RESUMO
D-bifunctional protein deficiency (D-BPD) is a rare, autosomal recessive peroxisomal disorder that affects the breakdown of long-chain fatty acids. Patients with D-BPD typically present during the neonatal period with hypotonia, seizures, and facial dysmorphism, followed by severe developmental delay and early mortality. While some patients have survived past two years of age, the detectable enzyme activity in these rare cases was likely a contributing factor. We report a D-BPD case and comment on challenges faced in diagnosis based on a narrative literature review. An overview of Romania's first patient diagnosed with D-BPD is provided, including clinical presentation, imaging, biochemical, molecular data, and clinical course. Establishing a diagnosis can be challenging, as the clinical picture is often incomplete or similar to many other conditions. Our patient was diagnosed with type I D-BPD based on whole-exome sequencing (WES) results revealing a pathogenic frameshift variant of the HSD17B4 gene, c788del, p(Pro263GInfs*2), previously identified in another D-BPD patient. WES also identified a variant of the SUOX gene with unclear significance. We advocate for using molecular diagnosis in critically ill newborns and infants to improve care, reduce healthcare costs, and allow for familial counseling.
Assuntos
Proteína Mitocondrial Trifuncional/deficiência , Proteína Multifuncional do Peroxissomo-2 , Humanos , Proteína Multifuncional do Peroxissomo-2/deficiência , Proteína Multifuncional do Peroxissomo-2/genética , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Recém-Nascido , Lactente , Masculino , Feminino , Sequenciamento do Exoma , Mutação da Fase de Leitura , 17-Hidroxiesteroide Desidrogenases/deficiência , 17-Hidroxiesteroide Desidrogenases/genética , Região de Recursos Limitados , Miopatias Mitocondriais , Cardiomiopatias , Doenças do Sistema Nervoso , RabdomióliseRESUMO
Long chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) is the only fatty acid oxidation disorder to develop a progressive chorioretinopathy resulting in vision loss; newborn screening (NBS) for this disorder began in the United States around 2004. We compared visual outcomes among 40 participants with LCHADD or trifunctional protein deficiency diagnosed symptomatically to those who were diagnosed via NBS or a family history. Participants completed ophthalmologic testing including measures of visual acuity, electroretinograms (ERG), fundal imaging, contrast sensitivity, and visual fields. Records were reviewed to document medical and treatment history. Twelve participants presented symptomatically with hypoglycemia, failure to thrive, liver dysfunction, cardiac arrest, or rhabdomyolysis. Twenty eight were diagnosed by NBS or due to a family history of LCHADD. Participants diagnosed symptomatically were older but had similar percent males and genotypes as those diagnosed by NBS. Treatment consisted of fasting avoidance, dietary long-chain fat restriction, MCT, C7, and/or carnitine supplementation. Visual acuity, rod- and cone-driven amplitudes on ERG, contrast sensitivity scores, and visual fields were all significantly worse among participants diagnosed symptomatically compared to NBS. In mixed-effects models, both age and presentation (symptomatic vs. NBS) were significant independent factors associated with visual outcomes. This suggests that visual outcomes were improved by NBS, but there was still lower visual function with advancing age in both groups. Early diagnosis and treatment by NBS is associated with improved visual outcomes and retinal function compared to participants who presented symptomatically. Despite the impact of early intervention, chorioretinopathy was greater with advancing age, highlighting the need for novel treatments.
Assuntos
Diagnóstico Precoce , Erros Inatos do Metabolismo Lipídico , Proteína Mitocondrial Trifuncional , Triagem Neonatal , Doenças Retinianas , Acuidade Visual , Humanos , Masculino , Feminino , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/terapia , Criança , Doenças Retinianas/diagnóstico , Doenças Retinianas/genética , Proteína Mitocondrial Trifuncional/deficiência , Adulto , Lactente , Pré-Escolar , Adolescente , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Adulto Jovem , Carnitina/análogos & derivados , Carnitina/uso terapêutico , Eletrorretinografia , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/genética , 3-Hidroxiacil-CoA Desidrogenases/deficiência , 3-Hidroxiacil-CoA Desidrogenases/genética , Cardiomiopatias/diagnóstico , Cardiomiopatias/genética , Resultado do Tratamento , Rabdomiólise/diagnóstico , Rabdomiólise/genética , Doenças do Sistema NervosoRESUMO
Mitochondrial diseases have a heterogeneous phenotype and can result from mutations in the mitochondrial or nuclear genomes, constituting a diagnostically and therapeutically challenging group of disorders. We report our center's experience with mitochondrial encephalopathies and myopathies with a cohort of 50 genetically and phenotypically diverse patients followed in the Neurology clinic over the last ten years. Seventeen patients had mitochondrial DNA mutations, presented over a wide range of ages with seizures, feeding difficulties, extraocular movements abnormalities, and had high rates of stroke-like episodes and regression. Twenty-seven patients had nuclear DNA mutations, presented early in life with feeding difficulty, failure-to-thrive, and seizures, and had high proportions of developmental delay, wheelchair dependence, spine abnormalities and dystonia. In six patients, a mutation could not be identified, but they were included for having mitochondrial disease confirmed by histopathology, enzyme analysis and clinical features. These patients had similar characteristics to patients with nuclear DNA mutations, suggesting missed underlying mutations in the nuclear genome. Management was variable among patients, but outcomes were universally poor with severe disability in all cases. Therapeutic entryways through elucidation of disease pathways and remaining unknown genes are acutely needed.
