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Cureus Jan 2024Pathogenic variants in mitochondrial calcium uptake 1 ( manifest phenotypically heterogeneously but most frequently in the brain and skeletal muscle. Dolichocephaly,...
Pathogenic variants in mitochondrial calcium uptake 1 ( manifest phenotypically heterogeneously but most frequently in the brain and skeletal muscle. Dolichocephaly, arachnodactyly, diplopia, and distal myopathy have not been reported in carriers of a pathogenic variant. The patient is a 23-year-old female with consanguineous parents (first cousins) who was a carrier of the homozygous variant c.553C>T, phenotypically presenting with developmental delay, intellectual disability, ataxia, dysmorphia (dolichocephaly, arachnodactyly, clinodactyly, hypertelorism, wide nasal bridge), myopathy (ptosis, double vision, strabismus, distal limb weakness, diffuse wasting, hypotonia), hyperextensible joints and hyperkyphosis. Features not previously described were dolichocephaly, arachnodactyly, broad nasal bridge, double vision, and distal myopathy. She was treated with physical therapy, speech therapy, and occupational therapy and received escitalopram and mirtazapine for concomitant depression, anxiety disorder, and insomnia. The presented case shows that the phenotypic heterogeneity of pathogenic variants is even greater than previously assumed. Treatment of -related phenotypes is symptomatic, but these patients benefit from physical therapy, behavioral therapy, speech therapy, and antidepressant treatment.
PubMed: 38380193
DOI: 10.7759/cureus.52672 -
Iranian Journal of Child Neurology 2024Dihydrolipoamide dehydrogenase (DLD) deficiency is a rare disease of genetic origin due to the malfunctioning of a shared subunit of three mitochondrial multi-enzyme...
Dihydrolipoamide dehydrogenase (DLD) deficiency is a rare disease of genetic origin due to the malfunctioning of a shared subunit of three mitochondrial multi-enzyme complexes. Phenotypes of this disease are a set of clinical manifestations ranging from neonatal disorders to myopathy or recurrent episodes of liver failures, and vomiting for which no adequate or definitive treatment is currently available. This study described a case involving a 16-year-old boy who had experienced recurrent vomiting of unknown cause from age two. Normal value ranges for the basic metabolic panel were reported in previous years. The patient was admitted with Wernicke's encephalopathy after the last vomiting attack, also indicating metabolites of organic acids compatible with DLD deficiency. Whole exome sequencing identified a known pathogenic mutation in the DLD gene, leading to a diagnosis of DLD deficiency. Our patient was treated with a high dose of thiamine supplementation and continued treatment, has not experienced any vomiting attacks or related problems in the last two years and has adequately responded to the treatment prescribed. Normal urine organic acid levels in patients with recurrent vomiting cannot roll out DLD deficiency. However, although thiamine deficiency typically induces Wernicke's encephalopathy, it can also be implicated in pyruvate dehydrogenase complex (PDHc) deficiency, and high-dose thiamine therapy (with doses up to 30 mg/kg) is recommended for deficient patients.
PubMed: 38375122
DOI: 10.22037/ijcn.v18i1.38971 -
Journal of Cardiology Cases Feb 2024Myocardial complications in the setting of inflammatory myopathy associated with anti-mitochondrial antibody (AMA) cause various cardiovascular complications. A...
UNLABELLED
Myocardial complications in the setting of inflammatory myopathy associated with anti-mitochondrial antibody (AMA) cause various cardiovascular complications. A 64-year-old Japanese man was diagnosed with inflammatory myopathy associated with AMA, and three years after diagnosis, the patient was referred to our hospital with leg edema and dyspnea on exertion. Right ventricular endomyocardial biopsy showed no disease-specific findings, with neither inflammatory cell infiltration nor non-caseating epithelioid cell granuloma, and only mild fibrosis; therefore, we finally diagnosed this patient with cardiac involvement in inflammatory myopathy associated with AMA. I-β-methyl--iodophenyl-pentadecanoic acid (BMIPP) cardiac scintigraphy showed decreased uptake in wider areas discordant with late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR). One month after starting prednisolone (PSL), the symptoms of congestive heart failure and left ventricular (LV) systolic function had improved. Additionally, BMIPP uptake in the LV myocardium significantly improved compared to that before PSL administration, although decreased BMIPP uptake remained in areas concordant with LGE on CMR. Moreover, it is suggested that recovery of cardiac metabolic function after high-dose PSL administration, which was confirmed through improvement in BMIPP uptake in the LV myocardium, may have led to the improvement in both LV systolic function and heart failure.
