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Brain Communications 2024Autosomal recessive pathogenetic variants in the gene cause deficiency of deoxyguanosine kinase activity and mitochondrial deoxynucleotides pool imbalance,...
Autosomal recessive pathogenetic variants in the gene cause deficiency of deoxyguanosine kinase activity and mitochondrial deoxynucleotides pool imbalance, consequently, leading to quantitative and/or qualitative impairment of mitochondrial DNA synthesis. Typically, patients present early-onset liver failure with or without neurological involvement and a clinical course rapidly progressing to death. This is an international multicentre study aiming to provide a retrospective natural history of deoxyguanosine kinase deficient patients. A systematic literature review from January 2001 to June 2023 was conducted. Physicians of research centres or clinicians all around the world caring for previously reported patients were contacted to provide followup information or additional clinical, biochemical, histological/histochemical, and molecular genetics data for unreported cases with a confirmed molecular diagnosis of deoxyguanosine kinase deficiency. A cohort of 202 genetically confirmed patients, 36 unreported, and 166 from a systematic literature review, were analyzed. Patients had a neonatal onset (≤ 1 month) in 55.7% of cases, infantile (>1 month and ≤ 1 year) in 32.3%, pediatric (>1 year and ≤18 years) in 2.5% and adult (>18 years) in 9.5%. Kaplan-Meier analysis showed statistically different survival rates ( < 0.0001) among the four age groups with the highest mortality for neonatal onset. Based on the clinical phenotype, we defined four different clinical subtypes: hepatocerebral (58.8%), isolated hepatopathy (21.9%), hepatomyoencephalopathy (9.6%), and isolated myopathy (9.6%). Muscle involvement was predominant in adult-onset cases whereas liver dysfunction causes morbidity and mortality in early-onset patients with a median survival of less than 1 year. No genotype-phenotype correlation was identified. Liver transplant significantly modified the survival rate in 26 treated patients when compared with untreated. Only six patients had additional mild neurological signs after liver transplant. In conclusion, deoxyguanosine kinase deficiency is a disease spectrum with a prevalent liver and brain tissue specificity in neonatal and infantile-onset patients and muscle tissue specificity in adult-onset cases. Our study provides clinical, molecular genetics and biochemical data for early diagnosis, clinical trial planning and immediate intervention with liver transplant and/or nucleoside supplementation.
PubMed: 38756539
DOI: 10.1093/braincomms/fcae160 -
BioRxiv : the Preprint Server For... Apr 2024Barth syndrome (BTHS) is a rare mitochondrial disease caused by pathogenic variants in the gene TAFAZZIN, which leads to abnormal cardiolipin (CL) metabolism on the...
Barth syndrome (BTHS) is a rare mitochondrial disease caused by pathogenic variants in the gene TAFAZZIN, which leads to abnormal cardiolipin (CL) metabolism on the inner mitochondrial membrane. Although is ubiquitously expressed, BTHS involves a complex combination of tissue specific phenotypes including cardiomyopathy, neutropenia, skeletal myopathy, and growth delays, with a relatively minimal neurological burden. To understand both the developmental and functional effects of TAZ-deficiency in different tissues, we generated isogenic TAZ knockout (TAZ- KO) and WT cardiomyocytes (CMs) and neural progenitor cells (NPCs) from CRISPR-edited induced pluripotent stem cells (iPSCs). In TAZ-KO CMs we discovered evidence of dysregulated mitophagy including dysmorphic mitochondria and mitochondrial cristae, differential expression of key autophagy-associated genes, and an inability of TAZ-deficient CMs to properly initiate stress-induced mitophagy. In TAZ-deficient NPCs we identified novel phenotypes including a reduction in CIV abundance and CIV activity in the CIII2&CIV2 intermediate complex. Interestingly, while CL acyl chain manipulation was unable to alter mitophagy defects in TAZ-KO CMs, we found that linoleic acid or oleic acid supplementation was able to partially restore CIV abundance in TAZ-deficient NPCs. Taken together, our results have implications for understanding the tissue-specific pathology of BTHS and potential for tissue-specific therapeutic targeting. Moreover, our results highlight an emerging role for mitophagy in the cardiac pathophysiology of BTHS and reveal a potential neuron-specific bioenergetic phenotype.
