RARE DISEASE
Pearson syndrome
Pearson syndrome
Pearson syndrome
Synonyms: PMPS, Pearson marrow-pancreas syndrome
Synonyms: PMPS, Pearson marrow-pancreas syndrome
Synonyms: PMPS, Pearson marrow-pancreas syndrome
Drug discovery
1
drug
With orphan designation
Overview
Pearson syndrome is a rare, multisystem mitochondrial disorder caused by single large-scale mitochondrial DNA deletions, leading to bone marrow failure (sideroblastic anemia), pancreatic exocrine insufficiency, and metabolic crises. It typically manifests in infancy with lactic acidosis, failure to thrive, and multi-organ dysfunction. Approximately 50% of affected children die in early childhood; survivors often develop Kearns-Sayre syndrome [1][6][17].
Categories: rare endocrine diseases, rare gastroenterological diseases, rare genetic diseases, rare hematological diseases, rare inborn errors of metabolism
Research Papers
29 drug discovery papers about Pearson syndrome, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
29 drug discovery papers about Pearson syndrome, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-05-20 | Progressive short stature in Pearson syndrome and the impact of organ failure.
Pearson syndrome (PS) is a rare, unique primary mitochondrial disorder characterized by single large-scale mitochondrial DNA deletions, bone marrow failure, lactic acidosis, and progressive multi-organ complications. We retrospectively evaluated anthropometric data from 25 patients with PS. The median height, weight, and body mass index (BMI) standard deviation scores (SDS) at the last measurement were - 1.95 (range: -7.32 to 1.09), -1.70 (range: -12.26 to 0.11), and - 1.52 (range: -5.01 to 2.19), respectively; 50%, 40%, and 37.5% of patients, respectively, had values below -2 SDS. Longitudinal data from 18 patients showed that height and weight SDS declined progressively with age in most patients, whereas BMI SDS fluctuated without a clear age-related trend. Initiation of tube feeding improved weight and BMI SDS in some patients, while height SDS continued to decline without catch-up growth. Patients with organ failure exhibited an earlier decline in height SDS than those without organ failure. Patients with PS are generally short and underweight, and their short stature worsens over time. The presence of organ failure further exacerbates growth impairment.
2025-07-22 | Mitophagy modulation rescues single large-scale mitochondrial DNA deletion (SLSMD) disease symptoms in the C. elegans uaDf5 animal model.
S ingle large s cale m itochondrial DNA (mtDNA) d eletions (SLSMD) underlie a range of sporadic or maternally inherited primary mitochondrial diseases having significant morbidity and mortality, including Pearson syndrome, Kearns-Sayre Syndrome, or Chronic Progressive External Ophthalmoplegia. Therapeutic development has been hindered by limited existing knowledge on mtDNA quality control and a lack of SLSMD animal models. To address this challenge, we utilized the C. elegans heteroplasmic SLSMD strain, uaDf5, to objectively screen for potential therapies. As mitophagy modulation has been implicated in mtDNA homeostasis, we screened a library of mitophagy modulating compounds to determine their comparative effects to rescue mitochondrial unfolded protein (UPR mt ) stress induction in in uaDf5 SLSMD worms. Interestingly, Thiamine was discovered to be an effective positive control, significantly reducing mitochondrial stress in this model. Two lead therapeutic candidates from the mitophagy library screen were Hemin and Celastrol (Tripterin). Celastrol is a mitophagy activating anti-inflammatory and metabolic modifying natural product derived compound, that rescued multiple fitness outcomes (thrashing, development, survival) and reduced the mitochondrial stress in uaDf5 animals in a mitophagy-dependent fashion. This study highlights the utility of the uaDf5 worm model to enable preclinical identification of therapeutic candidate leads for SLSMD-based heteroplasmic mtDNA diseases and identifies possible therapeutic candidates that serve as mitophagy modulators to improve health and specifically reduce heteroplasmy levels in SLSMD diseases.
