ABSTRACT
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.
Subject(s)
DNA, Mitochondrial , Fibroblasts , Lysosomes , Mitochondria , Mitochondrial Encephalomyopathies , Nucleosides , Thymidine Phosphorylase , Humans , Lysosomes/metabolism , Thymidine Phosphorylase/metabolism , Thymidine Phosphorylase/deficiency , Thymidine Phosphorylase/genetics , Mitochondrial Encephalomyopathies/metabolism , Mitochondrial Encephalomyopathies/pathology , Mitochondrial Encephalomyopathies/genetics , Fibroblasts/metabolism , Fibroblasts/pathology , DNA, Mitochondrial/genetics , DNA, Mitochondrial/metabolism , Mitochondria/metabolism , Nucleosides/metabolism , Intestinal Pseudo-Obstruction/metabolism , Intestinal Pseudo-Obstruction/pathology , Intestinal Pseudo-Obstruction/enzymology , Intestinal Pseudo-Obstruction/genetics , Ophthalmoplegia/metabolism , Ophthalmoplegia/pathology , Ophthalmoplegia/congenital , Muscular Dystrophy, Oculopharyngeal/metabolism , Muscular Dystrophy, Oculopharyngeal/pathology , Male , Female , Skin/pathology , Skin/metabolism , Lysosomal-Associated Membrane Protein 2/metabolismABSTRACT
Mitochondrial diseases have a heterogeneous phenotype and can result from mutations in the mitochondrial or nuclear genomes, constituting a diagnostically and therapeutically challenging group of disorders. We report our center's experience with mitochondrial encephalopathies and myopathies with a cohort of 50 genetically and phenotypically diverse patients followed in the Neurology clinic over the last ten years. Seventeen patients had mitochondrial DNA mutations, presented over a wide range of ages with seizures, feeding difficulties, extraocular movements abnormalities, and had high rates of stroke-like episodes and regression. Twenty-seven patients had nuclear DNA mutations, presented early in life with feeding difficulty, failure-to-thrive, and seizures, and had high proportions of developmental delay, wheelchair dependence, spine abnormalities and dystonia. In six patients, a mutation could not be identified, but they were included for having mitochondrial disease confirmed by histopathology, enzyme analysis and clinical features. These patients had similar characteristics to patients with nuclear DNA mutations, suggesting missed underlying mutations in the nuclear genome. Management was variable among patients, but outcomes were universally poor with severe disability in all cases. Therapeutic entryways through elucidation of disease pathways and remaining unknown genes are acutely needed.
Subject(s)
DNA, Mitochondrial , Mitochondrial Encephalomyopathies , Mutation , Humans , Male , Female , Child , Child, Preschool , Mitochondrial Encephalomyopathies/genetics , Infant , Adolescent , DNA, Mitochondrial/genetics , Adult , Young Adult , Tertiary Care Centers , Mitochondrial Myopathies/geneticsABSTRACT
Mitochondria are essential for human metabolic function. Over 350 genetic mutations are associated with mitochondrial diseases, which are inherited in a matrilineal fashion. In mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), defective mitochondrial function and resultant impaired cellular energy production compromise vascular perfusion in affected tissues. Early diagnostic criteria suggested the diagnosis should be considered in those under 40. However, a broader range of phenotypes are now recognised, including those that present for the first time later in life. The primary presenting feature in MELAS is a stroke-like episode invariably resulting in patients undergoing neuroradiological imaging. We present a case of a woman with a first presentation of a stroke-like episode and seizures in her 40s who was eventually diagnosed with MELAS. We detail her clinical presentation, treatment and diagnosis, emphasising the role of serial imaging in her diagnosis.
Subject(s)
Acidosis, Lactic , MELAS Syndrome , Mitochondrial Diseases , Mitochondrial Encephalomyopathies , Stroke , Female , Humans , MELAS Syndrome/diagnosis , MELAS Syndrome/diagnostic imaging , Stroke/etiology , Stroke/complications , Mitochondrial Diseases/complicationsABSTRACT
Mitochondrial encephalopathy is a neurological disorder caused by impaired mitochondrial function and energy production. One of the genetic causes of this condition is the mutation of MT-TN, a gene that encodes the mitochondrial transfer RNA (tRNA) for asparagine. MT-TN mutations affect the stability and structure of the tRNA, resulting in reduced protein synthesis and complex enzymatic deficiency of the mitochondrial respiratory chain. Our patient cohort manifests with epileptic encephalopathy, ataxia, hypotonia, and bilateral basal ganglia calcification, which differs from previously reported cases. MT-TN mutation deficiency leads to decreased basal and maximal oxygen consumption rates, disrupted spare respiratory capacity, declined mitochondrial membrane potential, and impaired ATP production. Moreover, MT-TN mutations promote mitophagy, a process of selective degradation of damaged mitochondria by autophagy. Excessive mitophagy further leads to mitochondrial biogensis as a compensatory mechanism. In this study, we provided evidence of pathogenicity for two MT-TN mutations, m.5688 T > C and m.G5691A, explored the molecular mechanisms, and summarized the clinical manifestations of MT-TN mutations. Our study expanded the genotype and phenotypic spectrum and provided new insight into mt-tRNA (Asn)-associated mitochondrial encephalopathy.
