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1.
J Neurochem ; 167(2): 218-247, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37694499

RESUMO

Traumatic brain injury (TBI) causes significant neurological deficits and long-term degenerative changes. Primary injury in TBI entails distinct neuroanatomical zones, i.e., contusion (Ct) and pericontusion (PC). Their dynamic expansion could contribute to unpredictable neurological deterioration in patients. Molecular characterization of these zones compared with away from contusion (AC) zone is invaluable for TBI management. Using proteomics-based approach, we were able to distinguish Ct, PC and AC zones in human TBI brains. Ct was associated with structural changes (blood-brain barrier (BBB) disruption, neuroinflammation, axonal injury, demyelination and ferroptosis), while PC was associated with initial events of secondary injury (glutamate excitotoxicity, glial activation, accumulation of cytoskeleton proteins, oxidative stress, endocytosis) and AC displayed mitochondrial dysfunction that could contribute to secondary injury events and trigger long-term degenerative changes. Phosphoproteome analysis in these zones revealed that certain differentially phosphorylated proteins synergistically contribute to the injury events along with the differentially expressed proteins. Non-synaptic mitochondria (ns-mito) was associated with relatively more differentially expressed proteins (DEPs) compared to synaptosomes (Syn), while the latter displayed increased protein oxidation including tryptophan (Trp) oxidation. Proteomic analysis of immunocaptured complex I (CI) from Syn revealed increased Trp oxidation in Ct > PC > AC (vs. control). Oxidized W272 in the ND1 subunit of CI, revealed local conformational changes in ND1 and the neighboring subunits, as indicated by molecular dynamics simulation (MDS). Taken together, neuroanatomical zones in TBI show distinct protein profile and protein oxidation representing different primary and secondary injury events with potential implications for TBI pathology and neurological status of the patients.

2.
Mitochondrion ; 61: 69-84, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34592422

RESUMO

Mitochondrial disorders are one of the most common neurometabolic disorders affecting all age groups. The phenotype-genotype heterogeneity in these disorders can be attributed to the dual genetic control on mitochondrial functions, posing a challenge for diagnosis. Though the advancement in the high-throughput sequencing and other omics platforms resulted in a "genetics-first" approach, the muscle biopsy remains the benchmark in most of the mitochondrial disorders. This review focuses on the myopathological aspects of primary mitochondrial disorders. The utility of muscle biopsy is not limited to analyse the structural abnormalities; rather it also proves to be a potential tool to understand the deranged sub-cellular functions.


Assuntos
Predisposição Genética para Doença , Doenças Mitocondriais/diagnóstico , Doenças Musculares/diagnóstico , Marcadores Genéticos , Humanos , Doenças Mitocondriais/patologia , Doenças Musculares/patologia
3.
Neuromuscul Disord ; 31(9): 859-864, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34419324

RESUMO

Whole exome sequencing (WES), analyzed with GENESIS and WeGET, revealed a homozygous deletion in the C1QBP gene in a patient with progressive external ophthalmoplegia (PEO) and multiple mtDNA deletions. The gene encodes the mitochondria-located complementary 1 Q subcomponent-binding protein, involved in mitochondrial homeostasis. Biallelic mutations in C1QBP cause mitochondrial cardiomyopathy and/or PEO with variable age of onset. Our patient showed only late-onset PEO-plus syndrome without overt cardiac involvement. Available data suggest that early-onset cardiomyopathy variants localize in important structural domains and PEO-plus variants in the coiled-coil region. Our patient demonstrates that C1QBP mutations should be considered in individuals with PEO with or without cardiomyopathy.


Assuntos
Proteínas de Transporte/genética , Sequenciamento do Exoma , Proteínas Mitocondriais/genética , Oftalmoplegia Externa Progressiva Crônica/genética , Adulto , DNA Mitocondrial/genética , Feminino , Homozigoto , Humanos , Mitocôndrias/genética , Mutação , Deleção de Sequência
4.
Mitochondrion ; 58: 64-71, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33639274

RESUMO

Ethylmalonic encephalopathy (EE) is a rare autosomal recessive inborn error of metabolism. To study the molecular effects of ETHE1 p. D165H mutation, we employed mass spectrometry-based mitochondrial proteome and phosphoproteome profiling in the human skeletal muscle. Eighty-six differentially altered proteins were identified, of which thirty-seven mitochondrial proteins were differentially expressed, and most of the proteins (37%) were down-regulated in the OXPHOS complex-IV. Also, nine phosphopeptides that correspond to eight mitochondrial proteins were significantly affected in EE patient. These altered proteins recognized are involved in several pathways and molecular functions, predominantly in oxidoreductase activity. This is the first study that has integrated proteome and phosphoproteome of skeletal muscle and identified multiple proteins associated in the pathogenesis of EE.


