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Background: Anemia exhibits complex causation mechanisms and genetic heterogeneity. Some cases result in poor outcomes with multisystemic dysfunction, including renal tubulopathy. Early diagnosis is crucial to improve management. Case–diagnosis/treatment: A 21-month-old female patient was admitted with severe anemia. Persistent neutropenia and dysplastic signs suggested myelodysplastic syndrome, but targeted gene panel results were negative. After multiple transfusions, spontaneous hematologic recovery was observed. At 4 years old, she presented failure to thrive, renal Fanconi syndrome, and severe metabolic acidosis. Differential diagnosis included Pearson syndrome (PS), a life-threatening condition associated with mitochondrial DNA (mtDNA), featuring anemia and pancreatic insufficiency. Further analysis revealed a ~ 7.5 kb mtDNA deletion. Until the age of 5, supportive care has been provided, without pancreatic insufficiency. Conclusions: This PS case highlights the importance of genetic testing, even in the absence of typical features. Understanding the nature of mitochondrial disorders enables treatment tailoring and counseling about the prognosis. [ABSTRACT FROM AUTHOR]

Abstract Single large‐scale mitochondrial deletion syndromes (SLSMDS) are ultra‐rare, progressive multi‐system diseases that make children largely dependent on their caregivers for both medical and non‐medical needs. Yet, few studies have examined the burden felt among caregivers. As part of a larger research study, 42 caregivers of children with SLSMDS completed two surveys to assess caregiver burden. The Mitochondrial Care Network Patient Needs Survey (MCN‐PNS) is a novel assessment that examines the logistical, time, and financial costs experienced by caregivers of children with SLSMDS. The Zarit Burden Interview (ZBI‐22) is a validated assessment that examines caregivers’ psychological health. Results demonstrate the unique burden experienced by caregivers of children with SLSMDS. One notable finding was the high psychological burden. Nearly 90% of caregivers experience psychological burden, with 20% of caregivers at risk for anxiety and depression. Caregivers were primarily concerned about what the future held for their child. Additional burdens included the time required to coordinate the child's healthcare visits and financial strains. Caregivers reported minimal delays in establishing care with a mitochondrial care specialist and felt confident in their understanding of their child's disease and treatment(s). Overall, there is a need for expanded logistical, financial, and psychological support from mitochondrial disease centers and advocacy groups for caregivers of children with SLSMDS.

Abstract Pearson syndrome (PS) is a rare fatal mitochondrial disorder caused by single large-scale mitochondrial DNA deletions (SLSMDs). Most patients present with anemia in infancy. Bone marrow cytology with vacuolization in erythroid and myeloid precursors and ring-sideroblasts guides to the correct diagnosis, which is established by detection of SLSMDs. Non hematological symptoms suggesting a mitochondrial disease are often lacking at initial presentation, thus PS is an important differential diagnosis in isolated hypogenerative anemia in infancy. Spontaneous resolution of anemia occurs in two-third of patients at the age of 1–3 years, while multisystem non-hematological complications such as failure to thrive, muscle hypotonia, exocrine pancreas insufficiency, renal tubulopathy and cardiac dysfunction develop during the clinical course. Some patients with PS experience a phenotypical change to Kearns-Sayre syndrome. In the absence of curative therapy, the prognosis of patients with PS is dismal. Most patients die of acute lactic acidosis and multi-organ failure in early childhood. There is a great need for the development of novel therapies to alter the natural history of patients with PS.

