RESUMEN
Inherited deficiency of thymidine phosphorylase (TP), encoded by TYMP, leads to a rare disease with multiple mitochondrial DNA (mtDNA) abnormalities, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the impact of TP deficiency on lysosomes remains unclear, which are important for mitochondrial quality control and nucleic acid metabolism. Muscle biopsy tissue and skin fibroblasts from MNGIE patients, patients with m.3243 A > G mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and healthy controls (HC) were collected to perform mitochondrial and lysosomal functional analyses. In addition to mtDNA abnormalities, compared to controls distinctively reduced expression of LAMP1 and increased mitochondrial content were detected in the muscle tissue of MNGIE patients. Skin fibroblasts from MNGIE patients showed decreased expression of LAMP2, lowered lysosomal acidity, reduced enzyme activity and impaired protein degradation ability. TYMP knockout or TP inhibition in cells can also induce the similar lysosomal dysfunction. Using lysosome immunoprecipitation (Lyso- IP), increased mitochondrial proteins, decreased vesicular proteins and V-ATPase enzymes, and accumulation of various nucleosides were detected in lysosomes with TP deficiency. Treatment of cells with high concentrations of dThd and dUrd also triggers lysosomal dysfunction and disruption of mitochondrial homeostasis. Therefore, the results provided evidence that TP deficiency leads to nucleoside accumulation in lysosomes and lysosomal dysfunction, revealing the widespread disruption of organelles underlying MNGIE.
Asunto(s)
ADN Mitocondrial , Fibroblastos , Lisosomas , Mitocondrias , Encefalomiopatías Mitocondriales , Nucleósidos , Timidina Fosforilasa , Humanos , Lisosomas/metabolismo , Timidina Fosforilasa/metabolismo , Timidina Fosforilasa/deficiencia , Timidina Fosforilasa/genética , Encefalomiopatías Mitocondriales/metabolismo , Encefalomiopatías Mitocondriales/patología , Encefalomiopatías Mitocondriales/genética , Fibroblastos/metabolismo , Fibroblastos/patología , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Mitocondrias/metabolismo , Nucleósidos/metabolismo , Seudoobstrucción Intestinal/metabolismo , Seudoobstrucción Intestinal/patología , Seudoobstrucción Intestinal/enzimología , Seudoobstrucción Intestinal/genética , Oftalmoplejía/metabolismo , Oftalmoplejía/patología , Oftalmoplejía/congénito , Distrofia Muscular Oculofaríngea/metabolismo , Distrofia Muscular Oculofaríngea/patología , Masculino , Femenino , Piel/patología , Piel/metabolismo , Proteína 2 de la Membrana Asociada a los Lisosomas/metabolismoRESUMEN
BACKGROUND Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) is an autosomal recessive disease caused by thymidine phosphorylase deficiency leading to progressive gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy and leukoencephalopathy. Although liver transplantation corrects thymidine phosphorylase deficiency, intestinal deficiency of the enzyme persists. Retrospective chart review was carried out to obtain clinical, biochemical, and pathological details. CASE REPORT We present a case of liver and subsequent intestine transplant in a 28-year-old man with MNGIE syndrome with gastrointestinal dysmotility, inability to walk, leukoencephalopathy, ptosis, cachexia, and elevated serum thymidine. To halt progression of neurologic deficit, he first received a left-lobe partial liver transplantation. Although his motor deficit improved, gastrointestinal dysmotility persisted, requiring total parenteral nutrition. After exhaustive intestinal rehabilitation, he was listed for intestine transplantation. Two-and-half years after liver transplantation, he received an intestine transplant. At 4 years after LT and 20 months after the intestine transplant, he remains off parenteral nutrition and is slowly gaining weight. CONCLUSIONS This is the first reported case of mitochondrial neurogastrointestinal encephalomyopathy to undergo successful sequential liver and intestine transplantation.
Asunto(s)
Seudoobstrucción Intestinal , Leucoencefalopatías , Encefalomiopatías Mitocondriales , Distrofia Muscular Oculofaríngea , Oftalmoplejía , Oftalmoplejía/congénito , Masculino , Humanos , Adulto , Caquexia , Estudios Retrospectivos , Encefalomiopatías Mitocondriales/cirugía , Encefalomiopatías Mitocondriales/patología , Oftalmoplejía/etiología , Oftalmoplejía/cirugía , Intestinos/patología , Hígado/patologíaRESUMEN
Encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome 13 (MTDPS13) is an autosomal recessive disorder arising from biallelic F-box and leucine-rich repeat (LRR) protein 4 (FBXL4) gene mutations. Recent advances have shown that excessive BCL2 interacting protein 3 (BNIP3)/ BCL2 interacting protein 3 like (BNIP3L)-dependent mitophagy underlies the molecular pathogenesis of MTDPS13. Here, we provide an overview of these groundbreaking findings and discuss potential therapeutic strategies for this fatal disease.