2013-04-25 | Brain uptake of Tc99m-HMPAO correlates with clinical response to the novel redox modulating agent EPI-743 in patients with mitochondrial disease.
While decreased ATP production and redox imbalance are central to mitochondrial disease pathogenesis, efforts to develop effective treatments have been hampered by the lack of imaging markers of oxidative stress. In this study we wished to determine if Tc99m-HMPAO, a SPECT imaging marker of cerebral blood flow and glutathione/protein thiol content, could be used to monitor the effect(s) of EPI-743, an oral redox modulating, para-benzoquinone based therapeutic for mitochondrial disease. We hypothesized that treatment changes in HMPAO uptake would be inversely proportional to changes in oxidative stress within the brain and directly correlate to clinical response to EPI-743 therapy. Twenty-two patients with mitochondrial disease were treated with EPI-743. Each underwent baseline and 3-month Tc99m-HMPAO SPECT scanning along with clinical/neurologic evaluations. Diseases treated were: Leigh syndrome (n=7), polymerase γ deficiency (n=5), MELAS (n=5), Friedreich ataxia (n=2), Kearns-Sayre syndrome, Pearson syndrome, and mtDNA depletion syndrome. Neuro-anatomic uptake analyses of HMPAO were performed with NeuroGam™ (Segami Corp.) statistical software and clinical response was assessed by the Newcastle Paediatric Mitochondrial Disease Scale or Newcastle Mitochondrial Disease Adult Scale depending on patient age. For all 22 patients there was a significant linear correlation between the change in cerebellar uptake of HMPAO and the improvement in Newcastle score (r=0.623, **p=0.00161). The MELAS subgroup showed a significant relationship of whole brain uptake (n=5, r=0.917, *p=0.028) to improvement in Newcastle score. We conclude that Tc99m-HMPAO SPECT scanning has promise as a general marker of the oxidative state of the brain and its response to redox modulating therapies. Further studies will be needed to confirm these findings in a more homogenous study population.
2013-04-01 | Depolymerization of fucosylated chondroitin sulfate from sea cucumber, Pearsonothuria graeffei, via 60Co irradiation
A method for depolymerization of a novel fucosylated chondroitin sulfate from Pearsonothuria graeffei (fCS-Pg) using (60)Co irradiation in water solution was developed in the current study. Fragments with varying molecular weights were obtained by (60)Co irradiation at different dosages and sample concentrations. The chemical compositions and structures of these fragments were further investigated using high-performance liquid chromatography (HPLC), infrared spectroscopy (IR) and nuclear magnetic resonance spectroscopy (NMR). Our results indicated that (60)Co irradiation induced depolymerization via selective breakage of glucuronic acid units in the fCS-Pg backbone, with no obvious influence on sulfated fucose branches under mild conditions. The recommended conditions for fCS-Pg degradation were 2-10% solution concentration and irradiation dosages of 10-50kGy. The anticoagulant activities of the low molecular weight fragments were additionally evaluated. Notably, anticoagulant activities were reduced with decreasing molecular weights. Compared to the native fCS-Pg, low molecular weight fragments displayed significantly decreased anticoagulant activities. Based on the collective findings, we propose that these fragments are potentially applicable as antithrombotic agents with reduced bleeding risk relative to native fCS-Pg.