Subject(s)
Brain Diseases , Mitochondrial Encephalomyopathies , Mitophagy , Humans , Mitophagy/genetics , Mitochondria/genetics , Mitochondria/metabolism , Mutation , Brain Diseases/genetics , Brain Diseases/metabolism , RNA, Transfer/genetics , RNA, Mitochondrial/metabolismABSTRACT
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.
Subject(s)
Intestinal Pseudo-Obstruction , Leukoencephalopathies , Mitochondrial Encephalomyopathies , Muscular Dystrophy, Oculopharyngeal , Ophthalmoplegia , Ophthalmoplegia/congenital , Male , Humans , Adult , Cachexia , Retrospective Studies , Mitochondrial Encephalomyopathies/surgery , Mitochondrial Encephalomyopathies/pathology , Ophthalmoplegia/etiology , Ophthalmoplegia/surgery , Intestines/pathology , Liver/pathologySubject(s)
Intestinal Pseudo-Obstruction , Mitochondrial Encephalomyopathies , Muscular Dystrophy, Oculopharyngeal , Ophthalmoplegia/congenital , Humans , DNA Polymerase gamma/genetics , Phenotype , Intestinal Pseudo-Obstruction/genetics , Mitochondrial Encephalomyopathies/genetics , Mutation/genetics , DNA, Mitochondrial/geneticsABSTRACT
The MT-TL2 m.12315G>A pathogenic variant has previously been reported in five individuals with mild clinical phenotypes. Herein we report the case of a 5-year-old child with heteroplasmy for this variant who developed neurological regression and stroke-like episodes similar to those observed in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Biochemical evaluation revealed depletion of arginine on plasma amino acid analysis and low z-scores for citrulline on untargeted plasma metabolomics analysis. These findings suggested that decreased availability of nitric oxide may have contributed to the stroke-like episodes. The use of intravenous arginine during stroke-like episodes and daily enteral L-citrulline supplementation normalized her biochemical values of arginine and citrulline. Untargeted plasma metabolomics showed the absence of nicotinamide and 1-methylnicotinamide, and plasma total glutathione levels were low; thus, nicotinamide riboside and N-acetylcysteine therapies were initiated. This report expands the phenotype associated with the rare mitochondrial variant MT-TL2 m.12315G>A to include neurological regression and a MELAS-like phenotype. Individuals with this variant should undergo in-depth biochemical analysis to include untargeted plasma metabolomics, plasma amino acids, and glutathione levels to help guide a targeted approach to treatment.
Subject(s)
Acidosis, Lactic , MELAS Syndrome , Mitochondrial Encephalomyopathies , Stroke , Child, Preschool , Female , Humans , Arginine/genetics , Citrulline , Glutathione/metabolism , MELAS Syndrome/diagnosis , MELAS Syndrome/genetics , MELAS Syndrome/complications , Nitric Oxide Donors/metabolism , Stroke/complications , Stroke/drug therapySubject(s)
Intestinal Pseudo-Obstruction , Mitochondrial Encephalomyopathies , Muscular Dystrophy, Oculopharyngeal , Ophthalmoplegia , Humans , DNA Polymerase gamma/genetics , Phenotype , Intestinal Pseudo-Obstruction/genetics , DNA, Mitochondrial/genetics , Mutation/genetics , Mitochondrial Encephalomyopathies/geneticsABSTRACT
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.