Assuntos
DNA Mitocondrial , Encefalomiopatias Mitocondriais , Mutação , Humanos , Masculino , Feminino , Criança , Pré-Escolar , Encefalomiopatias Mitocondriais/genética , Lactente , Adolescente , DNA Mitocondrial/genética , Adulto , Adulto Jovem , Centros de Atenção Terciária , Miopatias Mitocondriais/genéticaRESUMO
Carnitine derivatives of disease-specific acyl-CoAs are the diagnostic hallmark for long-chain fatty acid ß-oxidation disorders (lcFAOD), including carnitine shuttle deficiencies, very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MPTD). The exact consequence of accumulating lcFAO-intermediates and their influence on cellular lipid homeostasis is, however, still unknown. To investigate the fate and cellular effects of the accumulating lcFAO-intermediates and to explore the presence of disease-specific markers, we used tracer-based lipidomics with deuterium-labeled oleic acid (D9-C18:1) in lcFAOD patient-derived fibroblasts. In line with previous studies, we observed a trend towards neutral lipid accumulation in lcFAOD. In addition, we detected a direct connection between the chain length and patterns of (un)saturation of accumulating acylcarnitines and the various enzyme deficiencies. Our results also identified two disease-specific candidate biomarkers. Lysophosphatidylcholine(14:1) (LPC(14:1)) was specifically increased in severe VLCADD compared to mild VLCADD and control samples. This was confirmed in plasma samples showing an inverse correlation with enzyme activity, which was better than the classic diagnostic marker C14:1-carnitine. The second candidate biomarker was an unknown lipid class, which we identified as S-(3-hydroxyacyl)cysteamines. We hypothesized that these were degradation products of the CoA moiety of accumulating 3-hydroxyacyl-CoAs. S-(3-hydroxyacyl)cysteamines were significantly increased in LCHADD compared to controls and other lcFAOD, including MTPD. Our findings suggest extensive alternative lipid metabolism in lcFAOD and confirm that lcFAOD accumulate neutral lipid species. In addition, we present two disease-specific candidate biomarkers for VLCADD and LCHADD, that may have significant relevance for disease diagnosis, prognosis, and monitoring.
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Cardiomiopatias , Síndrome Congênita de Insuficiência da Medula Óssea , Erros Inatos do Metabolismo Lipídico , Lipidômica , Doenças Mitocondriais , Miopatias Mitocondriais , Proteína Mitocondrial Trifuncional/deficiência , Doenças Musculares , Doenças do Sistema Nervoso , Rabdomiólise , Humanos , Doenças Mitocondriais/diagnóstico , Carnitina , Cisteamina , LipídeosRESUMO
Objective: To explore the clinical manifestations and genotype of an infant with hyperuricemia, pulmonary hypertension, renal failure in infancy, and alkalosis syndrome (HUPRAS). Methods: Clinical data of the patient were collected. Peripheral blood samples from the patient and his parents were acquainted for whole exome sequencing. The filtrated variants were verified by Sanger sequencing. The pathogenicity of the variants was predicted by bioinformatic tools. Results: The patient is a male infant of 6 months old, carrying two missense variants in the SARS2 allele: a paternal inherited c.1205G>A (p. Arg402His) and a maternal inherited c.680G>A (p. Arg227Gln). The two variants were in extremely low population frequencies. The pathogenetic prediction tools categorized them as deleterious. Arg402 and Arg227 were highly conserved in evolution. The variants led to changes in the hydrogen bonds and hydrophobicity of seryl-tRNA synthetase encoded by SARS2. Conclusions: c.1205G>A (p. Arg402His) and c.680G>A (p. Arg227Gln) are the possible causative variants of the HUPRA syndrome.
