Atypical presentation of Pearson syndrome in an infant with suspected myelodysplastic syndrome.

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.

Understanding the impact of pediatric single large-scale mtDNA deletion syndromes on caregivers: Burdens and challenges.

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.

Pearson syndrome: a multisystem mitochondrial disease with bone marrow failure.

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-like anemia induced by accumulation of mutant mtDNA and anemia with imbalanced white blood cell lineages induced by Drp1 deletion in a murine model.

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.

Congenital etiologies of exocrine pancreatic insufficiency.

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.

Case Report: Clinical and Genetic Characteristics of Pearson Syndrome in a Chinese Boy and 139 Patients.

Background: Pearson's syndrome (PS) is a rare multi-system disorder caused by mitochondrial DNA deletion. Most PS cases in the literature are individual reports, and there is a lack of systematic analysis of clinical features and gene mutations in large samples. Objective: To report a case of PS and summarize the clinical features and genetic characteristics of PS by reviewing the literature. Methods: We reported a case of PS in a boy with severe anemia and multi-system disorder. Genetic etiology was identified by mitochondrial DNA sequencing and whole-exon sequencing. Clinical features and gene mutations were summarized by literature review. Results: The patient had major clinical manifestations with recurrent anemia and multiple organ failure after infection. Mitochondrial DNA sequencing revealed a de novo heteroplasmic deletion of 3.063 kb (nt 6,224-9,287) with 75% heteroplasmy in peripheral blood. A total of 139 PS cases were retrieved after a literature search. The most common initial symptom was refractory anemia requiring repeated blood transfusion (86.2%), digestive system symptoms (26.9%), and failure to thrive (15.4%). During the course of disease, the observed symptoms were bone marrow failure (100%), metabolic disorders (61.87%) and gastrointestinal symptoms (61.87%), failure to thrive (48.9%), renal disorders (42.45%), and pancreatic exocrine insufficiency (39.6%). The mean heteroplasmy of mitochondrial DNA mutation in peripheral blood in deaths (76.29 ± 11.86%, n = 29) was higher than that in survivals (59.92 ± 23.87%, n = 26, p < 0.01). Among the patients with the 4.977 kb deletion, the heteroplasmy in peripheral blood in deaths (79.64 ± 9.71%, n = 11) was higher than that in survivals (56.67 ± 27.65%, n = 9, p < 0.05). Conclusion: PS can affect multiple systems, and mitochondrial DNA sequencing should be performed early. The heteroplasmy in peripheral blood is related to prognosis.

Extremely Rare Case of Fetal Anemia Due to Mitochondrial Disease Managed with Intrauterine Transfusion.

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.

Development and characterization of cell models harbouring mtDNA deletions for in vitro study of Pearson syndrome.

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.

Mitochondrial hepatopathy: Respiratory chain disorders- 'breathing in and out of the liver'.

Mitochondria, the powerhouse of a cell, are closely linked to the pathophysiology of various common as well as not so uncommon disorders of the liver and beyond. Evolution supports a prokaryotic descent, and, unsurprisingly, the organelle is worthy of being labeled an organism in itself. Since highly metabolically active organs require a continuous feed of energy, any dysfunction in the structure and function of mitochondria can have variable impact, with the worse end of the spectrum producing catastrophic consequences with a multisystem predisposition. Though categorized a hepatopathy, mitochondrial respiratory chain defects are not limited to the liver in time and space. The liver involvement is also variable in clinical presentation as well as in age of onset, from acute liver failure, cholestasis, or chronic liver disease. Other organs like eye, muscle, central and peripheral nervous system, gastrointestinal tract, hematological, endocrine, and renal systems are also variably involved. Diagnosis hinges on recognition of subtle clinical clues, screening metabolic investigations, evaluation of the extra-hepatic involvement, and role of genetics and tissue diagnosis. Treatment is aimed at both circumventing the acute metabolic crisis and long-term management including nutritional rehabilitation. This review lists and discusses the burden of mitochondrial respiratory chain defects, including various settings when to suspect, their evolution with time, including certain specific disorders, their tiered evaluation with diagnostic algorithms, management dilemmas, role of liver transplantation, and the future research tools.

