distrofias Neuroaxonais/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Transferases/genética , Humanos , Distúrbios do Metabolismo do Ferro/metabolismo , Distúrbios do Metabolismo do Ferro/patologia , Metabolismo dos Lipídeos/genética , Potencial da Membrana Mitocondrial/genética , Distrofias Neuroaxonais/metabolismo , Distrofias Neuroaxonais/patologia
7.
Biochemistry ; 58(18): 2318-2325, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-30986045

RESUMO

Neuroferritinopathy is a rare, adult-onset, dominantly inherited movement disorder caused by mutations in the ferritin gene. A ferritin light-chain variant related to neuroferritinopathy, in which alanine 96 is replaced with threonine (A96T), was expressed in Escherichia coli, purified, and characterized. The circular dichroism, analytical ultracentrifugation, and small-angle X-ray scattering studies have shown that both the subunit structure and the assembly of A96T are the same as those of wild-type human ferritin light chain (HuFTL). The iron-incorporation ability was also comparable to that of HuFTL. Although the structural stability against heat, acid, and denaturant was reduced, the structure was sufficiently stable under physiological conditions. The most remarkable defects observed for A96T were a lower refolding efficiency and a stronger propensity to aggregate. The possible relationship between folding deficiency and disease is discussed.


Assuntos
Apoferritinas/química , Ferritinas/química , Distúrbios do Metabolismo do Ferro/metabolismo , Distrofias Neuroaxonais/metabolismo , Agregação Patológica de Proteínas , Dobramento de Proteína , Apoferritinas/genética , Apoferritinas/metabolismo , Dicroísmo Circular , Ferritinas/genética , Ferritinas/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/patologia , Microscopia Eletrônica de Transmissão , Mutação de Sentido Incorreto , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/patologia , Estabilidade Proteica , Espalhamento a Baixo Ângulo , Temperatura , Difração de Raios X
9.
Mol Psychiatry ; 24(9): 1369-1382, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30899091

RESUMO

Alzheimer's disease (AD) is characterized by the presence of neuritic plaques in which dystrophic neurites (DNs) are typical constituents. We recently showed that DNs labeled by antibodies to the tubular endoplasmic reticulum (ER) protein reticulon-3 (RTN3) are enriched with clustered tubular ER. However, multi-vesicle bodies are also found in DNs, suggesting that different populations of DNs exist in brains of AD patients. To understand how different DNs evolve to surround core amyloid plaques, we monitored the growth of DNs in AD mouse brains (5xFAD and APP/PS1ΔE9 mice) by multiple approaches, including two-dimensional and three-dimensional (3D) electron microscopy (EM). We discovered that a pre-autophagosome protein ATG9A was enriched in DNs when a plaque was just beginning to develop. ATG9A-positive DNs were often closer to the core amyloid plaque, whereas RTN3 immunoreactive DNs were mostly located in the outer layers of ATG9A-positive DNs. Proteins such as RAB7 and LC3 appeared in DNs at later stages during plaque growth, likely accumulated as a part of large autophagy vesicles, and were distributed relatively furthest from the core amyloid plaque. Reconstructing the 3D structure of different morphologies of DNs revealed that DNs in AD mouse brains were constituted in three layers that are distinct by enriching different types of vesicles, as validated by immune-EM methods. Collectively, our results provide the first evidence that DNs evolve from dysfunctions of pre-autophagosomes, tubular ER, mature autophagosomes, and the ubiquitin proteasome system during plaque growth.


Assuntos
Doença de Alzheimer/metabolismo , Neuritos/patologia , Distrofias Neuroaxonais/patologia , Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Distrofias Neuroaxonais/classificação , Distrofias Neuroaxonais/diagnóstico por imagem , Placa Amiloide/metabolismo , Proteínas de Transporte Vesicular/metabolismo
11.
Zhonghua Yi Xue Za Zhi ; 99(5): 354-358, 2019 Jan 29.
Artigo em Chinês | MEDLINE | ID: mdl-30772976

