Search

Life balance is a new and important concept in occupational therapy. New measurements are needed to assess and evaluate life balance and interventions aimed to achieve this concept. This article describes the test-retest reliability of three life balance measures: the Activity Calculator (AC), Activity Card Sort (ACS-NL(18-64)) and Occupational Balance Questionnaire (OBQ11-NL). Data collection took place among 50 participants with neuromuscular diseases: facioscapulohumeral dystrophy (FSHD, n = 25) or mitochondrial myopathy (MM, n = 25). The AC, the ACS-NL(18–64) and the OBQ11-NL were assessed twice with an interval of one week. Intraclass correlation coefficients (ICC-agreement) were applied to examine test-retest reliability. The ICC of the AC-average total day score was.95 (95% CI.91-.97), whereas the ICC of the weights allocated to each activity was 0.80 (95% CI.77–0.82). The ICC of the ACS-NL(18–64) percentage retained activities was 0.92 (95% CI 0.86 − 0.96) and the ICC of the importance score per activity was-.76 (95% CI. 0.68–0.89). The ICC of the OBQ11-NL total score was.76 (95% CI 0.62–0.86). All three tools showed good to excellent test-retest reliability in a sample of patients with FSHD or MM, which is promising for its use in clinical practice and research. The AC, ACS-NL(18–64) and the OBQ11-NL are promising, reliable measures of life balance in patients with neuromuscular diseases. The development of three new instruments for life balance enlarges the possibility for health professionals to measure life balance in clinical practice and research. [ABSTRACT FROM AUTHOR]

Abstract Ferredoxin‐2 (FDX2) is an electron transport protein required for iron–sulfur clusters biosynthesis. Pathogenic variants in FDX2 have been associated with autosomal recessive FDX2‐related disorder characterized by mitochondrial myopathy with or without optic atrophy and leukoencephalopathy. We described a new case harboring compound heterozygous variants in FDX2 who presented with recurrent rhabdomyolysis with severe episodes affecting respiratory muscle. Biochemical analysis of the patients revealed hyperexcretion of 2‐hydroxyadipic acid, along with previously reported biochemical abnormalities. The proband demonstrated increased lactate and creatine kinase (CK) with increased amount of glucose infusion. Lactate and CK drastically decreased when parenteral nutrition containing high protein and lipid contents with low glucose was initiated. Overall, we described a new case of FDX2‐related disorder and compare clinical, biochemical and molecular findings with previously reported cases. We demonstrated that 2‐hydroxyadipic acid biomarker could be used as an adjunct biomarker for FDX2‐related disorder and the use of parenteral nutrition as a treatment option for the patient with FDX2‐related disorder during rhabdomyolysis episode. Highlights 2‐Hydroxyadipic acid can serve as a potential adjunct biomarker for iron‐sulfur assembly defects and lipoic acid biosynthesis disorders. Parenteral nutrition containing high lipid and protein content could be used to reverse acute rhabdomyolysis episodes in the patients with FDX2‐related disorder.

Aging is the major risk factor in most of the leading causes of mortality worldwide, yet its fundamental causes mostly remain unclear. One of the clear hallmarks of aging is mitochondrial dysfunction. Mitochondria are best known for their roles in cellular energy generation, but they are also critical biosynthetic and signaling organelles. They also undergo multiple changes with organismal age, including increased genetic errors in their independent, circular genome. A key group of studies looking at mice with increased mtDNA mutations showed that premature aging phenotypes correlated with increased deletions but not point mutations. This generated an interest in mitochondrial deletions as a potential fundamental cause of aging. However, subsequent studies in different models have yielded diverse results. This review summarizes the research on mitochondrial deletions in various organisms to understand their possible roles in causing aging while identifying the key complications in quantifying deletions across all models. [ABSTRACT FROM AUTHOR]

Mitochondria undergo morphological changes during spermatogenesis in some animals. The mechanism and role of mitochondrial morphology regulation, however, remain somewhat unclear. In this study, we analyzed the molecular characteristics, expression dynamics and subcellular localization of optic atrophy protein 1 (OPA1), a mitochondrial fusion and cristae maintenance-related protein, to reveal the possible regulatory mechanisms underlying mitochondrial morphology in Phascolosoma esculenta spermiogenesis. The full-length cDNA of the P. esculenta opa1 gene (Pe-opa1) is 3 743 bp in length and encodes 975 amino acids. The Pe-OPA1 protein is highly conservative and includes a transmembrane domain, a GTPase domain, two helical bundle domains, and a lipid-interacting stalk. Gene and protein expression was higher in the coelomic fluid (a site of spermatid development) of male P. esculenta and increased first and then decreased from March to December. Moreover, their expression during the breeding stage was significantly higher than during the non-breeding stage, suggesting that Pe-OPA1 is involved in P. esculenta reproduction. The Pe-OPA1 protein was more abundant in components consisting of many spermatids than in components without, indicating that Pe-OPA1 mainly plays a role in the spermatid in coelomic fluid. Moreover, Pe-OPA1 was mainly detected in the spermatid mitochondria. Immunofluorescence experiments showed that the Pe-OPA1 are constitutively expressed and co-localized with mitochondria during spermiogenesis, suggesting its involvement in P. esculenta spermiogenesis. These results provide evidence for Pe-OPA1's involvement in the regulation of mitochondrial morphology during spermiogenesis. [ABSTRACT FROM AUTHOR]

Inflammatory myopathies are autoimmune disorders rarely seen in childhood. Normally high-dose corticosteroid is the current treatment for inflammatory myopathies. For a specific subgroup of patients with inflammatory myopathy with cytochrome oxidase (COX)-negative myofibers that do not typically respond to corticosteroid treatment, and methotrexate (MTX) is used for therapy. Herein we present a 10-year-old girl who initially received clinical diagnosis of juvenile inflammatory myopathy which did not respond to corticosteroid treatment. Examination of her muscle biopsy specimen showed the presence of COX-negative muscle fibers which are very rarely seen in childhood inflammatory myopathies, and she was diagnosed as inflammatory myopathy characterized with COX-negative myofibers. The patient, who recovered with MTX therapy underwent genetic examination 3 years after the treatment was terminated. The sequence analyses of mitochondrial DNA (mtDNA) identified 19 variants in the rRNA, ND2, ND4, ND5, COX1, COX3, and CytB genes of the mtDNA of the patient and her mother. These mutations generally induce the production of synonym amino acids. However, four missense mutations on the ND4, ATP6, and CytB genes have caused structural changes in amino acids. None of these mutations have been previously reported as pathogenic variants. We have thought that these variations in such essential genes might destabilize mtDNA and could probably affect the ATP synthesis in our patient. Our final diagnosis was established based on abnormal inflammatory response induced by a hereditary mtDNA defect in a child with mitochondrial myopathy, rather than an inflammatory myopathy with COX deficiency.