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COVID-19 , Hipertensão Pulmonar , Síndrome de Kearns-Sayre , Miopatias Mitocondriais , Humanos , Lactente , Masculino , Mutação , Hipertensão Pulmonar/genética , Mutação de Sentido Incorreto , GenótipoRESUMO
Fatty acid oxidation (FAO) disorders are autosomal recessive genetic disorders affecting either the transport or the oxidation of fatty acids. Acute symptoms arise during prolonged fasting, intercurrent infections, or intense physical activity. Metabolic crises are characterized by alteration of consciousness, hypoglycemic coma, hepatomegaly, cardiomegaly, arrhythmias, rhabdomyolysis, and can lead to death. In this retrospective and multicentric study, the data of 54 patients with FAO disorders were collected. Overall, 35 patients (64.8%) were diagnosed after newborn screening (NBS), 17 patients on clinical presentation (31.5%), and two patients after family screening (3.7%). Deficiencies identified included medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (75.9%), very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (11.1%), long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency (3.7%), mitochondrial trifunctional protein (MTP) deficiency (1.8%), and carnitine palmitoyltransferase 2 (CPT 2) deficiency (7.4%). The NBS results of 25 patients were reviewed and the neurological outcome of this population was compared with that of the patients who were diagnosed on clinical presentation. This article sought to provide a comprehensive overview of how NBS implementation in Southern Belgium has dramatically improved the neurological outcome of patients with FAO disorders by preventing metabolic crises and death. Further investigations are needed to better understand the physiopathology of long-term complications in order to improve the quality of life of patients and to ensure optimal management.
Assuntos
Acil-CoA Desidrogenase/deficiência , Cardiomiopatias , Carnitina O-Palmitoiltransferase/deficiência , Erros Inatos do Metabolismo Lipídico , Erros Inatos do Metabolismo , Proteína Mitocondrial Trifuncional/deficiência , Triagem Neonatal , Rabdomiólise , Humanos , Recém-Nascido , Estudos Retrospectivos , Masculino , Feminino , Triagem Neonatal/métodos , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/complicações , Bélgica/epidemiologia , Lactente , Síndrome Congênita de Insuficiência da Medula Óssea/complicações , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Ácidos Graxos/metabolismo , Pré-Escolar , Doenças Musculares/diagnóstico , Criança , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/complicações , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/complicações , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/diagnósticoRESUMO
This paper provides an overview of the different types of mitochondrial myopathies (MM), associated phenotypes, genotypes as well as a practical clinical approach towards disease diagnosis, surveillance, and management. nDNA-related MM are more common in pediatric-onset disease whilst mtDNA-related MMs are more frequent in adults. Genotype-phenotype correlation in MM is challenging due to clinical and genetic heterogeneity. The multisystemic nature of many MMs adds to the diagnostic challenge. Diagnostic approaches utilizing genetic sequencing with next generation sequencing approaches such as gene panel, exome and genome sequencing are available. This aids molecular diagnosis, heteroplasmy detection in MM patients and furthers knowledge of known mitochondrial genes. Precise disease diagnosis can end the diagnostic odyssey for patients, avoid unnecessary testing, provide prognosis, facilitate anticipatory management, and enable access to available therapies or clinical trials. Adjunctive tests such as functional and exercise testing could aid surveillance of MM patients. Management requires a multi-disciplinary approach, systemic screening for comorbidities, cofactor supplementation, avoidance of substances that inhibit the respiratory chain and exercise training. This update of the current understanding on MMs provides practical perspectives on current diagnostic and management approaches for this complex group of disorders.