Pearson syndrome (PS) is a rare fatal mitochondrial disorder caused by single large-scale mitochondrial DNA deletions (SLSMDs). Most patients present with anemia in infancy. Bone marrow cytology with vacuolization in erythroid and myeloid precursors and ring-sideroblasts guides to the correct diagnosis, which is established by detection of SLSMDs. Non hematological symptoms suggesting a mitochondrial disease are often lacking at initial presentation, thus PS is an important differential diagnosis in isolated hypogenerative anemia in infancy. Spontaneous resolution of anemia occurs in two-third of patients at the age of 1-3 years, while multisystem non-hematological complications such as failure to thrive, muscle hypotonia, exocrine pancreas insufficiency, renal tubulopathy and cardiac dysfunction develop during the clinical course. Some patients with PS experience a phenotypical change to Kearns-Sayre syndrome. In the absence of curative therapy, the prognosis of patients with PS is dismal. Most patients die of acute lactic acidosis and multi-organ failure in early childhood. There is a great need for the development of novel therapies to alter the natural history of patients with PS. [ABSTRACT FROM AUTHOR]

Congenital exocrine pancreatic insufficiency is a rare condition. In a vast majority of patients, exocrine dysfunction occurs as part of a multisystemic disease, the most prevalent being cystic fibrosis and Shwachman-Bodian-Diamond syndrome. Recent fundamental studies have increased our understanding of the pathophysiology of these diseases. Exocrine pancreatic dysfunction should be considered in children with failure to thrive and fatty stools. Treatment is mainly supportive and consists of pancreatic enzyme replacement and liposoluble vitamins supplementation.

Fifteen-month-old male child, known to have a congenital bone marrow failure syndrome, presented in a state of shock with severe lactic acidosis following a brief episode of vomiting. Hospital stay was complicated by recurrent bouts of metabolic acidosis and progressive hepatic failure. Blood mitochondrial DNA sequencing revealed a large heteroplasmic 4,977 bp mitochondrial deletion (approximately 40% of all mitochondrial copies) suggestive of Pearson marrow-pancreas syndrome. By virtue of natural disease course, within a month of admission child succumbed to end-stage liver failure with multi-organ failure and died.

This report describes a rare case of fetal anemia, confirmed as a mitochondrial disease after birth, treated with intrauterine transfusion (IUT). Although mitochondrial diseases have been described in newborns, research on their prenatal features is lacking. A patient was referred to our institution at 32 gestational weeks owing to fetal hydrops. Fetal anemia was confirmed by cordocentesis. After IUT had been performed three times, the anemia and associated fetal hydrops showed improvement. However, after birth, the neonate had recurrent pancytopenia and lactic acidosis. He was eventually diagnosed with Pearson syndrome and died 2 months after birth. This is the first case report of fetal anemia associated with mitochondrial disease managed with IUT. [ABSTRACT FROM AUTHOR]

Pearson syndrome is a mitochondrial cytopathy with multisystemic involvement that typically presents in infancy and has poor prognosis. We aim to present a case that is distinct due to the timing of presentation and associated anomalies. We report the case of preterm monochorionic twins with transfusion dependent fetal anemia that had post-natal multisystem dysfunction which led to the diagnosis of Pearson syndrome. This case highlights the possibility of antenatal presentation of Pearson syndrome, which should be considered in cases of severe fetal anemia without an apparent cause. [ABSTRACT FROM AUTHOR]

Pearson syndrome is a rare multisystem disease caused by single large-scale mitochondrial DNA deletions (SLSMDs). The syndrome presents early in infancy and is mainly characterised by refractory sideroblastic anaemia. Prognosis is poor and treatment is supportive, thus the development of new models for the study of Pearson syndrome and new therapy strategies is essential. In this work, we report three different cell models carrying an SLMSD: fibroblasts, transmitochondrial cybrids and induced pluripotent stem cells (iPSCs). All studied models exhibited an aberrant mitochondrial ultrastructure and defective oxidative phosphorylation system function, showing a decrease in different parameters, such as mitochondrial ATP, respiratory complex IV activity and quantity or oxygen consumption. Despite this, iPSCs harbouring ‘common deletion’ were able to differentiate into three germ layers. Additionally, cybrid clones only showed mitochondrial dysfunction when heteroplasmy level reached 70%. Some differences observed among models may depend on their metabolic profile; therefore, we consider that these three models are useful for the in vitro study of Pearson syndrome, as well as for testing new specific therapies. This article has an associated First Person interview with the first author of the paper.