Isolated mitochondrial respiratory chain Complex IV (Cytochrome c Oxidase or COX) deficiency is the second most frequent isolated respiratory chain defect. Causative mutations are mainly identified in structural COX subunits or in proteins involved in the maturation and assembly of the COX holocomplex. We describe an Italian familial case of mitochondrial myopathy due to a variant in the COX assembly factor 8 gene (COA8). Patient 1 is a 52-year-old woman who presented generalized epilepsy and retinitis pigmentosa at 10 years of age. From her early adulthood she complained about cramps and myalgia after exercise, and bilateral hearing loss emerged. Last neurological examination (52 years of age) showed bilateral ptosis, muscle weakness, peripheral neuropathy, mild dysarthria and dysphonia, cognitive impairment. Muscle biopsy had shown the presence of ragged-red fibers. Patient 2 (Patient 1's sister) is a 53-year-old woman presenting fatigability, myalgia, and hearing loss. Neurological examination showed ptosis and muscle weakness. Muscle biopsy displayed a diffuse reduction of COX activity staining and ragged-red fibers. Both sisters presented secondary amenorrhea. After ruling out mtDNA mutations, Whole Exome Sequencing analysis identified the novel homozygous COA8 defect c.170_173dupGACC, p.(Pro59fs) in the probands. Loss-of-function COA8 mutations have been associated with cavitating leukoencephalopathy with COX deficiency in 9 reported individuals. Disease course shows an earlyonset rapid clinical deterioration, affecting both cognitive and motor functions over months, followed by stabilization and slow improvement over several years. Our findings expand the clinical spectrum of COA8-related disease. We confirm the benign course of this rare disorder, highlighting its (intrafamilial) clinical variability. [ABSTRACT FROM AUTHOR]

• Mutations in mitochondrial t-RNA are associated with a complex group of diseases characterized by different clinical presentations and involvement of various organs. The affected tissues are those with higher energy requirement, such as the skeletal muscle, where a defect in the proteins involved in the respiratory chain determines significant impairment of tissue function. Consequently, myopathy is frequently present. • A history of exercise-induced fatigability and swelling of the masseter muscles after prolonged chewing, associated metabolic acidosis with hyperlactatemia, should suggest the presence of a pathogenic variant in the MT-TP gene. • Cardiac involvement may be present in patients with MT-TP mutations, therefore cardiac function should be closely monitored throughout their life. A 16-year-old boy was evaluated for a history of exercise-induced fatigability associated with nausea even after minimal effort, lower limbs muscle hypotrophy, and swelling of the masseter muscles after chewing. Laboratory tests were remarkable for hyperlactatemia and metabolic acidosis after short physical activity. The muscle biopsy showed non-specific mitochondrial alterations and an increase in intrafibral lipids. Biochemical analysis showed reduced activity of the respiratory chain complexes. Mitochondrial DNA sequencing revealed the presence of a homoplasmic variant m.15992A> T in the MT-TP gene, coding for the mt-tRNAPro in the patient, in his mother and in his brother. Pathogenic or likely pathogenic variants in MT-TP gene are rare. They are responsible for different clinical presentation, almost ever involving the muscle tissue. We report the first family with exercise-induced muscle weakness and swelling of the chewing muscles due to m.15992A> T variant in absence of J1c10 haplogroup, confirming its pathogenicity. [ABSTRACT FROM AUTHOR]

Inflammatory myopathies are autoimmune disorders rarely seen in childhood. Normally high-dose corticosteroid is the current treatment for inflammatory myopathies. For a specific subgroup of patients with inflammatory myopathy with cytochrome oxidase (COX)-negative myofibers that do not typically respond to corticosteroid treatment, and methotrexate (MTX) is used for therapy. Herein we present a 10-year-old girl who initially received clinical diagnosis of juvenile inflammatory myopathy which did not respond to corticosteroid treatment. Examination of her muscle biopsy specimen showed the presence of COX-negative muscle fibers which are very rarely seen in childhood inflammatory myopathies, and she was diagnosed as inflammatory myopathy characterized with COX-negative myofibers. The patient, who recovered with MTX therapy underwent genetic examination 3 years after the treatment was terminated. The sequence analyses of mitochondrial DNA (mtDNA) identified 19 variants in the rRNA, ND2, ND4, ND5, COX1, COX3, and CytB genes of the mtDNA of the patient and her mother. These mutations generally induce the production of synonym amino acids. However, four missense mutations on the ND4, ATP6, and CytB genes have caused structural changes in amino acids. None of these mutations have been previously reported as pathogenic variants. We have thought that these variations in such essential genes might destabilize mtDNA and could probably affect the ATP synthesis in our patient. Our final diagnosis was established based on abnormal inflammatory response induced by a hereditary mtDNA defect in a child with mitochondrial myopathy, rather than an inflammatory myopathy with COX deficiency. [ABSTRACT FROM AUTHOR]

Histological assessment of a muscle biopsy is one of the most complex techniques which, currently in the UK, is only provided in very few specialist centres. This requires specialist laboratory skills in handling fresh tissue, freezing under optimal conditions, performing complex histochemical and immunohistochemistry staining on frozen tissue and specialist training for the histopathologists for interpretation and clinicopathological discussion. Access to electron microscopy and Genomic testing is also vital. This review will focus firstly on generic information on clinical indications, specimen handling, panel of histochemical and immunohistochemical stains and histological features of a normal paediatric muscle biopsy. The second section will focus on diagnostic features of a muscle biopsy specifically in the work-up of paediatric neuromuscular and metabolic conditions using case examples. The final section will focus on recent developments in genomic testing and the future prospects of muscle biopsy interpretation. Although complex, muscle biopsy interpretation is mentally stimulating and challenging, and it follows a schematic approach similar to medical liver or renal biopsies. In view of the complexity involved in procuring and handling the sample, muscle biopsy is usually not part of the early stages of work up. This makes it an extremely precious sample, but equally a rewarding exercise when histological interpretation provides the diagnosis and/or guides further genetic testing. [ABSTRACT FROM AUTHOR]

Mitochondrial myopathy is a severe metabolic myopathy related to nuclear or mitochondrial DNA dysfunction. We present a rare case of mitochondrial myopathy, presented with multiple episodes of proximal muscle weakness, lactic acidosis, and severe rhabdomyolysis (CPK 319,990 U/L, lactic acid 22.31 mmol/L, and GFR 3.82 mL/min/1.73m2). She was hospitalized in the pediatric intensive care unit due to acute kidney injury, elevated blood pressure, and deterioration of respiratory and cardiac function. Investigation for inherited metabolic disorders showed elevated levels of ammonia, lactic acid to pyruvic acid ratio, and urine ketone bodies. Exome sequencing detected a homozygous pathogenic variant in FDX2 (ENST00000541276:p.Met4Leu/c.10A > T) and a heterozygous variant of uncertain significance in MSTO1 (ENST00000538143:p.Leu137Pro/c.410 T > C). After Sanger sequencing, the p.Met4Leu pathogenic variant in FDX2 (ENST00000541276:p.Met4Leu/c.10A > T) was identified in a heterozygous state in both her parents and sister. Recently, pathogenic variants in the FDX2 gene have been associated with mitochondrial myopathy, lactic acidosis, optic atrophy, and leukoencephalopathy. Only four reports of FDX2‐related rhabdomyolysis have been described before, but none of the previous patients had hyperammonemia. This is a rare case of severe mitochondrial myopathy in a pediatric patient related to a pathogenic FDX2 variant, suggesting the need for genetic analysis of the FDX2 gene in cases of suspicion of mitochondrial myopathies. [ABSTRACT FROM AUTHOR]

Introduction: Spinal muscular atrophy, Jokela type (SMAJ) is a rare autosomal dominantly hereditary form of spinal muscular atrophy caused by a point mutation c.197G>T in CHCHD10. CHCHD10 is known to be involved in the regulation of mitochondrial function even though patients with SMAJ do not present with multiorgan symptoms of mitochondrial disease. We aimed to characterize the cardiopulmonary oxidative capacity of subjects with SMAJ compared to healthy controls and patients with mitochondrial myopathy. Methods: Eleven patients with genetically verified SMAJ, 26 subjects with mitochondrial myopathy (MM), and 28 healthy volunteers underwent a cardiopulmonary exercise test with lactate and ammonia sampling. The effect of the diagnosis group on the test results was analysed using a linear model. Results: Adjusted for sex, age, and BMI, the SMAJ group had lower power output (p < 0.001), maximal oxygen consumption (VO2 max) (p < 0.001), and mechanical efficiency (p < 0.001) compared to the healthy controls but like that in MM. In the SMAJ group and healthy controls, plasma lactate was lower than in MM measured at rest, light exercise, and 30 min after exercise (p ≤ 0.001-0.030) and otherwise lactate in SMAJ was lower than controls and MM, in longitudinal analysis p = 0.018. In MM, the ventilatory equivalent for oxygen was higher (p = 0.040), and the fraction of end-tidal CO2 lower in maximal exercise compared to healthy controls (p = 0.023) and subjects with SMAJ. Conclusion: In cardiopulmonary exercise test, subjects with SMAJ showed a similar decrease in power output and oxidative capacity as subjects with mitochondrial myopathy but did not exhibit findings typical of mitochondrial disease. [ABSTRACT FROM AUTHOR]

