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1.
Int J Mol Sci ; 25(9)2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38732076

ABSTRACT

Mitochondrial diseases (MDs) affect 4300 individuals, with different ages of presentation and manifestation in any organ. How defects in mitochondria can cause such a diverse range of human diseases remains poorly understood. In recent years, several published research articles regarding the metabolic and protein profiles of these neurogenetic disorders have helped shed light on the pathogenetic mechanisms. By investigating different pathways in MDs, often with the aim of identifying disease biomarkers, it is possible to identify molecular processes underlying the disease. In this perspective, omics technologies such as proteomics and metabolomics considered in this review, can support unresolved mitochondrial questions, helping to improve outcomes for patients.


Subject(s)
Biomarkers , Metabolomics , Mitochondria , Mitochondrial Diseases , Proteomics , Humans , Metabolomics/methods , Mitochondria/metabolism , Proteomics/methods , Mitochondrial Diseases/metabolism , Mitochondrial Diseases/genetics , Mitochondrial Diseases/diagnosis , Animals
2.
Hum Mol Genet ; 33(R1): R3-R11, 2024 May 22.
Article in English | MEDLINE | ID: mdl-38779777

ABSTRACT

Mutations of mitochondrial (mt)DNA are a major cause of morbidity and mortality in humans, accounting for approximately two thirds of diagnosed mitochondrial disease. However, despite significant advances in technology since the discovery of the first disease-causing mtDNA mutations in 1988, the comprehensive diagnosis and treatment of mtDNA disease remains challenging. This is partly due to the highly variable clinical presentation linked to tissue-specific vulnerability that determines which organs are affected. Organ involvement can vary between different mtDNA mutations, and also between patients carrying the same disease-causing variant. The clinical features frequently overlap with other non-mitochondrial diseases, both rare and common, adding to the diagnostic challenge. Building on previous findings, recent technological advances have cast further light on the mechanisms which underpin the organ vulnerability in mtDNA diseases, but our understanding is far from complete. In this review we explore the origins, current knowledge, and future directions of research in this area.


Subject(s)
DNA, Mitochondrial , Mitochondrial Diseases , Mutation , Organ Specificity , Humans , DNA, Mitochondrial/genetics , Mitochondrial Diseases/genetics , Mitochondrial Diseases/pathology , Mitochondrial Diseases/diagnosis , Organ Specificity/genetics , Mitochondria/genetics , Animals
3.
Medicine (Baltimore) ; 103(18): e37847, 2024 May 03.
Article in English | MEDLINE | ID: mdl-38701254

ABSTRACT

RATIONALE: Mitochondrial diseases are a group of disorders in which mutations in mitochondrial DNA or nuclear DNA lead to dysfunctional oxidative phosphorylation of cells, with mutations in mitochondrial DNA being the most common cause of mitochondrial disease, and mutations in nuclear genes being rarely reported. The echocardiographic findings of mitochondrial diseases with nuclear gene mutations in children's hearts are even rarer. Even more valuable is that we followed up the patient for 4 years and dynamically observed the cardiac echocardiographic manifestations of mitochondrial disease. Provide ideas for the clinical diagnosis and prognosis of mitochondrial diseases. PATIENT CONCERNS: The patient was seen in the pediatric outpatient clinic for poor strength and mental retardation. echocardiography: mild left ventricular (LV) enlargement and LV wall thickening. Nuclear genetic testing: uanosine triphosphate binding protein 3 (GTPBP3) gene mutation. Diagnosis of mitochondrial disease. DIAGNOSES: Mitochondrial disease with GTPBP3 gene mutations. OUTCOMES: After receiving drug treatment, the patient exhibited a reduction in lactate levels, an enhanced physical condition compared to prior assessments, and demonstrated average intellectual development. LESSONS SUBSECTIONS: For echocardiographic indications of LV wall thickening and LV enlargement, one needs to be alert to the possibility of hereditary cardiomyopathy, especially in children.