RESUMO

Objective: To analyze the clinical presentation, imaging features, and the mutation of the pathogenic genes in a Chinese Han atypical neuroaxonal dystrophy pedigree. Methods: A family of atypical neuroaxonal dystrophy pedigree who came to Henan Provincal People's Hospital in July 2016 was included. Clinical presentation, imaging features of the pedigree were analyzed, and all exon gene detection of the proband was performed to capture the target variations, then verified by sanger sequence. Another 4 family members' and 100 normal healthy controls' gene sequence of the mutations were also verified. Results: The proband(Ⅱ(3)) of the family presented with walking unsteadily, intellectual disability, glossolalia, dystonia, epilepsy, and autonomic nervous dysfunction. The magnetic resonance imaging (MRI) of the proband showed cerebellar atrophy and iron deposit in basal ganglia. The gene detection showed the PLA2G6 gene compound complicated mutation of 80 codon p.A80T in the exon 3 and 331 codon p.D331Y in the exon 7. The two sisters of the proband (Ⅱ(1),Ⅱ(2)) had the same mutation, the father of the proband carried the p.A80T, however, the mother carried the D331Y mutation. One of the proband's sister (Ⅱ(1)), whose onset age was 10 years old, had the similar symptoms with the proband. The proband's another sister(Ⅱ(1)) had abnormal gait at 24 years old. However, the MRI of the two sisters all showed cerebellar atrophy. Conclusion: We report a PLA2G6 compound complicated mutation in an atypical neuroaxonal dystrophy Chinese family, that is the p. A80T and p.D331Y mutation, which may be a pathogenic mutation to cause the family's disease.


Assuntos
Fosfolipases A2 do Grupo VI/genética , Distúrbios do Metabolismo do Ferro , Distrofias Neuroaxonais , Criança , Humanos , Distúrbios do Metabolismo do Ferro/genética , Mutação , Distrofias Neuroaxonais/genética , Linhagem , Adulto Jovem
12.
Parkinsonism Relat Disord ; 61: 179-186, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30340910

RESUMO

INTRODUCTION: PLA2G6-associated neurodegeneration (PLAN) comprises a continuum of three phenotypes with overlapping clinical and radiologic features. METHODS: Observational clinical study in a cohort of infantile and childhood onset PLAN patients and genetic analysis of the PLA2G6 gene. We analysed chronological evolution in terms of age at onset and disease course through a 66-item questionnaire. We performed qualitative and quantitative assessment of MRI abnormalities and searched for clinical and radiological phenotype and genotype correlations. RESULTS: Sixteen PLAN patients (mean age: 10.2 years, range 3-33) were evaluated, with a median onset (years) of signs/symptoms as follows: neurological regression (1.5), oculomotor abnormalities (1.5), hypotonia (1.8), gait loss (2.2), pyramidal signs (3.0), axonal neuropathy (3.0), dysphagia (4.0), optic atrophy (4.0), psychiatric symptoms (4.0), seizures (5.9), joint contractures (6.0), dystonia (8.0), bladder dysfunction (13.0) and parkinsonism (15.0). MRI assessment identified cerebellar atrophy (19/19), brain iron deposition (10/19), clava hypertrophy (8/19) and T2/FLAIR hyperintensity of the cerebellar cortex (6/19). The mid-sagittal vermis relative diameter (MVRD) correlated with age at onset of clinical variants, meaning that the earlier the onset, the more severe the cerebellar atrophy. All patients harboured missense, nonsense and frameshift mutations in PLA2G6, including four novel variants. CONCLUSIONS: Cerebellar atrophy was a universal radiological sign in infantile and childhood onset PLAN, and correlated with the severity of the phenotype. Iron accumulation within the globus pallidum and substantia nigra was also a common and strikingly uniform feature regardless of the phenotype.