Objectives: Clinical spectrum of mitochondrial myopathy extends beyond chronic progressive external ophthalmoplegia (CPEO). While information on encephalomyopathies is abundant, clinical data on predominant myopathic presentation of mitochondrial disorders are lacking. Materials and Methods: Clinical, electrophysiological, biochemical, and follow-up data of patients with predominant myopathic presentation and muscle biopsy confirmed primary mitochondrial myopathy was obtained. We excluded known syndromes of mitochondrial cytopathies and encephalomyopathies. Results: Among 16 patients, 7 had CPEO, 4 had CPEO with limb-girdle muscle weakness (LGMW), and 5 had isolated LGMW. Systemic features included seizures with photosensitivity (n = 3), diabetes (n = 1), cardiomyopathy (n = 1), and sensorineural hearing loss (n = 1) and were more common in isolated LGMW. Elevated serum creatine kinase (CK) and lactate levels and electromyography (EMG) myopathic potentials were more frequent with LGMW. During follow-up, LGMW had more severe progression of weakness. Conclusion: We identified three subsets of mitochondrial myopathy with distinct clinical features and evolutionary patterns. Isolated LGMW was seen in 30% of patients and would represent severe end of the spectrum. [ABSTRACT FROM AUTHOR]

Ocular involvement has been shown in many of the primary mitochondrial diseases. Herein, we report a pediatric case of an extraordinary fundus appearance of bilateral plaque-like macular atrophy and hypopigmented flecks with homozygous MFF gene mutation. A case report. An eighteen-month-old male infant presented with a lack of object tracking which was recognized in the last few months. Along with regression in normal development, myoclonic epilepsy signs and encephalomyelopathy were detected. Therefore, the patient was evaluated for mitochondrial diseases. Fundus examination revealed bilateral fine hypopigmented lesions in retinal pigment epithelium at midperiphery and periphery. Additionally, there was bilateral geographic atrophy that was separated from the adjacent normal retina with distinct borders in the fovea. Homozygous pT198A (c.592A>G) missense variation was detected in the MFF gene. Maculopathy could be encountered in patients with MFF gene variation. Specific variants or some undiscovered genomic mutations may be the reason for this novel clinical appearance. [ABSTRACT FROM AUTHOR]

Abstract Background Mitochondrial myopathies (MMs) are a group of multi-system diseases caused by abnormalities in mitochondrial DNA (mtDNA) or mutations of nuclear DNA (nDNA). The diagnosis of mitochondrial myopathy (MM) is reliant on the combination of history and physical examination, muscle biopsy, histochemical studies, and next-generation sequencing. Patients with MMs have diverse clinical manifestations. In the contemporary literature, there is a paucity of reports on cardiac structure and function in this rare disease. We report a Chinese man with MM accompanied with both acute right heart failure and left ventricular hypertrophy. Case presentation A 49-year-old man presented with clinical features suggestive of MM, i.e., ophthalmoparesis, weakness of the pharyngeal and extremity muscles, and respiratory muscles which gradually progressed to respiratory insufficiency. He had a family history of mitochondrial myopathy. He had increased levels of serum creatine kinase and lactate. Muscle biopsy of left lateral thigh revealed 8% ragged red fibers (RRF) and 42% COX-negative fibers. Gene sequencing revealed a novel heterozygote TK2 variant (NM_001172644: c.584T>C, p.Leu195Pro) and another heterozygous variant (NM_004614.4:c.156+958G>A; rs1965661603) in the intron of TK2 gene. Based on these findings, we diagnosed the patient as a case of MM. Echocardiography revealed right heart enlargement, pulmonary hypertension, left ventricular hypertrophy, and thickening of the main pulmonary artery and its branches. The patient received non-invasive ventilation and coenzyme Q10 (CoQ10). The cardiac structure and function were restored at 1-month follow-up. Conclusions This is the first report of reversible cardiac function impairment and left ventricular hypertrophy in a case of adult-onset MM, nocturnal hypoxia is a potential mechanism for left ventricular hypertrophy in patients with MM.

Background: Mitochondrial myopathy is a group of diseases caused by abnormal mitochondrial structure or function. The mitochondrial myopathy impacts muscles of the whole body and exhibits variable symptoms. Respiratory muscle deficits deteriorate pulmonary function in patients with severe pneumonia. Case presentation: We report the case of a male patient with severe pneumonia-induced respiratory failure. He was abnormally dependent invasive ventilator-assisted ventilation after his condition had improved. Then we found abnormal ventilator waveform and a decline in muscle strength of him. Mitochondrial myopathy was ultimately confirmed by muscle pathological biopsy and body fluid genetic testing. Vitamin B complex, coenzyme Q10, Neprinol AFD, l-arginine, and MITO-TONIC were used to improve mitochondrial function and muscle metabolism. After treatment, discomfort associated with chest tightness, fatigue, cough, and sputum disappeared, and the patient was discharged. Conclusion: This case presented an uncommon cause of difficult weaning and extubation—acute onset of mitochondrial myopathy. Muscle biopsy and genetic testing of body fluid are essential for diagnosing mitochondrial myopathy. The A3243G mutation in the MT-TL1 gene of mitochondrial DNA contributes to pathogenesis of this case.

Isolated mitochondrial respiratory chain Complex IV (Cytochrome c Oxidase or COX) deficiency is the second most frequent isolated respiratory chain defect. Causative mutations are mainly identified in structural COX subunits or in proteins involved in the maturation and assembly of the COX holocomplex. We describe an Italian familial case of mitochondrial myopathy due to a variant in the COX assembly factor 8 gene (COA8). Patient 1 is a 52-year-old woman who presented generalized epilepsy and retinitis pigmentosa at 10 years of age. From her early adulthood she complained about cramps and myalgia after exercise, and bilateral hearing loss emerged. Last neurological examination (52 years of age) showed bilateral ptosis, muscle weakness, peripheral neuropathy, mild dysarthria and dysphonia, cognitive impairment. Muscle biopsy had shown the presence of ragged-red fibers. Patient 2 (Patient 1’s sister) is a 53-year-old woman presenting fatigability, myalgia, and hearing loss. Neurological examination showed ptosis and muscle weakness. Muscle biopsy displayed a diffuse reduction of COX activity staining and ragged-red fibers. Both sisters presented secondary amenorrhea. After ruling out mtDNA mutations, Whole Exome Sequencing analysis identified the novel homozygous COA8 defect c.170_173dupGACC, p.(Pro59fs) in the probands. Loss-of-function COA8 mutations have been associated with cavitating leukoencephalopathy with COX deficiency in 9 reported individuals. Disease course shows an early-onset rapid clinical deterioration, affecting both cognitive and motor functions over months, followed by stabilization and slow improvement over several years. Our findings expand the clinical spectrum of COA8-related disease. We confirm the benign course of this rare disorder, highlighting its (intrafamilial) clinical variability.

