A new syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction

Pearson, Howard A.; Lobel, Jeffrey S.; Kocoshis, Samuel A.; Naiman, J. Lawrence; Windmiller, Joan; Lammi, Ahti; Hoffman, Ronald; Marsh, John C.

doi:10.1016/s0022-3476(79)80286-3

Cited by 393 publications

(209 citation statements)

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“…Large deletions in mtDNA are the hallmark of Pearson's syndrome, a rare congenital disorder with lactic acidosis, pancreatic insufficiency and sideroblastic anemia (Pearson et al, 1979;Rotig et al, 1991) (Table 1). Sideroblastic anemias are characterized by Fe overload in the mitochondria that are revealed by Perls staining as a ring around the nucleus in basophilic and polychromatophilic erythroblasts (Figure 1).…”

Section: Mitochondrial Dna Mutations In Hematopoietic Cell Aging and mentioning

confidence: 99%

Mitochondria in hematopoiesis and hematological diseases

et al. 2006

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Section: Mitochondrial Dna Mutations In Hematopoietic Cell Aging and mentioning

confidence: 99%

Mitochondria in hematopoiesis and hematological diseases

et al. 2006

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“…Phenotypically, single large‐scale mtDNA deletions are associated with several clinical syndromes including Pearson syndrome,2 Kearns–Sayre syndrome,3 and chronic progressive external ophthalmoplegia (CPEO) 4. A recent prospective study noted ptosis, ophthalmoplegia, muscle weakness, exercise intolerance, and hearing loss as the most common symptoms present at onset 5…”

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confidence: 99%

Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions

Rocha

Rosa

Grady

et al. 2018

Annals of Neurology

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ObjectiveSingle, large‐scale deletions in mitochondrial DNA (mtDNA) are a common cause of mitochondrial disease. This study aimed to investigate the relationship between the genetic defect and molecular phenotype to improve understanding of pathogenic mechanisms associated with single, large‐scale mtDNA deletions in skeletal muscle.MethodsWe investigated 23 muscle biopsies taken from adult patients (6 males/17 females with a mean age of 43 years) with characterized single, large‐scale mtDNA deletions. Mitochondrial respiratory chain deficiency in skeletal muscle biopsies was quantified by immunoreactivity levels for complex I and complex IV proteins. Single muscle fibers with varying degrees of deficiency were selected from 6 patient biopsies for determination of mtDNA deletion level and copy number by quantitative polymerase chain reaction.ResultsWe have defined 3 “classes” of single, large‐scale deletion with distinct patterns of mitochondrial deficiency, determined by the size and location of the deletion. Single fiber analyses showed that fibers with greater respiratory chain deficiency harbored higher levels of mtDNA deletion with an increase in total mtDNA copy number. For the first time, we have demonstrated that threshold levels for complex I and complex IV deficiency differ based on deletion class.InterpretationCombining genetic and immunofluorescent assays, we conclude that thresholds for complex I and complex IV deficiency are modulated by the deletion of complex‐specific protein‐encoding genes. Furthermore, removal of mt‐tRNA genes impacts specific complexes only at high deletion levels, when complex‐specific protein‐encoding genes remain. These novel findings provide valuable insight into the pathogenic mechanisms associated with these mutations. Ann Neurol 2018;83:115–130

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“…Pearson's syndrome is a sporadic infant-onset mitochondrial disorder caused by a heteroplasmic mitochondrial DNA (mtDNA) deletion and characterized by severe anaemia. This multi-organ disorder is often fatal during early years of life 3,4 . These patients have been reported to have vacuolization of bone-marrow precursors 4 , but the pathogenic mechanisms of Pearson's anaemia are unknown.…”

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confidence: 99%

“…This multi-organ disorder is often fatal during early years of life 3,4 . These patients have been reported to have vacuolization of bone-marrow precursors 4 , but the pathogenic mechanisms of Pearson's anaemia are unknown. Some patients recover from the blood manifestation after the first years of life along with the loss of mtDNA deletion in leucocytes 4 .…”

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confidence: 99%

“…These patients have been reported to have vacuolization of bone-marrow precursors 4 , but the pathogenic mechanisms of Pearson's anaemia are unknown. Some patients recover from the blood manifestation after the first years of life along with the loss of mtDNA deletion in leucocytes 4 . Similar to patients with Pearson's syndrome, mice carrying a heteroplasmic primary single mtDNA deletion (Mitomice) develop anaemia and kidney dysfunction, and die at 6 months of age 5,6 .…”

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MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction

et al. 2015

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Haematopoietic progenitor cells show special sensitivity to mitochondrial DNA (mtDNA) mutagenesis, which suggests that increased mtDNA mutagenesis could underlie anemias. Here we show that elevated mtDNA mutagenesis in mice with a proof-reading deficient mtDNA polymerase (PolG) leads to incomplete mitochondrial clearance, with asynchronized iron loading in erythroid precursors, and increased total and free cellular iron content. The resulting Fenton chemistry leads to oxidative damage and premature destruction of erythrocytes by splenic macrophages. Our data indicate that mitochondria actively contribute to their own elimination in reticulocytes and modulate iron loading. Asynchrony of this sequence of events causes severe mitochondrial anaemia by depleting the organism of red blood cells and the bone marrow of iron. Our findings account for the anaemia development in a progeroid mouse model and may have direct relevance to the anemias associated with human mitochondrial disease and ageing.

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A new syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction

Cited by 393 publications

References 30 publications

Mitochondria in hematopoiesis and hematological diseases

Mitochondria in hematopoiesis and hematological diseases

Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions

MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction

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