Assuntos
Doenças Mitocondriais , Miopatias Mitocondriais , Humanos , Criança , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/genética , Miopatias Mitocondriais/terapia , Mitocôndrias , Sequenciamento de Nucleotídeos em Larga Escala , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Doenças Mitocondriais/terapiaRESUMO
OBJECTIVE: To develop an updated staging system for long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency (LCHADD) chorioretinopathy based on contemporary multimodal imaging and electrophysiology. METHODS: We evaluated forty cases of patients with genetically confirmed LCHADD or trifunctional protein deficiency (TFPD) enrolled in a prospective natural history study. Wide-field fundus photographs, fundus autofluorescence (FAF), optical coherence tomography (OCT), and full-field electroretinogram (ffERG) were reviewed and graded for severity. RESULTS: Two independent experts first graded fundus photos and electrophysiology to classify the stage of chorioretinopathy based upon an existing published system. With newer imaging modalities and improved electrophysiology, many patients did not fit cleanly into a single traditional staging group. Therefore, we developed a novel staging system that better delineated the progression of LCHADD retinopathy. We maintained the four previous delineated stages but created substages A and B in stages 2 to 3 to achieve better differentiation. DISCUSSION: Previous staging systems of LCHADD chorioretinopathy relied on only on the assessment of standard 30 to 45-degree fundus photographs, visual acuity, fluorescein angiography (FA), and ffERG. Advances in recordings of ffERG and multimodal imaging with wider fields of view, allow better assessment of retinal changes. Following these advanced assessments, seven patients did not fit neatly into the original classification system and were therefore recategorized under the new proposed system. CONCLUSION: The new proposed staging system improves the classification of LCHADD chorioretinopathy, with the potential to lead to a deeper understanding of the disease's progression and serve as a more reliable reference point for future therapeutic research.
Assuntos
Cardiomiopatias , Doenças da Coroide , Erros Inatos do Metabolismo Lipídico , Miopatias Mitocondriais , Proteína Mitocondrial Trifuncional/deficiência , Doenças do Sistema Nervoso , Doenças Retinianas , Rabdomiólise , Humanos , Estudos Prospectivos , Doenças Retinianas/diagnóstico , Retina/metabolismo , Tomografia de Coerência Óptica , Angiofluoresceinografia/métodosRESUMO
OBJECTIVE: This study aims to elucidate the long-term benefit of newborn screening (NBS) for individuals with long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiency, inherited metabolic diseases included in NBS programs worldwide. METHODS: German national multicenter study of individuals with confirmed LCHAD/MTP deficiency identified by NBS between 1999 and 2020 or selective metabolic screening. Analyses focused on NBS results, confirmatory diagnostics, and long-term clinical outcomes. RESULTS: Sixty-seven individuals with LCHAD/MTP deficiency were included in the study, thereof 54 identified by NBS. All screened individuals with LCHAD deficiency survived, but four with MTP deficiency (14.8%) died during the study period. Despite NBS and early treatment neonatal decompensations (28%), symptomatic disease course (94%), later metabolic decompensations (80%), cardiomyopathy (28%), myopathy (82%), hepatopathy (32%), retinopathy (17%), and/or neuropathy (22%) occurred. Hospitalization rates were high (up to a mean of 2.4 times/year). Disease courses in screened individuals with LCHAD and MTP deficiency were similar except for neuropathy, occurring earlier in individuals with MTP deficiency (median 3.9 vs. 11.4 years; p = 0.0447). Achievement of dietary goals decreased with age, from 75% in the first year of life to 12% at age 10, and consensus group recommendations on dietary management were often not achieved. INTERPRETATION: While NBS and early treatment result in improved (neonatal) survival, they cannot reliably prevent long-term morbidity in screened individuals with LCHAD/MTP deficiency, highlighting the urgent need of better therapeutic strategies and the development of disease course-altering treatment.
Assuntos
Cardiomiopatias , Erros Inatos do Metabolismo Lipídico , Miopatias Mitocondriais , Proteína Mitocondrial Trifuncional , Doenças do Sistema Nervoso , Rabdomiólise , Humanos , Recém-Nascido , Ácidos Graxos/metabolismo , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/terapia , Erros Inatos do Metabolismo Lipídico/metabolismo , 3-Hidroxiacil-CoA Desidrogenase de Cadeia Longa/metabolismo , Proteína Mitocondrial Trifuncional/metabolismo , Proteína Mitocondrial Trifuncional/deficiência , Lactente , Pré-Escolar , CriançaRESUMO
AIM: We describe the ophthalmic manifestations of Neuropathy, ataxia, retinitis pigmentosa (NARP) syndrome in three related patients. METHODS: We examined a mother and her two children, who were carriers of the mt 8993T>G mutation. The mother, patient I, is the first known carrier within the family pedigree. Patients II and III are her children from a non-carrier father. NARP syndrome and the heteroplasmy levels were established prior to the first referral of the patients to the Ophthalmology department.We performed a visual acuity testing, followed by a biomicroscopic and fundus examination, as well as additional multimodal imaging testing: optical coherence tomography (OCT) and fundus autofluorescence (FAF), and functional testing: electroretinogram and visual field. RESULTS: All patients had the clinical manifestations of NARP syndrome, which were variably expressed symptomatically, on the fundus exams, electroretinogram, and visual fields. CONCLUSIONS: Once genetically established, NARP syndrome, as other mitochondrial disorders, has a very variable progression with different degrees of severity. A multimodal approach involving both neurological and ophthalmological diagnosis of NARP syndrome is necessary in order to establish the course of the disease and the measures to be taken.
