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• W3142015507 abstract "Pearson syndrome (PS), a rare multisystem mitochondrial disorder caused by single large-scale mitochondrial DNA (mtDNA) deletions (SLSMDs), commonly presents with anaemia in infancy.1, 2 Progressive multi-organ dysfunction such as lactic acidosis, pancreatic and renal dysfunction, failure to thrive and endocrine disorders can develop during the course.1, 3 Interestingly, anaemia often resolves spontaneously; the frequency and prognostic impact of this observation is unknown. Patients with PS have a dismal prognosis, most patients die before the age of 5 years.3, 4 The few patients with PS surviving into later childhood develop a Kearns–Sayre syndrome. To date, ~100 cases of PS have been reported in the literature. Here we report on the natural history of 25 patients with PS focussing on the haematological presentation. In 25 cases referred between 1992 and 2019 to our reference centre for undiagnosed cytopenias, a diagnosis of PS was suspected from cytology of peripheral blood (PB) and bone marrow (BM) cells, and subsequently confirmed by detection of SLSMDs in PB with long-range polymerase chain reaction and/or Southern blots following informed consent.4-7 Three of these 25 cases had previously been reported.5-7 Clinical data were collected retrospectively by review of medical charts and documents. The study was approved by the Institutional Ethics Committee (University of Freiburg, 325/20). Anaemia was the first clinical sign in all patients and diagnosed between birth and 31 months of age (median 5 months). In two-thirds of patients (n = 17), anaemia was the only symptom at presentation suggesting that PS should be excluded in all infants with hyporegenerative anaemia of unclear aetiology. One-third of patients (n = 8) had additional symptoms at haematological presentation including failure to thrive (n = 3), feeding difficulties (n = 2), diarrhoea and vomiting (n = 1), intracerebral bleeding (n = 1), lactic acidosis (n = 3) or congenital malformations (n = 1, omphalocele, oesophageal atresia and renal dystopia). The median initial haemoglobin level was 63 (19−98) g/l (Table I). Mean corpuscular volume of red cells and haemoglobin F concentration were increased in 76% and 80% of patients respectively. Most of the patients also had neutropenia and thrombocytopenia. BM cellularity was decreased in nine of the 24 (38%) patients evaluated. These haematological features resemble those of other inherited BM failure syndromes. In particular, Diamond–Blackfan anaemia shares the common features of hyporegenerative anemia in infancy. Indeed, 10 patients in our present cohort had severe erythroid hypoplasia. However, vacuolisation in marrow precursors and ring sideroblasts noted in 100% and 70% of cases in the present cohort respectively, led to the correct diagnosis of PS. Early during the clinical course, all 25 patients required red cell transfusions, and nine received platelet transfusions. Subsequent spontaneous haematological improvement with transfusion independency for both cell lineages was observed in 13 patients (cumulative incidence: 66%; Figure 1a, Figure S1) and generally occurred between 1 and 3 years of age. This has to be kept in mind when considering a possible indication for haematopoietic stem cell transplantation (HSCT) due to persistent cytopenia. None of the patients in the present study had an allogeneic HSCT. Due to the high rate of haematological recovery and the potential risk for irreversible organ damage by chemotherapy prior to HSCT and transplant-related complications, HSCT should not be considered before the age of 3–4 years. The outcomes of five of patients with PS with HSCT reported in the literature were diverse; two died, one developed acute myeloid leukaemia of recipient origin, and two were alive 3 years and 20 months after HSCT respectively.8-11 The mechanism of spontaneous haematological recovery remains obscure; it has been hypothesised that a positive selection of HSCs harbouring a low amount of deleted mtDNA may occur during the course. Indeed, Katada et al., 12 demonstrated in a mouse model of PS that the proportion of deleted mtDNA in blood and liver decreases with age. Similarly, studies in a few patients with PS have shown that the amount of deleted mtDNA in blood cells decreased