LEARNING OBJECTIVE
Although the definitive diagnosis of cardiac involvement in inflammatory myopathy associated with anti-mitochondrial antibody is difficult because of the rarity of this condition and no disease-specific findings in imaging and histology, physicians should consider this in patients with cardiac dysfunction and muscle weakness. I-β-methyl--iodophenyl-pentadecanoic acid scintigraphy should be used to assess cardiac metabolic function and treatment efficacy and should be considered for patient management.
PubMed: 38362584
DOI: 10.1016/j.jccase.2023.10.014 -
Nefrologia Dec 2023Mitochondrial diseases are a phenotype and genotype heterogeneous group of disorders that typically have a multisystemic involvement. The m.3243A>G pathogenic variant is... (Review)
Review
Mitochondrial diseases are a phenotype and genotype heterogeneous group of disorders that typically have a multisystemic involvement. The m.3243A>G pathogenic variant is the most frequent mitochondrial DNA defect, and it causes several different clinical syndromes, such as mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and the maternally inherited diabetes and deafness (MIDD) syndromes. Not frequently reported, renal involvement in these diseases is probably underestimated, yet it increases morbidity. It generally manifests as subnephrotic proteinuria and progressive deterioration of kidney function. Adult presentation of mitochondrial diseases is hard to recognize, especially in oligosymptomatic patients or those with exclusive kidney involvement. However, suspicion should always arise when family history, particularly on the maternal side, and multisystemic symptoms, most often of the central nervous system and skeletal muscles, are present. In this review we discuss the clinical diagnosis and approach of patients with renal manifestations in the context of the mtDNA m.3243A>G pathogenic variant.
Topics: Adult; Humans; DNA, Mitochondrial; MELAS Syndrome; Mitochondrial Diseases; Diabetes Mellitus, Type 2; Kidney; Hearing Loss, Sensorineural; Deafness
PubMed: 38355238
DOI: 10.1016/j.nefroe.2024.01.017 -
Scientific Reports Feb 2024Previously, we showed that fluvastatin treatment induces myofibrillar damage and mitochondrial phenotypes in the skeletal muscles of Drosophila. However, the sequential...
Previously, we showed that fluvastatin treatment induces myofibrillar damage and mitochondrial phenotypes in the skeletal muscles of Drosophila. However, the sequential occurrence of mitochondrial phenotypes and myofibril damage remains elusive. To address this, we treated flies with fluvastatin for two and five days and examined their thorax flight muscles using confocal microscopy. In the two-day fluvastatin group, compared to the control, thorax flight muscles exhibited mitochondrial morphological changes, including fragmentation, rounding up and reduced content, while myofibrils remained organized in parallel. In the five-day fluvastatin treatment, not only did mitochondrial morphological changes become more pronounced, but myofibrils became severely disorganized with significantly increased thickness and spacing, along with myofilament abnormalities, suggesting myofibril damage. These findings suggest that fluvastatin-induced mitochondrial changes precede myofibril damage. Moreover, in the five-day fluvastatin group, the mitochondria demonstrated elevated HO and impaired fatty acid oxidation compared to the control group, indicating potential mitochondrial dysfunction. Surprisingly, knocking down Hmgcr (Drosophila homolog of HMGCR) showed normal mitochondrial respiration in all parameters compared to controls or five-day fluvastatin treatment, which suggests that fluvastatin-induced mitochondrial dysfunction might be independent of Hmgcr inhibition. These results provide insights into the sequential occurrence of mitochondria and myofibril damage in statin-induced myopathy for future studies.
Topics: Animals; Fluvastatin; Reactive Oxygen Species; Hydrogen Peroxide; Mitochondria; Muscle, Skeletal; Drosophila; Mitochondrial Diseases; Fatty Acids, Monounsaturated
PubMed: 38336990
DOI: 10.1038/s41598-024-53446-w -
The Journal of Biological Chemistry Mar 2024Cardiolipin (CL), the signature lipid of the mitochondrial inner membrane, is critical for maintaining optimal mitochondrial function and bioenergetics. Disruption of CL...