Assuntos
Hipopituitarismo , Miopatias Mitocondriais , Mães , Retinose Pigmentar , Criança , Feminino , Humanos , Irmãos , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/genética , Ataxia/diagnóstico , Ataxia/genética , Mutação , Tomografia de Coerência ÓpticaRESUMO
Mitochondrial dysfunction in skeletal muscle fibres occurs with both healthy aging and a range of neuromuscular diseases. The impact of mitochondrial dysfunction in skeletal muscle and the way muscle fibres adapt to this dysfunction is important to understand disease mechanisms and to develop therapeutic interventions. Furthermore, interactions between mitochondrial dysfunction and skeletal muscle biology, in mitochondrial myopathy, likely have important implications for normal muscle function and physiology. In this review, we will try to give an overview of what is known to date about these interactions including metabolic remodelling, mitochondrial morphology, mitochondrial turnover, cellular processes and muscle cell structure and function. Each of these topics is at a different stage of understanding, with some being well researched and understood, and others in their infancy. Furthermore, some of what we know comes from disease models. Whilst some findings are confirmed in humans, where this is not yet the case, we must be cautious in interpreting findings in the context of human muscle and disease. Here, our goal is to discuss what is known, highlight what is unknown and give a perspective on the future direction of research in this area.
Assuntos
Miopatias Mitocondriais , Músculo Esquelético , Humanos , Músculo Esquelético/metabolismo , Miopatias Mitocondriais/genética , Miopatias Mitocondriais/metabolismo , Mitocôndrias/metabolismo , Renovação Mitocondrial , BiologiaRESUMO
SIGNIFICANCE STATEMENT: Several recent studies identified mitochondrial mutations in patients with Gitelman or Fanconi syndrome. Mitochondrial cytopathies are generally not considered in the diagnostic workup of patients with electrolyte disorders. In this systematic review, we investigated the presence of electrolyte disorders in patients with mitochondrial cytopathies to determine the relevance of mitochondrial mutation screening in this population. Our analysis demonstrates that electrolyte disorders are commonly reported in mitochondrial cytopathies, often as presenting symptoms. Consequently, more clinical attention should be raised for mitochondrial disease as cause for disturbances in electrolyte homeostasis. Further prospective cohort studies are required to determine the exact prevalence of electrolyte disorders in mitochondrial cytopathies. BACKGROUND: Electrolyte reabsorption in the kidney has a high energy demand. Proximal and distal tubular epithelial cells have a high mitochondrial density for energy release. Recently, electrolyte disorders have been reported as the primary presentation of some mitochondrial cytopathies. However, the prevalence and the pathophysiology of electrolyte disturbances in mitochondrial disease are unknown. Therefore, we systematically investigated electrolyte disorders in patients with mitochondrial cytopathies. METHODS: We searched PubMed, Embase, and Google Scholar for articles on genetically confirmed mitochondrial disease in patients for whom at least one electrolyte is reported. Patients with a known second genetic anomaly were excluded. We evaluated 214 case series and reports (362 patients) as well as nine observational studies. Joanna Briggs Institute criteria were used to evaluate the quality of included studies. RESULTS: Of 362 reported patients, 289 had an electrolyte disorder, with it being the presenting or main symptom in 38 patients. The average number of different electrolyte abnormalities per patient ranged from 2.4 to 1.0, depending on genotype. Patients with mitochondrial DNA structural variants seemed most affected. Reported pathophysiologic mechanisms included renal tubulopathies and hormonal, gastrointestinal, and iatrogenic causes. CONCLUSIONS: Mitochondrial diseases should be considered in the evaluation of unexplained electrolyte disorders. Furthermore, clinicians should be aware of electrolyte abnormalities in patients with mitochondrial disease.