2013-04-01 | Sulfation pattern of the fucose branch is important for the anticoagulant and antithrombotic activities of fucosylated chondroitin sulfates
The aim is to compare the structures, anticoagulant and antithrombotic activities of two fucosylated chondroitin sulfates isolated from sea cucumbers Isostichopus badionotus (fCS-Ib) and Pearsonothuria graeffei (fCS-Pg), which were known to have different sulfation patterns on the fucose branches. The structures of fCSs were identified using 2D NMR. Anticoagulant activities were measured by activated partial thromboplastin time (APTT) and thrombin time (TT), and inhibition of factors IIa, Xa and XIIa was assessed in vitro. Antithrombotic activity was determined ex vivo by measuring the length and weight of the thrombus generated. The two fCSs had identical chondroitin sulfate E backbones and similar fucose branches, but different sulfation patterns of the fucose branches. The fucose branch in fCS-Ib was mainly 2,4-O-sulfated whereas that in fCS-Pg was mainly 3,4-O-sulfated. In vitro assay indicated that fCS-Pg possessed much lower potency than fCS-Ib in prolonging APTT/TT and in inhibition of thrombin. However, they both exhibited similar inhibitory effects on factor X activation by intrinsic tenase complex, and on thrombus generation. Furthermore, both fCSs significantly activated factor XII, which has been proved to be associated with adverse clinical events associated with heparin contaminated by oversulfated chondroitin sulfate. The 2,4-O-sulfated fucose branch is the key structural factor of fCSs for prolonged APTT/TT and inhibition of thrombin, whereas the inhibitory effect of fCSs on factor X, XII activation and thrombus generation was attributed to the overall structure of fCS polysaccharide. Both fCSs have well defined structures and can be readily quality-controlled, and therefore may be potential alternatives for heparin as anticoagulant and antithrombotic drugs.
gene therapies
2025-10-11 | Genotype-Phenotype Correlations in Chinese Pediatric Patients With Single Large-Scale Mitochondrial DNA Deletion Disorders.
This study investigated clinical and genetic characteristics of Chinese pediatric patients with single large-scale mitochondrial DNA deletions (SLSMD). We analyzed 28 patients (July 2004-March 2025) using long-range PCR and next-generation sequencing. Spearman correlation and ANOVA assessed genotype-phenotype relationships. Patients (mean age 5.52 ± 3.96 years) exhibited multi-organ involvement (5.43 ± 1.87 organs). Common initial presentations included ocular (29%), neurologic, and endocrine dysfunction. Only 14.3% had the classic 4977 bp deletion, and 23 novel deletions were identified in 25 patients. Larger deletions correlated with more deleted MRC complexes (r = 0.516, p = 0.0123) and more deleted tRNAs (r = 0.534, p = 0.0103). Kearns-Sayre syndrome (KSS) patients had later onset (p = 0.0337), larger deletions (p = 0.0263), and greater tRNA/MRC complex (p = 0.0263, p = 0.0319) involvement than non-KSS patients. SLSMD in Chinese children primarily causes KSS, Pearson syndrome (PS), and progressive ophthalmoplegia with multi-organ involvement. Genotype-phenotype correlations exist, particularly between deletion size, onset age, and disease severity. KSS patients show distinct genetic and clinical profiles, suggesting slower progression. This study expands the known SLSMD spectrum and underscores mitochondrial testing in pediatric multi-organ disorders.
2025-09-17 | Molecular Aspects of Mitochondrial Dysfunction in Diabetes, Pearson and Kearns-Sayre Syndromes, and Neurodegenerative Disorders.
Mitochondrial dysfunction results in complex pathophysiological alterations associated with clinical disease states including cancer, cardiovascular diseases, diabetes mellitus, and anxiety disorders. As a key organelle within mammalian cells, the mitochondrion serves as the energetic source of cellular function which are crucial to cellular homeostasis, and cell death. In this report, we review key molecular causes of mitochondrial dysfunction and discuss how it influences insulin resistance, Pearson Syndrome and Kearns-Sayre syndrome, the latter of which occur due to pathogenic variants in mitochondrial DNA that lead to direct cellular pathology. We discuss the molecular and cellular pathophysiological mechanisms, disease interplays, and clinical considerations related to these diseases influenced by mitochondrial dysfunction.
2025-02-22 | Recognizing the evolution of clinical syndrome spectrum progression in individuals with single large-scale mitochondrial DNA deletion syndromes (SLSMDS).