Subject(s)
Echocardiography , Mitochondrial Diseases , Mutation , Female , Humans , Echocardiography/methods , GTP-Binding Proteins/genetics , Mitochondrial Diseases/genetics , Mitochondrial Diseases/diagnostic imaging , Mitochondrial Diseases/diagnosis , Child
4.
BMC Genomics ; 25(1): 538, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38822239

ABSTRACT

BACKGROUND: Mitochondrial diseases (MDs) can be caused by single nucleotide variants (SNVs) and structural variants (SVs) in the mitochondrial genome (mtDNA). Presently, identifying deletions in small to medium-sized fragments and accurately detecting low-percentage variants remains challenging due to the limitations of next-generation sequencing (NGS). METHODS: In this study, we integrated targeted long-range polymerase chain reaction (LR-PCR) and PacBio HiFi sequencing to analyze 34 participants, including 28 patients and 6 controls. Of these, 17 samples were subjected to both targeted LR-PCR and to compare the mtDNA variant detection efficacy. RESULTS: Among the 28 patients tested by long-read sequencing (LRS), 2 patients were found positive for the m.3243 A > G hotspot variant, and 20 patients exhibited single or multiple deletion variants with a proportion exceeding 4%. Comparison between the results of LRS and NGS revealed that both methods exhibited similar efficacy in detecting SNVs exceeding 5%. However, LRS outperformed NGS in detecting SNVs with a ratio below 5%. As for SVs, LRS identified single or multiple deletions in 13 out of 17 cases, whereas NGS only detected single deletions in 8 cases. Furthermore, deletions identified by LRS were validated by Sanger sequencing and quantified in single muscle fibers using real-time PCR. Notably, LRS also effectively and accurately identified secondary mtDNA deletions in idiopathic inflammatory myopathies (IIMs). CONCLUSIONS: LRS outperforms NGS in detecting various types of SNVs and SVs in mtDNA, including those with low frequencies. Our research is a significant advancement in medical comprehension and will provide profound insights into genetics.


Subject(s)
DNA, Mitochondrial , High-Throughput Nucleotide Sequencing , Mitochondrial Diseases , Humans , DNA, Mitochondrial/genetics , High-Throughput Nucleotide Sequencing/methods , Mitochondrial Diseases/genetics , Mitochondrial Diseases/diagnosis , Female , Male , Sequence Analysis, DNA/methods , Adult , Middle Aged , Polymorphism, Single Nucleotide , Polymerase Chain Reaction/methods
5.
J Transl Med ; 22(1): 386, 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38664838

ABSTRACT

BACKGROUND: Sequencing the mitochondrial genome has been increasingly important for the investigation of primary mitochondrial diseases (PMD) and mitochondrial genetics. To overcome the limitations originating from PCR-based mtDNA enrichment, we set out to develop and evaluate a PCR-independent approach in this study, named Pime-Seq (PCR-independent mtDNA enrichment and next generation Sequencing). RESULTS: By using the optimized mtDNA enrichment procedure, the mtDNA reads ratio reached 88.0 ± 7.9% in the sequencing library when applied on human PBMC samples. We found the variants called by Pime-Seq were highly consistent among technical repeats. To evaluate the accuracy and reliability of this method, we compared Pime-Seq with lrPCR based NGS by performing both methods simultaneously on 45 samples, yielding 1677 concordant variants, as well as 146 discordant variants with low-level heteroplasmic fraction, in which Pime-Seq showed higher reliability. Furthermore, we applied Pime-Seq on 4 samples of PMD patients retrospectively, and successfully detected all the pathogenic mtDNA variants. In addition, we performed a prospective study on 192 apparently healthy pregnant women during prenatal screening, in which Pime-Seq identified pathogenic mtDNA variants in 4 samples, providing extra information for better health monitoring in these cases. CONCLUSIONS: Pime-Seq can obtain highly enriched mtDNA in a PCR-independent manner for high quality and reliable mtDNA deep-sequencing, which provides us an effective and promising tool for detecting mtDNA variants for both clinical and research purposes.