Assuntos
Síndrome de Kearns-Sayre , Doenças Mitocondriais , Miopatias Mitocondriais , Desequilíbrio Hidroeletrolítico , Humanos , Miopatias Mitocondriais/genética , Síndrome de Kearns-Sayre/genética , Doenças Mitocondriais/complicações , Doenças Mitocondriais/epidemiologia , Doenças Mitocondriais/genética , Mitocôndrias , DNA Mitocondrial/genéticaRESUMO
BACKGROUND: Mitochondrial myopathies (MMs) are a group of multi-system diseases caused by abnormalities in mitochondrial DNA (mtDNA) or mutations of nuclear DNA (nDNA). The diagnosis of mitochondrial myopathy (MM) is reliant on the combination of history and physical examination, muscle biopsy, histochemical studies, and next-generation sequencing. Patients with MMs have diverse clinical manifestations. In the contemporary literature, there is a paucity of reports on cardiac structure and function in this rare disease. We report a Chinese man with MM accompanied with both acute right heart failure and left ventricular hypertrophy. CASE PRESENTATION: A 49-year-old man presented with clinical features suggestive of MM, i.e., ophthalmoparesis, weakness of the pharyngeal and extremity muscles, and respiratory muscles which gradually progressed to respiratory insufficiency. He had a family history of mitochondrial myopathy. He had increased levels of serum creatine kinase and lactate. Muscle biopsy of left lateral thigh revealed 8% ragged red fibers (RRF) and 42% COX-negative fibers. Gene sequencing revealed a novel heterozygote TK2 variant (NM_001172644: c.584T>C, p.Leu195Pro) and another heterozygous variant (NM_004614.4:c.156+958G>A; rs1965661603) in the intron of TK2 gene. Based on these findings, we diagnosed the patient as a case of MM. Echocardiography revealed right heart enlargement, pulmonary hypertension, left ventricular hypertrophy, and thickening of the main pulmonary artery and its branches. The patient received non-invasive ventilation and coenzyme Q10 (CoQ10). The cardiac structure and function were restored at 1-month follow-up. CONCLUSIONS: This is the first report of reversible cardiac function impairment and left ventricular hypertrophy in a case of adult-onset MM, nocturnal hypoxia is a potential mechanism for left ventricular hypertrophy in patients with MM.
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Hipertrofia Ventricular Esquerda , Miopatias Mitocondriais , Adulto , Masculino , Humanos , Pessoa de Meia-Idade , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/genética , População do Leste Asiático , Coração , Miopatias Mitocondriais/complicações , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/genética , CardiomegaliaRESUMO
Mitochondrial myopathy is a severe metabolic myopathy related to nuclear or mitochondrial DNA dysfunction. We present a rare case of mitochondrial myopathy, presented with multiple episodes of proximal muscle weakness, lactic acidosis, and severe rhabdomyolysis (CPK 319,990 U/L, lactic acid 22.31 mmol/L, and GFR 3.82 mL/min/1.73m2 ). She was hospitalized in the pediatric intensive care unit due to acute kidney injury, elevated blood pressure, and deterioration of respiratory and cardiac function. Investigation for inherited metabolic disorders showed elevated levels of ammonia, lactic acid to pyruvic acid ratio, and urine ketone bodies. Exome sequencing detected a homozygous pathogenic variant in FDX2 (ENST00000541276:p.Met4Leu/c.10A > T) and a heterozygous variant of uncertain significance in MSTO1 (ENST00000538143:p.Leu137Pro/c.410 T > C). After Sanger sequencing, the p.Met4Leu pathogenic variant in FDX2 (ENST00000541276:p.Met4Leu/c.10A > T) was identified in a heterozygous state in both her parents and sister. Recently, pathogenic variants in the FDX2 gene have been associated with mitochondrial myopathy, lactic acidosis, optic atrophy, and leukoencephalopathy. Only four reports of FDX2-related rhabdomyolysis have been described before, but none of the previous patients had hyperammonemia. This is a rare case of severe mitochondrial myopathy in a pediatric patient related to a pathogenic FDX2 variant, suggesting the need for genetic analysis of the FDX2 gene in cases of suspicion of mitochondrial myopathies.
