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Orphanet Journal of Rare Diseases Oct 2023Mitochondrial Diseases (MDs) are a diverse group of neurometabolic disorders characterized by impaired mitochondrial oxidative phosphorylation and caused by pathogenic...
BACKGROUND
Mitochondrial Diseases (MDs) are a diverse group of neurometabolic disorders characterized by impaired mitochondrial oxidative phosphorylation and caused by pathogenic variants in more than 400 genes. The implementation of next-generation sequencing (NGS) technologies helps to increase the understanding of molecular basis and diagnostic yield of these conditions. The purpose of the study was to investigate diagnostic and genotypic spectrum in patients with suspected MD. The comprehensive analysis of mtDNA variants using Sanger sequencing was performed in the group of 83 unrelated individuals with clinically suspected mitochondrial disease. Additionally, targeted next generation sequencing or whole exome sequencing (WES) was performed for 30 patients of the study group.
RESULTS
The overall diagnostic rate was 21.7% for the patients with suspected MD, increasing to 36.7% in the group of patients where NGS methods were applied. Mitochondrial disease was confirmed in 11 patients (13.3%), including few classical mitochondrial syndromes (MELAS, MERRF, Leigh and Kearns-Sayre syndrome) caused by pathogenic mtDNA variants (8.4%) and MDs caused by pathogenic variants in five nDNA genes. Other neuromuscular diseases caused by pathogenic variants in seven nDNA genes, were confirmed in seven patients (23.3%).
CONCLUSION
The wide spectrum of identified rare mitochondrial or neurodevelopmental diseases proves that MD suspected patients would mostly benefit from an extensive genetic profiling allowing rapid diagnostics and improving the care of these patients.
Topics: Humans; Mutation; Mitochondrial Diseases; DNA, Mitochondrial; Mitochondria; Genotype
PubMed: 37784170
DOI: 10.1186/s13023-023-02921-0 -
European Heart Journal. Case Reports Sep 2023Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome is a rare mitochondrial disorder caused by mutations in mitochondrial DNA,...
BACKGROUND
Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome is a rare mitochondrial disorder caused by mutations in mitochondrial DNA, resulting in impaired energy production and affecting multiple organs. We present a suspected MELAS syndrome case with the initial symptom of chest tightness.
CASE SUMMARY
A 46-year-old man sought medical attention due to progressively worsening chest tightness during physical activity. He had been receiving treatment for type 2 diabetes for 15 years. One year ago, he presented with symptoms of hearing impairment. Transthoracic echocardiography revealed increased thickness of the left ventricular wall. Serum protein electrophoresis showed no evidence of light-chain amyloidosis, and the 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scan showed no definite uptake in the heart muscle. The patient's head magnetic resonance imaging (MRI) indicated lacunar infarcts. The lactate threshold test was positive. The biopsy of the skeletal muscle showed broken red fibre infiltration on modified Gomori trichrome staining, and electron microscopy revealed signs of mitochondrial cardiomyopathy, including mild mitochondrial swelling, lipid accumulation, and myofibril damage. A whole-exome genetic test was used to detect the m.3243A>G mutation in the MT-TL1 gene. Based on these findings, MELAS syndrome was the most probable diagnosis.
DISCUSSION
The patient presented with chest tightness in adulthood, without any accompanying psychoneurological symptoms. However, the patient presented with other symptoms, including diabetes mellitus, hearing loss, abnormal lactate levels, ischaemic lesions on head MRI, and left ventricular hypertrophy. By identifying a mutation in the MT-TL1 gene and conducting a muscle biopsy, the diagnosis of MELAS syndrome was definitively confirmed.
PubMed: 37767231
DOI: 10.1093/ehjcr/ytad441 -
Frontiers in Neurology 2023Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a group of maternally inherited disorders caused by mutations or deletions in...
BACKGROUND
Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a group of maternally inherited disorders caused by mutations or deletions in mitochondrial genes with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes as the main clinical manifestations.
CASE PRESENTATION
We reported a 20-year-old female patient with MELAS syndrome combined with autoimmune abnormalities. She suffered from an intermittent headache in the right temporal region with no obvious cause, and then, after strenuous exercise in dance class, the headache became aggravated, accompanied by unresponsiveness, blurred vision, and diplopia. Her blood lactate levels were elevated, her antinuclear antibodies were positive, and the antimetabolic glutamate receptors 5 in her serum were positive. Brain DWI showed a hypertensive signal in the right temporo-parietal-occipital cortex and subcortical area. Brain MRS showed decreased NAA peak and increased Lac peak. Muscle biopsy showed myogenic damage, and the modified Gomori trichrome (MGT) staining showed ragged red fibers (RRF). A genetic study revealed a mitochondrial DNA A3243G mutation.