IntroductionSpinal muscular atrophy, Jokela type (SMAJ) is a rare autosomal dominantly hereditary form of spinal muscular atrophy caused by a point mutation c.197G>T in CHCHD10. CHCHD10 is known to be involved in the regulation of mitochondrial function even though patients with SMAJ do not present with multiorgan symptoms of mitochondrial disease. We aimed to characterize the cardiopulmonary oxidative capacity of subjects with SMAJ compared to healthy controls and patients with mitochondrial myopathy.MethodsEleven patients with genetically verified SMAJ, 26 subjects with mitochondrial myopathy (MM), and 28 healthy volunteers underwent a cardiopulmonary exercise test with lactate and ammonia sampling. The effect of the diagnosis group on the test results was analysed using a linear model.ResultsAdjusted for sex, age, and BMI, the SMAJ group had lower power output (p

Mitochondrial diseases are inherited metabolic disorders in which energy metabolism is impaired. They are one of the most prevalent genetic disorders affecting an estimated 1 in every 5000 adults. Impaired energy metabolism because of the mitochondrial or nuclear genome defects results in an increased risk for a wide range of complications affecting every system in the human body. Mitochondrial disorders substantially affect major organs with high metabolic requirements, such as the nervous system, muscles, heart, and gastrointestinal tract. Due to an increased susceptibility to metabolic stress during surgery, patients with mitochondrial diseases require increased consideration during anesthetic management. In this article we would like to discuss the top ten facts you need to know about perioperative management of patienst with mitochondrial disease. [ABSTRACT FROM AUTHOR]

Skeletal muscle is a dynamic organ requiring tight regulation of energy metabolism in order to provide bursts of energy for effective function. Several inborn errors of muscle energy metabolism (IEMEM) affect skeletal muscle function and therefore the ability to initiate and sustain physical activity. Exercise testing can be valuable in supporting diagnosis, however its use remains limited due to the inconsistency in data to inform its application in IEMEM populations. While exercise testing is often used in adults with IEMEM, its use in children is far more limited. Once a physiological limitation has been identified and the aetiology defined, habitual exercise can assist with improving functional capacity, with reports supporting favourable adaptations in adult patients with IEMEM. Despite the potential benefits of structured exercise programs, data in paediatric populations remain limited. This review will focus on the utilisation and limitations of exercise testing and prescription for both adults and children, in the management of McArdle Disease, long chain fatty acid oxidation disorders, and primary mitochondrial myopathies. [ABSTRACT FROM AUTHOR]

Primary mitochondrial myopathies (PMM) are rare disorders with diverse and progressive symptom presentations that cause a substantial, detrimental impact on the quality of life of patients and their caregivers. The burden of symptoms is compounded by their visibility and their unpredictable, progressive nature, leading to a sense of social stigmatization, limited autonomy, social isolation, and grief. There is also a lack of awareness and expertise in the medical community, which presents huge obstacles to diagnosis and provision of coordinated multidisciplinary care for these patients, along with a lack of disease-modifying treatments. The present commentary serves to raise awareness of the challenges faced by patients with PMM and their caregivers in their own words, including diagnostic delays, the burden of disease, and the need for further trials to develop disease-modifying treatments and improved understanding of the disease course. We also provide commentary on considerations for clinical practice, including the need for holistic care and multidisciplinary care teams, details of common 'red flag' symptoms, proposed diagnostic approaches, and suggested descriptions of multisystemic symptoms for physician-patient dialogue. In addition, we highlight the role patient advocacy and support groups play in supporting patients and providing access to reliable, up-to-date information and educational resources on these rare diseases. [ABSTRACT FROM AUTHOR]

Mitochondrial diseases are a heterogeneous group of monogenic disorders that result from impaired oxidative phosphorylation (OXPHOS). As neuromuscular tissues are highly energy‐dependent, mitochondrial diseases often affect skeletal muscle. Although genetic and bioenergetic causes of OXPHOS impairment in human mitochondrial myopathies are well established, there is a limited understanding of metabolic drivers of muscle degeneration. This knowledge gap contributes to the lack of effective treatments for these disorders. Here, we discovered fundamental muscle metabolic remodeling mechanisms shared by mitochondrial disease patients and a mouse model of mitochondrial myopathy. This metabolic remodeling is triggered by a starvation‐like response that evokes accelerated oxidation of amino acids through a truncated Krebs cycle. While initially adaptive, this response evolves in an integrated multiorgan catabolic signaling, lipid store mobilization, and intramuscular lipid accumulation. We show that this multiorgan feed‐forward metabolic response involves leptin and glucocorticoid signaling. This study elucidates systemic metabolic dyshomeostasis mechanisms that underlie human mitochondrial myopathies and identifies potential new targets for metabolic intervention. Synopsis: In patients affected by OXPHOS defects and a mouse model of mitochondrial myopathy, metabolic adaptations initiated by mitochondrial integrated stress response (ISRmt) are part of inter‐organ crosstalk coordinated by myokines and hormonal signaling.In human patients and COX10 KO mice, increased glutamate oxidation and alanine release are adaptive responses to muscle OXPHOS defect.Muscle ISRmt activation and FGF21 release are early events in the COX10 KO mouse.Increased WAT lipolysis and impaired muscle fatty acid oxidation result in adipose store depletion and intramuscular lipid accumulation.Inter‐organ crosstalk through the hypothalamic–pituitary–adrenocortical axis, driven by low leptin, increases glucocorticoids, stimulates lipolysis, and triggers liver ketogenesis, gluconeogenesis, and ureagenesis.Glucocorticoid signaling inhibition by RU486 improves adipose stores in COX10 KO mice. [ABSTRACT FROM AUTHOR]

The diagnosis of primary mitochondrial myopathy is often delayed by years due to non-specific clinical symptoms as well as variable testing of mitochondrial disorders. The aim of this review is to summarize and discuss the collective findings and novel insights regarding the diagnosing, testing, and clinical presentation of primary mitochondrial myopathy (PMM). PMM results from a disruption of the oxidative phosphorylation (OXPHOS) chain in mitochondria due to mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Although there are many named syndromes caused by mitochondrial mutations, this review will focus on PMM, which are mitochondrial disorders mainly affecting, but not limited to, the skeletal muscle. Clinical presentation may include muscle weakness, exercise intolerance, myalgia, and rhabdomyolysis. Although skeletal muscle and respiratory function are most frequently affected due to their high energy demand, multisystem dysfunction may also occur, which may lead to the inclusion of mitochondrial myopathies on the differential. Currently, there are no effective disease-modifying treatments, and treatment programs typically only focus on managing the symptomatic manifestations of the disease. Although the field has a large unmet need regarding treatment options, diagnostic pathways are better understood and can help shorten the diagnostic journey to aid in disease management and clinical trial enrollment.

The article focuses on a retrospective study of 16 patients with mitochondrial myopathy, identifying three subtypes and noting extramuscular manifestations such as seizures and cardiomyopathy. Topics include the limitations of a small sample size affecting the phenotypic spectrum, the need for genetic confirmation and biochemical studies to fully assess mitochondrial defects, and the potential misattribution of respiratory symptoms to myopathy.

Abstract Mitochondrial diseases are a heterogeneous group of monogenic disorders that result from impaired oxidative phosphorylation (OXPHOS). As neuromuscular tissues are highly energy‐dependent, mitochondrial diseases often affect skeletal muscle. Although genetic and bioenergetic causes of OXPHOS impairment in human mitochondrial myopathies are well established, there is a limited understanding of metabolic drivers of muscle degeneration. This knowledge gap contributes to the lack of effective treatments for these disorders. Here, we discovered fundamental muscle metabolic remodeling mechanisms shared by mitochondrial disease patients and a mouse model of mitochondrial myopathy. This metabolic remodeling is triggered by a starvation‐like response that evokes accelerated oxidation of amino acids through a truncated Krebs cycle. While initially adaptive, this response evolves in an integrated multiorgan catabolic signaling, lipid store mobilization, and intramuscular lipid accumulation. We show that this multiorgan feed‐forward metabolic response involves leptin and glucocorticoid signaling. This study elucidates systemic metabolic dyshomeostasis mechanisms that underlie human mitochondrial myopathies and identifies potential new targets for metabolic intervention.

