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1.
Curr Opin Ophthalmol ; 30(6): 476-483, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31436541

RESUMO

PURPOSE OF REVIEW: Inherited myopathies, and in particular mitochondrial myopathies, are heterogeneous disorders, and ocular manifestations may be the presenting feature or offer important diagnostic clues. The ophthalmologist may be key to diagnosis, facilitating recognition of associated potentially life-threatening organ manifestations and an integral part of multidisciplinary care. This review, focusing especially on mitochondrial myopathies, provides updates on clinical features, diagnosis and recent therapeutic developments. RECENT FINDINGS: Ptosis and/or ophthalmoplegia is present in over half of patients with mitochondrial disease, and associated clinical features imply specific genetic associations. Advances in next-generation sequencing have led to rapid evolution in the field, improving diagnosis rates, facilitating identification of novel genes, mutations and phenotypes, and providing important insights into disease mechanisms and therapeutic possibilities. Improved understanding of molecular mechanisms in inherited myopathies is enabling the development of experimental molecular therapies with clinical potential. SUMMARY: Genetic advances are driving progress in the field of inherited myopathies, influencing diagnosis, understanding of disease and development of therapies. Recognition of key features can impact diagnosis and management of these important conditions.


Assuntos
Oftalmopatias Hereditárias/genética , Mitocôndrias Musculares/patologia , Miopatias Mitocondriais/genética , Músculos Oculomotores/patologia , Oftalmoplegia Externa Progressiva Crônica/genética , Oftalmopatias Hereditárias/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Miopatias Mitocondriais/diagnóstico , Oftalmoplegia Externa Progressiva Crônica/diagnóstico
2.
Int J Rheum Dis ; 22(6): 1152-1156, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30968563

RESUMO

Mitochondrial diseases are a group of disorders presenting mainly during infancy due to pathological dysfunction of the mitochondrial respiratory chain. We report a case of mitochondrial disease in an elderly woman complaining of generalized myalgia. A 69-year-old woman was admitted due to fatigue, general weakness, and a drowsy mental status. A brain magnetic resonance imaging (MRI) demonstrated multifocal lesions of increased T2 signal intensity, and laboratory findings were consistent with Fanconi syndrome. During her hospital course, she developed seizures, stress-induced cardiomyopathy, and respiratory failure. A muscle biopsy demonstrated ragged-red fibers in the muscle tissues seen in mitochondrial myopathy. We confirmed an 8 kb deletion in her mitochondrial DNA. Following treatment with l-carnitine, coenzyme Q10, and supportive measures, brain lesions on MRI scans disappeared, and the general symptoms gradually improved.


Assuntos
Síndrome de Fanconi/diagnóstico , Miopatias Mitocondriais/diagnóstico , Vasculite Sistêmica/diagnóstico , Idade de Início , Idoso , Diagnóstico Diferencial , Síndrome de Fanconi/genética , Síndrome de Fanconi/terapia , Feminino , Humanos , Miopatias Mitocondriais/genética , Miopatias Mitocondriais/terapia , Valor Preditivo dos Testes , Prognóstico
4.
Neurotherapeutics ; 15(4): 943-953, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30406383

RESUMO

Mitochondrial myopathies are progressive muscle conditions caused primarily by the impairment of oxidative phosphorylation (OXPHOS) in the mitochondria. This causes a deficit in energy production in the form of adenosine triphosphate (ATP), particularly in skeletal muscle. The diagnosis of mitochondrial myopathy is reliant on the combination of numerous techniques including traditional histochemical, immunohistochemical, and biochemical testing combined with the fast-emerging molecular genetic techniques, namely next-generation sequencing (NGS). This has allowed for the diagnosis to become more effective in terms of determining causative or novel genes. However, there are currently no effective or disease-modifying treatments available for the vast majority of patients with mitochondrial myopathies. Existing therapeutic options focus on the symptomatic management of disease manifestations. An increasing number of clinical trials have investigated the therapeutic effects of various vitamins, cofactors, and small molecules, though these trials have failed to show definitive outcome measures for clinical practice thus far. In addition, new molecular strategies, specifically mtZFNs and mtTALENs, that cause beneficial heteroplasmic shifts in cell lines harboring varying pathogenic mtDNA mutations offer hope for the future. Moreover, recent developments in the reproductive options for patients with mitochondrial myopathies mean that for some families, the possibility of preventing transmission of the mutation to the next generation is now possible.