Subject(s)
DNA, Mitochondrial , High-Throughput Nucleotide Sequencing , Mitochondrial Diseases , Polymerase Chain Reaction , Humans , DNA, Mitochondrial/genetics , High-Throughput Nucleotide Sequencing/methods , Female , Polymerase Chain Reaction/methods , Mitochondrial Diseases/genetics , Mitochondrial Diseases/diagnosis , Pregnancy , Reproducibility of Results , Male , Adult
6.
BMJ Case Rep ; 17(4)2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38684350

ABSTRACT

The POLG mutation, a leading cause of mitochondrial diseases, exhibits a wide-ranging age of onset and a complex clinical presentation. We encountered an atypical clinical profile in an elderly man with a POLG mutation, characterised by a stroke-like episode, chronic insomnia and transient oculomasticatory rhythmic movement. History revealed chronic constipation since his 50s and progressive bilateral ophthalmoplegia since his early 60s. Subsequently, he had experienced acute encephalopathy and later developed chronic insomnia. The present neurological examination showed bilateral complete ophthalmoplegia, ptosis, and rhythmic ocular and jaw movements. Imaging indicated findings suggestive of a stroke-like episode and eventual genetic analysis revealed a homozygous missense mutation in the POLG gene. This case expands the clinical spectrum of POLG mutations in individuals over 60 years, showcasing the rare combination of a stroke-like episode, chronic insomnia and oculomasticatory rhythmic movement.


Subject(s)
DNA Polymerase gamma , Sleep Initiation and Maintenance Disorders , Humans , Male , DNA Polymerase gamma/genetics , Sleep Initiation and Maintenance Disorders/genetics , Stroke/genetics , Stroke/complications , Mutation, Missense , Mitochondrial Diseases/genetics , Mitochondrial Diseases/complications , Mitochondrial Diseases/diagnosis , Aged , Middle Aged , Ophthalmoplegia/genetics , Ophthalmoplegia/diagnosis , Blepharoptosis/genetics , Mutation
7.
Front Biosci (Schol Ed) ; 16(1): 7, 2024 Mar 14.
Article in English | MEDLINE | ID: mdl-38538347

ABSTRACT

Disorders of mitochondrial function are responsible for many inherited neuromuscular and metabolic diseases. Their combination of high mortality, multi-systemic involvement, and economic burden cause devastating effects on patients and their families. Molecular diagnostic tools are becoming increasingly important in providing earlier diagnoses and guiding more precise therapeutic treatments for patients suffering from mitochondrial disorders. This review addresses fundamental molecular concepts relating to the pathogenesis of mitochondrial dysfunction and disorders. A series of short cases highlights the various clinical presentations, inheritance patterns, and pathogenic mutations in nuclear and mitochondrial genes that cause mitochondrial diseases. Graphical and tabular representations of the results are presented to guide the understanding of the important concepts related to mitochondrial molecular genetics and pathology. Emerging technology is incorporating preimplantation genetic testing for mtDNA disorders, while mitochondrial replacement shows promise in significantly decreasing the transfer of diseased mitochondrial DNA (mtDNA) to embryos. Medical professionals must maintain an in-depth understanding of the gene mutations and molecular mechanisms underlying mitochondrial disorders. Continued diagnostic advances and comprehensive management of patients with mitochondrial disorders are essential to achieve robust clinical impacts from comprehensive genomic testing. This is especially true when supported by non-genetic tests such as biochemical analysis, histochemical stains, and imaging studies. Such a multi-pronged investigation should improve the management of mitochondrial disorders by providing accurate and timely diagnoses to reduce disease burden and improve the lives of patients and their families.


Subject(s)
Mitochondrial Diseases , Humans , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Mitochondrial Diseases/pathology , DNA, Mitochondrial/genetics , DNA, Mitochondrial/metabolism , Mitochondria/genetics , Mitochondria/metabolism , Mitochondria/pathology , Mutation , Genes, Mitochondrial
9.
FASEB J ; 38(4): e23478, 2024 Feb 29.
Article in English | MEDLINE | ID: mdl-38372965

ABSTRACT

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.


Subject(s)
Cardiomyopathies , Congenital Bone Marrow Failure Syndromes , Lipid Metabolism, Inborn Errors , Lipidomics , Mitochondrial Diseases , Mitochondrial Myopathies , Mitochondrial Trifunctional Protein/deficiency , Muscular Diseases , Nervous System Diseases , Rhabdomyolysis , Humans , Mitochondrial Diseases/diagnosis , Carnitine , Cysteamine , Lipids
10.
Eur J Paediatr Neurol ; 49: 60-65, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38377647

ABSTRACT

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.