Bilateral lower extremity weakness and swelling can have several causes. Although often underdiagnosed, mitochondrial myopathy is more prevalent in the general population than more commonly suspected diseases, such as Guillain-Barre syndrome. The clinical manifestations of mitochondrial disease can be broadly classified into 3 categories: chronic progressive external ophthalmoplegia, skeletal muscle-central nervous system syndromes, or pure myopathy. Cardiac abnormalities occur in 30% to 32% of cases, mostly in the form of hypertrophic cardiomyopathy, dilated cardiomyopathy, or conduction abnormalities. We report a case of a 21-year-old student who developed bilateral lower limb weakness, pain, and swelling diagnosed with mitochondrial myopathy on muscle biopsy. Initial laboratory tests revealed elevated creatinine kinase, brain natriuretic peptide, troponin, myoglobin, and lactic acid and reduced serum bicarbonate. Cardiac workup revealed systolic heart failure with a reduced ejection fraction. Endomyocardial biopsy revealed punctate foci of lymphocytic myocarditis. However, cardiac magnetic resonance imaging did not reveal either myocarditis or an infiltrative cardiac disease. An extensive autoimmune and infection work-up was negative. A muscle biopsy from the patient's rectus femoris revealed scattered ragged-blue fibers (stained with NADH dehydrogenase), scattered ragged-red fibers on modified Gomori trichrome stain, and cytochrome-c oxidase negative fibers with increased perimysial and endomysial connective tissue, consistent with active and chronic primary mitochondrial myopathy. The patient was treated successfully with furosemide, metoprolol, and methylprednisolone. Adult-onset mitochondrial myopathy is a rare clinical disorder, and our experience stresses the importance of using an inter-disciplinary team approach to diagnose uncommon clinical disorders with widely variable multisystem involvement. [ABSTRACT FROM AUTHOR]

MELAS syndrome is an acronym so named because of the characteristic clinical and pathophysiologic features including mitochondrial encephalo-myopathy, lactic aci- dosis, and stroke-like episodes. As the disorder impacts mitochondrial function and oxidative phosphorylation, clinical symptoms characteristically involve tissues and organ systems with high energy requirements including the skeletal muscle, the heart, and the central nervous sys- tem. Classically considered in the group of disorders known as mitochondrial myopathies, specific periopera- tive concerns must be considered in such patients given the effect of various anesthetic agents including propofol or the volatile anesthetic agents on patients with myopa- thic conditions or disorders of mitochondrial function. We report an 1-year-old with MELAS syndrome who re- quired anesthetic care during eye muscle surgery. Due to potential concerns with volatile anesthetic agents and propofol, we used the novel benzodiazepine, remimazo- lam, with dexmedetomidine and remifentanil to provide maintenance anesthesia. Previous reports of anesthetic care in patients with MELAS syndrome are reviewed and the use of the novel benzodiazepine, remimazolam, is dis- cussed.

Primary mitochondrial myopathies (PMM) are a clinically and genetically highly heterogeneous group that, in some cases, may manifest exclusively as fatigue and exercise intolerance, with minimal or no signs on examination. On these occasions, the symptoms can be confused with the much more common chronic fatigue syndrome (CFS). Nonetheless, other possibilities must be excluded for the final diagnosis of CFS, with PMM being one of the primary differential diagnoses. For this reason, many patients with CFS undergo extensive studies, including extensive genetic testing and muscle biopsies, to rule out this possibility. This study evaluated the diagnostic performance of growth differentiation factor-15 (GDF-15) as a potential biomarker to distinguish which patient with chronic fatigue has a mitochondrial disorder. We studied 34 adult patients with symptoms of fatigue and exercise intolerance with a definitive diagnosis of PMM (7), CFS (22), or other non-mitochondrial disorders (5). The results indicate that GDF-15 can accurately discriminate between patients with PMM and CFS (AUC = 0.95) and between PMM and patients with fatigue due to other non-mitochondrial disorders (AUC = 0.94). Therefore, GDF-15 emerges as a promising biomarker to select which patients with fatigue should undergo further studies to exclude mitochondrial disease. [ABSTRACT FROM AUTHOR]

The diagnosis of primary mitochondrial myopathy is often delayed by years due to non-specific clinical symptoms as well as variable testing of mitochondrial disorders. The aim of this review is to summarize and discuss the collective findings and novel insights regarding the diagnosing, testing, and clinical presentation of primary mitochondrial myopathy (PMM). PMM results from a disruption of the oxidative phosphorylation (OXPHOS) chain in mitochondria due to mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Although there are many named syndromes caused by mitochondrial mutations, this review will focus on PMM, which are mitochondrial disorders mainly affecting, but not limited to, the skeletal muscle. Clinical presentation may include muscle weakness, exercise intolerance, myalgia, and rhabdomyolysis. Although skeletal muscle and respiratory function are most frequently affected due to their high energy demand, multisystem dysfunction may also occur, which may lead to the inclusion of mitochondrial myopathies on the differential. Currently, there are no effective disease-modifying treatments, and treatment programs typically only focus on managing the symptomatic manifestations of the disease. Although the field has a large unmet need regarding treatment options, diagnostic pathways are better understood and can help shorten the diagnostic journey to aid in disease management and clinical trial enrollment. [ABSTRACT FROM AUTHOR]

We identified a case of probable mitochondrial myopathy (MM) in a soldier with dyspnea and reduced exercise tolerance through cardiopulmonary exercise testing (CPET) following Southwest Asia (SWA) deployment. Muscle biopsy showed myopathic features. We compared demographic, occupational exposure, and clinical characteristics in symptomatic military deployers with and without probable MM diagnosed by CPET criteria. We evaluated 235 symptomatic military personnel who deployed to SWA and/or Afghanistan between 2010 and 2021. Of these, 168 underwent cycle ergometer maximal CPET with an indwelling arterial line. We defined probable MM based on five CPET criteria: arterial peak exercise lactate >12 mEq/L, anaerobic threshold (AT) ≤50%, maximum oxygen consumption (VO2max) <95% predicted, oxygen (O2) pulse percent predicted (pp) at least 10% lower than heart rate pp, and elevated ventilatory equivalent for O2 at end exercise (VE/VO2 ≥ 40). We characterized demographics, smoking status/pack‐years, spirometry, and deployment exposures, and used descriptive statistics to compare findings in those with and without probable MM. We found 9/168 (5.4%) deployers with probable MM. Compared to symptomatic deployers without probable MM, they were younger (p = 0.0025) and had lower mean BMI (p = 0.02). They had a higher mean forced expiratory volume (FEV1)pp (p = 0.02) and mean arterial oxygen partial pressure (PaO2) at maximum exercise (p = 0.0003). We found no significant differences in smoking status, deployment frequency/duration, or inhalational exposures. Our findings suggest that mitochondrial myopathy may be a cause of dyspnea and reduced exercise tolerance in a subset of previously deployed military personnel. CPET with arterial line may assist with MM diagnosis and management. After identifying a case of probable mitochondrial myopathy (MM) in a soldier with dyspnea and reduced exercise tolerance on cardiopulmonary exercise testing (CPET), we examined 168 CPETs and identified 9 cases of probable MM. Although there were no significant differences in smoking status, deployment frequency/duration, or inhalational exposures between those with and without probable MM, soldiers with MM were younger, had lower body mass index, higher forced expiratory volume in one second percent predicted values on spirometry and greater mean arterial oxygen partial pressure (PaO2) measurements at maximum exercise than dyspneic soldiers without probable MM. Cardiopulmonary exercise testing may aid in the diagnosis of mitochondrial myopathy in Southwest Asia‐deployed veterans with persistent, disabling and unexplained shortness of breath. [ABSTRACT FROM AUTHOR]