Assuntos
Encefalopatias Metabólicas Congênitas/genética , Mitocôndrias Musculares/fisiologia , Proteínas Mitocondriais/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Mutação , Proteínas de Transporte Nucleocitoplasmático/genética , Proteoma , Púrpura/genética , Adulto , Encefalopatias Metabólicas Congênitas/fisiopatologia , Regulação para Baixo , Humanos , Masculino , Fosforilação Oxidativa , Proteômica/métodos , Púrpura/fisiopatologia , Transdução de Sinais
5.
Sci Rep ; 11(1): 1483, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33452321

RESUMO

Mitochondrial dysfunction and neurodegeneration underlie movement disorders such as Parkinson's disease, Huntington's disease and Manganism among others. As a corollary, inhibition of mitochondrial complex I (CI) and complex II (CII) by toxins 1-methyl-4-phenylpyridinium (MPP+) and 3-nitropropionic acid (3-NPA) respectively, induced degenerative changes noted in such neurodegenerative diseases. We aimed to unravel the down-stream pathways associated with CII inhibition and compared with CI inhibition and the Manganese (Mn) neurotoxicity. Genome-wide transcriptomics of N27 neuronal cells exposed to 3-NPA, compared with MPP+ and Mn revealed varied transcriptomic profile. Along with mitochondrial and synaptic pathways, Autophagy was the predominant pathway differentially regulated in the 3-NPA model with implications for neuronal survival. This pathway was unique to 3-NPA, as substantiated by in silico modelling of the three toxins. Morphological and biochemical validation of autophagy markers in the cell model of 3-NPA revealed incomplete autophagy mediated by mechanistic Target of Rapamycin Complex 2 (mTORC2) pathway. Interestingly, Brain Derived Neurotrophic Factor (BDNF), which was elevated in the 3-NPA model could confer neuroprotection against 3-NPA. We propose that, different downstream events are activated upon neurotoxin-dependent CII inhibition compared to other neurotoxins, with implications for movement disorders and regulation of autophagy could potentially offer neuroprotection.


Assuntos
Autofagia/fisiologia , Complexo II de Transporte de Elétrons/metabolismo , Neurônios/metabolismo , 1-Metil-4-fenilpiridínio/farmacologia , Animais , Morte Celular , Linhagem Celular , Sobrevivência Celular , Células Cultivadas , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Complexo I de Transporte de Elétrons/metabolismo , Complexo II de Transporte de Elétrons/antagonistas & inibidores , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Mitocôndrias/metabolismo , Transtornos dos Movimentos/fisiopatologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Neuroproteção , Neurotoxinas/toxicidade , Nitrocompostos/farmacologia , Propionatos/farmacologia , Ratos , Transcriptoma/genética
6.
J Mol Neurosci ; 71(11): 2219-2228, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33469851

RESUMO

Polymerase γ catalytic subunit (POLG), a nuclear gene, encodes the enzyme responsible for mitochondrial DNA (mtDNA) replication. POLG mutations are a major cause of inherited mitochondrial diseases. They present with varied phenotypes, age of onset, and severity. Reports on POLG mutations from India are limited. Hence, this study aimed to describe the clinico-pathological and molecular observations of POLG mutations. A total of 446 patients with clinical diagnosis of mitochondrial disorders were sequenced for all exons and intron-exon boundaries of POLG. Of these, 19 (4.26%) patients (M:F: 10:9) had POLG mutations. The age of onset ranged from 5 to 55 years with an overlapping phenotypic spectrum. Ptosis, peripheral neuropathy, seizures, and ataxia were the common neurological features observed. The most common clinical phenotype was chronic progressive external ophthalmoplegia (CPEO) and CPEO plus (n = 14). Muscle biopsy showed characteristic features of mitochondrial myopathy in fourteen patients (14/19) and respiratory chain enzyme deficiency in eleven patients (11/19). Multiple mtDNA deletions were seen in 47.36% (9/19) patients. Eight pathogenic POLG variations including two novel variations (p.G132R and p.V1106A) were identified. The common pathogenic mutation identified was p.L304R, being present in eight patients (42.1%) predominantly in the younger age group followed by p.W748S in four patients (21%). To the best of our knowledge, this is the first extensive study from India, highlights the clinico-pathological and molecular spectrum of POLG mutations.