Subject(s)
Acyl-CoA Dehydrogenase/deficiency , Cardiomyopathies , Carnitine O-Palmitoyltransferase/deficiency , Lipid Metabolism, Inborn Errors , Metabolism, Inborn Errors , Mitochondrial Trifunctional Protein/deficiency , Neonatal Screening , Rhabdomyolysis , Humans , Infant, Newborn , Retrospective Studies , Male , Female , Neonatal Screening/methods , Lipid Metabolism, Inborn Errors/diagnosis , Lipid Metabolism, Inborn Errors/complications , Belgium/epidemiology , Infant , Congenital Bone Marrow Failure Syndromes/complications , Congenital Bone Marrow Failure Syndromes/diagnosis , Acyl-CoA Dehydrogenase, Long-Chain/deficiency , Fatty Acids/metabolism , Child, Preschool , Muscular Diseases/diagnosis , Child , Mitochondrial Myopathies/diagnosis , Mitochondrial Myopathies/complications , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/complications , Nervous System Diseases/etiology , Nervous System Diseases/diagnosis
11.
Syst Biol Reprod Med ; 70(1): 38-51, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38323618

ABSTRACT

Mitochondrial diseases are distinct types of metabolic and/or neurologic abnormalities that occur as a consequence of dysfunction in oxidative phosphorylation, affecting several systems in the body. There is no effective treatment modality for mitochondrial disorders so far, emphasizing the clinical significance of preventing the inheritance of these disorders. Various reproductive options are available to reduce the probability of inheriting mitochondrial disorders, including in vitro fertilization (IVF) using donated oocytes, preimplantation genetic testing (PGT), and prenatal diagnosis (PND), among which PGT not only makes it possible for families to have genetically-owned children but also PGT has the advantage that couples do not have to decide to terminate the pregnancy if a mutation is detected in the fetus. PGT for mitochondrial diseases originating from nuclear DNA includes analyzing the nuclear genome for the presence or absence of corresponding mutations. However, PGT for mitochondrial disorders arising from mutations in mitochondrial DNA (mtDNA) is more intricate, due to the specific characteristics of mtDNA such as multicopy nature, heteroplasmy phenomenon, and exclusive maternal inheritance. Therefore, the present review aims to discuss the utility and challenges of PGT as a preventive approach to inherited mitochondrial diseases caused by mtDNA mutations.


Subject(s)
Mitochondrial Diseases , Preimplantation Diagnosis , Pregnancy , Female , Child , Humans , DNA, Mitochondrial/genetics , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Mitochondrial Diseases/prevention & control , Genetic Testing , Mitochondria , Fertilization in Vitro
12.
Diabetes Metab J ; 48(3): 482-486, 2024 May.
Article in English | MEDLINE | ID: mdl-38311059

ABSTRACT

Maternally inherited diabetes and deafness (MIDD) is a rare mitochondrial disorder primarily resulting from m.3243A>G mutation. The clinical characteristics of MIDD exhibit significant heterogeneity. Our study aims to delineate these characteristics and determine the potential correlation with m.3243A>G heteroplasmy levels. This retrospective, descriptive study encompassed patients with confirmed m.3243A>G mutation and diabetes mellitus at Seoul National University Hospital. Our cohort comprises 40 patients with MIDD, with a mean age at study enrollment of 33.3±12.9 years and an average % of heteroplasmy of 30.0%± 14.6% in the peripheral blood. The most prevalent comorbidity was hearing loss (90%), followed by albuminuria (61%), seizure (38%), and stroke (33%). We observed a significant negative correlation between % of heteroplasmy and age at diabetes diagnosis. These clinical features can aid in the suspicion of MIDD and further consideration of genetic testing for m.3243A>G mutation.