Assuntos
Cerebelo/patologia , Globo Pálido/metabolismo , Distrofias Neuroaxonais/patologia , Distrofias Neuroaxonais/fisiopatologia , Substância Negra/metabolismo , Adolescente , Adulto , Idade de Início , Atrofia/patologia , Cerebelo/diagnóstico por imagem , Criança , Pré-Escolar , Estudos Transversais , Globo Pálido/diagnóstico por imagem , Fosfolipases A2 do Grupo VI/genética , Humanos , Imagem por Ressonância Magnética , Distrofias Neuroaxonais/diagnóstico por imagem , Fenótipo , Índice de Gravidade de Doença , Substância Negra/diagnóstico por imagem , Adulto Jovem
17.
Cells ; 8(1)2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30577457

RESUMO

The current landscape of therapeutics designed to treat multiple sclerosis (MS) and its pathological sequelae is saturated with drugs that modify disease course and limit relapse rates. While these small molecules and biologicals are producing profound benefits to patients with reductions in annualized relapse rates, the repair or reversal of demyelinated lesions with or without axonal damage, remains the principle unmet need for progressive forms of the disease. Targeting the extracellular pathological milieu and the signaling mechanisms that drive neurodegeneration are potential means to achieve neuroprotection and/or repair in the central nervous system of progressive MS patients. The Nogo-A receptor-dependent signaling mechanism has raised considerable interest in neurological disease paradigms since it can promulgate axonal transport deficits, further demyelination, and extant axonal dystrophy, thereby limiting remyelination. If specific therapeutic regimes could be devised to directly clear the Nogo-A-enriched myelin debris in an expedited manner, it may provide the necessary CNS environment for neurorepair to become a clinical reality. The current review outlines novel means to achieve neurorepair with biologicals that may be directed to sites of active demyelination.


Assuntos
Axônios/efeitos dos fármacos , Terapia Baseada em Transplante de Células e Tecidos , Esclerose Múltipla/tratamento farmacológico , Bainha de Mielina/efeitos dos fármacos , Receptores Nogo , Axônios/patologia , Humanos , Bainha de Mielina/patologia , Distrofias Neuroaxonais/tratamento farmacológico , Proteínas Nogo/metabolismo , Receptores Nogo/antagonistas & inibidores , Receptores Nogo/metabolismo , Remielinização/efeitos dos fármacos
19.
Neurogenetics ; 19(4): 257-260, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30392167

RESUMO

Neurodegeneration with brain iron accumulation type 4 (NBIA4) also known as MPAN (mitochondria protein-associated neurodegeneration) is a rare neurological disorder which main feature is brain iron accumulation most frequently in the globus pallidus and substantia nigra. Whole exome sequencing (WES) in a 12-year-old patient revealed 2 variants in the C19orf12 gene, a previously reported common 11 bp deletion c.204_214del11, p.(Gly69Argfs*10) and a novel splicing variant c.193+5G>A. Functional analysis of novel variant showed skipping of the second exon, resulting in a formation of a truncated nonfunctional protein. This is the first functionally annotated pathogenic splicing variant in NBIA4.


Assuntos
Distúrbios do Metabolismo do Ferro/genética , Proteínas Mitocondriais/genética , Distrofias Neuroaxonais/genética , Processamento de RNA/genética , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Análise Mutacional de DNA , Feminino , Humanos , Ferro/metabolismo , Imagem por Ressonância Magnética , Linhagem , Isoformas de Proteínas/genética , República de Belarus
20.
Neurocase ; 24(3): 161-165, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-30088953

RESUMO

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an autosomal recessive disorder caused by mutation in the C19orf12 gene. We report a compound heterozygous c.[32C>T];[205G>A;424A>G] (p.[Thr11Met];[Gly69Arg;Lys142Glu]) Czech patient who manifested with right foot dystonia, impaired handwriting, attention deficit, and signs of iron accumulation on brain MRI. Gradually, he developed dysarthria, spastic-dystonic gait, pedes cavi, and atrophy of leg muscles. Additionally, we report demographic parameters, clinical signs, and allelic frequencies of C19orf12 mutations of all published MPAN cases. We compared the most frequent mutations, p.Thr11Met and p.Gly69ArgfsX10; the latter was associated with younger age at onset and more frequent optic atrophy in homozygotes.


Assuntos
Interleucinas/genética , Distúrbios do Metabolismo do Ferro , Proteínas de Transporte da Membrana Mitocondrial , Distrofias Neuroaxonais , Adulto , Humanos , Distúrbios do Metabolismo do Ferro/diagnóstico por imagem , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/fisiopatologia , Masculino , Distrofias Neuroaxonais/diagnóstico por imagem , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/fisiopatologia , Adulto Jovem
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