Assuntos
Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/terapia , Trifosfato de Adenosina/metabolismo , Humanos , Músculo Esquelético/metabolismo
5.
Orphanet J Rare Dis ; 13(1): 122, 2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-30029694

RESUMO

BACKGROUND: Mitochondrial trifunctional protein (MTP) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency are long-chain fatty acid oxidation disorders with particularly high morbidity and mortality. Outcome can be favorable if diagnosed in time, prompting the implementation in newborn screening programs. Sporadic cases missed by the initial screening sample have been reported. However, little is known on pitfalls during confirmatory testing resulting in fatal misconception of the diagnosis. RESULTS: We report a series of three patients with MTP and LCHAD deficiency, in whom diagnosis was missed by newborn screening, resulting in life-threatening metabolic decompensations within the first half year of life. Two of the patients showed elevated concentrations of primary markers C16-OH and C18:1-OH but were missed by confirmatory testing performed by the maternity clinic. A metabolic center was not consulted. Confirmatory testing consisted of analyses of acylcarnitines in blood and organic acids in urine, the finding of normal excretion of organic acids led to rejection and underestimation of the diagnosis, respectively. The third patient, a preterm infant, was not identified in the initial screening sample due to only moderate elevations of C16-OH and C18:1-OH and normal secondary markers and analyte ratios. CONCLUSION: Our observations highlight limitations of newborn screening for MTP/LCHAD deficiency. They confirm that analyses of acylcarnitines in blood and organic acids in urine alone are not suitable for confirmatory testing and molecular or functional analysis is crucial in diagnosing MTP/LCHAD deficiency. Mild elevations of primary biomarkers in premature infants need to trigger confirmatory testing. Our report underscores the essential role of specialized centers in confirming or ruling out diagnoses in suspicious screening results.


Assuntos
Biomarcadores/metabolismo , Cardiomiopatias/diagnóstico , Cardiomiopatias/metabolismo , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/metabolismo , 3-Hidroxiacil-CoA Desidrogenase de Cadeia Longa/metabolismo , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/metabolismo , Proteína Mitocondrial Trifuncional/deficiência , Triagem Neonatal/métodos , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/metabolismo , Rabdomiólise/diagnóstico , Rabdomiólise/metabolismo , Humanos , Lactente , Recém-Nascido , Proteína Mitocondrial Trifuncional/metabolismo , Oxirredução , Estudos Retrospectivos
7.
Am J Kidney Dis ; 71(5): 754-757, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29224958

RESUMO

We report a case of a patient who had the mitochondrial cytopathy complex of neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome diagnosed at age 11 years with a biopsy-proven kidney involvement that progressed to end-stage renal disease at age 21 years. Mutations of mitochondrial DNA (mtDNA) are maternally inherited and lead to mitochondrial cytopathies with predominant neurologic manifestations: psychomotor retardation, epilepsy, ataxia, neuropathy, and myopathy. Given the ubiquitous nature of mitochondria, cellular dysfunction can also appear in tissues with high metabolic turnover; thus, there can be cardiac, digestive, ophthalmologic, and kidney complications. Mutations in the MT-ATP6 gene of mtDNA have been shown to cause NARP syndrome without renal involvement. We report a patient who had NARP syndrome diagnosed at age 11 years in whom glomerular proteinuria was present very early after diagnosis. Although neurologic manifestations were stable over time, he developed worsening proteinuria and kidney function. He started dialysis therapy at age 21 years. Kidney biopsy confirmed the mitochondrial cytopathy histologically, with abnormal mitochondria seen on electron microscopy. The MT-ATP6 gene mutation was detected in the kidney biopsy specimen.