Subject(s)
DNA, Mitochondrial , Deafness , Mitochondrial Diseases , Mutation , Humans , Female , Male , DNA, Mitochondrial/genetics , Retrospective Studies , Adult , Republic of Korea/epidemiology , Mitochondrial Diseases/genetics , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/epidemiology , Middle Aged , Deafness/genetics , Young Adult , Diabetes Mellitus/genetics , Diabetes Mellitus/epidemiology , Adolescent , Heteroplasmy , Hearing Loss/genetics , Diabetes Mellitus, Type 2
13.
Neurotherapeutics ; 21(1): e00311, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38266483

ABSTRACT

Mitochondrial disorders are a group of rare and heterogeneous genetic diseases characterized by dysfunctional mitochondria leading to deficient adenosine triphosphate synthesis and chronic energy deficit in patients. The majority of these patients exhibit a wide range of phenotypic manifestations targeting several organ systems, making their clinical diagnosis and management challenging. Bridging translational to clinical research is crucial for improving the early diagnosis and prognosis of these intractable mitochondrial disorders and for discovering novel therapeutic drug candidates and modalities. This review provides the current state of clinical testing in mitochondrial disorders, discusses the challenges and opportunities for converting basic discoveries into clinical settings, explores the most suited patient-centric approaches to harness the extraordinary heterogeneity among patients affected by the same primary mitochondrial disorder, and describes the current outlook of clinical trials.


Subject(s)
Mitochondria , Mitochondrial Diseases , Humans , Mitochondria/genetics , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Mitochondrial Diseases/therapy , Precision Medicine
14.
Neurotherapeutics ; 21(1): e00325, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38295557

ABSTRACT

Mitochondrial diseases encompass a heterogeneous group of disorders with a wide range of clinical manifestations, most classically resulting in neurological, muscular, and metabolic abnormalities, but having the potential to affect any organ system. Over the years, substantial progress has been made in identifying and characterizing various biomarkers associated with mitochondrial diseases. This review summarizes the current knowledge of mitochondrial biomarkers based on a literature review and discusses the evidence behind their use in clinical practice. A total of 13 biomarkers were thoroughly reviewed including lactate, pyruvate, lactate:pyruvate ratio, creatine kinase, creatine, amino acid profiles, glutathione, malondialdehyde, GDF-15, FGF-21, gelsolin, neurofilament light-chain, and circulating cell-free mtDNA. Most biomarkers had mixed findings depending on the study, especially when considering their utility for specific mitochondrial diseases versus mitochondrial conditions in general. However, in large biomarker comparison studies, GDF-15 followed by FGF-21, seem to have the greatest value though they are still not perfect. As such, additional studies are needed, especially in light of newer biomarkers that have not yet been thoroughly investigated. Understanding the landscape of biomarkers in mitochondrial diseases is crucial for advancing early detection, improving patient management, and developing targeted therapies.


Subject(s)
Growth Differentiation Factor 15 , Mitochondrial Diseases , Humans , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Biomarkers , Pyruvic Acid , Lactic Acid , DNA, Mitochondrial
15.
Curr Protoc ; 4(1): e955, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38284225

ABSTRACT

The international Mitochondrial Disease Sequence Data Resource Consortium (MSeqDR) Quick-Mitome (QM) is a web-based platform enabling automated variant interpretation of whole-exome sequencing (WES) datasets for the genetic diagnosis of primary mitochondrial diseases (PMD). Designed specifically to address the unique dual genome nature of PMD etiologies, QM includes features for both nuclear and mitochondrial DNA (mtDNA) genome analysis. QM requires VCF variant lists, HPO ID clinical phenotypes, and pedigree files for multiple-sample VCF inputs. QM maps phenotypes to HPO terms before analysis. QM analysis requires 2 to 20 min for 100,000 variants on an 8-vCPU AWS server using Exomiser's "PASS_ONLY" mode for nuclear variants. QM ranks variants based on allele frequency, phenotype-gene association, functional impact, and inheritance mode. Variants are further annotated with multiple data sources such as OMIM, ClinVar, dbNSFP, gnoMAD, MITOMAP, and MSeqDR. In addition to standard Exomiser results, QM generates an Analysis Report and QM Integrated Report with add-on mtDNA-specific analyses, including haplogroup prediction with Phy-Mer, heteroplasmy calculation, and mvTool annotations. We developed the Mitochondrial Disease Variant (MDV) classifier using XGBoost to predict variant pathogenicity for PMD. The MDV classifier was trained on >120 features and performance benchmarking showed that it correctly classified >98% of nuclear gene variants as being pathogenic or benign, and predicted PMD-causing variants with 94% precision. The MSeqDR QM server is an open-access resource for phenotype-driven dual-genome analyses for PMD diagnosis by the global mitochondrial disease community. It is publicly available for non-commercial, non-clinical research use at https://mseqdr.org/quickmitome.php. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Standardizing clinical phenotypes into human phenotype ontology (HPO) terms as the phenotype input for Quick-Mitome (QM) Basic Protocol 2: Prepare the pedigree input for multiple-sample VCF Basic Protocol 3: Quick-Mitome (QM) analysis Basic Protocol 4: Reviewing and understanding the QM Integrated Report and Analysis Report.