Subject(s)
Mitochondrial Encephalomyopathies , Mitophagy , Humans , Mitophagy/genetics , Mitochondria/metabolism , DNA, Mitochondrial/genetics , Mutation , Mitochondrial Encephalomyopathies/genetics , Mitochondrial Encephalomyopathies/metabolism , Mitochondrial Encephalomyopathies/pathology , Proto-Oncogene Proteins c-bcl-2/metabolism , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Proto-Oncogene Proteins/genetics , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolismABSTRACT
Mitochondrial dysfunction, especially perturbation of oxidative phosphorylation and adenosine triphosphate (ATP) generation, disrupts cellular homeostasis and is a surprisingly frequent cause of central and peripheral nervous system pathology. Mitochondrial disease is an umbrella term that encompasses a host of clinical syndromes and features caused by in excess of 300 different genetic defects affecting the mitochondrial and nuclear genomes. Patients with mitochondrial disease can present at any age, ranging from neonatal onset to late adult life, with variable organ involvement and neurological manifestations including neurodevelopmental delay, seizures, stroke-like episodes, movement disorders, optic neuropathy, myopathy, and neuropathy. Until relatively recently, analysis of skeletal muscle biopsy was the focus of diagnostic algorithms, but step-changes in the scope and availability of next-generation sequencing technology and multiomics analysis have revolutionized mitochondrial disease diagnosis. Currently, there is no specific therapy for most types of mitochondrial disease, although clinical trials research in the field is gathering momentum. In that context, active management of epilepsy, stroke-like episodes, dystonia, brainstem dysfunction, and Parkinsonism are all the more important in improving patient quality of life and reducing mortality.
Subject(s)
Mitochondrial Diseases , Mitochondrial Encephalomyopathies , Stroke , Adult , Infant, Newborn , Humans , Mitochondrial Encephalomyopathies/diagnosis , Mitochondrial Encephalomyopathies/genetics , DNA, Mitochondrial/genetics , Quality of Life , Mitochondrial Diseases/geneticsABSTRACT
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive multisystem disorder that often presents with gastrointestinal and neurological symptoms. Here we report a 33-year-old male who presented with a 16-year history of diarrhea with black stool and progressive weight loss. He complained of progressive bilateral blurred vision, upper eyelids heaviness, ocular motility impairment, and color blindness. Peripheral neuropathy, bilateral sensorineural deafness, hyperlactatemia, diabetes mellitus, hepatic steatosis, blood coagulation dysfunction, and diffuse leukoencephalopathy were detected in the systemic evaluation. Based on the novel homozygous pathogenic variant in the TYMP gene (c.1159+1G>A), he was diagnosed with MNGIE. On ophthalmic examinations, the thickness of the inner retina and ganglion cell complex significantly decreased. ERG showed diffusely decreased amplitudes. The electronegative electroretinogram, which was first reported in MNGIE, indicated a more severe inner retina impairment. The bilateral papillomacular bundle defect and central vision loss in MNGIE are consistent with classical mitochondrial optic neuropathies' features. According to the literature, pigmentary retinopathy, optic neuropathy, and abnormal pupillary reflexes are uncommon ocular features of MNGIE. This study contributes to a better understanding of ocular manifestations in MNGIE and demonstrates that MNGIE may have dyschromatopsia and an electronegative electroretinogram.
Subject(s)
Mitochondrial Encephalomyopathies , Ophthalmoplegia , Peripheral Nervous System Diseases , Male , Humans , Adult , Mutation , Mitochondrial Encephalomyopathies/diagnosis , Mitochondrial Encephalomyopathies/genetics , Eye/pathology , Ophthalmoplegia/diagnosis , Ophthalmoplegia/geneticsABSTRACT
OBJECTIVES: Pathogenic variants in AIFM1 have been associated with a wide spectrum of disorders, spanning from CMT4X to mitochondrial encephalopathy. Here we present a novel phenotype and review the existing literature on AIFM1-related disorders. METHODS: We performed EEG recordings, brain MRI and MR Spectroscopy, metabolic screening, echocardiogram, clinical exome sequencing (CES) and family study. Effects of the variant were established on cultured fibroblasts from skin punch biopsy. RESULTS: The patient presented with drug-resistant, electro-clinical, multifocal seizures 6 h after birth. Brain MRI revealed prominent brain swelling of both hemispheres and widespread signal alteration in large part of the cortex and of the thalami, with sparing of the basal nuclei. CES analysis revealed the likely pathogenic variant c.5T>C; p.(Phe2Ser) in the AIFM1 gene. The affected amino acid residue is located in the mitochondrial targeting sequence. Functional studies on cultured fibroblast showed a clear reduction in AIFM1 protein amount and defective activities of respiratory chain complexes I, III and IV. No evidence of protein mislocalization or accumulation of precursor protein was observed. Riboflavin, Coenzyme Q10 and thiamine supplementation was therefore given. At 6 months of age, the patient exhibited microcephaly but did not experience any further deterioration. He is still fed orally and there is no evidence of muscle weakness or atrophy. INTERPRETATION: This is the first AIFM1 case associated with neonatal seizures and diffuse white matter involvement with relative sparing of basal ganglia, in the absence of clinical signs suggestive of myopathy or motor neuron disease.