Asunto(s)
Encefalomiopatías Mitocondriales , Mitofagia , Humanos , Mitofagia/genética , Mitocondrias/metabolismo , ADN Mitocondrial/genética , Mutación , Encefalomiopatías Mitocondriales/genética , Encefalomiopatías Mitocondriales/metabolismo , Encefalomiopatías Mitocondriales/patología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a well-known mitochondrial depletion syndrome. Since Van Goethem et al. described MNGIE syndrome with pathogenic POLG1 mutations in 2003, POLG1 gene became a target for MNGIE patients. Cases with POLG1 mutations strikingly differ from classic MNGIE patients due to a lack of leukoencephalopathy. Here we present a female patient with very early onset disease and leukoencephalopathy compatible with classic MNGIE disease who turned out to have homozygous POLG1 mutation compatible with MNGIE-like syndrome, mitochondrial depletion syndrome type 4b.
Asunto(s)
Leucoencefalopatías , Encefalomiopatías Mitocondriales , Humanos , Femenino , Encefalomiopatías Mitocondriales/complicaciones , Encefalomiopatías Mitocondriales/genética , Encefalomiopatías Mitocondriales/patología , Timidina Fosforilasa/genética , Mutación/genética , Leucoencefalopatías/genética , Leucoencefalopatías/complicaciones , SíndromeRESUMEN
Plasma thymidine levels in rodents are higher than in other mammals including humans, possibly due to a different pattern and lower level of thymidine phosphorylase expression. Here, we generated a novel knock-in (KI) mouse line with high systemic expression of human thymidine phosphorylase to investigate this difference in nucleotide metabolism in rodents. The KI mice showed growth retardation around weaning and died by 4 weeks of age with a decrease in plasma thymidine level compared with the litter-control WT mice. These phenotypes were completely or partially rescued by administration of the thymidine phosphorylase inhibitor 5-chloro-6-(2-iminopyrrolidin-1-yl) methyl-2,4(1H,3H)-pyrimidinedione hydrochloride or thymidine, respectively. Interestingly, when thymidine phosphorylase inhibitor administration was discontinued in adult animals, KI mice showed deteriorated grip strength and locomotor activity, decreased bodyweight, and subsequent hind-limb paralysis. Upon histological analyses, we observed axonal degeneration in the spinal cord, muscular atrophy with morphologically abnormal mitochondria in quadriceps, retinal degeneration, and abnormality in the exocrine pancreas. Moreover, we detected mitochondrial DNA depletion in multiple tissues of KI mice. These results indicate that the KI mouse represents a new animal model for mitochondrial diseases and should be applicable for the study of differences in nucleotide metabolism between humans and mice.
Asunto(s)
Encefalomiopatías Mitocondriales , Miopatías Mitocondriales , Animales , Humanos , Ratones , ADN Mitocondrial/metabolismo , Trastornos del Crecimiento/genética , Mamíferos/metabolismo , Encefalomiopatías Mitocondriales/genética , Encefalomiopatías Mitocondriales/patología , Nucleótidos , Timidina , Timidina Fosforilasa/genética , Timidina Fosforilasa/metabolismoRESUMEN
In this study, we report on a novel heteroplasmic pathogenic variant in mitochondrial DNA (mtDNA). The studied patient had myoclonus, epilepsy, muscle weakness, and hearing impairment and harbored a heteroplasmic m.8315A>C variant in the MTTK gene with a mutation load ranging from 71% to >96% in tested tissues. In muscle mitochondria, markedly decreased activities of respiratory chain complex I + III and complex IV were observed together with mildly reduced amounts of complex I and complex V (with the detection of V*- and free F1-subcomplexes) and a diminished level of complex IV holoenzyme. This pattern was previously seen in other MTTK pathogenic variants. The novel variant was not present in internal and publicly available control databases. Our report further expands the spectrum of MTTK variants associated with mitochondrial encephalopathies in adults.