Single large-scale mtDNA deletions (SLSMD) result in single large-scale deletion syndromes (SLSMDS). SLSMDS presentations have classically been recognized to encompass at least 3 distinct clinical phenotypes: Pearson syndrome (PS), Kearns-Sayre syndrome (KSS), and chronic progressive ophthalmoplegia. A facilitated review of electronic medical records, manual charts, and Research Electronic Data Capture research databases was performed to complete a retrospective natural history study of 30 participants with SLSMDS in a single health system between 2002 and 2020. The evaluated characteristics included genetic and clinical laboratory test values, growth parameters, signs and symptoms, demographics, and patient-reported outcome measures of fatigue, quality of life, and overall function. Detailed cohort characterization highlighted that a recurrent deleted region involving MT-ND5 (HGNC:7641) occurs in 96% of participants with SLSMDS regardless of the clinical phenotype, which tends to evolve over time. Higher blood heteroplasmy correlated with an earlier age of onset. Growth differentiation factor 15 levels were elevated in all participants with SLSMDS. A history of PS was associated with poor survival prognosis. Furthermore, increased fatigue and decreased quality of life have been reported in patients with SLSMD with advanced age. A retrospective natural history study of patients with SLSMDS demonstrated the evolution of classically considered PS, Kearns-Sayre syndrome, and chronic progressive ophthalmoplegia clinical presentations in affected individuals, which may inform future clinical trial developments.
2024-01-01 | Rare disease reported in a pediatric patient: Pearson syndrome
Pearson Syndrome (PS) is a congenital multisystem disorder caused by mitochondrial DNA deletions. The main clinical manifestations are: Sideroblastic anemia, neutropenia, thrombocytopenia and exocrine pancreatic insufficiency. Organs such as the heart, kidneys, eyes, ears and brain are the most affected due to the greater energy demand they need. Diagnosis is often challenging due to phenotypic heterogeneity and should always be suspected in multisystemic manifestations. It is confirmed by genetic testing, through mitochondrial DNA sequencing. It is a disease that has no cure, however, there is treatment with co-factors that reduce the signs and symptoms, in addition to ongoing research in gene therapy. Supportive measures aim to avoid physiological stressors. It is a syndrome that is usually fatal in childhood, and those who survive develop signs and symptoms of Kearns-Sayre Syndrome. This case report aims to guide and favor the diagnosis of similar clinical conditions, since PS is probably underdiagnosed, as few physicians are aware of the existence of the disease, much less of its signs and symptoms.
2014-10-06 | Pearson syndrome in a Diamond-Blackfan anemia cohort.
In this issue of Blood, Gagne et al describe a cohort of 362 patients clinically classified as having Diamond-Blackfan anemia (DBA), in which 175 (48%) were found to have mutations and deletions in ribosomal protein genes or GATA1, and 8 of the remaining patients (2.2% overall) had mitochondrial gene deletions consistent with Pearson marrow-pancreas syndrome (PS). The authors propose that all patients with presumptive DBA should be tested for mitochondrial DNA (mtDNA) deletion during their initial genetic evaluation.
cell therapies
2026-01-30 | Outcomes of kidney transplantation in three patients with single large-scale mitochondrial DNA deletion syndromes.
Single large-scale mitochondrial DNA deletion syndromes (SLSMDS) are a clinical continuum of three classic discrete clinical syndromes: Pearson marrow-pancreas syndrome, Kearns-Sayre syndrome, and chronic progressive ophthalmoplegia. Kidney manifestations, including chronic kidney disease with progression kidney failure has emerged as significant cause of morbidity and mortality in SLSMDS. Despite this recognition, reports of kidney transplantation in this population are limited. Here, we describe outcomes of kidney transplantation in three patients with SLSMDS and kidney failure over a 1-2.5-year follow-up period. All three patients had multisystem involvement at the time of transplantation. In all three patients, surgery was uncomplicated without evidence of acute metabolic decompensation in the perioperative period and standard immunosuppressive protocols were well tolerated. One patient developed post-transplant lymphoproliferative disease at 9 months status-post transplant which was ultimately fatal. The two surviving patients remain with stable graft function and functional quality of life at 1- and 3.5-years post-transplant.
