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Ischemic optic neuropathy as first presentation in patient with m.3243 A > G MELAS classic mutation.BMC Neurology Apr 2023Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a systemic disorder in which multi-organ dysfunction may occur from...
BACKGROUND
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a systemic disorder in which multi-organ dysfunction may occur from mitochondrial metabolism failure. Maternally inherited mutations in the MT-TL1 gene are the most frequent causes for this disorder. Clinical manifestations may include stroke-like episodes, epilepsy, dementia, headache and myopathy. Among these, acute visual failure, usually in association with cortical blindness, can occur because of stroke-like episodes affecting the occipital cortex or the visual pathways. Vision loss due to optic neuropathy is otherwise considered a typical manifestation of other mitochondrial diseases such as Leber hereditary optic neuropathy (LHON).
CASE PRESENTATION
Here we describe a 55-year-old woman, sister of a previously described patient with MELAS harbouring the m.3243A > G (p.0, MT-TL1) mutation, with otherwise unremarkable medical history, that presented with subacute, painful visual impairment of one eye, accompanied by proximal muscular pain and headache. Over the next weeks, she developed severe and progressive vision loss limited to one eye. Ocular examination confirmed unilateral swelling of the optic nerve head; fluorescein angiography showed segmental perfusion delay in the optic disc and papillary leakage. Neuroimaging, blood and CSF examination and temporal artery biopsy ruled out neuroinflammatory disorders and giant cell arteritis (GCA). Mitochondrial sequencing analysis confirmed the m.3243A > G transition, and excluded the three most common LHON mutations, as well as the m.3376G > A LHON/MELAS overlap syndrome mutation. Based on the constellation of clinical symptoms and signs presented in our patient, including the muscular involvement, and the results of the investigations, the diagnosis of optic neuropathy as a stroke-like event affecting the optic disc was performed. L-arginine and ubidecarenone therapies were started with the aim to improve stroke-like episode symptoms and prevention. The visual defect remained stable with no further progression or outbreak of new symptoms.
CONCLUSIONS
Atypical clinical presentations must be always considered in mitochondrial disorders, even in well-described phenotypes and when mutational load in peripheral tissue is low. Mitotic segregation of mitochondrial DNA (mtDNA) does not allow to know the exact degree of heteroplasmy existent within different tissue, such as retina and optic nerve. Important therapeutic implications arise from a correct diagnosis of atypical presentation of mitochondrial disorders.
Topics: Female; Humans; MELAS Syndrome; Optic Neuropathy, Ischemic; Acidosis, Lactic; Mutation; Stroke; Optic Nerve Diseases; Optic Atrophy, Hereditary, Leber; DNA, Mitochondrial; Vision Disorders; Headache
PubMed: 37095452
DOI: 10.1186/s12883-023-03198-3 -
Endocrinology, Diabetes & Metabolism... Apr 2023Mitochondrial diseases are a group of rare diseases presenting with heterogeneous clinical, biochemical, and genetic disorders caused by mutations in the mitochondrial...
SUMMARY
Mitochondrial diseases are a group of rare diseases presenting with heterogeneous clinical, biochemical, and genetic disorders caused by mutations in the mitochondrial or nuclear genome. Multiple organs can be affected, particularly those with high energy demand. Diabetes is a common endocrine manifestation of mitochondrial diseases. The onset of mitochondrial diabetes can be latent or acute, and the presenting phenotype can be type 1- or type 2-like. Studies show that diabetes ais associated with latent progression of cognitive decline in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Herein, we report a case of rapid cognitive decline after the acute onset of diabetes in a patient with MELAS syndrome. The patient was a 36-year-old woman who was hospitalized due to hyperglycemic crisis and seizures. She was diagnosed with MELAS syndrome two years previously, and had gradually progressing dementia and hearing loss. However, following the acute onset of diabetes, she developed rapid cognitive decline and loss of ability to perform daily activities. In conclusion, the acute onset of diabetes could be an associated risk factor for rapid cognitive decline in patients with MELAS syndrome. Thus, these patients as well as healthy carriers with related genetic mutations should undergo diabetes education and screening tests. Moreover, clinicians should be aware of the possibility for acute onset of hyperglycemic crisis, particularly in the presence of triggering factors.