Asunto(s)
Síndrome MERRF , Encefalomiopatías Mitocondriales , Adulto , ADN Mitocondrial/genética , Complejo IV de Transporte de Electrones , Humanos , Síndrome MERRF/genética , Síndrome MERRF/patología , Mitocondrias Musculares/metabolismo , Encefalomiopatías Mitocondriales/patologíaRESUMEN
AIMS: Mitochondrial diseases form one of the largest groups of inborn errors of metabolism. The birth prevalence is approximately 1/5000 in well-studied populations, but little has been reported from Sub-Saharan Africa. The aim of this study was to describe the genetics underlying mitochondrial disease in South Africa. METHODS: An audit was performed on all mitochondrial disease genetic testing performed in Cape Town, South Africa. RESULTS: Of 1614 samples tested for mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) variants in South Africa between 1994 and 2019, there were 155 (9.6 %) positive results. Pathogenic mtDNA variants accounted for 113 (73%)/155, from 96 families. Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes, 37 (33%)/113, Leber's hereditary optic neuropathy, 26 (23%)/113, and single large mtDNA deletions, 22 (20%)/113, accounted for 76%. Thirty eight of 42 nDNA-positive results were homozygous for the MPV17 pathogenic variant c.106C>T (p.[Gln36Ter, Ser25Profs*49]) causing infantile neurohepatopathy, one of the largest homozygous groups reported in the literature. The other nDNA variants were in TAZ1, CPT2, BOLA3 and SERAC1. None were identified in SURF1, POLG or PDHA1. CONCLUSIONS: Finding a large group with a homozygous nuclear pathogenic variant emphasises the importance of looking for possible founder effects. The absence of other widely described pathogenic nDNA variants in this cohort may be due to reduced prevalence or insufficient testing. As advances in therapeutics develop, it is critical to develop diagnostic platforms on the African subcontinent so that population-specific genetic variations can be identified.
Asunto(s)
Variación Genética , Proteínas de la Membrana/genética , Enfermedades Mitocondriales/genética , Encefalomiopatías Mitocondriales/genética , Proteínas Mitocondriales/genética , Atrofia Óptica Hereditaria de Leber/genética , Acidosis Láctica/genética , Acidosis Láctica/patología , África del Sur del Sahara , Núcleo Celular/genética , Estudios de Cohortes , Pruebas Genéticas , Homocigoto , Humanos , Mitocondrias/genética , Enfermedades Mitocondriales/patología , Encefalomiopatías Mitocondriales/patología , Mutación , Atrofia Óptica Hereditaria de Leber/patologíaRESUMEN
In a Dutch non-consanguineous patient having mitochondrial encephalomyopathy with complex I and complex IV deficiency, whole exome sequencing revealed two compound heterozygous variants in SLIRP. SLIRP gene encodes a stem-loop RNA-binding protein that regulates mitochondrial RNA expression and oxidative phosphorylation (OXPHOS). A frameshift and a deep-intronic splicing variant reduced the amount of functional wild-type SLIRP RNA to 5%. Consequently, in patient fibroblasts, MT-ND1, MT-ND6, and MT-CO1 expression was reduced. Lentiviral transduction of wild-type SLIRP cDNA in patient fibroblasts increased MT-ND1, MT-ND6, and MT-CO1 expression (2.5-7.2-fold), whereas mutant cDNAs did not. A fourfold decrease of citrate synthase versus total protein ratio in patient fibroblasts indicated that the resulting reduced mitochondrial mass caused the OXPHOS deficiency. Transduction with wild-type SLIRP cDNA led to a 2.4-fold increase of this ratio and partly restored OXPHOS activity. This confirmed causality of the SLIRP variants. In conclusion, we report SLIRP variants as a novel cause of mitochondrial encephalomyopathy with OXPHOS deficiency.
Asunto(s)
Encefalomiopatías Mitocondriales/genética , Proteínas de Unión al ARN/genética , Células Cultivadas , Niño , Complejo I de Transporte de Electrón/metabolismo , Complejo IV de Transporte de Electrones/metabolismo , Fibroblastos/metabolismo , Genes Recesivos , Humanos , Masculino , Encefalomiopatías Mitocondriales/patología , Mutación , Proteínas de Unión al ARN/metabolismoRESUMEN
Mitochondrial ultrastructure is highly adaptable and undergoes dynamic changes upon physiological and energetic cues. MICOS (mitochondrial contact site and cristae organizing system), a large oligomeric protein complex, maintains mitochondrial ultrastructure as it is required for formation of crista junctions (CJs) and contact sites. MIC13 acts as a critical bridge between two MICOS subcomplexes. Deletion of MIC13 causes loss of CJs resulting in cristae accumulating as concentric rings and specific destabilization of the MIC10-subcomplex. Mutations in MIC13 are associated with infantile lethal mitochondrial hepato-encephalopathy, yet functional regions within MIC13 were not known. To identify and characterize such regions, we systemically generated 20 amino-acids deletion variants across the length of MIC13. While deletion of many of these regions of MIC13 is dispensable for its stability, the N-terminal region and a stretch between amino acid residues 84 and 103 are necessary for the stability and functionality of MIC13. We could further locate conserved motifs within these regions and found that a GxxxG motif in the N-terminal transmembrane segment and an internal WN motif are essential for stability of MIC13, formation of the MIC10-subcomplex, interaction with MIC10- and MIC60-subcomplexes and maintenance of cristae morphology. The GxxxG motif is required for membrane insertion of MIC13. Overall, we systematically found important conserved residues of MIC13 that are required to perform the bridging between the two MICOS subcomplexes. The study improves our understanding of the basic molecular function of MIC13 and has implications for its role in the pathogenesis of a severe mitochondrial disease.