The TRNT1 gene encodes tRNA nucleotidyltransferase 1, which catalyzes the addition of cytosine-cytosine-adenosine (CCA) to the ends of cytoplasmic and mitochondrial tRNAs. The most common clinical phenotype associated with TRNT1 is autosomal recessive sideroblastic anemia with B-cell immunodeficiency, periodic fever, and developmental delay (SIFD). Muscle involvement has rarely been reported in TRNT1-related disorders. Here we report a Chinese patient with incomplete SIFD and hyperCKemia, and explored the skeletal muscle pathological changes. The patient was a 3-year-old boy with sensorineural hearing loss, sideroblastic anemia, and developmental delay since infancy. At the age of 11 months, significantly increased levels of creatine kinase were noted, accompanied by mild muscle weakness. Whole-exome sequencing revealed compound heterozygous variants of the TRNT1 gene, c.443C > T (p.Ala148Val) and c.692C > G (p.Ala231Gly), in the patient. Western blot showed a decreased expression of TRNT1 and cytochrome c oxidase subunit IV (COX IV) in the skeletal muscle of the patient. Electron microscopy observation of skeletal muscle pathology revealed abnormal mitochondria of various sizes and shapes, supporting a diagnosis of mitochondrial myopathy. The present case indicates that in addition to the classic SIFD phenotype, TRNT1 mutations can cause mitochondrial myopathy, a rare clinical phenotype of TRNT1-related disorders.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.1.

Abstract We identified a case of probable mitochondrial myopathy (MM) in a soldier with dyspnea and reduced exercise tolerance through cardiopulmonary exercise testing (CPET) following Southwest Asia (SWA) deployment. Muscle biopsy showed myopathic features. We compared demographic, occupational exposure, and clinical characteristics in symptomatic military deployers with and without probable MM diagnosed by CPET criteria. We evaluated 235 symptomatic military personnel who deployed to SWA and/or Afghanistan between 2010 and 2021. Of these, 168 underwent cycle ergometer maximal CPET with an indwelling arterial line. We defined probable MM based on five CPET criteria: arterial peak exercise lactate >12 mEq/L, anaerobic threshold (AT) ≤50%, maximum oxygen consumption (VO2max)

Abstract Background MtDNA 3243 A > G mutation leads to mitochondrial myopathies with predominant hyperlactatemia. Given the ubiquitous nature of mitochondria, cellular dysfunction can also appear in tissues with high metabolic turnover; thus, there can be cardiac, digestive, ophthalmologic, and kidney complications. MtDNA 3243 A > G mutation has been shown to be with renal involvement in the previous cases of which are FSGS and tubularinterstitial nephritis. Case presentation We report a case of patient who had the mitochondrial myopathy with mitochondrial DNA (mtDNA) 3243 A > G mutation diagnosed membranous nephropathy by kidney biopsy, which was never reported before. Our patient was found to have chest tightness and shortness of breath with hyperlactatemia and was diagnosed mitochondrial myopathy with mtDNA 3243 A > G mutation 11 months ago. Acute kidney injury occurred with hyperuricemia (urid acid 1011umol/L) which may be associated with mtDNA mutation. Since then, persistent proteinuria was also found and the 24-h urine protein quantitative was around 2 g. Kidney biopsy was performed and the result was consistent with membranous nephropathy, with abnormal mitochondria seen in renal tubules by electron microscopy. Conclusions Patients with mitochondrial myopathy could also have renal presentation of membranous nephropathy. Patients with mtDNA mutation may have various renal manifestations so that more attention should be paid on their kidneys.

Abstract By whole-exome sequencing, we found the heterozygous POLG variant c.3542G>A; p.Ser1181Asn in a family of four affected individuals, presenting with a mixed neuro-myopathic phenotype. The variant is located within the active site of polymerase gamma, in a cluster region associated with an autosomal dominant inheritance. In adolescence, the index developed distal atrophies and weakness, sensory loss, afferent ataxia, double vision, and bilateral ptosis. One older sister presented with Charcot-Marie-Tooth-like symptoms, while the youngest sister and father reported exercise-induced muscle pain and proximal weakness. In none of the individuals, we observed any involvement of the central nervous system. Muscle biopsies obtained from the father and the older sister showed ragged-red fibers, and electron microscopy confirmed mitochondrial damage. We conclude that this novel POLG variant explains this family’s phenotype.

Abstract Background Mitochondrial myopathy caused by the long-term use of nucleos(t)ide analogue in patients with chronic hepatitis B (CHB) is mostly characterized by myasthenia and myalgia. Cases with respiratory failure as the prominent manifestation and multisystem symptoms have not been reported. Case report We report a case of mitochondrial myopathy associated with the long-term use of entecavir for CHB. The patient was a 54-year-old male who was treated with entecavir for 9 years. During the treatment, hepatitis B virus (HBV) DNA was negative and liver function was normal. However, generalized fatigue, poor appetite, dysosmia and other discomforts gradually presented starting at the 5th year of treatment, and respiratory failure was the prominent manifestation in the later stage of disease progression. The diagnosis was based on histopathology examination. The dysosmia, hypoxemia and digestive tract symptoms were gradually improved after withdrawal of entecavir. Discussion Mitochondrial myopathy is a rare side effect of entecavir and can be diagnosed by muscle biopsy. Although the incidence is extremely low, but the severe cases can lead to respiratory failure. We should receive adequate attention in clinical practice.

MELAS syndrome is an acronym so named because of the characteristic clinical and pathophysiologic features including mitochondrial encephalo-myopathy, lactic acidosis, and stroke-like episodes. As the disorder impacts mitochondrial function and oxidative phosphorylation, clinical symptoms characteristically involve tissues and organ systems with high energy requirements including the skeletal muscle, the heart, and the central nervous system. Classically considered in the group of disorders known as mitochondrial myopathies, specific perioperative concerns must be considered in such patients given the effect of various anesthetic agents including propofol or the volatile anesthetic agents on patients with myopathic conditions or disorders of mitochondrial function. We report an 1-year-old with MELAS syndrome who required anesthetic care during eye muscle surgery. Due to potential concerns with volatile anesthetic agents and propofol, we used the novel benzodiazepine, remimazolam, with dexmedetomidine and remifentanil to provide maintenance anesthesia. Previous reports of anesthetic care in patients with MELAS syndrome are reviewed and the use of the novel benzodiazepine, remimazolam, is discussed. [ABSTRACT FROM AUTHOR]

Background and objective: TK2 deficiency (TK2d) is a rare mitochondrial disorder that manifests predominantly as a progressive myopathy with a broad spectrum of severity and age of onset. The rate of progression is variable, and the prognosis is poor due to early and severe respiratory involvement. Early and accurate diagnosis is particularly important since a specific treatment is under development. This study aims to evaluate the diagnostic value of lower limb muscle MRI in adult patients with TK2d. Methods: We studied a cohort of 45 genetically confirmed patients with mitochondrial myopathy (16 with mutations in TK2, 9 with mutations in other nuclear genes involved in mitochondrial DNA [mtDNA] synthesis or maintenance, 10 with single mtDNA deletions, and 10 with point mtDNA mutations) to analyze the imaging pattern of fat replacement in lower limb muscles. We compared the identified pattern in patients with TK2d with the MRI pattern of other non-mitochondrial genetic myopathies that share similar clinical characteristics. Results: We found a consistent lower limb muscle MRI pattern in patients with TK2d characterized by involvement of the gluteus maximus, gastrocnemius medialis, and sartorius muscles. The identified pattern in TK2 patients differs from the known radiological involvement of other resembling muscle dystrophies that share clinical features. Conclusions: By analyzing the largest cohort of muscle MRI from patients with mitochondrial myopathies studied to date, we identified a characteristic and specific radiological pattern of muscle involvement in patients with TK2d that could be useful to speed up its diagnosis. [ABSTRACT FROM AUTHOR]