Subject(s)
Mitochondrial Diseases , Humans , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Phenotype , DNA, Mitochondrial/genetics , Mitochondria , Machine Learning
16.
Eur J Neurol ; 31(5): e16216, 2024 May.
Article in English | MEDLINE | ID: mdl-38247216

ABSTRACT

BACKGROUND AND PURPOSE: Identifying vestibular causes of dizziness and unsteadiness in multi-sensory neurological disease can be challenging, with problems typically attributed to central or peripheral nerve involvement. Acknowledging vestibular dysfunction as part of the presentation provides an opportunity to access targeted vestibular rehabilitation, for which extensive evidence exists. A diagnostic framework was developed and validated to detect vestibular dysfunction, benign paroxysmal positional vertigo or vestibular migraine. The specificity and sensitivity of the diagnostic framework was tested in patients with primary mitochondrial disease. METHODS: Adults with a confirmed diagnosis of primary mitochondrial disease were consented, between September 2020 and February 2022. Participants with and without dizziness or unsteadiness underwent remote physiotherapy assessment and had in-person detailed neuro-otological assessment. The six framework question responses were compared against objective neuro-otological assessment or medical notes. The output was binary, with sensitivity and specificity calculated. RESULTS: Seventy-four adults completed the study: age range 20-81 years (mean 48 years, ±SD 15.05 years); ratio 2:1 female to male. The framework identified a vestibular diagnosis in 35 participants, with seven having two diagnoses. The framework was able to identify vestibular diagnoses in adults with primary mitochondrial disease, with a moderate (40-59) to very high (90-100) sensitivity and positive predictive value, and moderate to high (60-74) to very high (90-100) specificity and negative predictive value. CONCLUSIONS: Overall, the clinical framework identified common vestibular diagnoses with a moderate to very high specificity and sensitivity. This presents an opportunity for patients to access effective treatment in a timely manner, to reduce falls and improve quality of life.


Subject(s)
Migraine Disorders , Mitochondrial Diseases , Vestibular Diseases , Adult , Humans , Male , Female , Young Adult , Middle Aged , Aged , Aged, 80 and over , Dizziness/diagnosis , Dizziness/etiology , Quality of Life , Vertigo/diagnosis , Vertigo/complications , Migraine Disorders/diagnosis , Migraine Disorders/complications , Mitochondrial Diseases/complications , Mitochondrial Diseases/diagnosis , Vestibular Diseases/diagnosis , Vestibular Diseases/complications , Benign Paroxysmal Positional Vertigo/complications
17.
Neurotherapeutics ; 21(1): e00304, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38241155

ABSTRACT

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.


Subject(s)
Mitochondrial Diseases , Mitochondrial Myopathies , Humans , Child , Mitochondrial Myopathies/diagnosis , Mitochondrial Myopathies/genetics , Mitochondrial Myopathies/therapy , Mitochondria , High-Throughput Nucleotide Sequencing , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Mitochondrial Diseases/therapy
18.
Hepatol Commun ; 8(1)2024 Jan 01.
Article in English | MEDLINE | ID: mdl-38180987