2024-11-05 | T-Lymphoblastic Lymphoma in a Patient with Pearson Syndrome Following Mitochondrial Augmentation
Pearson syndrome (PS) is an ultra-rare childhood disease caused by a deletion in the mitochondrial DNA (mtDNA). PS is associated with bone marrow dysfunction at young age, with later progression to multisystem dysfunction. A few events of myelodysplasia were reported in PS patients. Recently, mitochondrial-augmentation therapy (MAT), a process in which autologous mobilized hematopoietic CD34+ cells are infused after ex-vivo enrichment with healthy mitochondria, has been studied in patients with PS (NCT03384420 and NCT06017869). We report on a patient diagnosed with PS at the age of 12 months, harboring a 6.7kB mtDNA deletion (m.9102-m.15815) with a 69% heteroplasmy. Her disease manifestations included anemia, thrombocytopenia, pancreatic insufficiency, hypoparathyroidism, failure to thrive and recurrent metabolic crisis events. She was treated with mitochondrial augmentation therapy at 2 years of age through a compassionate use program. Following MAT, weight gain and motor improvement were observed. Despite this, one year post MAT she had declining renal function and worsening pancytopenia. Repeated bone marrow biopsies demonstrated low cellularity per age (30-50%), with a decreased number of neutrophils and occasional small and slightly atypical megakaryocytes. Fluorescent in situ hybridization assays did not detect aberrations in chromosomes 5 or 7. The patient was diagnosed with a mediastinal mass 26 months after MAT. A core needle biopsy was diagnostic of T-lymphoblastic lymphoma, positive for CD3, CD5, CD2, CD7, CD4, CD8, CD1a and TdT on immunohistochemistry. A polymerase-chain reaction for T-cell receptor gamma rearrangement demonstrated a monoclonal peak. An additional bone marrow biopsy confirmed low cellularity per age without evidence of leukemic involvement. mtDNA fragments were reported to integrate into the genomic DNA, a process termed numtogenesis, occurring throughout evolution as well as in cancer. We performed long-read NGS PacBio sequencing to the tumor sample as well as pre-MAT peripheral blood DNA. The reads were mapped against the genome and the mitochondrial sequences to identify mtDNA regions inserted in the nuclear genome. The 6.7kb mtDNA deletion was confirmed in both samples, with similar heteroplasmy of ~70%. We identified 8 areas in which mtDNA-specific sequences were integrated within the nuclear genomic DNA. All regions were identical between the tumor sample and the pre-MAT peripheral blood, four were known NUMT sites, and the longer sites were confirmed to have a different haplotype from the patients (and maternal) mitochondria. In addition, somatic mutations in T-cell malignancy associated genes were found in the tumor itself, including mutations in NRAS, FBXW7, PHF6, SUZ12, PTEN and BCOR. The patient was treated with a combination of corticosteroids, vincristine, ARA-C, 6-mercaptopurine and methotrexate, and is currently in remission for more than 18 months. Events of T-cell malignancies were never reported in PS patients. Despite no direct genomic integration involved in MAT, the concern of T-cell malignancies in genetically-engineered cell products initiated our investigation. We could not prove novel disruptive tumor-specific numtogenesis events. The contribution of the MAT to tumor development cannot be ruled out.
2022-12-23 | Mitochondrial augmentation of hematopoietic stem cells in children with single large-scale mitochondrial DNA deletion syndromes.
