The presence of anaemia negatively influences survival in patients with POLG disease

Hikmat, Omar; Tzoulis, Charalampos; Klingenberg, Claus; Rasmussen, Magnhild; Tallaksen, Chantal; Brodtkorb, Eylert; Fiskerstrand, Torunn; McFarland, Robert; Rahman, Shamima; Bindoff, Laurence A.

doi:10.1007/s10545-017-0084-9

Cited by 11 publications

(17 citation statements)

References 34 publications

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“…1; Table 2). Other less frequently reported phenotypes include distal myopathy 56 , premature menopause 40,41,57 and cataracts 40,45,56 . Neuropsychiatric manifestations, including recurrent major depression, are well known 15 .…”

Section: [H2] Other Phenotypesmentioning

confidence: 99%

“…One study of POLG-related epilepsy suggested that homozygous mutations in the linker region of the enzyme were associated with later onset and longer survival compared with compound heterozygous mutations affecting the same domain 36,65 . Another study suggested that the presence of anemia correlates with worse outcomes in POLG-related disease 45 . Liver failure in POLGrelated disorders is usually fatal, although one report describes a patient who recovered spontaneously from acute liver failure and remained well 6 years later 96 .…”

Section: [H1] Natural Historymentioning

confidence: 99%

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POLG-related disorders and their neurological manifestations

2018

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The POLG gene encodes the mitochondrial DNA polymerase that is responsible for replication of the mitochondrial genome. Mutations in POLG can cause early childhood mitochondrial DNA (mtDNA) depletion syndromes or later-onset syndromes arising from mtDNA deletions. POLG mutations are the most common cause of inherited mitochondrial disorders, with as many as 2% of the population carrying POLG mutations. POLG-related disorders comprise a continuum of overlapping phenotypes with onset from infancy to late adulthood. The six leading disorders caused by POLG mutations are Alpers-Huttenlocher syndrome, which is one of the most severe phenotypes; childhood myocerebrohepatopathy spectrum, which presents within the first 3 years of life; myoclonic epilepsy myopathy sensory ataxia; ataxia neuropathy spectrum; autosomal recessive progressive external ophthalmoplegia; and Autosomal dominant progressive external ophthalmoplegia. This Review describes the clinical features, pathophysiology, natural history and treatment of POLG-related disorders, focusing particularly on the neurological manifestations of these conditions.

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Section: [H2] Other Phenotypesmentioning

confidence: 99%

Section: [H1] Natural Historymentioning

confidence: 99%

POLG-related disorders and their neurological manifestations

2018

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“…As we observed the IFN-Idependent elevation of Ly6C hi monocytes in mutator mice, it is likely that the restoration of peripheral erythrocyte numbers in Ifnar -/mutator blood is results from less GMP skewing in the bone marrow and reduced destruction of erythrocytes by inflammatory hemophagocytes. Anemia is the most frequent hematological abnormality observed in patients with MD, and the presence of anemia negatively influences survival in patients with POLG-related disease (87,88). Our work provides a strong rationale for translational research to explore whether IFN-I-Nrf2 signaling imbalances potentiate anemia in elderly/frail populations and patients with POLG-related MD.…”

Section: Discussionmentioning

confidence: 79%

Type I interferon potentiates metabolic dysfunction, inflammation, and accelerated aging in mtDNA mutator mice

Lei

Martinez

Torres-Odio

et al. 2020

Preprint

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Mitochondrial dysfunction is a key driver of inflammatory responses in human disease. However, it remains unclear whether alterations in mitochondria-innate immune crosstalk contribute to the pathobiology of mitochondrial disorders and aging. Using the polymerase gamma (POLG) mutator model of mitochondrial DNA (mtDNA) instability, we report that aberrant activation of the type I interferon (IFN-I) innate immune axis potentiates immunometabolic dysfunction, reduces healthspan, and accelerates aging in mutator mice. Mechanistically, elevated IFN-I signaling suppresses activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which increases oxidative stress, enhances pro-inflammatory cytokine responses, and accelerates metabolic dysfunction. Ablation of IFN-I signaling attenuates hyper-inflammatory phenotypes by restoring Nrf2 activity and reducing aerobic glycolysis, which combine to lessen cardiovascular and myeloid dysfunction in aged mutator mice. These findings further advance our knowledge of how mitochondrial dysfunction shapes innate immune responses and provide a framework for understanding mitochondria-driven immunopathology in POLG-related diseases and aging.

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“…Less frequent causes of mitochondrial sideroblastic anaemia include TRNT1 deficiency [78,106] and the syndrome of myopathy, lactic acidosis and sideroblastic anaemia (MLASA), which has been linked to deficiencies of PUS1 and YARS2 [17,108]. Anaemia is a frequent finding in children with mitochondrial disease and is emerging as an adverse prognostic indicator [19]. Interestingly, a laboratory‐based study identified iron as the most important stimulator of mitochondrial biogenesis [110].…”

Section: Other Phenotypes: a Systems Approach To Mitochondrial Diseasmentioning

confidence: 99%