CONCLUSION
Mitochondrial encephalomyopathy is a rare clinical condition; however, the association with autoimmune diseases is not yet clear and still needs further research and analysis.
PubMed: 37693769
DOI: 10.3389/fneur.2023.1239664 -
JCI Insight Sep 2023Pathogenic mutations in mitochondrial (mt) tRNA genes that compromise oxidative phosphorylation (OXPHOS) exhibit heteroplasmy and cause a range of multisyndromic...
Pathogenic mutations in mitochondrial (mt) tRNA genes that compromise oxidative phosphorylation (OXPHOS) exhibit heteroplasmy and cause a range of multisyndromic conditions. Although mitochondrial disease patients are known to suffer from abnormal immune responses, how heteroplasmic mtDNA mutations affect the immune system at the molecular level is largely unknown. Here, in mice carrying pathogenic C5024T in mt-tRNAAla and in patients with mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) syndrome carrying A3243G in mt-tRNALeu, we found memory T and B cells to have lower pathogenic mtDNA mutation burdens than their antigen-inexperienced naive counterparts, including after vaccination. Pathogenic burden reduction was less pronounced in myeloid compared with lymphoid lineages, despite C5024T compromising macrophage OXPHOS capacity. Rapid dilution of the C5024T mutation in T and B cell cultures could be induced by antigen receptor-triggered proliferation and was accelerated by metabolic stress conditions. Furthermore, we found C5024T to dysregulate CD8+ T cell metabolic remodeling and IFN-γ production after activation. Together, our data illustrate that the generation of memory lymphocytes shapes the mtDNA landscape, wherein pathogenic variants dysregulate the immune response.
Topics: Animals; Mice; Mutation; Receptors, Antigen; DNA, Mitochondrial; Acidosis, Lactic; RNA, Transfer
PubMed: 37681412
DOI: 10.1172/jci.insight.167656 -
Molecular Genetics and Metabolism Nov 2023Mitochondrial DNA m.3243A > G mutation causes mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and its associated multi-organ disorders,...
Mitochondrial DNA m.3243A > G mutation causes mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and its associated multi-organ disorders, including diabetes. To clarify associations between m.3243A > G organ heteroplasmy and clinical phenotypes, including the age at death, we combined genetic and pathological examinations from seven unreported and 36 literature cases of autopsied subjects. Clinical characteristics of subjects were as follows: male, 13; female, 28; unknown, 2; the age at death, 36.9 ± 20.2 [4-82] years; BMI, 16.0 ± 2.9 [13.0-22.3]; diabetes, N = 21 (49%), diabetes onset age 38.6 ± 14.2 years; deafness, N = 27 (63%); stroke-like episodes (StLEp), N = 25 (58%); congestive heart failure (CHF), N = 15 (35%); CHF onset age, 51.3 ± 14.5 years. Causes of death (N = 32) were as follows: cardiac, N = 13 (41%); infection, N = 8 (25%); StLEp, N = 4 (13%); gastrointestinal, N = 4 (13%); renal, N = 2 (6%); hepatic, N = 1 (2%). High and low heteroplasmies were confirmed in non-regenerative and regenerative organs, respectively. Heteroplasmy of the liver, spleen, leukocytes, and kidney for all subjects was significantly associated with the age at death. Furthermore, the age at death was related to juvenile-onset (any m.3243A > G-related symptoms appeared before 20) and stroke-like episodes. Multiple linear regression analysis with the age at death as an objective variable showed the significant contribution of liver heteroplasty and juvenile-onset to the age at death. m.3243A > G organ heteroplasmy levels, particularly hepatic heteroplasmy, are significantly associated with the age at death in deceased cases.
Topics: Humans; Male; Female; Adult; Middle Aged; Aged; Child, Preschool; Child; Adolescent; Young Adult; Aged, 80 and over; Heteroplasmy; DNA, Mitochondrial; Mutation; Diabetes Mellitus; Stroke; Liver; MELAS Syndrome
PubMed: 37660570
DOI: 10.1016/j.ymgme.2023.107691 -
American Journal of Medical Genetics.... Dec 2023Mitochondrial disorders can present with a wide range of clinical and biochemical phenotypes. Mitochondrial DNA variants may be influenced by factors such as degree of...