Patients with single large-scale mitochondrial DNA (mtDNA) deletion syndromes (SLSMDs) usually present with multisystemic disease, either as Pearson syndrome in early childhood or as Kearns-Sayre syndrome later in life. No disease-modifying therapies exist for SLSMDs. We have developed a method to enrich hematopoietic cells with exogenous mitochondria, and we treated six patients with SLSMDs through a compassionate use program. Autologous CD34+ hematopoietic cells were augmented with maternally derived healthy mitochondria, a technology termed mitochondrial augmentation therapy (MAT). All patients had substantial multisystemic disease involvement at baseline, including neurologic, endocrine, or renal impairment. We first assessed safety, finding that the procedure was well tolerated and that all study-related severe adverse events were either leukapheresis-related or related to the baseline disorder. After MAT, heteroplasmy decreased in the peripheral blood in four of the six patients. An increase in mtDNA content of peripheral blood cells was measured in all six patients 6 to 12 months after MAT as compared baseline. We noted some clinical improvement in aerobic function, measured in patients 2 and 3 by sit-to-stand or 6-min walk testing, and an increase in the body weight of five of the six patients suffering from very low body weight before treatment. Quality-of-life measurements as per caregiver assessment and physical examination showed improvement in some parameters. Together, this work lays the ground for clinical trials of MAT for the treatment of patients with mtDNA disorders.
2022-03-31 | 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.
2022-02-21 | Clinical and genetic features of four patients with Pearson syndrome: An observational study.
Pearson syndrome (PS) is a multisystem mitochondrial cytopathy arising from deletions in mitochondrial DNA. Pearson syndrome is a sporadic disease that affects the hematopoietic system, pancreas, eyes, liver, and heart and the prognosis is poor. Causes of morbidity include metabolic crisis, bone marrow dysfunction, sepsis, and liver failure in early infancy or childhood. Early diagnosis may minimize complications, but suspicion of the disease is difficult and only mitochondrial DNA gene testing can identify mutations. There is no specific treatment for PS, which remains supportive care according to symptoms; however, hematopoietic stem cell transplantation may be considered in cases of bone marrow failure.We herein describe the clinical and genetic characteristics of four patients with PS. One patient presented with hypoglycemia, two developed pancytopenia, and the final patient had hypoglycemia and acute hepatitis as the primary manifestation. All patients had lactic acidosis. Additionally, all patients showed a variety of clinical features including coagulation disorder, pancreatic, adrenal, and renal tubular insufficiencies. Two patients with pancytopenia died in their early childhood. Our experience expands the phenotypic spectrum associated with PS and its clinical understanding.
small molecules
2026-05-20 | Progressive short stature in Pearson syndrome and the impact of organ failure.
Pearson syndrome (PS) is a rare, unique primary mitochondrial disorder characterized by single large-scale mitochondrial DNA deletions, bone marrow failure, lactic acidosis, and progressive multi-organ complications. We retrospectively evaluated anthropometric data from 25 patients with PS. The median height, weight, and body mass index (BMI) standard deviation scores (SDS) at the last measurement were - 1.95 (range: -7.32 to 1.09), -1.70 (range: -12.26 to 0.11), and - 1.52 (range: -5.01 to 2.19), respectively; 50%, 40%, and 37.5% of patients, respectively, had values below -2 SDS. Longitudinal data from 18 patients showed that height and weight SDS declined progressively with age in most patients, whereas BMI SDS fluctuated without a clear age-related trend. Initiation of tube feeding improved weight and BMI SDS in some patients, while height SDS continued to decline without catch-up growth. Patients with organ failure exhibited an earlier decline in height SDS than those without organ failure. Patients with PS are generally short and underweight, and their short stature worsens over time. The presence of organ failure further exacerbates growth impairment.
2025-07-22 | Mitophagy modulation rescues single large-scale mitochondrial DNA deletion (SLSMD) disease symptoms in the C. elegans uaDf5 animal model.