There is a limited understanding of system-level clinical outcomes and interventions associated with single large-scale mitochondrial DNA deletion syndromes (SLSMDS). Additionally, no research exists that describes patient reported outcomes (PROs) of children with SLSMDS. A global and observational registry was established to understand the multi-systemic course of SLSMDS and track clinical outcomes. The development and design of the registry is described. Demographic characteristics, history and diagnoses, and system level prevalence of problems and interventions are reported for 42 children. System level problems and interventions include information on the following body systems: audiology, cardiac, endocrine, gastrointestinal (including pancreatic and hepatobiliary system), hematological, metabolic, neurological (including autonomic, mobility, & learning), ophthalmic, psychiatric, renal, and respiratory. Results emphasize the need of patient registries and suggest that the diagnostic odyssey and burden of disease for children with SLSMDS is significant. System-level findings may help families and clinical providers with diagnosis, prognostication, and treatment. A multidisciplinary team of clinical experts with a central coordinating specialist for children with SLSMDS is recommended. [ABSTRACT FROM AUTHOR]

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. 2 The blood count at initial BM examination is given except for patient PSR23 in whom BM examination was not performed; instead the blood count at time of genetic diagnosis of PS is provided. BM cellularity was studied in BM biopsy in eight patients (§), in the other patients, the cell content was evaluated in BM smears. Keywords: Pearson syndrome; mitochondrial disease; single large-scale mitochondrial DNA deletion; hematological recovery EN Pearson syndrome mitochondrial disease single large-scale mitochondrial DNA deletion hematological recovery 1283 1287 5 06/18/21 20210615 NES 210615 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. [Extracted from the article]

This report describes a rare case of fetal anemia, confirmed as a mitochondrial disease after birth, treated with intrauterine transfusion (IUT). Although mitochondrial diseases have been described in newborns, research on their prenatal features is lacking. A patient was referred to our institution at 32 gestational weeks owing to fetal hydrops. Fetal anemia was confirmed by cordocentesis. After IUT had been performed three times, the anemia and associated fetal hydrops showed improvement. However, after birth, the neonate had recurrent pancytopenia and lactic acidosis. He was eventually diagnosed with Pearson syndrome and died 2 months after birth. This is the first case report of fetal anemia associated with mitochondrial disease managed with IUT.

Pearson syndrome (PS) is a multisystem mitochondrial respiratory chain disorder typically characterized by sideroblastic anemia and exocrine pancreatic insufficiency. PS is caused by a single large‐scale mitochondrial DNA (mtDNA) deletion. PS classically presents in the first year of life and may be fatal in infancy. Children who survive PS may progress to develop Kearns–Sayre syndrome later in life. The full phenotypic spectrum and prognosis of the condition continue to evolve. Here we report five new patients with PS with unique clinical presentations, including four patients with onset later than previously reported in the literature, and one patient with prenatal onset of symptoms. The timing and unique features of these presentations support an expanded phenotypic spectrum of single large‐scale mtDNA deletion syndromes (SLSMDS) and reinforce the importance of including SLSMDS in the differential for children with complex multisystem presentations. [ABSTRACT FROM AUTHOR]

Defects in the mitochondrial genome (mitochondrial DNA (mtDNA)) are associated with both congenital and acquired disorders in humans. Nuclear-encoded DNA polymerase subunit gamma (POLG) plays an important role in mtDNA replication, and proofreading and mutations in POLG have been linked with increased mtDNA deletions. SSBP1 is also a crucial gene for mtDNA replication. Here, we describe a patient diagnosed with Pearson syndrome with large mtDNA deletions that were not detected in the somatic cells of the mother. Exome sequencing was used to evaluate the nuclear factors associated with the patient and his family, which revealed a paternal POLG mutation (c.868C > T) and a maternal SSBP1 mutation (c.320G > A). The patient showed lower POLG and SSBP1 expression than his healthy brothers and the general population of a similar age. Notably, c.868C in the wild-type allele was highly methylated in the patient compared to the same site in both his healthy brothers. These results suggest that the co- deficient expression of POLG and SSBP1 genes could contribute to the development of mtDNA deletion.