Cardiolipin (CL), the signature lipid of the mitochondrial inner membrane, is critical for maintaining optimal mitochondrial function and bioenergetics. Disruption of CL metabolism, caused by mutations in the CL remodeling enzyme TAFAZZIN, results in the life-threatening disorder Barth syndrome (BTHS). While the clinical manifestations of BTHS, such as dilated cardiomyopathy and skeletal myopathy, point to defects in mitochondrial bioenergetics, the disorder is also characterized by broad metabolic dysregulation, including abnormal levels of metabolites associated with the tricarboxylic acid (TCA) cycle. Recent studies have identified the inhibition of pyruvate dehydrogenase (PDH), the gatekeeper enzyme for TCA cycle carbon influx, as a key deficiency in various BTHS model systems. However, the molecular mechanisms linking aberrant CL remodeling, particularly the primary, direct consequence of reduced tetralinoleoyl-CL (TLCL) levels, to PDH activity deficiency are not yet understood. In the current study, we found that remodeled TLCL promotes PDH function by directly binding to and enhancing the activity of PDH phosphatase 1 (PDP1). This is supported by our findings that TLCL uniquely activates PDH in a dose-dependent manner, TLCL binds to PDP1 in vitro, TLCL-mediated PDH activation is attenuated in the presence of phosphatase inhibitor, and PDP1 activity is decreased in Tafazzin-knockout (TAZ-KO) C2C12 myoblasts. Additionally, we observed decreased mitochondrial calcium levels in TAZ-KO cells and treating TAZ-KO cells with calcium lactate (CaLac) increases mitochondrial calcium and restores PDH activity and mitochondrial oxygen consumption rate. Based on our findings, we conclude that reduced mitochondrial calcium levels and decreased binding of PDP1 to TLCL contribute to decreased PDP1 activity in TAZ-KO cells.
Topics: Acyltransferases; Barth Syndrome; Calcium; Cardiolipins; Mitochondria; Oxidoreductases; Pyruvate Dehydrogenase (Lipoamide)-Phosphatase; Animals; Mice; Gene Knockout Techniques; Protein Binding
PubMed: 38301889
DOI: 10.1016/j.jbc.2024.105697 -
Clinical and Experimental Rheumatology Feb 2024Impairment in cellular bioenergetics as either the cause, consequence, or major contributor of tissue damage has drawn increasing scientific curiosity across aging and... (Review)
Review
Impairment in cellular bioenergetics as either the cause, consequence, or major contributor of tissue damage has drawn increasing scientific curiosity across aging and chronic health conditions, with mitochondrial dysfunction emerging as a central mechanism in the pathogenesis of a variety of inflammatory and degenerative disorders. Beyond bioenergetics, mitochondria play critical regulatory roles in programmed cell death of dysfunctional/defective cells as well as in metabolite synthesis and metabolic signalling. Further, extra-cellular exposure to fragmentation of injured mitochondria is associated with incitement of systemic and organ-based inflammation. Thus, mitochondrial function has recently drawn intense, spectral scientific interest as an integral component across maladies.In muscle, mitochondrial dysfunction is clinically associated with atrophy and diminished endurance. Direct myo-histopathological evidence characterising loss of mitochondrial integrity as a hallmark of muscle compromise was first noticed in inclusion body myositis (IBM). This was followed by the discovery of multiple deletions in mitochondrial DNA in sarcopenia, IBM, and other inflammatory myopathies, like dermatomyositis. Though fraught with bioethical considerations, the transplant technology of mitochondrial transfer is swiftly gaining prominence in cellular biology and muscle physiology to remediate mitochondrial diminution and dysfunction. Assembling seminal works and recent developments, this review ventures into the rapidly evolving landscape of mitochondrial transfer, focusing on its implications on muscle function, and offers an integrated perspective on the potential roles of mitochondrial transfer and its implications for preserving and restoring muscle health. Presented here is a consolidated viewpoint on mitochondrial transfer in idiopathic inflammatory myopathies.