Assuntos
Predisposição Genética para Doença , Nefropatias/patologia , Nefropatias/terapia , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/genética , ATPases Mitocondriais Próton-Translocadoras/genética , Retinite Pigmentosa/diagnóstico , Retinite Pigmentosa/genética , Adolescente , Ataxia/fisiopatologia , Biópsia por Agulha , Criança , Progressão da Doença , Seguimentos , Humanos , Imuno-Histoquímica , Síndrome de Kearns-Sayre/fisiopatologia , Nefropatias/fisiopatologia , Masculino , Miopatias Mitocondriais/fisiopatologia , Miopatias Mitocondriais/terapia , Doenças Raras , Diálise Renal , Retinite Pigmentosa/fisiopatologia , Retinite Pigmentosa/terapia , Resultado do Tratamento , Adulto Jovem
8.
J Med Genet ; 54(12): 815-824, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29079705

RESUMO

BACKGROUND: Hereditary myopathy with lactic acidosis and myopathy with deficiency of succinate dehydrogenase and aconitase are variants of a recessive disorder characterised by childhood-onset early fatigue, dyspnoea and palpitations on trivial exercise. The disease is non-progressive, but life-threatening episodes of widespread weakness, metabolic acidosis and rhabdomyolysis may occur. So far, this disease has been molecularly defined only in Swedish patients, all homozygous for a deep intronic splicing affecting mutation in ISCU encoding a scaffold protein for the assembly of iron-sulfur (Fe-S) clusters. A single Scandinavian family was identified with a different mutation, a missense change in compound heterozygosity with the common intronic mutation. The aim of the study was to identify the genetic defect in our proband. METHODS: A next-generation sequencing (NGS) approach was carried out on an Italian male who presented in childhood with ptosis, severe muscle weakness and exercise intolerance. His disease was slowly progressive, with partial recovery between episodes. Patient's specimens and yeast models were investigated. RESULTS: Histochemical and biochemical analyses on muscle biopsy showed multiple defects affecting mitochondrial respiratory chain complexes. We identified a single heterozygous mutation p.Gly96Val in ISCU, which was absent in DNA from his parents indicating a possible de novo dominant effect in the patient. Patient fibroblasts showed normal levels of ISCU protein and a few variably affected Fe-S cluster-dependent enzymes. Yeast studies confirmed both pathogenicity and dominance of the identified missense mutation. CONCLUSION: We describe the first heterozygous dominant mutation in ISCU which results in a phenotype reminiscent of the recessive disease previously reported.


Assuntos
Genes Dominantes , Proteínas com Ferro-Enxofre/genética , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/genética , Mutação , Sequência de Aminoácidos , Biomarcadores , Biópsia , Biologia Computacional/métodos , Eletroencefalografia , Eletromiografia , Fibroblastos/metabolismo , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Proteínas com Ferro-Enxofre/química , Imagem por Ressonância Magnética , Masculino , Modelos Moleculares , Músculo Esquelético/patologia , Linhagem , Fenótipo , Análise de Sequência de DNA , Relação Estrutura-Atividade , Adulto Jovem
9.
J Hum Genet ; 62(9): 809-814, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28515471

RESUMO

Mitochondrial trifunctional protein (TFP) deficiency is an inherited metabolic disorder of mitochondrial fatty-acid oxidation. Isolated long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency is often reported in Caucasian countries due to a common mutation. However, the molecular and clinical basis of complete TFP deficiency has not been extensively reported. In this study, 14 Japanese cases (13 families) with complete TFP deficiency, including 9 previously reported cases, were analyzed to clarify the clinical and molecular characteristics of TFP deficiency. The clinical types of the 14 patients were as follows: 12 cases of neonatal (n=7) or myopathic (n=5) types and 2 cases of intermediate type. Peripheral neuropathy was found in four cases and hypocalcemia due to hypoparathyroidism, which is rarely reported in Caucasian patients, had developed in four cases. Maternal hemolysis, elevated liver enzymes and low platelet count syndrome and acute fatty liver of pregnancy were noted in two and one mothers, respectively. Fourteen mutations were identified in 26 alleles in Japanese patients, including two novel mutations (HADHA: c.361C>T, and HADHA-HADHB: g.26233880_ 26248855del), although no common mutations were found. This study suggests that the molecular and clinical aspects of Japanese patients with TFP deficiencies differ from those of Caucasian patients.


