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Mitochondrial encephalomyelopathy, lactic acidosis, and stroke-like episodes (MELAS)
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The MELAS syndrome is the result of mutation in mitochondrial genes for tRNA [41]. The most common is A-to-G transition at position 3243 of the tRNALeu(UUR) (see Figure 51.1) [4, 5]. Approximately 80 percent of affected individuals have this mutation in the dihydrouridine loop of the gene [8, 16, 42–44]. The other common mutation, occurring in about 8.5 percent of individuals, is also in the tRNALeu(UUR) at 3271 in the anticodon, where there is a T-to-C transversion [7]. The G-to-A transversion at 3252 of the same gene has been reported in mitochondrial encephalopathy [45]. Another mutation in the dihydrouridine loop at nucleotide 3250 is a T-to-C transition [42]. Another mutation in this gene is an A-to-T change at position 3256 [46]. A 5814G in the tRNACys gene was reported in a patient with cardiomyopathy and myopathy [35].
Cardiac Hypertrophy, Heart Failure and Cardiomyopathy
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
Other DCM associated with defects in the mitochondrial respiratory and oxidative systems due to mutations in mitochondrial DNA are maternally transmitted. Most mitochondrial genetic defects predominantly affect skeletal muscle, but the conduction system of the heart is also very susceptible. In the Kearns–Sayre syndrome, ocular paralysis is associated with progressive loss of conduction tissue leading to heart block without any myocardial contraction loss. The phenotypic expression of mitochondrial cardiac disease is very wide-ranging, from purely conduction tissue loss to a conventional DCM to an HCM. While, in the mitochondrial myopathies, the mitochondria under electron microscopy may appear large and abnormal, the ease with which fixation artefacts can distort the structure means that cardiac biopsy to confirm or exclude the diagnosis of a mitochondrial abnormality is not reliable. The pattern of inheritance down the female line provides the clue to proceed to formal genetic analysis of mitochondrial DNA. The heart primarily relies on the energy produced through aerobic respiration and is one of the organs that is most affected by mitochondrial disease. In general, myocardial hypertrophy is observed to accompany a diminished left ventricular function, cardiac arrhythmias and HF in patients with these conditions. The severity is directly linked to the mutation load. In addition, cardiotoxic drugs, such as anticancer drugs, can damage the myocardial mitochondria by altering matrix metalloproteases by enhancing the production of ROS, which induces apoptosis. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is caused by the most common mitochondrial 3243 A→G mutation.
Genetics of Endocrine Disorders and Diabetes Mellitus
Published in George H. Gass, Harold M. Kaplan, Handbook of Endocrinology, 2020
Bess Adkins Marshall, Abby Solomon Hollander
Hie maternal effect noted in the inheritance patterns of NIDDM suggests a role for mitochondrial genes in NIDDM susceptibility.4 Mitochondrial DNA carried the genes for the enzymes of oxidative phosphorylation and for the 2 ribosomal and 22 transfer RNA necessary for mitochondrial protein synthesis.126 The mitochondria are inherited exclusively from the mother. Several defects in mitochondrial genes have been reported in association with subtypes of diabetes. A mutation in the leucine transfer RNA (tRNAleu(UUR)), which has been found frequently in patients with the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS syndrome), has also been found in the families of patients with maternally transmitted late-onset diabetes and nerve deafness.127–132 One study estimates that mutation accounts for more than 1% of maternally inherited diabetes in Japan.131 The diabetic patients with the mutation tended to require insulin despite the absence of islet cell antibodies. There also was a lower incidence of obesity and a younger age of onset than NIDDM patients without the mutation.129 Some of the patients with the mutation had relatives with MELAS syndrome, but the patients themselves did not manifest MELAS syndrome, possibly because a smaller percentage of their mitochondrial DNA carried the mutation than in patients with MELAS and possibly because