Assuntos
DNA Polimerase gama/genética , Doenças Mitocondriais/genética , Mutação , Fenótipo , Adolescente , Adulto , Ataxia/genética , Ataxia/patologia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/patologia , Músculo Esquelético/metabolismo , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/patologia , Convulsões/genética , Convulsões/patologia
7.
J Neurol ; 268(6): 2192-2207, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33484326

RESUMO

BACKGROUND: Mitochondrial disorders are clinically complex and have highly variable phenotypes among all inherited disorders. Mutations in mitochon drial DNA (mtDNA) and nuclear genome or both have been reported in mitochondrial diseases suggesting common pathophysiological pathways. Considering the clinical heterogeneity of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) phenotype including focal neurological deficits, it is important to look beyond mitochondrial gene mutation. METHODS: The clinical, histopathological, biochemical analysis for OXPHOS enzyme activity, and electron microscopic, and neuroimaging analysis was performed to diagnose 11 patients with MELAS syndrome with a multisystem presentation. In addition, whole exome sequencing (WES) and whole mitochondrial genome sequencing were performed to identify nuclear and mitochondrial mutations. RESULTS: Analysis of whole mtDNA sequence identified classical pathogenic mutation m.3243A > G in seven out of 11 patients. Exome sequencing identified pathogenic mutation in several nuclear genes associated with mitochondrial encephalopathy, sensorineural hearing loss, diabetes, epilepsy, seizure and cardiomyopathy (POLG, DGUOK, SUCLG2, TRNT1, LOXHD1, KCNQ1, KCNQ2, NEUROD1, MYH7) that may contribute to classical mitochondrial disease phenotype alone or in combination with m.3243A > G mutation. CONCLUSION: Individuals with MELAS exhibit clinical phenotypes with varying degree of severity affecting multiple systems including auditory, visual, cardiovascular, endocrine, and nervous system. This is the first report to show that nuclear genetic factors influence the clinical outcomes/manifestations of MELAS subjects alone or in combination with m.3243A > G mutation.


Assuntos
Acidose Láctica , Síndrome MELAS , Acidente Vascular Cerebral , DNA Mitocondrial/genética , Genes Mitocondriais , Humanos , Síndrome MELAS/complicações , Síndrome MELAS/genética , Encefalomiopatias Mitocondriais , Mutação , Acidente Vascular Cerebral/genética
8.
Eur J Neurol ; 28(3): 992-1003, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33124102

RESUMO

BACKGROUND AND PURPOSE: Congenital muscular dystrophies (CMDs) and congenital myopathies (CMs) are a group of genetically and clinically heterogeneous degenerative primary muscle disorders with onset at birth or during infancy. Due to vast heterogeneity, clinical examination and protein-based analyses often fail to identify the genetic causes of these diseases. The aim of this study was to genetically diagnose a cohort of 36 difficult-to-diagnose CMD and CM cases of Indian origin using next-generation sequencing methods. METHODS: Whole-exome sequencing (WES) was performed to identify pathogenic mutations in previously reported CMD and CM-related genes using variant calling and stringent variant filtration process. Subsequently, in silico homology modelling and molecular dynamics simulations (MDS) studies were undertaken for a number of novel and missense variants. RESULTS: A total of 33 and 21 rare and deleterious mutations were identified in 28 genes previously reported in CMD and CM based on OMIM, ClinVar and Orphanet, respectively. We could accurately diagnose 54% patients (n = 12/22) in the CMD group and 35% patients (n = 5/14) in the CM group. Furthermore, MDS studies for mutations located in LMNA, LAMA2 and RYR1 suggest that the wild-type proteins are more stable than their mutant counterparts, implying a potential mechanism of pathogenesis. CONCLUSION: The WES findings led us to identify reported as well as novel variants for the first time in Indian patients with CMD and CM. This allowed us to achieve an accurate genetic diagnosis, which was difficult using conventional diagnostic tools. Transferring these WES findings to clinical practice will help guide clinical care of the affected patients and inform genetic counselling.