Assuntos
Cardiomiopatias/diagnóstico , Cardiomiopatias/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/genética , Proteína Mitocondrial Trifuncional/deficiência , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/genética , Rabdomiólise/diagnóstico , Rabdomiólise/genética , Adolescente , Grupo com Ancestrais do Continente Asiático/genética , Criança , Pré-Escolar , Ativação Enzimática , Grupo com Ancestrais do Continente Europeu/genética , Família , Feminino , Testes Genéticos , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Proteína Mitocondrial Trifuncional/genética , Subunidade alfa da Proteína Mitocondrial Trifuncional/genética , Subunidade alfa da Proteína Mitocondrial Trifuncional/metabolismo , Subunidade beta da Proteína Mitocondrial Trifuncional/genética , Subunidade beta da Proteína Mitocondrial Trifuncional/metabolismo , Mutação
10.
Brain Nerve ; 69(2): 111-117, 2017 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-28202819

RESUMO

Mitochondrial disease is caused by a deficiency in the energy supply to cells due to mitochondrial dysfunction. Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is a mitochondrial disease that presents with stroke-like episodes such as acute onset of neurological deficits and characteristic imaging findings. Stroke-like episodes in MELAS have the following features: 1) neurological deficits due to localization of lesions in the brain, 2) episodes often accompany epilepsy, 3) lesions do not follow the vascular supply area, 4) lesions are more often seen in the posterior brain than in the anterior brain, 5) lesions spread to an adjacent area in the brain, and 6) neurological symptoms often disappear together with imaging findings, but later relapse. About 80% of patients with MELAS have an A-to-G transition mutation at the nucleotide pair 3243 in the dihydrouridine loop of mitochondrial tRNALeu(UUR), which causes the absence of posttranscriptional taurine modification at the wobble nucleotide of mitochondrial tRNALeu(UUR) and disrupts protein synthesis. However, the precise pathophysiology of stroke-like episodes is under investigation, with possible hypotheses for these episodes including mitochondrial angiopathy, mitochondrial cytopathy, and neuron-astrocyte uncoupling. With regard to treatment, L-arginine and taurine have recently been suggested for relief of clinical symptoms.


Assuntos
Acidose Láctica/diagnóstico , Encéfalo/patologia , Síndrome de Kearns-Sayre/diagnóstico , Síndrome MELAS/diagnóstico , Miopatias Mitocondriais/diagnóstico , Acidente Vascular Cerebral/diagnóstico , Acidose Láctica/patologia , Acidose Láctica/terapia , Diagnóstico Diferencial , Humanos , Síndrome de Kearns-Sayre/patologia , Síndrome de Kearns-Sayre/terapia , Síndrome MELAS/patologia , Síndrome MELAS/terapia , Miopatias Mitocondriais/patologia , Miopatias Mitocondriais/terapia
11.
Intern Med ; 56(1): 95-99, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28050007

RESUMO

The clinical features of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) are not uniform. We herein report a male patient with unusual MELAS-like encephalopathy who had been experiencing isolated recurrent stroke-like episodes since he was 33 years old without any particular family history. Despite an extensive investigation, he had no other signs suggestive of MELAS. Although the muscle pathology showed a normal appearance, a mitochondrial genome sequence analysis of the biopsied muscle revealed a heteroplasmic m.10158T>C mutation in the mitochondrial complex I subunit gene, MT-ND3. To prevented further deterioration of the higher brain function, the early diagnosis and treatment of mitochondrial stroke-like episodes is important.


Assuntos
Acidose Láctica/diagnóstico , Encefalopatias/diagnóstico , DNA Mitocondrial/genética , Síndrome MELAS/diagnóstico , Miopatias Mitocondriais/diagnóstico , Doenças Musculares/genética , Doenças Musculares/patologia , Acidose Láctica/genética , Adulto , Biópsia , Encefalopatias/genética , Diagnóstico Precoce , Humanos , Síndrome MELAS/genética , Masculino , Miopatias Mitocondriais/genética , Mutação
12.
Rinsho Shinkeigaku ; 57(2): 82-87, 2017 02 25.
Artigo em Japonês | MEDLINE | ID: mdl-28132977