LEARNING POINTS
Diabetes is a common endocrine manifestation of mitochondrial diseases, presenting with a type 1- or type 2-like phenotype depending on the level of insulinopenia. Metformin should be avoided in patients with mitochondrial diseases to prevent metformin-induced lactic acidosis. Mitochondrial diabetes can manifest before or after the onset of MELAS syndrome. In patients with MELAS syndrome, diabetes can initially manifest with a life-threatening severe hyperglycemic crisis and can cause rapid cognitive decline. Diabetes screening tests (e.g. hemoglobin A1c, oral glucose tolerance test, or random blood glucose level measurement) should be performed either systematically or in the presence of symptoms, particularly after triggering events. Genetic testing and counseling should be provided to patients and their families for the purpose of better understanding the inheritance, progression, and possible outcomes of the disease.
PubMed: 37073829
DOI: 10.1530/EDM-22-0416 -
AJNR. American Journal of Neuroradiology May 2023An increased number of pathogenic variants have been described in mitochondrial encephalomyopathy lactic acidosis and strokelike episodes (MELAS). Different imaging... (Review)
Review
BACKGROUND AND PURPOSE
An increased number of pathogenic variants have been described in mitochondrial encephalomyopathy lactic acidosis and strokelike episodes (MELAS). Different imaging presentations have emerged in parallel with a growing recognition of clinical and outcome variability, which pose a diagnostic challenge to neurologists and radiologists and may impact an individual patient's response to therapeutic interventions. By evaluating clinical, neuroimaging, laboratory, and genetic findings, we sought to improve our understanding of the sources of potential phenotype variability in patients with MELAS.
MATERIALS AND METHODS
This retrospective single-center study included individuals who had confirmed mitochondrial DNA pathogenic variants and a diagnosis of MELAS and whose data were reviewed from January 2000 through November 2021. The approach included a review of clinical, neuroimaging, laboratory, and genetic data, followed by an unsupervised hierarchical cluster analysis looking for sources of phenotype variability in MELAS. Subsequently, experts identified "victory-variables" that best differentiated MELAS cohort clusters.
RESULTS
Thirty-five patients with a diagnosis of mitochondrial DNA-based MELAS (median age, 12 years; interquartile range, 7-24 years; 24 female) were eligible for this study. Fifty-three discrete variables were evaluated by an unsupervised cluster analysis, which revealed that two distinct phenotypes exist among patients with MELAS. After experts reviewed the variables, they selected 8 victory-variables with the greatest impact in determining the MELAS subgroups: developmental delay, sensorineural hearing loss, vision loss in the first strokelike episode, Leigh syndrome overlap, age at the first strokelike episode, cortical lesion size, regional brain distribution of lesions, and genetic groups. Ultimately, 2-step differentiating criteria were defined to classify atypical MELAS.
CONCLUSIONS
We identified 2 distinct patterns of MELAS: classic MELAS and atypical MELAS. Recognizing different patterns in MELAS presentations will enable clinical and research care teams to better understand the natural history and prognosis of MELAS and identify the best candidates for specific therapeutic interventions.
Topics: Female; Humans; Acidosis, Lactic; MELAS Syndrome; Retrospective Studies; Stroke; DNA, Mitochondrial; Phenotype
PubMed: 37024306
DOI: 10.3174/ajnr.A7837 -
Seizure Apr 2023
A response to the letter about the article 'Clinical features of epileptic seizures in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes'.
Topics: Humans; MELAS Syndrome; Stroke; Epilepsy; Seizures
PubMed: 37002120
DOI: 10.1016/j.seizure.2023.03.018 -
Nucleic Acids Research Aug 2023Mutations in mitochondrial (mt-)tRNAs frequently cause mitochondrial dysfunction. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes...
Mutations in mitochondrial (mt-)tRNAs frequently cause mitochondrial dysfunction. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and myoclonus epilepsy associated with ragged red fibers (MERRF) are major clinical subgroups of mitochondrial diseases caused by pathogenic point mutations in tRNA genes encoded in mtDNA. We previously reported a severe reduction in the frequency of 5-taurinomethyluridine (τm5U) and its 2-thiouridine derivative (τm5s2U) in the anticodons of mutant mt-tRNAs isolated from the cells of patients with MELAS and MERRF, respectively. The hypomodified tRNAs fail to decode cognate codons efficiently, resulting in defective translation of respiratory chain proteins in mitochondria. To restore the mitochondrial activity of MELAS patient cells, we overexpressed MTO1, a τm5U-modifying enzyme, in patient-derived myoblasts. We used a newly developed primer extension method and showed that MTO1 overexpression almost completely restored the τm5U modification of the MELAS mutant mt-tRNALeu(UUR). An increase in mitochondrial protein synthesis and oxygen consumption rate suggested that the mitochondrial function of MELAS patient cells can be activated by restoring the τm5U of the mutant tRNA. In addition, we confirmed that MTO1 expression restored the τm5s2U of the mutant mt-tRNALys in MERRF patient cells. These findings pave the way for epitranscriptomic therapies for mitochondrial diseases.