The article focuses on Pearson syndrome (PS) is a multisystem disorder characterized by hematological abnormalities, exocrine pancreatic dysfunction, and lactic acidosis. Topics include the symptoms are caused by mitochondrial DNA (mtDNA) deletions, and the establishment of an appropriate diagnosis of PS in newborns is often difficult because its clinical features usually overlap with other common diseases, and typical bone marrow features.

Background: In this retrospective study, we analysed clinical, biochemical and molecular genetic data of 47 Czech patients with Single, Large-Scale Mitochondrial DNA Deletions (SLSMD). Methods: The diagnosis was based on the long-range PCR (LX-PCR) screening of mtDNA isolated from muscle biopsy in 15 patients, and from the buccal swab, urinary epithelial cells and blood in 32 patients. Results: A total of 57% patients manifested before the age of 16. We did not find any significant difference between paediatric and adult manifestation in either the proportion of patients that would develop extraocular symptoms, or the timespan of its progression. The survival rate in patients with Pearson Syndrome reached 60%. Altogether, five patients manifested with atypical phenotype not fulfilling the latest criteria for SLSMD. No correlation was found between the disease severity and all heteroplasmy levels, lengths of the deletion and respiratory chain activities in muscle. Conclusions: Paediatric manifestation of Progressive External Ophthalmoplegia (PEO) is not associated with a higher risk of multisystemic involvement. Contrary to PEO and Kearns-Sayre Syndrome Spectrum, Pearson Syndrome still contributes to a significant childhood mortality. SLSMD should be considered even in cases with atypical presentation. To successfully identify carriers of SLSMD, a repeated combined analysis of buccal swab and urinary epithelial cells is needed.

Pearson syndrome is a genetic disorder caused by mutations in the mitochondrial genome, characterized by failure to thrive with hematological and gastrointestinal abnormalities. Individuals with Pearson syndrome may develop the symptoms and signs of Kearns-Sayre syndrome with multisystem involvement. Spontaneous recovery of hematological problems is reported as is the situation in the present case. The child reported here was born out of in-vitro fertilization. She was maintaining normal hemoglobin level for more than three and a half years but had been detected to have hypoparathyroidism. The diagnosis of Pearson syndrome was confirmed by presence of deletion in mitochondrial genome. Awareness about this rare disorder will help clinicians to broaden their differentials when dealing with common presentations like failure to thrive and anemia. [ABSTRACT FROM AUTHOR]

Pearson syndrome is a rare mitochondrial disorder confirmed by mt-DNA deletion which typically occurs in the first two years of life. That is to say children are at high fatal risk, most infants are marked with some common features especially anemia and pancreatitis, which results in death in early childhood. A 6-month-old Iranian female infant was presented with macrocytic anemia, required packed red blood cell transfusions. She also was affected by exocrine pancreatic dysfunction, in which she underwent Creon treatment. By first year of age she had experienced some severe metabolic crises intermittently. After hospitalized for some months she was expired unfortunately. In conclusion, Pearson syndrome, as a rare disease affects many organs, such as liver, kidney, pancreas, bone marrow, which led to anemia, failure to thrive, and multi organ failure. In such cases, a physician must consider and evaluate all possible damages, especially anemia and pancreatitis. We present a case of Pearson syndrome with anemia. [ABSTRACT FROM AUTHOR]

The article presents a case of a 17-month-old boy with bilateral corneal haze in the course of Pearson syndrome - a rare mitochondrial disease. In this paper the cause, course and ophthalmologic changes in this disease have been cited and discussed. [ABSTRACT FROM AUTHOR]