RESUMO

A 45-year-old man presented to us due to slowly progressive muscle weakness and sensory disturbances in his lower limbs since his 40's. He reported multiple episodes of exercise-induced severe muscle fatigue and brown urine in his childhood, which disappeared by age 20. A nerve conduction study showed peripheral axonal neuropathy and then Charcot-Marie-Tooth disease (CMT) was considered as the most likely diagnosis; however, exome sequencing failed to identify a mutation in the known genes of CMTs. Since age 55, he recurrently developed severe rhabdomyolysis that required hospitalization. On suspicion of lipid metabolism disorders, we performed serum acylcarnitine analysis, and which revealed mildly elevated long-chain fatty acids. We re-examined variants obtained via exome sequencing and found a mutation in HADHB. Mitochondrial trifunctional protein (MTP) deficiency is a rare autosomal recessive disorder of mitochondrial fatty acid beta-oxidation caused by HADHA or HADHB mutation. It can be a life-threatening multiorgan disorder with early infantile onset, but it can also present in childhood or adolescence with peripheral neuropathy and recurrent rhabdomyolysis. This case of adult-diagnosed MTP deficiency was characterized by slowly progressive peripheral neuropathy masquerading CMT in addition to muscular symptoms. MTP deficiency should be considered in patients with the combination of peripheral neuropathy and recurrent rhabdomyolysis.


Assuntos
Cardiomiopatias/diagnóstico , Erros Inatos do Metabolismo Lipídico/diagnóstico , Miopatias Mitocondriais/diagnóstico , Proteína Mitocondrial Trifuncional/deficiência , Doenças do Sistema Nervoso/diagnóstico , Rabdomiólise/diagnóstico , Biomarcadores/sangue , Cardiomiopatias/complicações , Cardiomiopatias/genética , Carnitina/análogos & derivados , Carnitina/sangue , Doença de Charcot-Marie-Tooth , Diagnóstico Diferencial , Progressão da Doença , Testes Genéticos , Humanos , Erros Inatos do Metabolismo Lipídico/complicações , Erros Inatos do Metabolismo Lipídico/genética , Masculino , Pessoa de Meia-Idade , Miopatias Mitocondriais/complicações , Miopatias Mitocondriais/genética , Proteína Mitocondrial Trifuncional/genética , Subunidade beta da Proteína Mitocondrial Trifuncional/genética , Mutação , Doenças do Sistema Nervoso/complicações , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso Periférico/etiologia , Recidiva , Rabdomiólise/complicações , Rabdomiólise/etiologia , Rabdomiólise/genética
13.
Continuum (Minneap Minn) ; 22(6, Muscle and Neuromuscular Junction Disorders): 1829-1851, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27922496

RESUMO

PURPOSE OF REVIEW: Metabolic myopathies are genetic disorders that impair intermediary metabolism in skeletal muscle. Impairments in glycolysis/glycogenolysis (glycogen-storage disease), fatty acid transport and oxidation (fatty acid oxidation defects), and the mitochondrial respiratory chain (mitochondrial myopathies) represent the majority of known defects. The purpose of this review is to develop a diagnostic and treatment algorithm for the metabolic myopathies. RECENT FINDINGS: The metabolic myopathies can present in the neonatal and infant period as part of more systemic involvement with hypotonia, hypoglycemia, and encephalopathy; however, most cases present in childhood or in adulthood with exercise intolerance (often with rhabdomyolysis) and weakness. The glycogen-storage diseases present during brief bouts of high-intensity exercise, whereas fatty acid oxidation defects and mitochondrial myopathies present during a long-duration/low-intensity endurance-type activity or during fasting or another metabolically stressful event (eg, surgery, fever). The clinical examination is often normal between acute events, and evaluation involves exercise testing, blood testing (creatine kinase, acylcarnitine profile, lactate, amino acids), urine organic acids (ketones, dicarboxylic acids, 3-methylglutaconic acid), muscle biopsy (histology, ultrastructure, enzyme testing), MRI/spectroscopy, and targeted or untargeted genetic testing. SUMMARY: Accurate and early identification of metabolic myopathies can lead to therapeutic interventions with lifestyle and nutritional modification, cofactor treatment, and rapid treatment of rhabdomyolysis.