ABSTRACT

BACKGROUND: Mitochondrial hepatopathies (MHs) are primary mitochondrial genetic disorders that can present as childhood liver disease. No recognized biomarkers discriminate MH from other childhood liver diseases. The protein biomarkers growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21) differentiate mitochondrial myopathies from other myopathies. We evaluated these biomarkers to determine if they discriminate MH from other liver diseases in children. METHODS: Serum biomarkers were measured in 36 children with MH (17 had a genetic diagnosis); 38 each with biliary atresia, α1-antitrypsin deficiency, and Alagille syndrome; 20 with NASH; and 186 controls. RESULTS: GDF15 levels compared to controls were mildly elevated in patients with α1-antitrypsin deficiency, Alagille syndrome, and biliary atresia-young subgroup, but markedly elevated in MH (p<0.001). FGF21 levels were mildly elevated in NASH and markedly elevated in MH (p<0.001). Both biomarkers were higher in patients with MH with a known genetic cause but were similar in acute and chronic presentations. Both markers had a strong performance to identify MH with a molecular diagnosis with the AUC for GDF15 0.93±0.04 and for FGF21 0.90±0.06. Simultaneous elevation of both markers >98th percentile of controls identified genetically confirmed MH with a sensitivity of 88% and specificity of 96%. In MH, independent predictors of survival without requiring liver transplantation were international normalized ratio and either GDF15 or FGF21 levels, with levels <2000 ng/L predicting survival without liver transplantation (p<0.01). CONCLUSIONS: GDF15 and FGF21 are significantly higher in children with MH compared to other childhood liver diseases and controls and, when combined, were predictive of MH and had prognostic implications.


Subject(s)
Alagille Syndrome , Biliary Atresia , Growth Differentiation Factor 15 , Non-alcoholic Fatty Liver Disease , Child , Humans , Alagille Syndrome/diagnosis , Biliary Atresia/diagnosis , Biomarkers , Growth Differentiation Factor 15/blood , Growth Differentiation Factor 15/chemistry , Mitochondrial Diseases/diagnosis
19.
Indian J Pediatr ; 91(2): 184-187, 2024 Feb.
Article in English | MEDLINE | ID: mdl-36773198

ABSTRACT

Progressive encephalopathy with brain edema and/or leukoencephalopathy type 1 (PEBEL1) is a nuclear mitochondrial disorder involving the NAD(P)HX repair mechanism due to a NAXE variation. PEBEL1 is characterized by rapid neurologic deterioration culminating in death following high-grade fever during infancy. Currently, 23 patients from 14 families are described in the literature, with only three survivors. The authors report two living children from unrelated families with PEBEL1. Both children presented in infancy with ptosis, squint, and ataxia with no skin manifestations. Whole-exome sequencing revealed previously reported c.804_807delInsA (p.Lys270del) variation in exon 6 of NAXE. This is the first Indian report of PEBEL1.


Subject(s)
Leukoencephalopathies , Mitochondrial Diseases , Child , Humans , Mutation , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Ataxia
20.
Lab Med ; 55(2): 227-233, 2024 Mar 07.
Article in English | MEDLINE | ID: mdl-37478467

ABSTRACT

OBJECTIVE: Different mitochondrial DNA genotypes can coexist in a cell population as well as in a single cell, a condition known as heteroplasmy. Here, we accurately determined the heteroplasmy levels of the m.3243A>G mutation, which is the most frequently identified mutation in patients with mitochondrial diseases, using droplet digital polymerase chain reaction (ddPCR). METHODS: The m.3243A>G heteroplasmy levels in artificial heteroplasmy controls mixed with various proportions of wild-type and mutant plasmids were measured using ddPCR, PCR-restriction fragment length polymorphism, and Sanger sequencing. The m.3243A>G heteroplasmy levels in DNA, extracted from the peripheral blood of patients with suspected mitochondrial disease and healthy subjects, were determined using ddPCR. RESULTS: The accuracy of the ddPCR method was high. The lower limit of detection was 0.1%, which indicated its higher sensitivity compared with other methods. The m.3243A>G heteroplasmy levels in peripheral blood, measured using ddPCR, correlated inversely with age at the time of analysis. The m.3243A>G mutation may be overlooked in the peripheral blood-derived DNA of elderly people, as patients >60 years of age have heteroplasmy levels <10%, which is difficult to detect using methods other than the highly sensitive ddPCR. CONCLUSION: ddPCR may be considered an accurate and sensitive method for measuring m.3243 A>G heteroplasmy levels of mitochondrial DNA.


Subject(s)
DNA, Mitochondrial , Mitochondrial Diseases , Humans , Aged , Mutation , DNA, Mitochondrial/genetics , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Polymerase Chain Reaction/methods , Polymorphism, Restriction Fragment Length
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