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Acidose Láctica , Miopatias Mitocondriais , Doenças Musculares , Rabdomiólise , Humanos , Feminino , Criança , Acidose Láctica/diagnóstico , Acidose Láctica/genética , Ferredoxinas/genética , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Doenças Musculares/complicações , Rabdomiólise/diagnóstico , Rabdomiólise/genética , Miopatias Mitocondriais/genética , Mutação , Ácido Láctico , Proteínas do Citoesqueleto/genética , Proteínas de Ciclo Celular/genéticaRESUMO
Primary mitochondrial myopathies (PMM) are rare disorders with diverse and progressive symptom presentations that cause a substantial, detrimental impact on the quality of life of patients and their caregivers. The burden of symptoms is compounded by their visibility and their unpredictable, progressive nature, leading to a sense of social stigmatization, limited autonomy, social isolation, and grief. There is also a lack of awareness and expertise in the medical community, which presents huge obstacles to diagnosis and provision of coordinated multidisciplinary care for these patients, along with a lack of disease-modifying treatments. The present commentary serves to raise awareness of the challenges faced by patients with PMM and their caregivers in their own words, including diagnostic delays, the burden of disease, and the need for further trials to develop disease-modifying treatments and improved understanding of the disease course. We also provide commentary on considerations for clinical practice, including the need for holistic care and multidisciplinary care teams, details of common 'red flag' symptoms, proposed diagnostic approaches, and suggested descriptions of multisystemic symptoms for physician-patient dialogue. In addition, we highlight the role patient advocacy and support groups play in supporting patients and providing access to reliable, up-to-date information and educational resources on these rare diseases.
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Miopatias Mitocondriais , Qualidade de Vida , Humanos , Miopatias Mitocondriais/terapia , Cuidadores , Efeitos Psicossociais da Doença , Diagnóstico TardioRESUMO
BACKGROUND AND OBJECTIVES: Primary mitochondrial myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely affecting physical function, exercise capacity, and quality of life (QoL). Current PMM standards of care address symptoms, with limited clinical impact, constituting a significant therapeutic unmet need. We present data from MMPOWER-3, a pivotal, phase-3, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of elamipretide in participants with genetically confirmed PMM. METHODS: After screening, eligible participants were randomized 1:1 to receive either 24 weeks of elamipretide at a dose of 40 mg/d or placebo subcutaneously. Primary efficacy endpoints included change from baseline to week 24 on the distance walked on the 6-minute walk test (6MWT) and total fatigue on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA). Secondary endpoints included most bothersome symptom score on the PMMSA, NeuroQoL Fatigue Short-Form scores, and the patient global impression and clinician global impression of PMM symptoms. RESULTS: Participants (N = 218) were randomized (n = 109 elamipretide; n = 109 placebo). The m0ean age was 45.6 years (64% women; 94% White). Most of the participants (n = 162 [74%]) had mitochondrial DNA (mtDNA) alteration, with the remainder having nuclear DNA (nDNA) defects. At screening, the most frequent bothersome PMM symptom on the PMMSA was tiredness during activities (28.9%). At baseline, the mean distance walked on the 6MWT was 336.7 ± 81.2 meters, the mean score for total fatigue on the PMMSA was 10.6 ± 2.5, and the mean T score for the Neuro-QoL Fatigue Short-Form was 54.7 ± 7.5. The study did not meet its primary endpoints assessing changes in the 6MWT and PMMSA total fatigue score (TFS). Between the participants receiving elamipretide and those receiving placebo, the difference in the least squares mean (SE) from baseline to week 24 on distance walked on the 6MWT was -3.2 (95% CI -18.7 to 12.3; p = 0.69) meters, and on the PMMSA, the total fatigue score was -0.07 (95% CI -0.10 to 0.26; p = 0.37). Elamipretide treatment was well-tolerated with most adverse events being mild to moderate in severity. DISCUSSION: Subcutaneous elamipretide treatment did not improve outcomes in the 6MWT and PMMSA TFS in patients with PMM. However, this phase-3 study demonstrated that subcutaneous elamipretide is well-tolerated. TRIAL REGISTRATION INFORMATION: Trial registered with clinicaltrials.gov, Clinical Trials Identifier: NCT03323749; submitted on October 12, 2017; first patient enrolled October 9, 2017. CLINICALTRIALS: gov/ct2/show/NCT03323749?term = elamipretide&draw = 2&rank = 9. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that elamipretide does not improve the 6MWT or fatigue at 24 weeks compared with placebo in patients with primary mitochondrial myopathy.