PubMed: 38746168
DOI: 10.1101/2024.04.28.591534 -
Nucleic Acids Research Jun 2024Mitochondrial single-stranded DNA-binding protein (mtSSB) is essential for mitochondrial DNA (mtDNA) replication. Recently, several mtSSB variants have been associated...
Mitochondrial single-stranded DNA-binding protein (mtSSB) is essential for mitochondrial DNA (mtDNA) replication. Recently, several mtSSB variants have been associated with autosomal dominant mitochondrial optic atrophy and retinal dystrophy. Here, we have studied at the molecular level the functional consequences of one of the most severe mtSSB variants, R107Q. We first studied the oligomeric state of this variant and observed that the mtSSBR107Q mutant forms stable tetramers in vitro. On the other hand, we showed, using complementary single-molecule approaches, that mtSSBR107Q displays a lower intramolecular ssDNA compaction ability and a higher ssDNA dissociation rate than the WT protein. Real-time competition experiments for ssDNA-binding showed a marked advantage of mtSSBWT over mtSSBR107Q. Combined, these results show that the R107Q mutation significantly impaired the ssDNA-binding and compacting ability of mtSSB, likely by weakening mtSSB ssDNA wrapping efficiency. These features are in line with our molecular modeling of ssDNA on mtSSB showing that the R107Q mutation may destabilize local interactions and results in an electronegative spot that interrupts an ssDNA-interacting-electropositive patch, thus reducing the potential mtSSB-ssDNA interaction sites.
Topics: Humans; DNA, Mitochondrial; DNA, Single-Stranded; DNA-Binding Proteins; Mitochondrial Proteins; Models, Molecular; Mutation; Protein Binding; Protein Structure, Quaternary
PubMed: 38742632
DOI: 10.1093/nar/gkae354 -
EXCLI Journal 2024Peripheral artery disease (PAD) is an atherosclerotic disease impacting over 200 million individuals and the prevalence increases with age. PAD occurs when plaque builds... (Review)
Review
Peripheral artery disease (PAD) is an atherosclerotic disease impacting over 200 million individuals and the prevalence increases with age. PAD occurs when plaque builds up within the peripheral arteries, leading to reduced blood flow and oxygen supply to the outer extremities. Individuals who experience PAD suffer from ischemia, which is typically accompanied by significant damage to skeletal muscles. Additionally, this tissue damage affects mitochondria, causing them to become dysregulated and dysfunctional, resulting in decreased metabolic rates. As there is no known cure for PAD, researchers are exploring potential therapeutic targets by examining coexisting cardiovascular conditions and metabolic risk factors, such as the aging process. Among these comorbidities, type-two diabetes mellitus and obesity are particularly common in PAD cases. These conditions, along with aging itself, are associated with an elevated accumulation of ectopic lipids within skeletal muscles, similar to what is observed in PAD. Researchers have attempted to reduce excess lipid accumulation by increasing the rate of fatty acid beta oxidation. Manipulating acetyl coenzyme A carboxylase 2, a key regulatory protein of fatty acid beta oxidation, has been the primary focus of such research. When acetyl coenzyme A carboxylase 2 is inhibited, it interrupts the conversion of acetyl-CoA into malonyl-CoA, resulting in an increase in the rate of fatty acid beta oxidation. By utilizing samples from PAD patients and applying the pharmacological strategies developed for acetyl coenzyme A carboxylase 2 in diabetes and obesity to PAD, a potential new therapeutic avenue may emerge, offering hope for improved quality of life for individuals suffering from PAD.
PubMed: 38741727
DOI: 10.17179/excli2024-7004 -
Journal of Translational Medicine May 2024Inherited deficiency of thymidine phosphorylase (TP), encoded by TYMP, leads to a rare disease with multiple mitochondrial DNA (mtDNA) abnormalities, mitochondrial...