Assuntos
Doenças Musculares , Distrofias Musculares , Exoma , Humanos , Recém-Nascido , Doenças Musculares/genética , Distrofias Musculares/genética , Mutação , Sequenciamento do Exoma
10.
J Proteomics ; 211: 103556, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31655151

RESUMO

Analysis of human muscle diseases highlights the role of mitochondrial dysfunction in the skeletal muscle. Our previous work revealed that diverse upstream events correlated with altered mitochondrial proteome in human muscle biopsies. However, several proteins showed relatively unchanged expression suggesting that post-translational modifications, mainly protein phosphorylation could influence their activity and regulate mitochondrial processes. We conducted mitochondrial phosphoprotein profiling, by proteomics approach, of healthy human skeletal muscle (n = 10) and three muscle diseases (n = 10 each): Dysferlinopathy, Polymyositis and Distal Myopathy with Rimmed Vacuoles. Healthy human muscle mitochondrial proteins displayed 253 phosphorylation sites (phosphosites), which contributed to metabolic and redox processes and mitochondrial organization etc. Electron transport chain complexes accounted for 84 phosphosites. Muscle pathologies displayed 33 hyperphosphorylated and 14 hypophorphorylated sites with only 5 common proteins, indicating varied phosphorylation profile across muscle pathologies. Molecular modelling revealed altered local structure in the phosphorylated sites of Voltage-Dependent Anion Channel 1 and complex V subunit ATP5B1. Molecular dynamics simulations in complex I subunits NDUFV1, NDUFS1 and NDUFV2 revealed that phosphorylation induced structural alterations thereby influencing electron transfer and potentially altering enzyme activity. We propose that altered phosphorylation at specific sites could regulate mitochondrial protein function in the skeletal muscle during physiological and pathological processes.


Assuntos
Proteínas Mitocondriais , Músculo Esquelético , Humanos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/metabolismo , Fosfoproteínas/metabolismo , Fosforilação
11.
J Neurochem ; 145(4): 323-341, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29424033

RESUMO

Mitochondria regulate the balance between lipid metabolism and storage in the skeletal muscle. Altered lipid transport, metabolism and storage influence the bioenergetics, redox status and insulin signalling, contributing to cardiac and neurological diseases. Lipid storage disorders (LSDs) are neurological disorders which entail intramuscular lipid accumulation and impaired mitochondrial bioenergetics in the skeletal muscle causing progressive myopathy with muscle weakness. However, the mitochondrial changes including molecular events associated with impaired lipid storage have not been completely understood in the human skeletal muscle. We carried out morphological and biochemical analysis of mitochondrial function in muscle biopsies of human subjects with LSDs (n = 7), compared to controls (n = 10). Routine histology, enzyme histochemistry and ultrastructural analysis indicated altered muscle cell morphology and mitochondrial structure. Protein profiling of the muscle mitochondria from LSD samples (n = 5) (vs. control, n = 5) by high-throughput mass spectrometric analysis revealed that impaired metabolic processes could contribute to mitochondrial dysfunction and ensuing myopathy in LSDs. We propose that impaired fatty acid and respiratory metabolism along with increased membrane permeability, elevated lipolysis and altered cristae entail mitochondrial dysfunction in LSDs. Some of these mechanisms were unique to LSD apart from others that were common to dystrophic and inflammatory muscle pathologies. Many differentially regulated mitochondrial proteins in LSD are linked with other human diseases, indicating that mitochondrial protection via targeted drugs could be a treatment modality in LSD and related metabolic diseases. Cover Image for this Issue: doi: 10.1111/jnc.14177.