Asunto(s)
Proteína Cofactora de Membrana/genética , Proteínas de la Membrana/genética , Mitocondrias/genética , Encefalomiopatías Mitocondriales/genética , Proteínas Mitocondriales/genética , Proteínas Musculares/genética , Secuencias de Aminoácidos/genética , Aminoácidos/genética , Eliminación de Gen , Humanos , Mitocondrias/patología , Encefalomiopatías Mitocondriales/patología , Membranas Mitocondriales/metabolismo , Mutación/genética , Mapas de Interacción de Proteínas/genéticaRESUMEN
Abnormal gut motility is a feature of several mitochondrial encephalomyopathies, and mutations in genes such as TYMP and POLG, have been linked to these rare diseases. The human genome encodes three DNA ligases, of which only one, ligase III (LIG3), has a mitochondrial splice variant and is crucial for mitochondrial health. We investigated the effect of reduced LIG3 activity and resulting mitochondrial dysfunction in seven patients from three independent families, who showed the common occurrence of gut dysmotility and neurological manifestations reminiscent of mitochondrial neurogastrointestinal encephalomyopathy. DNA from these patients was subjected to whole exome sequencing. In all patients, compound heterozygous variants in a new disease gene, LIG3, were identified. All variants were predicted to have a damaging effect on the protein. The LIG3 gene encodes the only mitochondrial DNA (mtDNA) ligase and therefore plays a pivotal role in mtDNA repair and replication. In vitro assays in patient-derived cells showed a decrease in LIG3 protein levels and ligase activity. We demonstrated that the LIG3 gene defects affect mtDNA maintenance, leading to mtDNA depletion without the accumulation of multiple deletions as observed in other mitochondrial disorders. This mitochondrial dysfunction is likely to cause the phenotypes observed in these patients. The most prominent and consistent clinical signs were severe gut dysmotility and neurological abnormalities, including leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder. A decrease in the number of myenteric neurons, and increased fibrosis and elastin levels were the most prominent changes in the gut. Cytochrome c oxidase (COX) deficient fibres in skeletal muscle were also observed. Disruption of lig3 in zebrafish reproduced the brain alterations and impaired gut transit in vivo. In conclusion, we identified variants in the LIG3 gene that result in a mitochondrial disease characterized by predominant gut dysmotility, encephalopathy, and neuromuscular abnormalities.
Asunto(s)
ADN Ligasa (ATP)/genética , Enfermedades Gastrointestinales/genética , Motilidad Gastrointestinal/genética , Encefalomiopatías Mitocondriales/genética , Proteínas de Unión a Poli-ADP-Ribosa/genética , Animales , Femenino , Enfermedades Gastrointestinales/patología , Humanos , Masculino , Encefalomiopatías Mitocondriales/patología , Mutación , Linaje , Pez CebraRESUMEN
The cytochrome c-oxidase (COX) enzyme, also known as mitochondrial complex IV (MT-C4D), is a transmembrane protein complex found in mitochondria. COX deficiency is one of the most frequent causes of electron transport chain defects in humans. Therefore, high energy demand organs and tissues are affected in patients with mutations in the COX15 gene, with variable phenotypic expressiveness. We describe the case of a male newborn with hypertrophic cardiomyopathy and serum and cerebrospinal fluid hyperlacticaemia, whose exome sequencing revealed two variants in a compound heterozygous state: c.232G > A; p.(Gly78Arg), classified as likely pathogenic, and c.452C > G; p.(Ser151Ter), as pathogenic; the former never previously described in the literature.