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.
Topics: Humans; Lysosomes; Thymidine Phosphorylase; Mitochondrial Encephalomyopathies; Fibroblasts; DNA, Mitochondrial; Mitochondria; Nucleosides; Intestinal Pseudo-Obstruction; Ophthalmoplegia; Muscular Dystrophy, Oculopharyngeal; Male; Female; Skin; Lysosomal-Associated Membrane Protein 2
PubMed: 38741129
DOI: 10.1186/s12967-024-05275-8 -
International Journal of Molecular... Apr 2024D-bifunctional protein deficiency (D-BPD) is a rare, autosomal recessive peroxisomal disorder that affects the breakdown of long-chain fatty acids. Patients with D-BPD... (Review)
Review
D-bifunctional protein deficiency (D-BPD) is a rare, autosomal recessive peroxisomal disorder that affects the breakdown of long-chain fatty acids. Patients with D-BPD typically present during the neonatal period with hypotonia, seizures, and facial dysmorphism, followed by severe developmental delay and early mortality. While some patients have survived past two years of age, the detectable enzyme activity in these rare cases was likely a contributing factor. We report a D-BPD case and comment on challenges faced in diagnosis based on a narrative literature review. An overview of Romania's first patient diagnosed with D-BPD is provided, including clinical presentation, imaging, biochemical, molecular data, and clinical course. Establishing a diagnosis can be challenging, as the clinical picture is often incomplete or similar to many other conditions. Our patient was diagnosed with type I D-BPD based on whole-exome sequencing (WES) results revealing a pathogenic frameshift variant of the gene, , , previously identified in another D-BPD patient. WES also identified a variant of the gene with unclear significance. We advocate for using molecular diagnosis in critically ill newborns and infants to improve care, reduce healthcare costs, and allow for familial counseling.
Topics: Humans; Peroxisomal Multifunctional Protein-2; Lipid Metabolism, Inborn Errors; Infant, Newborn; Infant; Male; Female; Exome Sequencing; Frameshift Mutation; 17-Hydroxysteroid Dehydrogenases; Resource-Limited Settings; Mitochondrial Myopathies; Cardiomyopathies; Nervous System Diseases; Mitochondrial Trifunctional Protein; Rhabdomyolysis
PubMed: 38732138
DOI: 10.3390/ijms25094924 -
Frontiers in Neurology 2024Inflammatory myopathy with mitochondrial pathology (IM-Mito) is a rare condition described in a few case series, and it is not clear whether it is a specific disease or...
INTRODUCTION
Inflammatory myopathy with mitochondrial pathology (IM-Mito) is a rare condition described in a few case series, and it is not clear whether it is a specific disease or a variant of Inclusion Body Myositis (IBM). Radiological data of IM-Mito patients has only been evaluated in one study.
AIM
To analyze whole-body muscle magnetic resonance imaging (MRI) features in patients with IM-Mito compared with individuals with IBM.
METHODS
Fourteen IM-Mito and ten IBM patients were included. IM-Mito was defined by endomysial inflammatory infiltrate, presence of at least 1% of Cytochrome C Oxidase negative fibers, and absence of rimmed vacuoles in muscle biopsy; and IBM was defined by the presence of dystrophic muscular abnormalities, endomysial inflammatory infiltrate, and rimmed vacuoles. Patients underwent clinical evaluation and whole-body muscle MRI to determine the presence of edema, and fatty infiltration in various muscles.
RESULTS
Muscle imaging abnormalities were asymmetric in most patients with IM-Mito and IBM. Muscles with the highest average degree of fatty infiltration in both conditions were the quadriceps and medial gastrocnemius. Most patients with IM-Mito and IBM showed imaging patterns of rectus femoris relatively spared compared to other quadriceps muscles. The flexor digitorum profundus was the most affected muscle of the upper limbs in both IBM and IM-Mito.
DISCUSSION
Although the results suggest some similarities in muscle imaging features between IM-Mito and IBM, there remains uncertainty whether these two conditions are part of the same clinical spectrum.