Pediatric single large-scale mtDNA deletion syndromes: The power of patient reported outcomes.

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.

Pearson syndrome in a child transplanted for Diamond-Blackfan anemia. / Síndrome de Pearson en un niño trasplantado debido a anemia de Diamond-Blackfan.

Pearson syndrome (PS), shares a number of overlapping features with Diamond-Blackfan anemia (DBA), including early onset of severe anemia, making differential diagnosis important. Differential diagnosis of DBA and PS is critical, since those with DBA may respond to treatment with steroids, may undergo remission, or may benefit from hematopoietic stem cell transplantation (HSCT). However, patients with PS have a different prognosis, with a very high risk of developing acidosis, metabolic problems, and pancreatic dysfunction, and a shorter life expectancy than those with DBA. Here we present a patient who underwent HSCT for DBA but was subsequently diagnosed with PS after developing some complications.

El síndrome de Pearson (SP) comparte varias características con la anemia de Diamond-Blackfan (ADB), incluida la anemia grave de inicio temprano, por lo que es importante hacer un diagnóstico diferencial. El diagnóstico diferencial de la ADB y el SP es fundamental, ya que los pacientes con ADB podrían responder al tratamiento con corticoesteroides, presentar remisión o beneficiarse del trasplante de células madre hematopoyéticas (TCMH). Sin embargo, los pacientes con SP tienen un pronóstico diferente, con un riesgo muy elevado de acidosis, problemas metabólicos y disfunción pancreática, y una expectativa de vida menor en comparación con aquellos con ADB. En este artículo, presentamos el caso de un paciente sometido a TCMH para la ADB, pero que luego fue diagnosticado con SP tras desarrollar algunas complicaciones.

Two Novel Variants in YARS2 Gene Are Responsible for an Extended MLASA Phenotype with Pancreatic Insufficiency.

Pathogenic variants in the mitochondrial tyrosyl-tRNA synthetase gene (YARS2) were associated with myopathy, lactic acidosis, and sideroblastic anemia (MLASA). However, patients can present mitochondrial myopathy, with exercise intolerance and muscle weakness, leading from mild to lethal phenotypes. Genes implicated in mtDNA replication were studied by Next Generation Sequencing (NGS) and whole exome sequence with the TruSeq Rapid Exome kit (Illumina, San Diego, CA, USA). Mitochondrial protein translation was studied following the Sasarman and Shoubridge protocol and oxygen consumption rates with Agilent Seahorse XF24 Analyzer Mitostress Test, (Agilent, Santa Clara, CA, USA). We report two siblings with two novel compound heterozygous pathogenic variants in YARS2 gene: a single nucleotide deletion in exon 1, c.314delG (p.(Gly105Alafs*4)), which creates a premature stop codon in the amino acid 109, and a single nucleotide change in exon 5 c.1391T>C (p.(Ile464Thr)), that cause a missense variant in amino acid 464. We demonstrate the pathogenicity of these new variants associated with reduced YARS2 mRNA transcript, reduced mitochondrial protein translation and dysfunctional organelle function. These pathogenic variants are responsible for late onset MLASA, herein accompanied by pancreatic insufficiency, observed in both brothers, clinically considered as Pearson's syndrome. Molecular study of YARS2 gene should be considered in patients presenting Pearson's syndrome characteristics and MLASA related phenotypes.