the MELAS patients carried another contributing defect.128 A 10.4-kb deletion on mitochondrial DNA has been associated with a similar subtype of maternally transmitted diabetes and nerve deafness.133 A mutation in the mitochondrial lysine transfer RNA has been described in a family with maternally transmitted diabetes, deafness, and myoclonic epilepsy with ragged red fibers (MERRF).134 Mitochondrial DNA mutations have been found in patients with Wolfram syndrome (also known as DIDMOAD for diabetes insipidus, diabetes mellitus, optic atrophy, and deafness).135 In summary, mitochondrial DNA mutations are responsible for diabetes in certain subtypes of diabetes. These patients may not be initially recognized as having one of these subtypes because the diabetes may precede the appearance of the deafness or other manifestations of disease.129
Laboratory testing for mitochondrial diseases: biomarkers for diagnosis and follow-up
Published in Critical Reviews in Clinical Laboratory Sciences, 2023
Abraham J. Paredes-Fuentes, Clara Oliva, Roser Urreizti, Delia Yubero, Rafael Artuch
The current “omics” techniques such as genomics, metabolomics, lipidomics, transcriptomics, and proteomics focus on revealing and deciphering disease biochemical signatures as a comprehensive approach for identifying mitochondrial dysfunction [22]. For example, metabolomic analyses of blood samples of patients with primary and secondary MDs demonstrated disease-specific fingerprints with potential treatment targets, biomarkers, and pathogenic pathways [121]. Sharma et al. conducted proteomic and metabolomic studies on plasma samples from MELAS syndrome patients and validated a panel of 20 monitoring biomarkers. This biosignature included traditionally used biomarkers, more recently identified biomarkers (such as GDF-15), and a set of new analytes that had not been previously linked to mitochondrial dysfunction (Table 1) [122].
Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome: a case report
Published in Ultrastructural Pathology, 2023
Yong-Xin Ru, Li Ying, Shu-Xu Dong, Hui-Ming Yi, Liu Jing, Zhang Yongqiang
MELAS syndrome is a group of heterogeneous disorders resulting from mutations in mitochondrial DNA (mtDNA).4–6 The most common mutation is m.3243ANG in the MT-TL1 gene encoding mitochondrial tRNALeu (UUR), which leads to shortage of mitochondrial energy production. The deficiency stimulates mitochondrial proliferation in smooth muscle and endothelial cells, leading to angiopathy and microvascular impediment in multiple organs.7 Mitochondrial malfunction is widely associated with various problems ranging from lethal encephalopathies and neurodegenerative conditions to amyotrophic disorders. Ragged-red fibers (RRFs) as revealed in muscle biopsy are a hallmark of MELAS syndrome, but the link between morphologic alteration and function is poorly understood as yet.8 Here, we studied the histopathologic characteristics of RRFs in gastrocnemius muscle from a patient with MELAS syndrome by light microscopy and TEM.
Ophthalmological Manifestations of Hereditary Myopathies
Published in Journal of Binocular Vision and Ocular Motility, 2022
Marta Saint-Gerons, Miguel Angel Rubio, Gemma Aznar, Ana Matheu
More than 30 pathogenic mutations for MELAS syndrome have been found but the m3243A>G mutation in the MT-TL1 gene encoding the mitochondrial tRNA(Leu(UUR)) still accounts for 78–80% of cases.28 The signs and symptoms of this disorder most often appear in childhood following a period of normal development, although they can begin at any age. Most affected individuals experience stroke-like episodes beginning before age 40. The typical clinical manifestations of MELAS include stroke-like episodes (84–99%),39 seizures (≥25%), short stature (50–74%), muscle weakness (7–89%), headache (≥25%), hearing loss (7–89%), PEO (25–30%),24 optic atrophy (20%), pigmentary retinopathy (16%), and maculopathies.23,40 Repeated stroke-like episodes can progressively damage the brain, leading to dementia (40–90%).39,40 Occipital and temporal cortical regions are primarily affected leading to hemianopia or hemi-paresis.41 Biochemical and histopathological features encompass the presence of elevated lactate in serum and cerebrospinal fluid, ragged-red fibers in muscle biopsy (80–100%), and strongly succinate dehydrogenase (SDH)- positive blood vessels.42