PubMed: 38715692
DOI: 10.3389/fneur.2024.1386293 -
Cureus Mar 2024A 51-year-old woman with mitochondrial myopathy and congestive heart failure with reduced left ventricular ejection fraction was admitted due to loss of appetite and...
A 51-year-old woman with mitochondrial myopathy and congestive heart failure with reduced left ventricular ejection fraction was admitted due to loss of appetite and progressive frailty. She presented with acute kidney injury (AKI) and severe acidemia. Given her medical history and physical examination (jugular vein distention was not obvious), prerenal causes (hypovolemia/hypotension) of AKI were considered most likely. However, with a significantly elevated N-terminal pro-b-type natriuretic peptide level of 14,700 pg/mL, a congestive kidney was also considered. Bedside echocardiography showed no evidence of low output syndrome, whereas venous excess ultrasound (VExUS) score was assessed as Grade 2 (moderate congestion). In addition to administering fluids for the suspected prerenal causes (hypovolemia/hypotension), sodium bicarbonate was administered suspecting a negative impact of severe acidemia on cardiac function. With the improvement of acidemia and only a small volume of fluid therapy, there was a rapid improvement in AKI with the normalization of the VExUS score. This suggested that the main cause of AKI was congestive kidney. In this case, VExUS helped us make a correct diagnosis of acidemia-induced congestive kidney rather than hypovolemia as a cause of AKI, leading to the appropriate treatment.
PubMed: 38681447
DOI: 10.7759/cureus.57096 -
Physiological Reports Apr 2024Desminopathy R350P is a human myopathy that is characterized by the progressive loss of muscle fiber organization. This results in the loss of muscle size, mobility, and...
Desminopathy R350P is a human myopathy that is characterized by the progressive loss of muscle fiber organization. This results in the loss of muscle size, mobility, and strength. In desminopathy, inflammation affects muscle homeostasis and repair, and contributes to progressive muscle deterioration. Mitochondria morphology was also suggested to affect desminopathy progression. Epicatechin (Epi)-a natural compound found in cacao-has been proposed to regulate inflammatory signaling and mitochondria morphology in human and animal models. Hence, we hypothesize chronic Epi consumption to improve inflammatory pathway and mitochondria morphology in the peripheral blood mononuclear cells (PBMCs) of a desminopathy R350P patient. We found that 12 weeks of Epi consumption partially restored TRL4 signaling, indicative of inflammatory signaling and mitochondria morphology in the desminopathy patient. Moreover, Epi consumption improved blood health parameters, including reduced HOMA-IR and IL-6 levels in the desminopathy patient. This indicates that Epi consumption could be a useful tool to slow disease progression in desminopathy patients.
Topics: Humans; Catechin; Leukocytes, Mononuclear; Mitochondria; Male; Muscular Dystrophies; Adult; Female; Inflammation; Cardiomyopathies; Desmin
PubMed: 38658362
DOI: 10.14814/phy2.16020 -
International Journal of Molecular... Mar 2024MELAS syndrome, characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, represents a devastating mitochondrial disease, with... (Review)
Review
MELAS syndrome, characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, represents a devastating mitochondrial disease, with the stroke-like episodes being its primary manifestation. Arginine supplementation has been used and recommended as a treatment for these acute attacks; however, insufficient evidence exists to support this treatment for MELAS. The mechanisms underlying the effect of arginine on MELAS pathophysiology remain unclear, although it is hypothesized that arginine could increase nitric oxide availability and, consequently, enhance blood supply to the brain. A more comprehensive understanding of these mechanisms is necessary to improve treatment strategies, such as dose and regimen adjustments; identify which patients could benefit the most; and establish potential markers for follow-up. This review aims to analyze the existing evidence concerning the mechanisms through which arginine supplementation impacts MELAS pathophysiology and provide the current scenario and perspectives for future investigations.
Topics: Humans; MELAS Syndrome; Acidosis, Lactic; Arginine; Stroke; Dietary Supplements
PubMed: 38612442
DOI: 10.3390/ijms25073629