Subject(s)
Mitochondrial Encephalomyopathies , Motor Neuron Disease , Male , Infant, Newborn , Humans , Mitochondria/genetics , Thiamine , Seizures , Apoptosis Inducing FactorABSTRACT
BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare mitochondrial disease caused by mutations in TYMP, encoding thymidine phosphorylase. Clinically it is characterized by severe gastrointestinal dysmotility associated with cachexia and a demyelinating sensorimotor polyneuropathy. Even though digestive manifestations are progressive and invariably lead to death, the features of gastrointestinal motor dysfunction have not been systematically evaluated. The objective of this study was to describe gastrointestinal motor dysfunction in MNGIE using state-of-the art techniques and to evaluate the relationship between motor abnormalities and symptoms. METHODS: Prospective study evaluating gastrointestinal motor function and digestive symptoms in all patients with MNGIE attended at a national referral center in Spain between January 2018 and July 2022. KEY RESULTS: In this period, five patients diagnosed of MNGIE (age range 16-46 years, four men) were evaluated. Esophageal motility by high-resolution manometry was abnormal in four patients (two hypoperistalsis, two aperistalsis). Gastric emptying by scintigraphy was mildly delayed in four and indicative of gastroparesis in one. In all patients, small bowel high-resolution manometry exhibited a common, distinctive dysmotility pattern, characterized by repetitive bursts of spasmodic contractions, without traces of normal fasting and postprandial motility patterns. Interestingly, objective motor dysfunctions were detected in the absence of severe digestive symptoms. CONCLUSIONS AND INFERENCES: MNGIE patients exhibit a characteristic motor dysfunction, particularly of the small bowel, even in patients with mild digestive symptoms and in the absence of morphological signs of intestinal failure. Since symptoms are not predictive of objective findings, early investigation is indicated.
Subject(s)
Gastrointestinal Diseases , Intestinal Pseudo-Obstruction , Mitochondrial Encephalomyopathies , Male , Humans , Adolescent , Young Adult , Adult , Middle Aged , Prospective Studies , Intestinal Pseudo-Obstruction/genetics , Mitochondrial Encephalomyopathies/diagnosis , Mitochondrial Encephalomyopathies/genetics , Mutation , Gastrointestinal Diseases/geneticsABSTRACT
Biallelic pathogenic variants in subunits of succinyl-CoA synthetase (SCS), a tricarboxylic acid (TCA) cycle enzyme, are associated with mitochondrial encephalomyopathy in humans. SCS catalyzes the interconversion of succinyl-CoA to succinate, coupled to substrate-level phosphorylation of either ADP or GDP, within the TCA cycle. SCS-deficient encephalomyopathy typically presents in infancy and early childhood, with many patients succumbing to the disease during childhood. Common symptoms include abnormal brain MRI, basal ganglia lesions and cerebral atrophy, severe hypotonia, dystonia, progressive psychomotor regression, and growth deficits. Although subunits of SCS were first identified as causal genes for progressive metabolic encephalomyopathy in the early 2000s, recent investigations are now beginning to unravel the pathomechanisms underlying this metabolic disorder. This article reviews the current understanding of SCS function within and outside the TCA cycle as it relates to the complex and multifactorial mechanisms underlying SCS-related mitochondrial encephalomyopathy.
Subject(s)
Mitochondrial Encephalomyopathies , Succinate-CoA Ligases , Child, Preschool , Humans , Mitochondrial Encephalomyopathies/genetics , Mitochondrial Encephalomyopathies/metabolism , Mitochondria/metabolism , Succinate-CoA Ligases/genetics , Succinate-CoA Ligases/metabolism , Oxidative StressABSTRACT
Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is an autosomal recessive disease associated with the mutation of the TYMP gene. MNGIE causes gastrointestinal and neurological symptoms, and the gastrointestinal symptoms are usually notable, which may lead to misdiagnosis. However, we herein report a 29-year-old female who presented with prominent neurological symptoms, while her gastrointestinal symptoms were mild. Brain MRI revealed prominent diffused leukoencephalopathy and peripheral neuropathy was confirmed by the nerve conduction velocity test. Biochemical tests showed elevated plasma thymidine, deoxyuridine, and lactate levels. Molecular genetic testing demonstrated a novel homozygous TYMP c. 447 dupG mutation and the patient's mother was heterozygous for the mutation but had no clinical features. MNGIE was diagnosed based on the results. Unlike other patients who had notable gastrointestinal symptoms, this patient presented with more prominent neurological symptoms than gastrointestinal symptoms, which might have been caused by the novel mutation in the TYMP gene.
Subject(s)
Mitochondrial Encephalomyopathies , Humans , Female , Adult , Mitochondrial Encephalomyopathies/complications , Mitochondrial Encephalomyopathies/diagnosis , Mitochondrial Encephalomyopathies/genetics , Thymidine Phosphorylase/genetics , Mutation/genetics , Genetic TestingABSTRACT
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.