Single large-scale mitochondrial deletion syndromes (SLSMDS) are ultra-rare, progressive multi-system diseases that make children largely dependent on their caregivers for both medical and non-medical needs. Yet, few studies have examined the burden felt among caregivers. As part of a larger research study, 42 caregivers of children with SLSMDS completed two surveys to assess caregiver burden. The Mitochondrial Care Network Patient Needs Survey (MCN-PNS) is a novel assessment that examines the logistical, time, and financial costs experienced by caregivers of children with SLSMDS. The Zarit Burden Interview (ZBI-22) is a validated assessment that examines caregivers' psychological health. Results demonstrate the unique burden experienced by caregivers of children with SLSMDS. One notable finding was the high psychological burden. Nearly 90% of caregivers experience psychological burden, with 20% of caregivers at risk for anxiety and depression. Caregivers were primarily concerned about what the future held for their child. Additional burdens included the time required to coordinate the child's healthcare visits and financial strains. Caregivers reported minimal delays in establishing care with a mitochondrial care specialist and felt confident in their understanding of their child's disease and treatment(s). Overall, there is a need for expanded logistical, financial, and psychological support from mitochondrial disease centers and advocacy groups for caregivers of children with SLSMDS., Competing Interests: McKenzie Chappell has no disclosures at this time. Elizabeth Reynolds declares she is the founder of The Champ Foundation, is a volunteer, and has no relevant financial conflicts of interest. Dr. Sumit Parikh serves on the Science Advisory Board of The Champ Foundation and principal investigator on the Champ Foundation Registry., (© 2023 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Regulation of mitochondrial respiration and morphology is important for maintaining steady-state hematopoiesis, yet few studies have comparatively evaluated the effects of abnormal mitochondrial respiration and dynamics on blood-cell differentiation in isolation or combination. This study sought to explore these effects in mouse models with one or both of the following deficits: a large-scale deletion of mitochondrial DNA (ΔmtDNA), accumulated to varying extents, or knockout of the mitochondrial fission factor Drp1. Each deficit was found to independently provoke anemia but with clearly different manifestations. The former showed signs of aberrant respiration, analogous to Pearson syndrome, while the latter showed signs of abnormal mitochondrial dynamics and was associated with changes in the relative proportions of leukocyte lineages. Combining these deficits acted to amplify abnormal iron metabolism in erythropoiesis, exacerbating anemia in an additive manner. Our results indicate that mitochondrial respiration and dynamics play distinct roles in different sets of processes and cell lineages in hematopoietic differentiation. [Display omitted] • Mutant mitochondrial DNA (mtDNA) accumulation induces Pearson syndrome-like anemia. • Drp1 knockout induces anemia with changes in proportions of leukocyte lineages. • Drp1 knockout exacerbates anemia induced by mutant mtDNA in an additive manner. • Mitochondrial respiration and dynamics play distinct roles in hematopoietic tissue. [ABSTRACT FROM AUTHOR]

Pearson syndrome (PS) is a rare, mitochondrial DNA (mtDNA) deletion disorder mainly affecting hematopoietic system and exocrine pancreas in early infancy, which is characterized by multi-organ involvement, variable manifestations and poor prognosis. Since the clinical complexity and uncertain outcome of PS, the ability to early diagnose and anticipate disease progression is of great clinical importance. We described a patient with severe anemia and hyperglycinemia at birth was diagnosed with neonatal diabetes mellitus, and later with PS. Genetic testing revealed that a novel mtDNA deletion existed in various non-invasive tissues from the patient. The disease course was monitored by mtDNA deletion heteroplasmy and mtDNA/nucleus DNA genome ratio in different tissues and at different time points, showing a potential genotype–phenotype correlation. Our findings suggest that for patient suspected for PS, it may be therapeutically important to first perform detailed mtDNA analysis on non-invasive tissues at the initial diagnosis and during disease progression. [ABSTRACT FROM AUTHOR]