Síndrome de Pearson en un niño trasplantado debido a anemia de Diamond-Blackfan / Pearson syndrome in a child transplanted for Diamond-Blackfan anemia

El síndrome de Pearson (SP) comparte varias características con la anemia de Diamond-Blackfan (ADB), incluida la anemia grave de inicio temprano, por lo que es importante hacer un diagnóstico diferencial. El diagnóstico diferencial de la ADB y el SP es fundamental, ya que los pacientes con ADB podrían res-ponder al tratamiento con corticoesteroides, presentar remisión o beneficiarse del trasplante de células madre hematopoyéti-cas (TCMH). Sin embargo, los pacientes con SP tienen un pronós-tico diferente, con un riesgo muy elevado de acidosis, problemas metabólicos y disfunción pancreática, y una expectativa de vida menor en comparación con aquellos con ADB. En este artículo, presentamos el caso de un paciente sometido a TCMH para la ADB, pero que luego fue diagnosticado con SP tras desarrollar algunas complicaciones.

Pearson syndrome (PS), shares a number of overlapping features with Diamond-Blackfan anemia (DBA), including early onset of severe anemia, making differential diagnosis important. Differential diagnosis of DBA and PS is critical, since those with DBA may respond to treatment with steroids, may undergo remission, or may benefit from hematopoietic stem cell transplantation (HSCT). However, patients with PS have a different prognosis, with a very high risk of developing acidosis, metabolic problems, and pancreatic dysfunction, and a shorter life expectancy than those with DBA. Here we present a patient who underwent HSCT for DBA but was subsequently diagnosed with PS after developing some complications

De Novo Development of mtDNA Deletion Due to Decreased POLG and SSBP1 Expression in Humans.

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.

Identification of a novel large deletion of the mitochondrial DNA in an infant with Pearson syndrome: a case report.

Pearson syndrome (PS), also known as Pearson marrow-pancreas syndrome, is a rare, multi-systemic disorder caused by large-scale deletion of mitochondrial DNA (mtDNA) ranging from 2.3 kb to 9 kb, with 4,977 bp in length as the most common variant. This paper reported a novel mtDNA deletion of 4,734 bp in size, spanning from nucleotide 11,220 to 15,953. The infant suffered from chronic hepatomegaly, liver dysfunction, anemia and lactic acidosis over 1 year. Evidences of any infections were negative. Bone marrow aspiration and whole exome sequencing covering nearly 20,000 nucleus genes were performed when aged 3.3 and 6 months, respectively, but no genetic cause was identified. However, at his age 13 months, multiplex ligation-dependent probe amplification assay of the mtDNA in the patient detected a large deletion of 4,734 bp in size spanning the mitochondrial genes MTND4, MTTH, MTTS2, MTTL2, MTND5, MTND6, MTTE, MTCYB and MTTT which were functionally crucial for the intact oxidative phosphorylation pathway and adenosine triphosphate production, and PS was thus definitely diagnosed. This large deletion was negative in his parents and elder brother. Oral ursodeoxycholic acid, fat-soluble vitamins and blood transfusions were administrated, his clinical and laboratory presentations remained stable so far, but the long-term prognosis needed to be followed up. These findings enriched the variant spectrum of mtDNA, and demonstrated the importance of considering mitochondrial disorder in patient with intractable anemia, liver dysfunction and lactic acidosis as well as the significance of appropriate choosing of relevant genetic tools in the etiology diagnosis of such patients.

Acquisition of monosomy 7 and a RUNX1 mutation in Pearson syndrome.

Pearson syndrome (PS) is a very rare and often fatal multisystem disease caused by deletions in mitochondrial DNA that result in sideroblastic anemia, vacuolization of marrow precursors, and pancreatic dysfunction. Spontaneous recovery from anemia is often observed within several years of diagnosis. We present the case of a 4-month-old male diagnosed with PS who experienced prolonged severe pancytopenia preceding the emergence of monosomy 7. Whole-exome sequencing identified two somatic mutations, including RUNX1 p.S100F that was previously reported as associated with myeloid malignancies. The molecular defects associated with PS may have the potential to progress to advanced myelodysplastic syndrome .

The Phenotypic Spectrum of 47 Czech Patients with Single, Large-Scale Mitochondrial DNA Deletions.

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.