Mitochondrial disorders can present with a wide range of clinical and biochemical phenotypes. Mitochondrial DNA variants may be influenced by factors such as degree of heteroplasmy and tissue distribution. We present a four-generation family in which 10 individuals carry a pathogenic mitochondrial variant (m.5537_5538insT, MT-TW gene) with differing levels of heteroplasmy and clinical features. This genetic variant has been documented in two prior reports, both in individuals with Leigh syndrome. In the current family, three individuals have severe mitochondrial symptoms including Leigh syndrome (patient 1, 100% in blood), MELAS (patient 2, 97% heteroplasmy in muscle), and MELAS-like syndrome (patient 3, 50% heteroplasmy in blood and 100% in urine). Two individuals have mild mitochondrial symptoms (patient 4, 50% in blood and 67% in urine and patient 5, 50% heteroplasmy in blood and 30% in urine). We observe that this variant is associated with multiple mitochondrial presentations and phenotypes, including MELAS syndrome for which this variant has not previously been reported. We also demonstrate that the level of heteroplasmy of the mitochondrial DNA variant correlates with the severity of clinical presentation; however, not with the specific mitochondrial syndrome.
Topics: Humans; MELAS Syndrome; Leigh Disease; Mitochondria; DNA, Mitochondrial; Mitochondrial Diseases
PubMed: 37654102
DOI: 10.1002/ajmg.a.63378 -
Mitochondrion Sep 2023Human induced pluripotent stem cells (hiPSCs) for MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) may allow deeper... (Review)
Review
Human induced pluripotent stem cells (hiPSCs) for MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) may allow deeper understanding of how tissue-specific mitochondrial dysfunction result in multi-systemic disease. Here, we summarize how the m.3243G mtDNA mutation affects mitochondrial function in different tissues using iPSC and iPSC-differentiated cell type disease models and what significant findings have been replicated in the independent studies. Through this brief review and with a focus on mitochondrial dysfunction in iPSC-differentiated cell types, namely fibroblast, neuron, and retinal pigment epithelium cells, we aim to bring awareness of hiPSC as a robust mitochondrial disease model even if many unanswered questions remain.
Topics: Humans; MELAS Syndrome; Induced Pluripotent Stem Cells; Acidosis, Lactic; Cell Differentiation; Mitochondria
PubMed: 37633406
DOI: 10.1016/j.mito.2023.08.003 -
European Heart Journal. Case Reports Aug 2023
PubMed: 37614625
DOI: 10.1093/ehjcr/ytad389 -
Parkinsonism & Related Disorders Oct 2023
Topics: Humans; MELAS Syndrome; Brain; Mutation; Head; DNA, Mitochondrial
PubMed: 37607851
DOI: 10.1016/j.parkreldis.2023.105801 -
Current Pediatric Reviews Aug 2023Appendicitis is a common childhood condition that can be diagnostically challenging. Severe cases may necessitate support in the critical or intensive care unit. These...
INTRODUCTION
Appendicitis is a common childhood condition that can be diagnostically challenging. Severe cases may necessitate support in the critical or intensive care unit. These "critical appendicitis diagnoses" have rarely been described.
CASE DESCRIPTION
We retrospective reviewed the PICU database of the Hong Kong Children's Hospital and identified cases of suspected and confirmed appendicitis. Clinical features, radiologic findings and final diagnosis of each case were summarized and reported in this case series. We review six anonymized cases of appendicitis managed in a paediatric intensive care unit (PICU) to illustrate the different age spectrum and clinical manifestations of the condition. Rupture of the inflamed appendix, peritonitis and pancreatitis were some of the complications encountered. Crohn disease was found in one case as an underlying diagnosis. Also, one girl clinically diagnosed with appendicitis was found to be a case of ruptured hepatoblastoma with no appendicitis (i.e., pseudoappendicitis).
CONCLUSION
Prompt diagnosis, surgical removal of the inflamed appendix, and use of appropriate antimicrobials when indicated are essential in reducing mortality and morbidity associated with severe appendicitis. Significant premorbid conditions such as acute myeloid leukemia, mitochondrial encephalopathy lactic acidosis syndrome (MELAS), inflammatory bowel disease and complications may be present in patients needing intensive care as is illustrated in the present cases. Pseudoappendicitis is an important differential diagnosis. Imaging is crucial and useful in establishing and confirming the diagnosis of appendicitis and pseudo-appendicitis in these PICU cases.
PubMed: 37592922
DOI: 10.2174/1573396320666230811092837