Assuntos
Doença de Depósito de Glicogênio Tipo VII/diagnóstico , Doença de Depósito de Glicogênio Tipo V/diagnóstico , Miopatias Mitocondriais/diagnóstico , Rabdomiólise/diagnóstico , Feminino , Doença de Depósito de Glicogênio Tipo V/sangue , Doença de Depósito de Glicogênio Tipo V/genética , Doença de Depósito de Glicogênio Tipo VII/sangue , Doença de Depósito de Glicogênio Tipo VII/genética , Glicogenólise/fisiologia , Humanos , Masculino , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Pessoa de Meia-Idade , Miopatias Mitocondriais/sangue , Miopatias Mitocondriais/genética , Doenças Musculares/sangue , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Rabdomiólise/sangue , Rabdomiólise/genética , Adulto Jovem
14.
J Pediatr Hematol Oncol ; 38(8): 661-662, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27769081

RESUMO

There are published reports stating that some of the congenital metabolic diseases, such as lysinuric protein intolerance, multiple sulphatase deficiency, galactosemia, Gaucher disease, Pearson syndrome, and galactosialidosis, might lead to secondary hemophagocytic lymphohistiocytosis (HLH). However, to date, to our knowledge, the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency has never been investigated among patients with HLH. Here, we report on a patient who was referred to our institution for a differential diagnosis of pancytopenia, liver failure, and rhabdomyolysis. The patient was diagnosed with HLH. Further investigation revealed an underlying diagnosis of the LCHAD deficiency. Our case was reported to contribute to the literature, as well as the HLH clinic, emphasizing the consideration of LCHAD deficiency, especially in 1 to 6 months' old infants with laboratory findings of hypoglycemia, metabolic acidosis, and elevated creatine kinase.


Assuntos
Cardiomiopatias/diagnóstico , Erros Inatos do Metabolismo Lipídico/diagnóstico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Miopatias Mitocondriais/diagnóstico , Proteína Mitocondrial Trifuncional/deficiência , Doenças do Sistema Nervoso/diagnóstico , Rabdomiólise/diagnóstico , Acidose , Cardiomiopatias/genética , Creatina Quinase , Análise Mutacional de DNA , Diagnóstico Diferencial , Humanos , Hipoglicemia , Lactente , Erros Inatos do Metabolismo Lipídico/genética , Miopatias Mitocondriais/genética , Proteína Mitocondrial Trifuncional/genética , Doenças do Sistema Nervoso/genética , Rabdomiólise/genética
16.
Ophthalmology ; 123(10): 2183-95, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27491397

RESUMO

PURPOSE: To assess long-term effects of genotype on chorioretinopathy severity in patients with mitochondrial trifunctional protein (MTP) disorders. DESIGN: Retrospective case series. PARTICIPANTS: Consecutive patients with MTP disorders evaluated at a single center from 1994 through 2015, including 18 patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and 3 patients with trifunctional protein deficiency (TFPD). METHODS: Local records from all visits were reviewed. Every participant underwent a complete ophthalmic examination and was evaluated by a metabolic physician and dietitian. Nine patients underwent ancillary funduscopic imaging including optical coherence tomography (OCT) and OCT angiography. MAIN OUTCOME MEASURES: The primary outcome measure was best-corrected visual acuity at the final visit. Secondary outcome measures included spherical equivalent refraction, visual fields, electroretinography B-wave amplitudes, and qualitative imaging findings. RESULTS: Participants were followed up for a median of 5.6 years (range 0.3-20.2 years). The median age of LCHADD participants at initial and final visits was 2.3 and 11.9 years, whereas that for TFPD participants at initial and final visits was 4.7 and 15.5 years, respectively. Four long-term survivors older than 16 years were included (3 with LCHADD and 1 with TFPD). The LCHADD participants demonstrated a steady decline in visual acuity from an average of 0.23 logarithm of the minimum angle of resolution (logMAR; Snellen equivalent, 20/34) at baseline to 0.42 logMAR (Snellen equivalent, 20/53) at the final visit, whereas TFPD patients maintained excellent acuity throughout follow-up. Participants with LCHADD, but not TFPD, showed an increasing myopia with a mean decrease in spherical equivalent refraction of 0.24 diopters per year. Visual fields showed sensitivity losses centrally associated with defects on OCT. Multimodal imaging demonstrated progressive atrophy of the outer retina in LCHADD, often preceded by the formation of outer retinal tubulations and choriocapillaris dropout. Electroretinography findings support the more severe clinical profile of LCHADD patients compared with TFPD patients; the function of both rods and cones are attenuated diffusely in LCHADD patients, but are within normal limits for TFPD patients. CONCLUSIONS: Despite improved survival with early diagnosis, medical management, and dietary treatment, participants with the LCHADD subtype of MTP disorder continue to demonstrate visually disabling chorioretinopathy. Multimodal imaging is most consistent with choriocapillaris loss exceeding photoreceptor loss.