with improvement of anaemia.13, 14 Interestingly, recent reports have suggested that patients with PS have a risk of clonal evolution with chromosome 7 aberration, but it was not observed in any patient in the present cohort.8, 10, 11 A wide spectrum of non-haematological complications developed during the course (Figure 1b). Most of the patients suffered from failure to thrive (n = 19) and muscle hypotonia (n = 13). Pancreatic insufficiency (n = 14) was the most common organ dysfunction, followed by renal tubulopathy (n = 8), endocrine disorders (n = 7), ophthalmological complications (n = 7), cardiac dysfunction (n = 5) and liver dysfunction (n = 4). Neurological signs in early childhood included mild motor developmental delay (n = 5). In contrast, ataxia (n = 3) appeared at a later age. Episodes of lactic acidosis often associated with infections were documented in 12 patients. The complexity of these organ dysfunctions underscores the importance of multidisciplinary team management of patients with PS. The 5-year overall survival of the cohort was 59% (95% confidential interval 37–81%) without reaching a plateau (Fig 1c); 14 patients had died at a median age of 49 months (range: 7 months to 15·3 years) and 11 patients were alive [last follow-up at a median (range) age of 32 (7–130) months]. The most common cause of death was lactic acidosis (n = 9). Two patients died of respiratory infections, one of liver/renal failure, and two of cardiac disease. There are currently no prediction factors for the outcome and survival of patients with PS. Unfortunately, there has been no apparent improvement in treatment or outcome over time within recent decades. Patients with haematological recovery also developed various non-haematological complications and had a similarly fatal clinical course (Figure 1c). Genotype–phenotype correlation remains controversial,4, 15 and no new conclusions can be drawn from our present data (Table SI). However, it is of interest that the two patients with the shortest mtDNA deletion [1500 base pairs (bp), patient identification number (ID) PSR11] or lowest proportion of mtDNA deletion (50%, patient ID PSR10) in PB both had a late onset of disease and longer survival. Due to the dismal prognosis and lack of effective therapy, patients, families and physicians are desperate to find novel treatments, which can alter the natural history of PS. New technologies of cell therapy will hopefully open a life-saving therapeutic window. The authors thank all patients and their families, as well as treating physicians. The authors acknowledge the support of Dr Ekkehard Wilichowski (University of Göttingen, Göttingen, Germany), Dr Elke Holinski-Feder (MGZ – Medizinisch Genetisches Zentrum, Munich, Germany) and Dr Ekkehart Lausch (University of Freiburg, Freiburg, Germany) for the genetic analysis and Dr Miriam Erlacher, Dr Brigitte Strahm and Dr Miriam van Buiren (University of Freiburg, Freiburg, Germany) and Dr Kyogo Suzuki (Nagoya University, Nagoya, Japan) for data collection and Mr Peter Nöllke (University of Freiburg, Freiburg, Germany) for the statistical analysis. We would like to thank Dr Kaori Ishikawa and Dr Kazuto Nakada (University of Tsukuba, Tsukuba, Japan), and Dr Yu-ichi Goto (National Center of Neurology and Psychiatry, Tokyo, Japan) for their advice and helpful discussions about PS. Ayami Yoshimi and Charlotte M. Niemeyer conceptualised and designed the study. Ayami Yoshimi, Sarah C. Grünert, Holger Cario, Aron Fisch, Ute Gross-Wieltsch, Kirsten Timmermann, Udo Kontny, Stephan Lobitz, Helen S. Odenthal, Irene Schmid, Barbara Uetz, Tanja Höll, Agnès Rötig, Thomas Lücke, Arndt Borkhardt, Gabriele Strauß, Alexander Hohnecker, Markus Metzler, Daniela Karall, Charlotte M. Niemeyer contributed to the enrolment of patients, diagnostic procedures and data collections. Ayami Yoshimi drafted the initial manuscript. All authors critically reviewed the paper. Table SI. Mitochondrial landscape with respect to patient’s age and outcome. Fig S1. Haemoglobin (Hb) concentration, leukocyte count and platelet count of patient PSR8 with haematological recovery. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W3142015507 title "Haematological characteristics and spontaneous haematological recovery in Pearson syndrome" @default.
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