Asunto(s)
Cardiomiopatía Hipertrófica/genética , Deficiencia de Citocromo-c Oxidasa/genética , Complejo IV de Transporte de Electrones/genética , Encefalomiopatías Mitocondriales/genética , Cardiomiopatía Hipertrófica/patología , Deficiencia de Citocromo-c Oxidasa/patología , Heterocigoto , Humanos , Recién Nacido , Masculino , Encefalomiopatías Mitocondriales/patología , Mutación , FenotipoRESUMEN
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by thymidine phosphorylase (TP) enzyme defect. As gastrointestinal changes do not revert in patients undergone TP replacement therapy, one can postulate that other unexplored mechanisms contribute to MNGIE pathophysiology. Hence, we focused on the local TP angiogenic potential that has never been considered in MNGIE. In this study, we investigated the enteric submucosal microvasculature and the effect of hypoxia on fibrosis and enteric neurons density in jejunal full-thickness biopsies collected from patients with MNGIE. Orcein staining was used to count blood vessels based on their size. Fibrosis was assessed using the Sirius Red and Fast Green method. Hypoxia and neoangiogenesis were determined via hypoxia-inducible-factor-1α (HIF-1α) and vascular endothelial cell growth factor (VEGF) protein expression, respectively. Neuron-specific enolase was used to label enteric neurons. Compared with controls, patients with MNGIE showed a decreased area of vascular tissue, but a twofold increase of submucosal vessels/mm2 with increased small size and decreased medium and large size vessels. VEGF positive vessels, fibrosis index, and HIF-1α protein expression were increased, whereas there was a diminished thickness of the longitudinal muscle layer with an increased interganglionic distance and reduced number of myenteric neurons. We demonstrated the occurrence of an angiopathy in the GI tract of patients with MNGIE. Neoangiogenetic changes, as detected by the abundance of small size vessels in the jejunal submucosa, along with hypoxia provide a morphological basis to explain neuromuscular alterations, vasculature breakdown, and ischemic abnormalities in MNGIE.NEW & NOTEWORTHY Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is characterized by a genetically driven defect of thymidine phosphorylase, a multitask enzyme playing a role also in angiogenesis. Indeed, major gastrointestinal bleedings are life-threatening complications of MNGIE. Thus, we focused on jejunal submucosal vasculature and showed intestinal microangiopathy as a novel feature occurring in this disease. Notably, vascular changes were associated with neuromuscular abnormalities, which may explain gut dysfunction and help to develop future therapeutic approaches in MNGIE.
Asunto(s)
Tracto Gastrointestinal/metabolismo , Seudoobstrucción Intestinal/metabolismo , Encefalomiopatías Mitocondriales/metabolismo , Distrofia Muscular Oculofaríngea/metabolismo , Neovascularización Patológica/metabolismo , Oftalmoplejía/congénito , Tracto Gastrointestinal/patología , Humanos , Seudoobstrucción Intestinal/patología , Encefalomiopatías Mitocondriales/patología , Distrofia Muscular Oculofaríngea/patología , Neovascularización Patológica/patología , Oftalmoplejía/metabolismo , Oftalmoplejía/patología , Timidina Fosforilasa/metabolismoRESUMEN
We report clinicopathological findings of a patient with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes/Leigh syndrome (MELAS/LS) associated with a novel m.3482A>G mutation in MT-ND1. A 41-year-old woman had experienced multiple stroke-like episodes since age 16. She developed akinetic mutism two months before admission to our hospital. Neurological examination revealed akinetic mutism, bilateral deafness, and muscular atrophy. Cerebrospinal fluid tests revealed elevated pyruvate and lactate levels. Fluid-attenuated inversion recovery images on magnetic resonance imaging showed hyperintense areas in the right frontal and both sides of temporal and occipital lobes, both sides of the striatum, and the midbrain. Muscle biopsy revealed strongly succinate dehydrogenase-reactive blood vessels. L-arginine therapy improved her consciousness and prevented further stroke-like episodes. However, she died from aspiration pneumonia. Postmortem autopsy revealed scattered infarct-like lesions with cavitation in the cerebral cortex and necrotic lesions in the striatum and midbrain. The patient was pathologically confirmed as having MELAS/LS based on two characteristic clinicopathological findings: presenting MELAS/LS overlap phenotype and effectiveness of L-arginine treatment.
Asunto(s)
Acidosis Láctica/patología , Enfermedad de Leigh/patología , Encefalomiopatías Mitocondriales/patología , Mutación , NADH Deshidrogenasa , Accidente Cerebrovascular/patología , Acidosis Láctica/complicaciones , Acidosis Láctica/genética , Adulto , Resultado Fatal , Femenino , Humanos , Enfermedad de Leigh/complicaciones , Enfermedad de Leigh/genética , Encefalomiopatías Mitocondriales/complicaciones , Encefalomiopatías Mitocondriales/genética , Mutación/genética , NADH Deshidrogenasa/genética , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/genéticaRESUMEN
BACKGROUND: Mitochondrial encephalomyopathy caused by bi-allelic deleterious variants in TARS2 is rare. To date, only two pedigrees were reported in the literature and the connection between the gene and disease needs further study. CASE PRESENTATION: We report one infant who presented with limb hypertonia, epilepsy, developmental delay, and increased serum lactate from a non-consanguineous Chinese family. Whole-genome sequencing was performed to help to underlie the cause. We identified compound heterozygous variants c.470C > G, p.Thr157Arg and c.2143G > A, p.Glu715Lys in TARS2 and the variants were confirmed by Sanger sequencing. The patient was diagnosed with combined oxidative phosphorylation deficiency 21 according to the Online Mendelian Inheritance in Man (OMIM) database based on the clinical data and the deleterious effect of the two variants in TARS2 predicted by in silico tools. CONCLUSIONS: We presented one case diagnosed with combined oxidative phosphorylation deficiency 21 based on clinical characteristics and genetic analysis. This is the first case in China and the fourth case in the world based on our document retrieval. This study facilitates the understanding of combined oxidative phosphorylation deficiency disease and demonstrates that the next-generation sequencing has a high potential to study inherited disease with high phenotypic heterogeneity and genetic heterogeneity including mitochondrial diseases such as combined oxidative phosphorylation deficiency.