Assuntos
Cardiomiopatias/complicações , Doenças da Coroide/etiologia , Previsões , Erros Inatos do Metabolismo Lipídico/complicações , Miopatias Mitocondriais/complicações , Proteína Mitocondrial Trifuncional/deficiência , Proteína Mitocondrial Trifuncional/genética , Doenças do Sistema Nervoso/complicações , Rabdomiólise/complicações , Acuidade Visual , Adolescente , Adulto , Cardiomiopatias/diagnóstico , Cardiomiopatias/genética , Criança , Pré-Escolar , Doenças da Coroide/diagnóstico , Doenças da Coroide/genética , Eletrorretinografia , Feminino , Angiofluoresceinografia , Seguimentos , Fundo de Olho , Genótipo , Humanos , Lactente , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Masculino , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/genética , Proteína Mitocondrial Trifuncional/metabolismo , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/genética , Prognóstico , Estudos Retrospectivos , Rabdomiólise/diagnóstico , Rabdomiólise/genética , Tomografia de Coerência Óptica , Campos Visuais , Adulto Jovem
17.
Mitochondrion ; 29: 53-8, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27223842

RESUMO

Due to the relative rarity of mitochondrial diseases, generating reference ranges is problematic in evaluation of respiratory chain activities particularly in pediatric cases. We determined the sample distribution of respiratory chain enzyme activities in skeletal muscle biopsies collected from pediatric patients suspected of neuromuscular disorders. Activities of NADH-ubiquinone reductase, NADH-cytochrome c reductase, succinate-cytochrome c reductase; ubiquinol-cytochrome c reductase and cytochrome c oxidase activities have log-normal distributions even when confirmed mitochondrial diseases were ruled out. Impact of the log-normal distribution of the respiratory chain enzyme activities on clinical diagnostics is discussed.


Assuntos
Biópsia , Complexo de Proteínas da Cadeia de Transporte de Elétrons/análise , Doenças Mitocondriais/diagnóstico , Miopatias Mitocondriais/diagnóstico , Músculo Esquelético/patologia , Doenças do Sistema Nervoso/diagnóstico , Adolescente , Criança , Pré-Escolar , Feminino , Atividades Humanas , Humanos , Lactente , Recém-Nascido , Masculino
18.
Biomed Res Int ; 2016: 3128735, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27123443

RESUMO

Megaconial congenital muscular dystrophy (OMIM 602541) is characterized with early-onset hypotonia, muscle wasting, proximal weakness, cardiomyopathy, mildly elevated serum creatine kinase (CK) levels, and mild-to-moderate intellectual disability. We report two siblings in a consanguineous family admitted for psychomotor delay. Physical examination revealed proximal muscle weakness, contractures in the knee of elder sibling, diffuse mild generalized muscle atrophy, and dry skin with ichthyosis together with multiple nummular eczema in both siblings. Serum CK values were elevated up to 500 U/L. For genetic work-up, we performed whole exome sequencing (WES) after Nimblegen enrichment on the Illumina platform. The WES revealed a novel homozygous missense mutation in the Choline Kinase-Beta (CHKB) gene c.1031G>A (p.R344Q) in exon 9. Ichthyosis-like skin changes with intense pruritus and nummular eczema may lead to clinical diagnosis in cases with megaconial congenital muscular dystrophy.