Assuntos
Erros Inatos do Metabolismo Lipídico/patologia , Erros Inatos do Metabolismo Lipídico/fisiopatologia , Mitocôndrias Musculares/patologia , Adolescente , Adulto , Biópsia , Feminino , Humanos , Masculino , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/ultraestrutura , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Músculo Esquelético/ultraestrutura , Adulto Jovem
12.
Neurol India ; 66(1): 77-82, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29322964

RESUMO

BACKGROUND: Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy. There are no large studies describing its natural course from India. MATERIALS AND METHODS: Immunohistochemically/genetically confirmed DMD patients diagnosed between 1998 and 2014 were ambispectively included. The main aim was to study the natural course of motor milestones, i.e., age at onset of wheelchair status, bedbound state, and age at death, which were considered as primary outcome measures. We also correlated the DMD genotype with the motor milestones and other phenotypic features. RESULTS: A total of 500 DMD patients were included and 275 participated in the study. The mean age at symptom onset was 3.7 ± 1.9 years, mean age at presentation was 8.1 ± 2.5 years, and mean duration of illness was 4.4 ± 2.6 years. On following them over 15 years, 155 (56.4%) had attained at least one of the primary outcome measures. Wheelchair status was attained in 124 (45.1%) [mean age: 10.4 ± 1.6 years] and bedbound state in 24 (8.7%; mean age: 11.8 ± 2.2 years) patients. Seven patients (2.6%) died during the follow-up period (mean age: 15.2 ± 2.4 years). There was no significant impact of the genotypic or phenotypic features on the primary outcome. CONCLUSION: The pattern of major motor milestones (primary outcome measures) in this large cohort is comparable with that of the Western population despite variability in medical care. The genotypic pattern was also similar to other large studies, which suggests that DMD is a more homogeneous disorder with limited ethnic variability in its geno-phenotypic expression.


Assuntos
Progressão da Doença , Limitação da Mobilidade , Distrofia Muscular de Duchenne/epidemiologia , Distrofia Muscular de Duchenne/fisiopatologia , Índice de Gravidade de Doença , Adolescente , Idade de Início , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Índia/epidemiologia , Lactente , Masculino , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/mortalidade
13.
Mult Scler Relat Disord ; 20: 84-92, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29353736

RESUMO

BACKGROUND: There is emerging evidence implicating mitochondrial dysfunction in the pathogenesis of acquired demyelinating disorders such as multiple sclerosis. On the other hand, some of the primary mitochondrial disorders such as mitochondrial leukoencephalopathies exhibit evidence of neuroinflammation on MRI. The inter-relationship between mitochondrial disorders and episodic CNS inflammation needs exploration because of the therapeutic implications. OBJECTIVE: We sought to analyze the clinical course and MRI characteristics in a cohort of patients with mitochondrial leukoencephalopathy to determine features, if any, that mimic primary demyelinating disorders. Therapeutic implications of these findings are discussed. PATIENTS AND METHODS: Detailed analysis of the clinical course, magnetic resonance imaging findings and therapeutic response was performed in 14 patients with mitochondrial leukoencephalopathy. The diagnosis was ascertained by clinical features, histopathology, respiratory chain enzyme assays and exome sequencing. RESULTS: Fourteen patients [Age at evaluation: 2-7 yrs, M: F-1:1] were included in the study. The genetic findings included variations in NDUFA1 (1); NDUFV1 (4); NDUFS2 (2); LYRM (2);MPV17(1); BOLA3(2); IBA57(2). Clinical Features which mimicked acquired demyelinating disorder included acute onset focal deficits associated with encephalopathy [10/14, 71%], febrile illness preceding the onset [7/14, 50%] unequivocal partial or complete steroid responsiveness [11/11], episodic/ relapsing remitting neurological dysfunction [10/14, 71%] and a subsequent stable rather than a progressive course [12/14, 85%]. MRI characteristics included confluent white matter lesions [14/14, 100%], diffusion restriction [11/14,78.5%], contrast enhancement [13/13,100%], spinal cord involvement [8/13,61.5%], lactate peak on MRS [13/13] and white matter cysts [13/14, 92.8%]. CONCLUSION: Clinical presentations of mitochondrial leukoencephalopathy often mimic an acquired demyelinating disorder. The therapeutic implications of these observations require further exploration.