Asunto(s)
Discapacidades del Desarrollo/genética , Epilepsia/genética , Enfermedades Mitocondriales/genética , Encefalomiopatías Mitocondriales/genética , Mutación , Treonina-ARNt Ligasa/genética , Pueblo Asiatico , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/etnología , Discapacidades del Desarrollo/patología , Epilepsia/diagnóstico , Epilepsia/etnología , Epilepsia/patología , Familia , Expresión Génica , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Ácido Láctico/sangre , Masculino , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/etnología , Enfermedades Mitocondriales/patología , Encefalomiopatías Mitocondriales/diagnóstico , Encefalomiopatías Mitocondriales/etnología , Encefalomiopatías Mitocondriales/patología , Linaje , Treonina-ARNt Ligasa/deficienciaRESUMEN
Complex I (also known as NADH-ubiquinone oxidoreductase) deficiency is the most frequent mitochondrial disorder present in childhood. NADH-ubiquinone oxidoreductase iron-sulfur protein 3 (NDUFS3) is a catalytic subunit of the mitochondrial complex I; NDUFS3 is conserved from bacteria and essential for complex I function. Mutations affecting complex I, including in the Ndufs3 gene, cause fatal neurodegenerative diseases, such as Leigh syndrome. No treatment is available for these conditions. We developed and performed a detailed molecular characterization of a neuron-specific Ndufs3 conditional KO mouse model. We showed that deletion of Ndufs3 in forebrain neurons reduced complex I activity, altered brain energy metabolism, and increased locomotor activity with impaired motor coordination, balance, and stereotyped behavior. Metabolomics analyses showed an increase of glycolysis intermediates, suggesting an adaptive response to the complex I defect. Administration of metformin to these mice delayed the onset of the neurological symptoms but not of neuronal loss. This improvement was likely related to enhancement of glucose uptake and utilization, which are known effects of metformin in the brain. Despite reports that metformin inhibits complex I activity, our findings did not show worsening a complex I defect nor increases in lactic acid, suggesting that metformin should be further evaluated for use in patients with mitochondrial encephalopathies.
Asunto(s)
Complejo I de Transporte de Electrón/deficiencia , Metformina/farmacología , Enfermedades Mitocondriales/complicaciones , Encefalomiopatías Mitocondriales/tratamiento farmacológico , NADH Deshidrogenasa/fisiología , Neuronas/efectos de los fármacos , Animales , Metabolismo Energético , Femenino , Glucólisis , Hipoglucemiantes/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Encefalomiopatías Mitocondriales/etiología , Encefalomiopatías Mitocondriales/metabolismo , Encefalomiopatías Mitocondriales/patología , Neuronas/metabolismo , Neuronas/patologíaRESUMEN
Epitranscriptomic systems enable post-transcriptional modifications of cellular RNA that are essential for regulating gene expression. Of the ~ 170 known RNA chemical modifications, methylation is among the most common. Loss of function mutations in NSUN3, encoding the 5-methylcytosine (m5C) methyltransferase NSun3, have been linked to multisystem mitochondrial disease associated with combined oxidative phosphorylation deficiency. Here, we report a patient with early-onset mitochondrial encephalomyopathy and seizures in whom the novel biallelic NSUN3 missense variants c.421G>C (p.A141P) and c.454T>A (p.C152S) were detected. Segregation studies and in silico functional analysis confirmed the likely pathogenic effects of both variants. These findings expand the molecular and phenotypic spectrum of NSUN3-related mitochondrial disease.