Topics: Humans; DNA, Mitochondrial; MELAS Syndrome; MERRF Syndrome; Mitochondria; Mutation; RNA, Transfer
PubMed: 36928678
DOI: 10.1093/nar/gkad139 -
Ideggyogyaszati Szemle Jan 2023
Objective – Stroke-like lesions (SLLs) are pathognomonic for mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes... (Review)
Review
Objective – Stroke-like lesions (SLLs) are pathognomonic for mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome but occur in other mitochondrial and non-mitochondrial disorders as well. This mini-review aims at summarising and discussing recent findings to open up future perspectives how to manage this fleeting phenomenon.
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Results – Typically, SLLs are dynamic lesions, which increase in size and intensity to regress after a nadir. SLLs are incongruent with a vascular territory, originate frequently from the cortex to spread subcortically, can be monofocal or multifocal, run through an acute (attack) and chronic (remission) stage, and may either completely disappear or end up as laminar cortical necrosis, white matter lesion, subcortical atrophy, cyst, or the toenail sign. On cerebral CT, SLLs are hypodense. SLLs can be best visualized on multimodal MRI showing up as hyperintensity on T2, FLAIR, DWI, and PWI, and as hypointensity on OEF-MRI. On MR-spectroscopy, SLLs typically present with a decreased N-acetyl-aspartate peak and an increased lactate peak. DTI in acute SLLs reveals reduced connectivity, increased global efficiency, and reduced focal efficiency. Tc-HMPAO SPECT of SLLs indicates hyperperfusion and L-iomazenil SPECT reduced tracer uptake. FDG-PET typically shows hypometabolism within a SLL.
Conclusion – SLLs present with typical findings on various imaging modalities but the combination of cerebral CT, multimodal MRI, MRS, and PET clearly delineate a SLL from other acute or chronic cerebral lesions.Topics: Humans; Stroke; MELAS Syndrome; Magnetic Resonance Imaging; Tomography, Emission-Computed, Single-Photon; Positron-Emission Tomography; Brain
PubMed: 36892301
DOI: 10.18071/isz.76.0005 -
Life (Basel, Switzerland) Feb 2023Mitochondrial tRNA is considered a hot-spot for non-syndromic and aminoglycoside-induced hearing loss. However, many patients have been described with more extensive... (Review)
Review
Mitochondrial tRNA is considered a hot-spot for non-syndromic and aminoglycoside-induced hearing loss. However, many patients have been described with more extensive neurological diseases, mainly including epilepsy, myoclonus, ataxia, and myopathy. We describe a novel homoplasmic m.7484A>G mutation in the tRNA gene affecting the third base of the anticodon triplet in a girl with profound intellectual disability, spastic tetraplegia, sensorineural hearing loss, a clinical history of epilepsia partialis continua and vomiting, typical of MELAS syndrome, leading to a myoclonic epilepticus status, and myopathy with severe COX deficiency at muscle biopsy. The mutation was also found in the homoplasmic condition in the mother who presented with mild cognitive deficit, cerebellar ataxia, myoclonic epilepsy, sensorineural hearing loss and myopathy with COX deficient ragged-red fibers consistent with MERRF syndrome. This is the first anticodon mutation in the tRNA and the second homoplasmic mutation in the anticodon triplet reported to date.
PubMed: 36836911
DOI: 10.3390/life13020554 -
Seizure Mar 2023This study aimed to characterize the clinical features of epilepsy in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and analyze the...
BACKGROUND AND PURPOSE
This study aimed to characterize the clinical features of epilepsy in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and analyze the clinical determinants for drug-resistant epilepsy in MELAS.
