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Annales D'endocrinologie Jun 2024Lipomatoses are benign proliferation of adipose tissue. Lipomas (benign fat tumors) are the most common component of lipomatosis. They may be unique or multiple,... (Review)
Review
Lipomatoses are benign proliferation of adipose tissue. Lipomas (benign fat tumors) are the most common component of lipomatosis. They may be unique or multiple, encapsulated or not, subcutaneous or sometimes visceral. In some cases, they form large areas of non-encapsulated fat hypertrophy, with a variable degree of fibrosis. They can develop despite the absence of obesity. They may be familial or acquired. At difference with lipodystrophy syndromes, they are not associated with lipoatrophy areas, except in some rare cases such as type 2 familial partial lipodystrophy syndromes (FPLD2). Their metabolic impact is variable in part depending on associated obesity. They may have functional or aesthetic consequences. Lipomatosis may be isolated, be part of a syndrome, or may be visceral. Isolated lipomatoses include multiple symmetrical lipomatosis (Madelung disease or Launois-Bensaude syndrome), familial multiple lipomatosis, the painful Dercum's disease also called Adiposis Dolorosa or Ander syndrome, mesosomatic lipomatosis also called Roch-Leri lipomatosis, familial angiolipomatosis, lipedema and hibernomas. Syndromic lipomatoses include PIK3CA-related disorders, Cowden/PTEN hamartomas-tumor syndrome, some lipodystrophy syndromes, and mitochondrial diseases, especially MERRF, multiple endocrine neoplasia type 1, neurofibromatosis type 1, Wilson disease, Pai or Haberland syndromes. Finally, visceral lipomatoses have been reported in numerous organs and sites: pancreatic, adrenal, abdominal, epidural, mediastinal, epicardial… The aim of this review is to present the main types of lipomatosis and their physiopathological component, when it is known.
Topics: Humans; Lipomatosis; Lipoma; Lipomatosis, Multiple Symmetrical; Lipodystrophy; Adipose Tissue; Adiposis Dolorosa
PubMed: 38871514
DOI: 10.1016/j.ando.2024.05.003 -
Cureus Dec 2023Myoclonic epilepsy with ragged red fibers (MERRF) syndrome is a primary mitochondrial disorder characterized by myoclonus, epilepsy, ataxia, and muscle fiber...
Myoclonic epilepsy with ragged red fibers (MERRF) syndrome is a primary mitochondrial disorder characterized by myoclonus, epilepsy, ataxia, and muscle fiber abnormalities. While traditionally associated with neurological features, MERRF's multisystem nature extends to endocrine dysfunction, including diabetes mellitus, thyroid disorders, and adrenal abnormalities. This case report explores the multifaceted nature of MERRF syndrome by presenting the clinical journey of a 70-year-old woman who sought care at the endocrinology clinic due to coexisting Addison's disease and diabetes mellitus, marked by recurrent hypoglycemia and suboptimal metabolic control. Over time, she developed a history of myoclonic epilepsy, effectively managed with lamotrigine, along with mild sensory axonal polyneuropathy and ataxia. The patient was diagnosed with MERRF syndrome following her son's diagnosis, which had a severe form. This case underscores the intricate interplay between mitochondrial dysfunction and endocrine manifestations in MERRF syndrome, highlighting the importance of a comprehensive and multidisciplinary approach to patient care. MERRF syndrome's array of endocrine manifestations substantially impacts patients' quality of life and morbidity. A comprehensive approach, uniting endocrinologists, neurologists, geneticists, and other specialists, is essential for effective patient care. Further research is warranted to unravel the complex mitochondrial-endocrine interactions in MERRF syndrome, offering potential insights for improved management.
PubMed: 38274904
DOI: 10.7759/cureus.51114 -
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 -
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 -
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