Asunto(s)
Metiltransferasas/genética , Encefalomiopatías Mitocondriales/genética , Convulsiones/genética , Encéfalo/diagnóstico por imagen , Femenino , Humanos , Masculino , Encefalomiopatías Mitocondriales/patología , Mutación Missense , Linaje , Fenotipo , Convulsiones/patologíaRESUMEN
RATIONALE: Mitochondrial encephalomyopathy with lactic acidosis and stroke- like episodes (MELAS) syndrome is caused by mitochondrial respiratory chain dysfunction and oxidative phosphorylation disorder. It is a rare clinical metabolic disease involved with multiple systems. PATIENT CONCERNS: A 22-year-old patient presented with limb convulsion accompanied by loss of consciousness, headache, partial blindness, blurred vision, and so on. DIAGNOSES: Brain magnetic resonance imaging showed a high-intensity area in bilateral occipital cortex, left parietal lobe and cerebellum on diffusion-weighted imaging. These focus did not distribute as vascular territory. The pathological examination of skeletal muscle revealed several succinate dehydrogenase reactive vessels with overreaction and increased content of lipid droplets in some muscle fibers. Genetic testing showed that the patient carried m.10158T>C mutation. INTERVENTIONS: She was provided with traditional arginine hydrochloride therapy and orally medication of coenzyme Q (10âmg). OUTCOMES: Mitochondrial DNA of blood and hair follicle of patient carried m.10158T>C mutation LESSONS:: For the suspected patients of MELAS syndrome, if the hot-spot mutation test is negative, more detection sites should be selected.
Asunto(s)
Acidosis Láctica/complicaciones , ADN Mitocondrial/genética , Síndrome MELAS/genética , Accidente Cerebrovascular/etiología , Administración Oral , Arginina/administración & dosificación , Arginina/uso terapéutico , Concienciación , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Femenino , Humanos , Síndrome MELAS/diagnóstico por imagen , Síndrome MELAS/tratamiento farmacológico , Síndrome MELAS/patología , Imagen por Resonancia Magnética/métodos , Micronutrientes/administración & dosificación , Micronutrientes/uso terapéutico , Encefalomiopatías Mitocondriales/diagnóstico , Encefalomiopatías Mitocondriales/etiología , Encefalomiopatías Mitocondriales/patología , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Mutación , Accidente Cerebrovascular/diagnóstico , Succinato Deshidrogenasa/metabolismo , Ubiquinona/administración & dosificación , Ubiquinona/uso terapéutico , Adulto JovenRESUMEN
Mitochondrial encephalomyopathies comprise a group of heterogeneous disorders resulting from impaired oxidative phosphorylation (OxPhos). Among a variety of symptoms progressive external ophthalmoplegia (PEO) seems to be the most common. The aim of this study is to present clinical and genetic characteristics of Polish patients with PEO. Clinical, electrophysiological, neuroradiological, and morphological data of 84 patients were analyzed. Genetic studies of mitochondrial DNA (mtDNA) were performed in all patients. Among nuclear DNA (nDNA) genes POLG was sequenced in 41 patients, TWNK (C10orf2) in 13 patients, and RNASEH1 in 2 patients. Total of 27 patients were included in the chronic progressive external ophthalmoplegia (CPEO) group, 24 in the CPEO+ group. Twenty-six patients had mitochondrial encephalomyopathy (ME), six patients Kearns-Sayre syndrome (KSS), and one patient sensory ataxic neuropathy, dysarthria, ophthalmoparesis (SANDO) syndrome. Genetic analysis of nDNA genes revealed the presence of pathogenic or possibly pathogenic variants in the POLG gene in nine patients, the TWNK gene in five patients and the RNASEH1 gene in two patients. Detailed patients' history and careful assessment of family history are essential in the diagnostic work-up. Genetic studies of both mtDNA and nDNA are necessary for the final diagnosis of progressive external ophthalmoplegia and for genetic counseling.
Asunto(s)
ADN Helicasas/genética , ADN Polimerasa gamma/genética , Síndrome de Kearns-Sayre/genética , Enfermedades Mitocondriales/genética , Encefalomiopatías Mitocondriales/genética , Proteínas Mitocondriales/genética , Oftalmoplejía Externa Progresiva Crónica/genética , Ribonucleasa H/genética , Adolescente , Adulto , Anciano , Cerebelo/diagnóstico por imagen , Cerebelo/metabolismo , Cerebelo/patología , Cerebro/diagnóstico por imagen , Cerebro/metabolismo , Cerebro/patología , Niño , ADN Helicasas/metabolismo , ADN Polimerasa gamma/metabolismo , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Diagnóstico Diferencial , Femenino , Expresión Génica , Humanos , Síndrome de Kearns-Sayre/diagnóstico por imagen , Síndrome de Kearns-Sayre/metabolismo , Síndrome de Kearns-Sayre/patología , Masculino , Persona de Mediana Edad , Mitocondrias/metabolismo , Mitocondrias/patología , Enfermedades Mitocondriales/diagnóstico por imagen , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Encefalomiopatías Mitocondriales/diagnóstico por imagen , Encefalomiopatías Mitocondriales/metabolismo , Encefalomiopatías Mitocondriales/patología , Proteínas Mitocondriales/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Oftalmoplejía Externa Progresiva Crónica/diagnóstico por imagen , Oftalmoplejía Externa Progresiva Crónica/metabolismo , Oftalmoplejía Externa Progresiva Crónica/patología , Linaje , Polonia , Polimorfismo Genético , Ribonucleasa H/metabolismo , Eliminación de SecuenciaRESUMEN
