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Reproductive Sciences (Thousand Oaks,... May 2023Polycystic ovary syndrome (PCOS) is a multi-causal condition. Among the genetic causes, variations in the mitochondrial DNA (mtDNA) are increasingly recognised as... (Review)
Review
Polycystic ovary syndrome (PCOS) is a multi-causal condition. Among the genetic causes, variations in the mitochondrial DNA (mtDNA) are increasingly recognised as causative. PCOS not only occurs in known syndromic mitochondrial disorders due to pathogenic variants in the mtDNA but also in non-syndromic mitochondrial disorders. Additionally, mtDNA variants not causing a multi-system mitochondrial disorder but exclusively PCOS have been reported. Among the syndromic mitochondrial disorders, PCOS has been described in myoclonic epilepsy with ragged-red fibre (MERRF) syndrome. Among the non-syndromic mitochondrial disorders, PCOS has been described in association with insulin resistance. Several other studies suggest that mtDNA point mutations or mtDNA deletions can be associated with PCOS without manifesting in organs other than the ovaries. Evidence from animal studies suggests that function, morphology, and biogenesis of mitochondria in ovarian tissue are generally impaired in PCOS patients. In conclusion, there is increasing evidence that mtDNA variants play a pathophysiological role in the development of PCOS. Further studies are needed to establish the causal link between mtDNA variants and PCOS.
Topics: Female; Humans; Animals; Polycystic Ovary Syndrome; Mitochondria; DNA, Mitochondrial; Mitochondrial Diseases
PubMed: 36221022
DOI: 10.1007/s43032-022-01100-z -
Metabolites Sep 2022Stroke-like episodes (SLEs) are significant clinical manifestations of metabolic disorders affecting the central nervous system. Morphological equivalents presented in... (Review)
Review
Stroke-like episodes (SLEs) are significant clinical manifestations of metabolic disorders affecting the central nervous system. Morphological equivalents presented in neuroimaging procedures are described as stroke-like lesions (SLLs). It is crucial to distinguish SLEs from cerebral infarction or intracerebral hemorrhage, mainly due to the variety in management. Another significant issue to underline is the meaning of the main pathogenetic hypotheses in the development of SLEs. The diagnostic process is based on the patient's medical history, physical and neurological examination, neuroimaging techniques and laboratory and genetic testing. Implementation of treatment is generally symptomatic and includes L-arginine supplementation and adequate antiepileptic management. The main aim of the current review was to summarize the basic and actual knowledge about the occurrence of SLEs in various inherited neurometabolic disorders, discuss the possible pathomechanism of their development, underline the role of neuroimaging in the detection of SLLs and identification of the electroencephalographic patterns as well as histological abnormalities in inherited disorders of metabolism.
PubMed: 36295831
DOI: 10.3390/metabo12100929 -
Journal of Clinical Medicine Nov 2021Mitochondrial disorders are a remarkably complex group of diseases caused by impairment of the mitochondrial respiratory chain (or electron transport chain) [...].
Mitochondrial disorders are a remarkably complex group of diseases caused by impairment of the mitochondrial respiratory chain (or electron transport chain) [...].
PubMed: 34830516
DOI: 10.3390/jcm10225235 -
Neurology International Apr 2022Ataxia is increasingly being recognized as a cardinal manifestation in primary mitochondrial diseases (PMDs) in both paediatric and adult patients. It can be caused by... (Review)
Review
Ataxia is increasingly being recognized as a cardinal manifestation in primary mitochondrial diseases (PMDs) in both paediatric and adult patients. It can be caused by disruption of cerebellar nuclei or fibres, its connection with the brainstem, or spinal and peripheral lesions leading to proprioceptive loss. Despite mitochondrial ataxias having no specific defining features, they should be included in hereditary ataxias differential diagnosis, given the high prevalence of PMDs. This review focuses on the clinical and neuropathological features and genetic background of PMDs in which ataxia is a prominent manifestation.
PubMed: 35466209
DOI: 10.3390/neurolint14020028 -
Polish Journal of Pathology : Official... 2020The interesting case about a patients with myoclonic epilepsy with ragged-red fibers (MERRF) syndrome due to the variant m.8344A>G with a heteroplasmy rate of 95%...
The interesting case about a patients with myoclonic epilepsy with ragged-red fibers (MERRF) syndrome due to the variant m.8344A>G with a heteroplasmy rate of 95% reported by Felczak et al. expands the phenotypic spectrum of MERRF syndrome. The authors reported a pituitary adenoma, calcium deposits in arterial walls, and an intra-cerebral lipoma in the corpus callosum in their patient. Shortcomings of the study are that the diagnostic criteria for MERRF were not accomplished, that the patient should be rather diagnosed as a mitochondrial, multiorgan disorder syndrome (MIMODS), that no pedigree and heteroplasmy rates in first degree relative were provided, that hormone levels were not provided despite obvious endocrinological involvement, and that no serum or cerebrospinal fluid (CSF) lactate levels were reported.
Topics: DNA, Mitochondrial; Humans; MERRF Syndrome; Mutation; Pedigree
PubMed: 33112121
DOI: 10.5114/pjp.2020.99797 -
Case Reports in Neurological Medicine 2020Although endocrinologic involvement and epilepsy are frequent features of myoclonic epilepsy with ragged-red fibers (MERRF), polycystic ovary syndrome (PCOS) and...