Topics: Humans; Myositis; Mitochondria; Myositis, Inclusion Body; Muscles; Mitochondrial Diseases
PubMed: 38293948
DOI: 10.55563/clinexprheumatol/5lfq5x -
Ophthalmic Genetics Apr 2024To develop an updated staging system for long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency (LCHADD) chorioretinopathy based on contemporary multimodal imaging...
OBJECTIVE
To develop an updated staging system for long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency (LCHADD) chorioretinopathy based on contemporary multimodal imaging and electrophysiology.
METHODS
We evaluated forty cases of patients with genetically confirmed LCHADD or trifunctional protein deficiency (TFPD) enrolled in a prospective natural history study. Wide-field fundus photographs, fundus autofluorescence (FAF), optical coherence tomography (OCT), and full-field electroretinogram (ffERG) were reviewed and graded for severity.
RESULTS
Two independent experts first graded fundus photos and electrophysiology to classify the stage of chorioretinopathy based upon an existing published system. With newer imaging modalities and improved electrophysiology, many patients did not fit cleanly into a single traditional staging group. Therefore, we developed a novel staging system that better delineated the progression of LCHADD retinopathy. We maintained the four previous delineated stages but created substages A and B in stages 2 to 3 to achieve better differentiation.
DISCUSSION
Previous staging systems of LCHADD chorioretinopathy relied on only on the assessment of standard 30 to 45-degree fundus photographs, visual acuity, fluorescein angiography (FA), and ffERG. Advances in recordings of ffERG and multimodal imaging with wider fields of view, allow better assessment of retinal changes. Following these advanced assessments, seven patients did not fit neatly into the original classification system and were therefore recategorized under the new proposed system.
CONCLUSION
The new proposed staging system improves the classification of LCHADD chorioretinopathy, with the potential to lead to a deeper understanding of the disease's progression and serve as a more reliable reference point for future therapeutic research.
Topics: Humans; Prospective Studies; Retinal Diseases; Nervous System Diseases; Retina; Choroid Diseases; Tomography, Optical Coherence; Fluorescein Angiography; Mitochondrial Myopathies; Rhabdomyolysis; Lipid Metabolism, Inborn Errors; Mitochondrial Trifunctional Protein; Cardiomyopathies
PubMed: 38288966
DOI: 10.1080/13816810.2024.2303682 -
Annals of Clinical and Translational... Apr 2024This study aims to elucidate the long-term benefit of newborn screening (NBS) for individuals with long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) and mitochondrial...
OBJECTIVE
This study aims to elucidate the long-term benefit of newborn screening (NBS) for individuals with long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiency, inherited metabolic diseases included in NBS programs worldwide.
METHODS
German national multicenter study of individuals with confirmed LCHAD/MTP deficiency identified by NBS between 1999 and 2020 or selective metabolic screening. Analyses focused on NBS results, confirmatory diagnostics, and long-term clinical outcomes.
RESULTS
Sixty-seven individuals with LCHAD/MTP deficiency were included in the study, thereof 54 identified by NBS. All screened individuals with LCHAD deficiency survived, but four with MTP deficiency (14.8%) died during the study period. Despite NBS and early treatment neonatal decompensations (28%), symptomatic disease course (94%), later metabolic decompensations (80%), cardiomyopathy (28%), myopathy (82%), hepatopathy (32%), retinopathy (17%), and/or neuropathy (22%) occurred. Hospitalization rates were high (up to a mean of 2.4 times/year). Disease courses in screened individuals with LCHAD and MTP deficiency were similar except for neuropathy, occurring earlier in individuals with MTP deficiency (median 3.9 vs. 11.4 years; p = 0.0447). Achievement of dietary goals decreased with age, from 75% in the first year of life to 12% at age 10, and consensus group recommendations on dietary management were often not achieved.
INTERPRETATION
While NBS and early treatment result in improved (neonatal) survival, they cannot reliably prevent long-term morbidity in screened individuals with LCHAD/MTP deficiency, highlighting the urgent need of better therapeutic strategies and the development of disease course-altering treatment.
Topics: Humans; Infant, Newborn; Cardiomyopathies; Fatty Acids; Lipid Metabolism, Inborn Errors; Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase; Mitochondrial Myopathies; Mitochondrial Trifunctional Protein; Nervous System Diseases; Rhabdomyolysis; Infant; Child, Preschool; Child
PubMed: 38263760
DOI: 10.1002/acn3.52002