Assuntos
Miopatias Mitocondriais , Qualidade de Vida , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Proteína 1 de Superfície de Merozoito/uso terapêutico , Miopatias Mitocondriais/tratamento farmacológico , Fadiga , Método Duplo-Cego , Resultado do TratamentoRESUMO
Bilateral lower extremity weakness and swelling can have several causes. Although often underdiagnosed, mitochondrial myopathy is more prevalent in the general population than more commonly suspected diseases, such as Guillain-Barre syndrome. The clinical manifestations of mitochondrial disease can be broadly classified into 3 categories: chronic progressive external ophthalmoplegia, skeletal muscle-central nervous system syndromes, or pure myopathy. Cardiac abnormalities occur in 30% to 32% of cases, mostly in the form of hypertrophic cardiomyopathy, dilated cardiomyopathy, or conduction abnormalities. We report a case of a 21-year-old student who developed bilateral lower limb weakness, pain, and swelling diagnosed with mitochondrial myopathy on muscle biopsy. Initial laboratory tests revealed elevated creatinine kinase, brain natriuretic peptide, troponin, myoglobin, and lactic acid and reduced serum bicarbonate. Cardiac workup revealed systolic heart failure with a reduced ejection fraction. Endomyocardial biopsy revealed punctate foci of lymphocytic myocarditis. However, cardiac magnetic resonance imaging did not reveal either myocarditis or an infiltrative cardiac disease. An extensive autoimmune and infection work-up was negative. A muscle biopsy from the patient's rectus femoris revealed scattered ragged-blue fibers (stained with NADH dehydrogenase), scattered ragged-red fibers on modified Gomori trichrome stain, and cytochrome-c oxidase negative fibers with increased perimysial and endomysial connective tissue, consistent with active and chronic primary mitochondrial myopathy. The patient was treated successfully with furosemide, metoprolol, and methylprednisolone. Adult-onset mitochondrial myopathy is a rare clinical disorder, and our experience stresses the importance of using an inter-disciplinary team approach to diagnose uncommon clinical disorders with widely variable multisystem involvement.
Assuntos
Miopatias Mitocondriais , Miocardite , Oftalmoplegia Externa Progressiva Crônica , Adulto , Masculino , Humanos , Adulto Jovem , Miocardite/patologia , Miopatias Mitocondriais/complicações , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/patologia , Músculo Esquelético/patologia , Oftalmoplegia Externa Progressiva Crônica/diagnóstico , Oftalmoplegia Externa Progressiva Crônica/patologia , Extremidade Inferior/patologiaRESUMO
Mitochondrial diseases are a heterogeneous group of monogenic disorders that result from impaired oxidative phosphorylation (OXPHOS). As neuromuscular tissues are highly energy-dependent, mitochondrial diseases often affect skeletal muscle. Although genetic and bioenergetic causes of OXPHOS impairment in human mitochondrial myopathies are well established, there is a limited understanding of metabolic drivers of muscle degeneration. This knowledge gap contributes to the lack of effective treatments for these disorders. Here, we discovered fundamental muscle metabolic remodeling mechanisms shared by mitochondrial disease patients and a mouse model of mitochondrial myopathy. This metabolic remodeling is triggered by a starvation-like response that evokes accelerated oxidation of amino acids through a truncated Krebs cycle. While initially adaptive, this response evolves in an integrated multiorgan catabolic signaling, lipid store mobilization, and intramuscular lipid accumulation. We show that this multiorgan feed-forward metabolic response involves leptin and glucocorticoid signaling. This study elucidates systemic metabolic dyshomeostasis mechanisms that underlie human mitochondrial myopathies and identifies potential new targets for metabolic intervention.
Assuntos
Doenças Mitocondriais , Miopatias Mitocondriais , Camundongos , Animais , Humanos , Miopatias Mitocondriais/genética , Miopatias Mitocondriais/metabolismo , Músculo Esquelético/metabolismo , Metabolismo Energético , LipídeosRESUMO
Metabolic myopathies are a set of rare inborn errors of metabolism leading to disruption in energy production. Relevant to skeletal muscle, glycogen storage disease and fatty acid oxidation defects can lead to exercise intolerance, rhabdomyolysis, and weakness in children and adults, distinct from the severe forms that involve multiple-organ systems. These nonspecific, dynamic symptoms along with conditions that mimic metabolic myopathies can make diagnosis challenging. Clinicians can shorten the time to diagnosis by recognizing the typical clinical phenotypes and performing next generation sequencing. With improved access and affordability of molecular testing, clinicians need to be well-versed in resolving variants of uncertain significance relevant to metabolic myopathies. Once identified, patients can improve quality of life, safely engage in exercise, and reduce episodes of rhabdomyolysis by modifying diet and lifestyle habits.