Objective: To investigate the ultrastructural features of muscle in patients with mitochondrial encephalomyopathy for its diagnosis and differential diagnosis. Methods: The clinical data of 27 mitochondrial encephalomyopathy patients who underwent left or right biceps brachii muscle biopsy at Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University from July 2006 to August 2017 were analyzed retrospectively. The muscle biopsy specimens were examined underlight microscope and transmission electron microscope. Results: There were 27 patients (17 males, 10 females) with an age range of 12 to 62 years (mean 29 years). The age of onset ranged from 3 to 38 years. The course of disease ranged from 1 month to 24 years. Twenty-two cases presented with lactic acidosis and stroke-like episodes (MELAS) syndrome, four with myoclonic epilepsy with ragged red fibers (MERRF) syndrome, and one with chronic progressive paralysis of extraocular muscle (CPEO) syndrome. Skeletal muscle biopsy showed abundant ragged red fibers and strongly SDH-reactive vessel. Genetic studies showed 17 of 22 cases of MELAS syndrome had A3243G mutation, and the other 5 cases had no abnormality. A8344G mutation was found in 3 of 4 cases of MERRF syndrome. No single or multiple mtDNA mutations were found in the single case of CPEO. Transmission electron microscopy of all 27 cases showed diffuse proliferation of mitochondria between the myofibrils and beneath the sarcolemma, with increased spacing between muscle cells. Seven cases showed numerous glycogen and four showed subsarcolemmal lipid droplets, 13 cases showed unusual mitochondrial morphology, including mitochondrial electron-dense substances and paracrystal line inclusions ("parking lot" change)in eight cases. Conclusions: Transmission electron microscopy shows significant differences in ultrastructural pathological changes among different patients with mitochondrial encephalomyopathy. Some patients with mild clinical symptoms have increased mitochondrial number, increased metabolism of glycogen and lipid droplets, while others with severe clinical symptoms have abnormal mitochondrial morphology. Typical crystalloid inclusions are found in mitochondria, which are of great value in the diagnosis of this disease.
Asunto(s)
Encefalomiopatías Mitocondriales/patología , Músculo Esquelético/patología , Adolescente , Adulto , Edad de Inicio , Niño , Femenino , Humanos , Síndrome MELAS/etiología , Síndrome MELAS/patología , Síndrome MERRF/genética , Síndrome MERRF/patología , Masculino , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Mitocondrias Musculares/patología , Mitocondrias Musculares/ultraestructura , Encefalomiopatías Mitocondriales/complicaciones , Encefalomiopatías Mitocondriales/genética , Músculo Esquelético/ultraestructura , Mutación , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Mutations in the mitochondrial alanyl-transfer (t)RNA synthetase 2 (AARS2,OMIM:612035) have been linked to leukoencephalopathy recently. Till now, there have been 19 cases reported so far. However, the clinical and genetic characteristics of this disease are not fully understood. We reported an adult-onset male leukoencephalopathy patient related to novel AARS2 gene mutations and reviewed all previous cases regarding the clinical and genetic features of AARS2 leukoencephalopathy. METHODS: The spectrum of clinical symptoms and the genetic analysis of the presented patient were identified and investigated. Besides this case, we assessed previously reported cases with AARS2 gene mutations. RESULTS: Here, we present a 30-year-old man with progressive motor deficits in the right lower limb and severe cerebellar ataxia for one year. MRI revealed extensive white matter lesions in periventricular regions and along the corticospinal tract. Genetic analysis revealed two new heterogeneous missense mutations in AARS2: c.179C>A and c.1703_1704del. We described the ragged red fiber (RRF) for the first time, suggesting that AARS2-related leukoencephalopathy be a new variant of mitochondrial encephalomyopathy. Gradual improvement in motor function was observed with intravenous coenzyme complex treatment. We also summarized our case and all previously reported cases to provide an overview of AARS2-related late-onset leukoencephalopathy. Then, we compared clinical and neuroimaging features of AARS2-related leukoencephalopathy with three other frequently diagnosed types of adult-onset leukoencephalopathy to provide insight into diagnostic strategies. CONCLUSION: The characteristic MRI abnormalities and clinical symptoms described here may help to distinguish AARS2-related leukoencephalopathy from other adult-onset leukoencephalopathies. The combination of encephalopathy and myopathy strongly suggest that AARS2-related leukoencephalopathy is a new variant of mitochondrial encephalomyopathy. The response to coenzyme complex will shed light on future therapy investigation.