Assuntos
Encéfalo/diagnóstico por imagem , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/fisiopatologia , Doenças Mitocondriais/diagnóstico por imagem , Doenças Mitocondriais/fisiopatologia , Substância Branca/diagnóstico por imagem , Biomarcadores/líquido cefalorraquidiano , Encéfalo/patologia , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Inflamação/diagnóstico por imagem , Inflamação/genética , Inflamação/fisiopatologia , Inflamação/terapia , Leucoencefalopatias/genética , Leucoencefalopatias/terapia , Imageamento por Ressonância Magnética , Masculino , Doenças Mitocondriais/genética , Doenças Mitocondriais/terapia , Estudos Retrospectivos , Substância Branca/patologia , Substância Branca/fisiopatologia
15.
Clin Neurol Neurosurg ; 164: 182-189, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29272804

RESUMO

OBJECTIVES: Studies exploring the outcome of epilepsy in patients with mitochondrial disorders are limited. This study examined the outcome of epilepsy in patients with mitochondrial disorders and its relation with the clinical phenotype, genotype and magnetic resonance imaging findings. PATIENTS AND METHODS: The cohort was derived from the database of 67 patients with definite genetic diagnosis of mitochondrial disorders evaluated over a period of 11years (2006-2016). Among this, 27 had epilepsy and were included in final analysis. Data were analyzed with special reference to clinical phenotypes, genotypes, epilepsy characteristics, EEG findings, anti epileptic drugs used, therapeutic response, and magnetic resonance imaging findings. Patients were divided into three groups according to the seizure frequency at the time of last follow up: Group I- Seizure free; Group II- Infrequent seizures; Group III- uncontrolled seizures. For each group the clinical phenotype, genotype, magnetic resonance imaging and duration of epilepsy were compared. RESULTS: The phenotypes & genotypes included Mitochondrial Encephalopathy Lactic Acidosis and Stroke like episodes (MELAS) & m.3243A>G mutation (n = 10), Myoclonic Epilepsy Ragged Red Fiber syndrome (MERRF) & m.8344A>G mutation (n = 4), Chronic Progressive External Ophthalmoplegia plus &POLG1 mutation (CPEO, n = 6), episodic neuroregression due to nuclear mutations (n = 6; NDUFV1 (n = 3), NDUFA1, NDUFS2, MPV17-1 one each), and one patient with infantile basal ganglia stroke syndrome, mineralizing angiopathy &MT-ND5 mutations. Seven patients (25.9%) were seizure free; seven had infrequent seizures (25.9%), while thirteen (48.1%) had frequent uncontrolled seizures. Majority of the subjects in seizure free group had episodic neuroregression & leukoencephalopathy due to nuclear mutations (85.7%). Patients in group II with infrequent seizures had CPEO, POLG1 mutation and a normal MRI (71%) while 62% of the subjects in group III had MELAS, m.3243A>G mutation and stroke like lesions on MRI. CONCLUSIONS: A fair correlation exists between the outcome of epilepsy, clinical phenotypes, genotypes and magnetic resonance imaging findings in patients with mitochondrial disorders. The recognition of these patterns is important clinically because of the therapeutic and prognostic implications.


Assuntos
Epilepsia/diagnóstico por imagem , Genótipo , Imageamento por Ressonância Magnética , Doenças Mitocondriais/diagnóstico por imagem , Fenótipo , Adolescente , Adulto , Criança , Estudos de Coortes , Eletroencefalografia/métodos , Epilepsia/fisiopatologia , Epilepsia/terapia , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Doenças Mitocondriais/fisiopatologia , Doenças Mitocondriais/terapia , Resultado do Tratamento , Adulto Jovem
16.
Neuromuscul Disord ; 27(11): 986-996, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28927828

RESUMO

Fatty acid oxidation disorders presenting as primary myopathy is relatively rare and also diagnostically challenging. Its association with "dropped head syndrome" is reported till date in single cases of carnitine deficiency and multiple acyl CoA dehydrogenase deficiency (MADD).We studied nineteen cases of primary progressive myopathy confirmed to have fatty acid oxidation defects by Tandem Mass Spectrometry. The detailed clinical, muscle histopathology, tandem mass spectrometry and muscle magnetic resonance imaging (MRI) findings are presented here. The fatty acid oxidation defects identified were sub-grouped into: medium chain acyl CoA dehydrogenase deficiency (MCAD) = 4; very long chain acyl CoA dehydrogenase deficiency (VLCAD) = 7; MADD = 6; carnitine uptake defect and short chain acyl CoA dehydrogenase (SCAD) deficiency = 1 each. The age at onset for MCAD, VLCAD and MADD ranged from 11.5 to 15, 8 to 17 and 10 to 38 years respectively. The patients with carnitine uptake defect and SCAD had onset at 29 and 15 years of age. The dominant symptoms were exertion induced myalgia and progressive proximal limb weakness in all. 12/19 (63.2%) had classical dropped head syndrome. Ptosis and bulbar weakness were present in a few cases. This study emphasizes that fatty acid oxidation disorders presenting as primary myopathy are probably under diagnosed and should be entertained in the differential diagnosis of acute or chronic limb girdle syndromes. Hitherto, unreported we describe "dropped head syndrome" as a prominent phenomenon in MCAD and VLCAD. The presence of ptosis and bulbar weakness in fatty acid oxidation defects expands the clinical spectrum.


