Pathogenic mitochondrial DNA 3243A&gt;G mutation: From genetics to phenotype

Li, Danyang; Liang, Chunmei; Zhang, Tao; Marley, Jordan Lee; Zou, Weiwei; Lian, Muqing; Ji, Dongmei

doi:10.3389/fgene.2022.951185

Cited by 25 publications

(26 citation statements)

References 113 publications

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“…For the MitoD groups, eligibility criteria for inclusion included the presence of a genetically ascertained diagnosis of symptomatic MitoD, which encompassed either (i) the m.3243A>G pathogenic variant, with 55 or without 54 the clinical manifestations of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), or (ii) a single, large-scale mitochondrial DNA deletion-associated presentation of chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS) 53 , or other syndromic variant. A standardized questionnaire was administered to all participants, collecting essential information including demographic attributes, age, gender, ethnicity, prevailing health status, socioeconomic status, and ongoing medication regimens.…”

Section: Methodsmentioning

confidence: 99%

Psychobiological regulation of plasma and saliva GDF15 dynamics in health and mitochondrial diseases

Huang,

Trumpff,

Monzel

et al. 2024

Preprint

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GDF15 (growth differentiation factor 15) is a marker of cellular energetic stress linked to physical-mental illness, aging, and mortality. However, questions remain about its dynamic properties and measurability in human biofluids other than blood. Here, we examine the natural dynamics and psychobiological regulation of plasma and saliva GDF15 in four human studies representing 4,749 samples from 188 individuals. We show that GDF15 protein is detectable in saliva (8% of plasma concentration), likely produced by salivary glands secretory duct cells. Plasma and saliva GDF15 levels are not correlated. Using a brief laboratory socio-evaluative stressor paradigm, we find that psychological stress increases plasma (+3.4-5.3%) and saliva GDF15 (+45%) with distinct kinetics, within minutes. Moreover, saliva GDF15 exhibits a robust awakening response, declining by ~42-92% within 30-45 minutes from its peak level at the time of waking up. Clinically, individuals with genetic mitochondrial OxPhos diseases show elevated baseline plasma and saliva GDF15, and post-stress GDF15 levels in both biofluids correlate with multi-system disease severity, exercise intolerance, and the subjective experience of fatigue. Taken together, our data establish the dynamic properties of saliva GDF15, reveal it as a stress-sensitive, and as a clinically relevant marker of mitochondrial diseases. These findings point to a shared psychobiological pathway integrating metabolic and mental stress.

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Section: Methodsmentioning

confidence: 99%

Psychobiological regulation of plasma and saliva GDF15 dynamics in health and mitochondrial diseases

Huang,

Trumpff,

Monzel

et al. 2024

Preprint

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“…The link between mitochondrial mutations and diabetes was first published in 1992, when a family with maternally inherited diabetes and deafness (MIDD) was found to harbor an mtDNA deletion [16]. MIDD is now linked to a variety of mitochondrial variants, but $80% of cases are caused by m.3243A>G, which likely alters the structure of tRNA-leu-1 encoded at this position, resulting in mitochondrial translation defects [17][18][19]. This variant is the most common heteroplasmic, pathogenic mtDNA variant and can result in MELAS or MIDD, among other manifestations [20].…”

Section: Diabetes Mellitusmentioning

confidence: 99%

Endocrine features of primary mitochondrial diseases

Romo,

Gold,

Walker

2023

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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Purpose of review Primary mitochondrial diseases are one of the most prevalent groups of multisystem genetic disorders. Endocrinopathies associated with mitochondrial diseases may have clinical features that are distinct from the more common forms. We provide an overview of mitochondrial disorder genetics and phenotypes, focusing on recent studies regarding identification and treatment of associated endocrinopathies. Recent findings Known endocrine phenotypes of mitochondrial disorders continue to expand, and now include growth hormone deficiency, hypogonadism, precocious puberty, hypoparathyroidism, hypo- and hyperthyroidism, diabetes, and adrenal insufficiency. Recent studies suggest several genotype-phenotype correlations, including those related to nuclear variants. Diagnosis is important, as special considerations should be made in the management of endocrinopathies in mitochondrial patients. Finally, new mitochondrial replacement strategies may soon be available for women interested in preventing mitochondrial disease transmission to offspring. Summary Patients with multiple endocrinopathies or atypical endocrinopathies should be evaluated for primary mitochondrial disease, as a diagnosis may impact management of these individuals.

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“…M.3243A>G MT-TL1 prevalence has been reported to be between 0.017% and 0.236% in adults 7 8. The transition of adenine to guanine at nucleotide 3243 in mitochondrial tRNA results in impaired protein formation and ultimately leads to defective formation of complexes 1, 3, 4 and 5 of the OXPHOS system 9 10. The resultant impairment in cellular energy production causes vascular lesions and compromised microvascular perfusion in affected tissues 10 11.…”

Section: Introductionmentioning

confidence: 99%

Late-onset mitochondrial encephalopathy with lactic acidosis and stroke-like episodes and the role of serial imaging

Ambrogetti,

Kavanagh,

ElTayeb

2024

BMJ Case Rep

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Mitochondria are essential for human metabolic function. Over 350 genetic mutations are associated with mitochondrial diseases, which are inherited in a matrilineal fashion. In mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), defective mitochondrial function and resultant impaired cellular energy production compromise vascular perfusion in affected tissues. Early diagnostic criteria suggested the diagnosis should be considered in those under 40. However, a broader range of phenotypes are now recognised, including those that present for the first time later in life. The primary presenting feature in MELAS is a stroke-like episode invariably resulting in patients undergoing neuroradiological imaging. We present a case of a woman with a first presentation of a stroke-like episode and seizures in her 40s who was eventually diagnosed with MELAS. We detail her clinical presentation, treatment and diagnosis, emphasising the role of serial imaging in her diagnosis.

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Pathogenic mitochondrial DNA 3243A>G mutation: From genetics to phenotype

Cited by 25 publications

References 113 publications

Psychobiological regulation of plasma and saliva GDF15 dynamics in health and mitochondrial diseases

Psychobiological regulation of plasma and saliva GDF15 dynamics in health and mitochondrial diseases

Endocrine features of primary mitochondrial diseases

Late-onset mitochondrial encephalopathy with lactic acidosis and stroke-like episodes and the role of serial imaging

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