Flavin adenine dinucleotide (FAD) synthase (EC 2.7.7.2), encoded by human flavin adenine dinucleotide synthetase 1 (FLAD1), catalyzes the last step of the pathway converting riboflavin (Rf) into FAD. FLAD1 variations were identified as a cause of LSMFLAD (lipid storage myopathy due to FAD synthase deficiency, OMIM #255100), resembling Multiple Acyl-CoA Dehydrogenase Deficiency, sometimes treatable with high doses of Rf; no alternative therapeutic strategies are available. We describe here cell morphological and mitochondrial alterations in dermal fibroblasts derived from a LSMFLAD patient carrying a homozygous truncating FLAD1 variant (c.745C > T) in exon 2. Despite a severe decrease in FAD synthesis rate, the patient had decreased cellular levels of Rf and flavin mononucleotide and responded to Rf treatment. We hypothesized that disturbed flavin homeostasis and Rf-responsiveness could be due to a secondary impairment in the expression of the Rf transporter 2 (RFVT2), encoded by SLC52A2, in the frame of an adaptive retrograde signaling to mitochondrial dysfunction. Interestingly, an antioxidant response element (ARE) is found in the region upstream of the transcriptional start site of SLC52A2. Accordingly, we found that abnormal mitochondrial morphology and impairments in bioenergetics were accompanied by increased cellular reactive oxygen species content and mtDNA oxidative damage. Concomitantly, an active response to mitochondrial stress is suggested by increased levels of PPARγ-co-activator-1α and Peroxiredoxin III. In this scenario, the treatment with high doses of Rf might compensate for the secondary RFVT2 molecular defect, providing a molecular rationale for the Rf responsiveness in patients with loss of function variants in FLAD1 exon 2. FAD synthase deficiency alters mitochondrial morphology and bioenergetics; FAD synthase deficiency triggers a mitochondrial retrograde response; FAD synthase deficiency evokes nuclear signals that adapt the expression of RFVT2. [ABSTRACT FROM AUTHOR]

Two homoplasmic variants in tRNAGlu (m.14674T>C/G) are associated with reversible infantile respiratory chain deficiency. This study sought to further characterize the expression of the individual mitochondrial respiratory chain complexes and to describe the natural history of the disease. Seven patients from four families with mitochondrial myopathy associated with the homoplasmic m.14674T>C variant were investigated. All patients underwent skeletal muscle biopsy and mtDNA sequencing. Whole‐genome sequencing was performed in one family. Western blot and immunohistochemical analyses were used to characterize the expression of the individual respiratory chain complexes. Patients presented with hypotonia and feeding difficulties within the first weeks or months of life, except for one patient who first showed symptoms at 4 years of age. Histopathological findings in muscle included lipid accumulation, numerous COX‐deficient fibers, and mitochondrial proliferation. Ultrastructural abnormalities included enlarged mitochondria with concentric cristae and dense mitochondrial matrix. The m.14674T>C variant in MT‐TE was identified in all patients. Immunohistochemistry and immunoblotting demonstrated pronounced deficiency of the complex I subunit NDUFB8. The expression of MTCO1, a complex IV subunit, was also decreased, but not to the same extent as NDUFB8. Longitudinal follow‐up data demonstrated that not all features of the disorder are entirely transient, that the disease may be progressive, and that signs and symptoms of myopathy may develop during childhood. This study sheds new light on the involvement of complex I in reversible infantile respiratory chain deficiency, it shows that the disorder may be progressive, and that myopathy can develop without an infantile episode. [ABSTRACT FROM AUTHOR]

Myopathy, lactic acidosis, and sideroblastic anemia 2 (MLASA2) is an autosomal recessive mitochondrial disorder caused by pathogenic variants in YARS2. YARS2 variants confer heterogeneous phenotypes ranging from the full MLASA syndrome to a clinically unaffected state. Symptom onset is most common in the first decade of life but can occur in adulthood and has been reported following intercurrent illness. Early death can result from respiratory muscle weakness and cardiomyopathy. We report a case of MLASA2 with compound heterozygous YARS2 pathogenic variants; a known pathogenic nonsense variant [NM_001040436.3:c.98C>A (p.Ser33Ter)] and a likely pathogenic missense variant not previously associated with disease [NM_001040436.3:c.948G>T (p.Arg316Ser)]. The proband initially presented with a relatively mild phenotype of myopathy and lactic acidosis. During pregnancy, anemia emerged as an additional feature and in the postpartum period she experienced severe decompensation of cardiorespiratory function. This is the first reported case of pregnancy‐related complications in a patient with YARS2‐related mitochondrial disease. This case highlights the need for caution and careful counseling when considering pregnancy in mitochondrial disease, due to the risk of disease exacerbation and pregnancy complications. [ABSTRACT FROM AUTHOR]

Aarskog–Scott syndrome (AAS) is a developmental disorder, caused by disease‐causing hemizygous variants in the FGD1 gene. AAS is characterized by dysmorphic features, genital malformation, skeletal anomalies, and in some cases, intellectual disability and behavioral difficulties. Myopathy has only been reported once in two affected siblings diagnosed with AAS. Only few adult cases have been reported. This article reports four adults with AAS (three male cases and one female carrier) from two unrelated Danish families, all males presented with variable features suggestive of myopathy. All four carried novel hemizygous pathogenic variants in the FGD1 gene; one family presented with the c.2266dup, p.Cys756Leufs*19 variant while the c.527dup; p.Leu177Thrfs*40 variant was detected in the second family. All males had some mild myopathic symptoms or histological abnormalities. Case 1 had the most severe myopathic phenotype with prominent proximal muscular fatigue and exercise intolerance. In addition, he had multiple deletions of mtDNA and low respiratory chain activity. His younger nephew, case 3, had difficulties doing sports in his youth and had a mildly abnormal muscle biopsy and relatively decreased mitochondrial enzyme activity. The singular case from family 2 (case 4), had a mildly myopathic muscle biopsy, but no overt myopathic symptoms. Our findings suggest that myopathic involvement should be considered in AAS. [ABSTRACT FROM AUTHOR]

The mitochondria are responsible for producing energy within the cell, and in mitochondrial myopathy, there is a defect in the energy production process. The CHCHD10 gene codes for a protein called coiled-coil-helix-coiled-coil-helix domain-containing protein 10 (CHCHD10), which is found in the mitochondria and is involved in the regulation of mitochondrial function. G58R mutation has been shown to disrupt the normal function of CHCHD10, leading to mitochondrial dysfunction and ultimately to the development of mitochondrial myopathy. The structures of G58R mutant CHCHD10 and how G58R mutation impacts the wild-type CHCHD10 protein at the monomeric level are unknown. To address this problem, we conducted homology modeling, multiple run molecular dynamics simulations and bioinformatics calculations. We represent herein the structural ensemble properties of the G58R mutant CHCHD10 (CHCHD10 G58R ) in aqueous solution. Moreover, we describe the impacts of G58R mutation on the structural ensembles of wild-type CHCHD10 (CHCHD10 WT ) in aqueous solution. The dynamics properties as well as structural properties of CHCHD10 WT are impacted by the mitochondrial myopathy-related G58R mutation. Specifically, the secondary and tertiary structure properties, root mean square fluctuations, Ramachandran diagrams and results from principal component analysis demonstrate that the CHCHD10 WT and CHCHD10 G58R proteins possess different structural ensemble characteristics and describe the impacts of G58R mutation on CHCHD10 WT . These findings may be helpful for designing new treatments for mitochondrial myopathy.Communicated by Ramaswamy H. Sarma.