Assuntos
Acil-CoA Desidrogenase/deficiência , Erros Inatos do Metabolismo Lipídico/diagnóstico , Doenças Musculares/diagnóstico , Adolescente , Adulto , Idade de Início , Criança , Estudos de Coortes , Feminino , Cabeça , Humanos , Erros Inatos do Metabolismo Lipídico/patologia , Erros Inatos do Metabolismo Lipídico/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Doenças Musculares/patologia , Doenças Musculares/fisiopatologia , Síndrome , Adulto Jovem
17.
Invest Ophthalmol Vis Sci ; 58(10): 3923-3930, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28768321

RESUMO

Purpose: Leber's hereditary optic neuropathy (LHON; OMIM 535000) is one of the most common maternally inherited mitochondrial disorders. Three mitochondrial DNA point mutations-m.3460G>A (MT-ND1), m.11778G>A (MT-ND4), and m.14484T>C (MT-ND6)-account for the majority of reported LHON cases. Only approximately 50% of males and approximately 10% of females carrying these mutations develop optic neuropathy and blindness. Additional factors, such as mtDNA/nuclear genetic background and environmental modifiers, are likely to contribute toward the observed incomplete penetrance and gender bias. We aimed to investigate whether mtDNA haplogroup influences LHON clinical expression in Indian patients harboring the m.11778G>A mutation. Methods: Detailed clinical assessment and complete mitochondrial genome sequencing was undertaken in 64 LHON families harboring the m.11778G>A mutation. Mitochondrial haplogroup was assigned based on evolutionarily conserved mtDNA variations. Results: A total of 543 individuals (295 male, 248 female) from 64 unrelated families harboring the m.11778G>A mutation were recruited to the study. The overall disease penetrance was 27.07% (146 of 543) and higher in males (37.9%; 112 of 295) than females (13.7%; 34 of 248). The mtDNA haplogroup analysis revealed that all affected probands belonged to different mtDNA haplogroups. No association between the m.11778G>A mutation and the background mtDNA haplogroup was detected. Conclusions: The first detailed study of Indian LHON patients confirm that the m.11778G>A-related LHON in India coexists with multiple different mtDNA haplogroups, unlike the preferential association of west Eurasian haplogroup J and the reported increased clinical penetrance with the J2 subhaplogroup. However, we observed variable penetrance of LHON in different Indian mtDNA haplogroup backgrounds, indicating their possible influence on clinical expression. These data suggest that a similar heterogeneity, resulting from the mtDNA haplogroup, might also exist in other mitochondrial diseases among Indian populations.


Assuntos
Povo Asiático/genética , DNA Mitocondrial/genética , NADH Desidrogenase/genética , Atrofia Óptica Hereditária de Leber/genética , Mutação Puntual , Adulto , Análise Mutacional de DNA , Família , Feminino , Haplótipos/genética , Humanos , Índia/epidemiologia , Masculino , Mitocôndrias/genética , Atrofia Óptica Hereditária de Leber/epidemiologia , Atrofia Óptica Hereditária de Leber/patologia , Linhagem , Adulto Jovem
18.
J Neurochem ; 143(3): 334-358, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28801915