OBJECTIVES
Although endocrinologic involvement and epilepsy are frequent features of myoclonic epilepsy with ragged-red fibers (MERRF), polycystic ovary syndrome (PCOS) and photosensitive epilepsy have not been reported. . A 32-year-old female was diagnosed with MERRF at age 19 y upon presence of the four canonical features and the variant m.8344A > G in () (blood heteroplasmy rate: 50%). She experienced recurrent photosensitive focal and generalised seizures since age 19 y, which could be triggered by flickering light or by looking at small stones, leaves, or dirty snow on the ground. Since the last 42 months, she was seizure-free upon levetiracetam (4000 mg/d), clonazepam (1.5 mg/d), and topiramate (25 mg/d). Additionally, she suffered from secondary amenorrhoea since adolescence. She was married between ages 19 y and 25 y but did not get pregnant. PCOS was diagnosed and treated with desogestrel plus estradiol. Nonetheless, the course was progressive, particularly with regard to ataxia, myocloni, and myopathy.
CONCLUSIONS
The phenotypic spectrum of MERRF is broader than anticipated and may additionally include PCOS and photosensitive epilepsy. PCOS in MERRF may respond to hormone substitution and photosensitive epilepsy to levetiracetam, clonazepam, and topiramate.
PubMed: 33062354
DOI: 10.1155/2020/8876272 -
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 -
Journal of Biomedical Science Aug 2023Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is a rare inherited mitochondrial disease mainly caused by the m.8344A > G mutation in mitochondrial tRNA...
BACKGROUND
Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is a rare inherited mitochondrial disease mainly caused by the m.8344A > G mutation in mitochondrial tRNA gene, and usually manifested as complex neurological disorders and muscle weakness. Currently, the pathogenic mechanism of this disease has not yet been resolved, and there is no effective therapy for MERRF syndrome. In this study, MERRF patients-derived iPSCs were used to model patient-specific neurons for investigation of the pathogenic mechanism of neurological disorders in mitochondrial disease.
METHODS
MERRF patient-derived iPSCs were differentiated into excitatory glutamatergic neurons to unravel the effects of the m.8344A > G mutation on mitochondrial bioenergetic function, neural-lineage differentiation and neuronal function. By the well-established differentiation protocol and electrophysiological activity assay platform, we examined the pathophysiological behaviors in cortical neurons of MERRF patients.
RESULTS
We have successfully established the iPSCs-derived neural progenitor cells and cortical-like neurons of patients with MERRF syndrome that retained the heteroplasmy of the m.8344A > G mutation from the patients' skin fibroblasts and exhibited the phenotype of the mitochondrial disease. MERRF neural cells harboring the m.8344A > G mutation exhibited impaired mitochondrial bioenergetic function, elevated ROS levels and imbalanced expression of antioxidant enzymes. Our findings indicate that neural immaturity and synaptic protein loss led to the impairment of neuronal activity and plasticity in MERRF neurons harboring the m.8344A > G mutation. By electrophysiological recordings, we monitored the in vivo neuronal behaviors of MERRF neurons and found that neurons harboring a high level of the m.8344A > G mutation exhibited impairment of the spontaneous and evoked potential-stimulated neuronal activities.
CONCLUSIONS
We demonstrated for the first time the link of mitochondrial impairment and synaptic dysfunction to neurological defects through impeding synaptic plasticity in excitatory neurons derived from iPSCs of MERRF patients harboring the m.8344A > G mutation. This study has provided new insight into the pathogenic mechanism of the tRNA gene mutation of mtDNA, which is useful for the development of a patient-specific iPSCs platform for disease modeling and screening of new drugs to treat patients with MERRF syndrome.
Topics: Humans; MERRF Syndrome; RNA, Transfer, Lys; Neurons; Mitochondria; Neural Stem Cells
PubMed: 37605213
DOI: 10.1186/s12929-023-00966-8 -
Journal of Neuromuscular Diseases 2020Neuropathies in Myoclonic Epilepsy with Ragged Red Fibers (MERRF) syndrome are frequent but ganglionopathies have never been reported. We retrospectively identified 24...
Neuropathies in Myoclonic Epilepsy with Ragged Red Fibers (MERRF) syndrome are frequent but ganglionopathies have never been reported. We retrospectively identified 24 patients with MERRF mutations in the neuromuscular center Nord/Est/Ile de France (Pitié-Salpêtrière, Paris, France). Seventeen nerve conduction studies (NCS) were available. Five patients had MERRF syndrome and ganglionopathy, a pure sensory neuropathy. All of them displayed ataxia and mild clinical sensory abnormalities. Ganglionopathies have been reported in mitochondrial diseases but never in MERRF syndrome. We suggest that patients presenting with ganglionopathy, especially if associated with myopathy, lipomatosis or epilepsy, should be screened for MERRF mutations.
Topics: Adult; Ataxia; Ganglia, Spinal; Humans; MERRF Syndrome; Neural Conduction; Peripheral Nervous System Diseases; Retrospective Studies; Sensation Disorders
PubMed: 32538863
DOI: 10.3233/JND-200513