Abstract Background No curative therapy for mitochondrial disease (MD) exists, prioritizing supportive treatment for symptom relief. In animal and cell models ketones decrease oxidative stress, increase antioxidants and scavenge free radicals, putting ketogenic diets (KDs) on the list of management options for MD. Furthermore, KDs are well-known, safe and effective treatments for epilepsy, a frequent symptom of MD. This systematic review evaluates efficacy and safety of KD for MD. Methods We searched Pubmed, Cochrane, Embase and Cinahl (November 2020) with search terms linked to MD and KD. From the identified records, we excluded studies on Pyruvate Dehydrogenase Complex deficiency. From these eligible reports, cases without a genetically confirmed diagnosis and cases without sufficient data on KD and clinical course were excluded. The remaining studies were included in the qualitative analysis. Results Only 20 cases (14 pediatric) from the 694 papers identified met the inclusion criteria (one controlled trial (n = 5), 15 case reports). KD led to seizure control in 7 out of 8 cases and improved muscular symptoms in 3 of 10 individuals. In 4 of 20 cases KD reversed the clinical phenotype (e.g. cardiomyopathy, movement disorder). In 5 adults with mitochondrial DNA deletion(s) related myopathy rhabdomyolysis led to cessation of KD. Three individuals with POLG mutations died while being on KD, however, their survival was not different compared to individuals with POLG mutations without KD. Conclusion Data on efficacy and safety of KD for MD is too scarce for general recommendations. KD should be considered in individuals with MD and therapy refractory epilepsy, while KD is contraindicated in mitochondrial DNA deletion(s) related myopathy. When considering KD for MD the high rate of adverse effects should be taken into account, but also spectacular improvements in individual cases. KD is a highly individual management option in this fragile patient group and requires an experienced team. To increase knowledge on this—individually—promising management option more (prospective) studies using adequate outcome measures are crucial.

Orofacial clefts (OFC) are one of the most common birth defects that affects the lip, palate, or lip and palate of an infant. The deterioration of clefts is multifactorial involving multiple genes, various interactions from environmental factor and most forgotten, mitochondrial abnormality. The aim of this review is to highlight the importance of mitochondrial activity related to non-syndromic OFC deformity. Despite its important role in cells, the study on mitochondrial activity in cleft pathology was scarce and almost forgotten compared to other genetic investigations. This systematic review was completed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. The literature search was done via the following databases: Google Scholar, Pubmed and Scopus with a total of nine studies of mitochondrial abnormalities were included. We hypothesise that mitochondria play an important role in early craniofacial development. A decreased in its function or activity may result in cleft lip formation. Hence, we would like to shed light on the remarkable role of mitochondria activity in the pathogenesis of non-syndromic OFC. [ABSTRACT FROM AUTHOR]

Anesthetic management of the patient with mitochondrial disease (MD) requires thoughtful preoperative planning and hypervigilant perioperative monitoring. MD affects 1 in 4,000 persons and is often an unfamiliar topic to the anesthesia provider. This review aims to inform the anesthetist on important considerations in perioperative management of MD. Patients with MD have impaired mitochondrial energy formation pathways affecting function of cardiac, central nervous, and musculoskeletal systems. All general anesthetics interfere with these mitochondrial bioenergetic pathways. MD patients exhibit hypersensitivity to volatile anesthetics. Propofol interferes with mitochondrial function via multiple pathways thus its use should be limited. MD is not at increased risk for malignant hyperthermia and should not be managed with prolonged propofol infusion. Succinylcholine is contraindicated due to hyperkalemia and myotonic risks. Nondepolarizing agents should be used with caution given unpredictable effects. No single anesthetic plan has been found to be safer than another in patients with MD. Intravenous and volatile anesthetics should be titrated incrementally while monitoring anesthetic depth clinically or via processed electroencephalogram (EEG). All MD patients should be optimized by minimizing fasting times, careful fluid selection to avoid lactate, and hypervigilant temperature management aimed at reducing the detrimental effects of catabolic stress during the perioperative period. [ABSTRACT FROM AUTHOR]

Myopathy with extrapyramidal signs (MPXPS) is a rarely reported entity worldwide, manifesting as a muscular dystrophy with movement disorders. It results from mutations in the mitochondrial calcium uptake 1 (MICU1) gene. We hereby describe a 17-year-old boy who presented with proximal myopathy, calf muscle hypertrophy, and skeletal deformities along with choreiform movements of his upper extremities. Muscle MRI revealed a distinctively early involvement of adductors with sparing of antero-lateral compartment of thigh. This report expands the clinico-radiological presentation and to the best of our knowledge, is the first report of MICU-related MPXPS from India. [ABSTRACT FROM AUTHOR]

Retro-mode illumination imaging can provide good visualization of chorio-retinal atrophy and of the retinal pigment epithelial alterations occurring in m.3243A > G associated retinopathy.

• TK2 deficiency (TK2d) can present as a progressive adult-onset myopathy, often leading to premature death from respiratory failure. • Patients with adult-onset TK2d have mtDNA multiple deletions in muscle, without significant reduction in mtDNA copy number. • Early treatment with nucleosides can halt disease progression in severely affected patients with early onset TK2d, but response in adult-onset cases remains uncertain. • We present a patient with adult-onset TK2d treated with nucleosides who shows great improvement in motor function and stabilization of lung function. • The GDF15 levels, a biomarker of mitochondrial dysfunction, normalized after treatment, in paralel with clinical improvement. Thymidine kinase 2 deficiency (TK2d) is a rare autosomal recessive mitochondrial disorder. It manifests as a continuous clinical spectrum, from fatal infantile mitochondrial DNA depletion syndromes to adult-onset mitochondrial myopathies characterized by ophthalmoplegia-plus phenotypes with early respiratory involvement. Treatment with pyrimidine nucleosides has recently shown striking effects on survival and motor outcomes in the more severe infantile-onset clinical forms. We present the response to treatment in a patient with adult-onset TK2d. An adult with ptosis, ophthalmoplegia, facial, neck, and proximal muscle weakness, non-invasive nocturnal mechanical ventilation, and dysphagia due to biallelic pathogenic variants in TK2 received treatment with 260 mg/kg/day of deoxycytidine (dC) and deoxythymidine (dT) under a Compassionate Use Program. Prospective motor and respiratory assessments are presented. After 27 months of follow-up, the North Star Ambulatory Assessment improved by 11 points, he walked 195 m more in the 6 Minute-Walking-Test, ran 10 s faster in the 100-meter time velocity test, and the Forced Vital Capacity stabilized. Growth Differentiation Factor-15 (GDF15) levels, a biomarker of respiratory chain dysfunction, normalized. The only reported side effect was dose-dependent diarrhea. Treatment with dC and dT can significantly improve motor performance and stabilize respiratory function safely in patients with adult-onset TK2d. [ABSTRACT FROM AUTHOR]

Primary mitochondrial myopathies (PMM) are a clinically and genetically highly heterogeneous group that, in some cases, may manifest exclusively as fatigue and exercise intolerance, with minimal or no signs on examination. On these occasions, the symptoms can be confused with the much more common chronic fatigue syndrome (CFS). Nonetheless, other possibilities must be excluded for the final diagnosis of CFS, with PMM being one of the primary differential diagnoses. For this reason, many patients with CFS undergo extensive studies, including extensive genetic testing and muscle biopsies, to rule out this possibility. This study evaluated the diagnostic performance of growth differentiation factor-15 (GDF-15) as a potential biomarker to distinguish which patient with chronic fatigue has a mitochondrial disorder. We studied 34 adult patients with symptoms of fatigue and exercise intolerance with a definitive diagnosis of PMM (7), CFS (22), or other non-mitochondrial disorders (5). The results indicate that GDF-15 can accurately discriminate between patients with PMM and CFS (AUC = 0.95) and between PMM and patients with fatigue due to other non-mitochondrial disorders (AUC = 0.94). Therefore, GDF-15 emerges as a promising biomarker to select which patients with fatigue should undergo further studies to exclude mitochondrial disease.