RESUMO

Idiopathic Parkinson's disease and manganese-induced atypical parkinsonism are characterized by movement disorder and nigrostriatal pathology. Although clinical features, brain region involved and responsiveness to levodopa distinguish both, differences at the neuronal level are largely unknown. We studied the morphological, neurophysiological and molecular differences in dopaminergic neurons exposed to the Parkinson's disease toxin 1-methyl-4-phenylpyridinium ion (MPP+ ) and manganese (Mn), followed by validation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and Mn mouse models. Morphological analysis highlighted loss of neuronal processes in the MPP+ and not the Mn model. Cellular network dynamics of dopaminergic neurons characterized by spike frequency and inter-spike intervals indicated major neuronal population (~ 93%) with slow discharge rates (0-5 Hz). While MPP+ exposure suppressed the firing of these neurons, Mn neither suppressed nor elevated the neuronal activity. High-throughput transcriptomic analysis revealed up-regulation of 694 and 603 genes and down-regulation of 428 and 255 genes in the MPP+ and Mn models respectively. Many differentially expressed genes were unique to either models and contributed to neuroinflammation, metabolic/mitochondrial function, apoptosis and nuclear function, synaptic plasticity, neurotransmission and cytoskeleton. Analysis of the Janus kinase-signal transducer and activator of transcription pathway with implications for neuritogenesis and neuronal proliferation revealed contrasting profile in both models. Genome-wide DNA methylomics revealed differences between both models and substantiated the epigenetic basis of the difference in the Janus kinase-signal transducer and activator of transcription pathway. We conclude that idiopathic Parkinson's disease and atypical parkinsonism have divergent neurotoxicological manifestation at the dopaminergic neuronal level with implications for pathobiology and evolution of novel therapeutics. Cover Image for this issue: doi. 10.1111/jnc.13821.


Assuntos
1-Metil-4-fenilpiridínio/toxicidade , Neurônios Dopaminérgicos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Manganês/toxicidade , Neurotoxinas/toxicidade , Potenciais de Ação/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Linhagem Celular Transformada , Sobrevivência Celular/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/ultraestrutura , L-Lactato Desidrogenase/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Redes Neurais de Computação , Ratos , Transdução de Sinais/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Transcriptoma/fisiologia , Tirosina 3-Mono-Oxigenase/metabolismo
19.
BMC Med Genet ; 18(1): 67, 2017 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-28610567

RESUMO

BACKGROUND: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive disorders caused by mutations in the DMD gene. The aim of this study was to predict the effect of gene mutations on the dystrophin protein and study its impact on clinical phenotype. METHODS: In this study, 415 clinically diagnosed patients were tested for mutations by Multiplex ligation dependent probe amplification (MLPA). Muscle biopsy was performed in 34 patients with negative MLPA. Phenotype-genotype correlation was done using PROVEAN, hydrophobicity and eDystrophin analysis. We have utilized bioinformatics tools in order to evaluate the observed mutations both at the level of primary as well as secondary structure. RESULTS: Mutations were identified in 75.42% cases, of which there were deletions in 91.6% and duplications in 8.30%. As per the reading frame rule, 84.6% out-of frame and 15.3% in-frame mutations were noted. Exon 50 was the most frequently deleted exon and the exon 45-52 region was the hot-spot for deletions in this cohort. There was no correlation noted between age of onset or creatine kinase (CK) values with extent of gene mutation. The PROVEAN analysis showed a deleterious effect in 94.5% cases and a neutral effect in 5.09% cases. Mutations in exon 45-54 (out of frame) and exon 46-54 (in-frame) regions in the central rod domain of dystrophin showed more negative scores compared to other domains in the present study. Hydrophobicity profile analysis showed that the hydrophobic regions I & III were equally affected. Analysis of deletions in hinge III hydrophobic region by the eDystrophin programme also predicted a hybrid repeat seen to be associated with a BMD like disease progression, thus making the hinge III region relatively tolerant to mutations. CONCLUSIONS: We found that, while the predictions made by the software utilized might have overall significance, the results were not convincing on a case by case basis. This reflects the inadequacy of the currently available tools and also underlines the possible inadequacy of MLPA to detect other minor mutations that might enhance or suppress the effect of the primary mutation in this large gene. Next Generation Sequencing or targeted Sanger sequencing on a case by case basis might improve phenotype- genotype correlation.


Assuntos
Distrofina/genética , Distrofia Muscular de Duchenne/genética , Biópsia , Criança , Simulação por Computador , Distrofina/química , Genótipo , Humanos , Índia , Modelos Moleculares , Reação em Cadeia da Polimerase Multiplex , Músculos/patologia , Distrofia Muscular de Duchenne/patologia , Mutação , Fenótipo , Conformação Proteica
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