Assuntos
Colina Quinase/genética , Deficiência Intelectual/genética , Miopatias Mitocondriais/genética , Distrofias Musculares/genética , Criança , Pré-Escolar , Diagnóstico Diferencial , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Ictiose/diagnóstico , Ictiose/genética , Ictiose/fisiopatologia , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/fisiopatologia , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/fisiopatologia , Distrofias Musculares/diagnóstico , Distrofias Musculares/fisiopatologia , Mutação , Prurido/diagnóstico , Prurido/genética , Prurido/fisiopatologia , Transtornos Psicomotores/diagnóstico , Transtornos Psicomotores/genética , Transtornos Psicomotores/fisiopatologia , Irmãos
19.
Mitochondrion ; 27: 32-8, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26855408

RESUMO

Megaconial congenital muscular dystrophy is a disease caused by pathogenic mutations in the gene encoding choline kinase beta (CHKB). Microscopically, the disease is hallmarked by the presence of enlarged mitochondria at the periphery of skeletal muscle fibres leaving the centre devoid of mitochondria. Clinical characteristics are delayed motor development, intellectual disability and dilated cardiomyopathy in half of reported cases. This study describes a patient presenting with the cardinal clinical features, in whom a homozygous nonsense mutation (c.248_249insT; p.Arg84Profs*209) was identified in CHKB and who was treated by heart transplantation. Microscopic evaluation of skeletal and heart muscles typically showed enlarged mitochondria. Spectrophotometric evaluation in both tissues revealed a mild decrease of all OXPHOS complexes. Using BN-PAGE analysis followed by activity staining subcomplexes of complex V were detected in both tissues, indicating incomplete complex V assembly. Mitochondrial DNA content was not depleted in analysed tissues. This is the first report describing the microscopic and biochemical abnormalities in the heart from an affected patient. A likely hypothesis is that the biochemical findings are caused by an abnormal lipid profile in the inner mitochondrial membrane resulting from a defective choline kinase B activity.


Assuntos
Colina Quinase/genética , Códon sem Sentido , Membranas Mitocondriais/fisiologia , Miopatias Mitocondriais/patologia , Distrofias Musculares/patologia , Miocárdio/patologia , Adenosina Trifosfatases/análise , Proteínas de Transporte/análise , Criança , Transplante de Coração , Humanos , Masculino , Proteínas de Membrana/análise , Microscopia , Mitocôndrias/patologia , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/genética , Miopatias Mitocondriais/terapia , ATPases Mitocondriais Próton-Translocadoras , Distrofias Musculares/diagnóstico , Distrofias Musculares/genética , Distrofias Musculares/terapia , Fosforilação Oxidativa
20.
Brain Nerve ; 68(2): 151-7, 2016 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-26873235

RESUMO

Stroke-like episodes are one of the cardinal features of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and occur in 84-99% of the patients. The affected areas detected on neuroimaging do not have classical vascular distribution, and involve predominantly the temporal, parietal and occipital lobes. Thus, the neurological symptoms including higher brain dysfunction correlate with this topographical distribution. In association with the occipital lobe involvement, the most frequent symptom is cortical blindness. Other symptoms have been occasionally reported in case reports: visual agnosia, prosopagnosia, cortical deafness, auditory agnosia, topographical disorientation, various types of aphasia, hemispatial neglect, and so on. On the other hand, cognitive decline associated with more diffuse brain impairment rather than with focal stroke-like lesions has been postulated. This condition is also known as mitochondrial dementia. Domains of cognitive dysfunction include abstract reasoning, verbal memory, visual memory, language (naming and fluency), executive or constructive functions, attention, and visuospatial function. Cognitive functions and intellectual abilities may decline from initially minimal cognitive impairment to dementia. To date, the neuropsychological and neurologic impairment has been reported to be associated with cerebral lactic acidosis as estimated by ventricular spectroscopic lactate levels.


Assuntos
Acidose Láctica/fisiopatologia , Agnosia/fisiopatologia , Encefalopatias/fisiopatologia , Encéfalo/patologia , Miopatias Mitocondriais/patologia , Acidente Vascular Cerebral/patologia , Acidose Láctica/diagnóstico , Agnosia/diagnóstico , Animais , Encéfalo/fisiopatologia , Encefalopatias/diagnóstico , Humanos , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/fisiopatologia , Acidente Vascular Cerebral/diagnóstico
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