METHODS
A single-center, retrospective study was conducted to investigate the clinical features of epilepsy in patients with MELAS. Collected variables included seizure semiology, electroencephalography (EEG), muscle biopsy, genetic testing, neuroimaging findings, resting serum lactic value and modified Rankin scale (mRS) of patients with MELAS. We also investigated the differences between the adult-onset group and the child-onset group and analyzed the risk factors for drug-resistant epilepsy in MELAS.
RESULTS
We studied 97 patients (56 males: 41 females) with confirmed MELAS. Epileptic seizure occurred in 100.0% of patients and the initial symptom of 69.1% patients was epileptic seizure. The average age of disease onset was 21.0 years, ranging from 2 to 60 years. The seizure types of these patients with MELAS were variable, with generalized onset (51.5%) to be the most common type. The EEG changes in the patients with MELAS were mainly slow wave (90.9%) and epileptiform discharge (68.2%). The child-onset group with earlier seizure onset presented significantly higher resting serum lactic value (p = 0.0048) and lower incidence of stroke-like lesion in the brain (p = 0.003), especially in the temporal lobe (p < 0.001), compared with the adult-onset group. Importantly, drug-resistant epilepsy in MELAS was demonstrated to be closely related to the earlier age of seizure onset (p = 0.013), as well as the higher mRS score (p < 0.001) and higher resting serum lactic value (p = 0.009).
CONCLUSION
Early identification of MELAS should be considered among individuals with recurrent epilepsy through clinical screening. Age of seizure onset and resting serum lactic value may predict the development of drug-resistant epilepsy in MELAS. Close observation and appropriate anti-epileptic treatment are indispensable for individuals with MELAS to improve the prognosis. Further studies with larger sample size are required to further evaluate the risk factors of drug-resistant epilepsy in MELAS and provide guidance on treatment of MELAS.
Topics: Adult; Male; Female; Humans; Young Adult; MELAS Syndrome; Retrospective Studies; Epilepsy; Seizures; Stroke
PubMed: 36827862
DOI: 10.1016/j.seizure.2023.02.014 -
Chonnam Medical Journal Jan 2023
PubMed: 36794245
DOI: 10.4068/cmj.2023.59.1.100 -
Molecular Genetics & Genomic Medicine May 2023Pathogenic variants of ATP1A2 (OMIM ID: 182340) are usually associated with familial hemiplegic migraine type 2 (FHM-2), alternating hemiplegia of childhood (AHC), early...
BACKGROUND
Pathogenic variants of ATP1A2 (OMIM ID: 182340) are usually associated with familial hemiplegic migraine type 2 (FHM-2), alternating hemiplegia of childhood (AHC), early infantile epileptic encephalopathy (EIEE), transient cytotoxic edema, and so on. Here, we present a novel heterozygous ATP1A2 variant in a girl with alternating hemiplegia, febrile seizures, developmental delay (which subsequently subsided), and MELAS-like syndrome (as indicated by brain MRI). The patient did not experience migraine with aura.
METHODS
The patient was an 8-year-old girl with normal growth and development. Beginning from the age of 3 years and 8 months, the patient experienced several episodes of alternating limb paralysis. The episodes were accompanied by the appearance of MELAS-like findings on brain MRI, which corresponded to the hemiplegia. There were abnormal linear signals in the cerebral cortex on the opposite side of the hemiplegic limb. Each time the patient recovered from hemiplegia, and each time MRI showed no lesions remained after recovery. No obvious abnormality was found in other examinations. Finally, the patient underwent whole-exome sequencing (WES).
RESULTS
WES revealed a novel and de novo heterozygous variant in the ATP1A2 (NM_000702.3) c.335C>A:p.Ala112Asp (not previously reported). We examined the variant position in the 3D protein structure and found that a missense mutation at this site is a nonconservative substitution. The variation is nonpolymorphic. It occurs at a very low frequency in the population, and its ACMG classification is likely pathogenic.
CONCLUSION
At present, there are limited reports of mutations in the ATP1A2 gene causing AHC. This is the first case of brain MRI showing MELAS-like imaging in an AHC patient, and more cases are needed for verification. Early genetic testing and family screening can aid in the diagnosis and treatment of genetic diseases. The relationship between ATP1A2 gene mutation genotype and clinical phenotype needs to be further studied.
Topics: Humans; East Asian People; Hemiplegia; MELAS Syndrome; Sodium-Potassium-Exchanging ATPase; Female; Child
PubMed: 36749827
DOI: 10.1002/mgg3.2146