S ingle large s cale m itochondrial DNA (mtDNA) d eletions (SLSMD) underlie a range of sporadic or maternally inherited primary mitochondrial diseases having significant morbidity and mortality, including Pearson syndrome, Kearns-Sayre Syndrome, or Chronic Progressive External Ophthalmoplegia. Therapeutic development has been hindered by limited existing knowledge on mtDNA quality control and a lack of SLSMD animal models. To address this challenge, we utilized the C. elegans heteroplasmic SLSMD strain, uaDf5, to objectively screen for potential therapies. As mitophagy modulation has been implicated in mtDNA homeostasis, we screened a library of mitophagy modulating compounds to determine their comparative effects to rescue mitochondrial unfolded protein (UPR mt ) stress induction in in uaDf5 SLSMD worms. Interestingly, Thiamine was discovered to be an effective positive control, significantly reducing mitochondrial stress in this model. Two lead therapeutic candidates from the mitophagy library screen were Hemin and Celastrol (Tripterin). Celastrol is a mitophagy activating anti-inflammatory and metabolic modifying natural product derived compound, that rescued multiple fitness outcomes (thrashing, development, survival) and reduced the mitochondrial stress in uaDf5 animals in a mitophagy-dependent fashion. This study highlights the utility of the uaDf5 worm model to enable preclinical identification of therapeutic candidate leads for SLSMD-based heteroplasmic mtDNA diseases and identifies possible therapeutic candidates that serve as mitophagy modulators to improve health and specifically reduce heteroplasmy levels in SLSMD diseases.
2013-04-25 | Brain uptake of Tc99m-HMPAO correlates with clinical response to the novel redox modulating agent EPI-743 in patients with mitochondrial disease.
While decreased ATP production and redox imbalance are central to mitochondrial disease pathogenesis, efforts to develop effective treatments have been hampered by the lack of imaging markers of oxidative stress. In this study we wished to determine if Tc99m-HMPAO, a SPECT imaging marker of cerebral blood flow and glutathione/protein thiol content, could be used to monitor the effect(s) of EPI-743, an oral redox modulating, para-benzoquinone based therapeutic for mitochondrial disease. We hypothesized that treatment changes in HMPAO uptake would be inversely proportional to changes in oxidative stress within the brain and directly correlate to clinical response to EPI-743 therapy. Twenty-two patients with mitochondrial disease were treated with EPI-743. Each underwent baseline and 3-month Tc99m-HMPAO SPECT scanning along with clinical/neurologic evaluations. Diseases treated were: Leigh syndrome (n=7), polymerase γ deficiency (n=5), MELAS (n=5), Friedreich ataxia (n=2), Kearns-Sayre syndrome, Pearson syndrome, and mtDNA depletion syndrome. Neuro-anatomic uptake analyses of HMPAO were performed with NeuroGam™ (Segami Corp.) statistical software and clinical response was assessed by the Newcastle Paediatric Mitochondrial Disease Scale or Newcastle Mitochondrial Disease Adult Scale depending on patient age. For all 22 patients there was a significant linear correlation between the change in cerebellar uptake of HMPAO and the improvement in Newcastle score (r=0.623, **p=0.00161). The MELAS subgroup showed a significant relationship of whole brain uptake (n=5, r=0.917, *p=0.028) to improvement in Newcastle score. We conclude that Tc99m-HMPAO SPECT scanning has promise as a general marker of the oxidative state of the brain and its response to redox modulating therapies. Further studies will be needed to confirm these findings in a more homogenous study population.
2013-04-01 | Depolymerization of fucosylated chondroitin sulfate from sea cucumber, Pearsonothuria graeffei, via 60Co irradiation
A method for depolymerization of a novel fucosylated chondroitin sulfate from Pearsonothuria graeffei (fCS-Pg) using (60)Co irradiation in water solution was developed in the current study. Fragments with varying molecular weights were obtained by (60)Co irradiation at different dosages and sample concentrations. The chemical compositions and structures of these fragments were further investigated using high-performance liquid chromatography (HPLC), infrared spectroscopy (IR) and nuclear magnetic resonance spectroscopy (NMR). Our results indicated that (60)Co irradiation induced depolymerization via selective breakage of glucuronic acid units in the fCS-Pg backbone, with no obvious influence on sulfated fucose branches under mild conditions. The recommended conditions for fCS-Pg degradation were 2-10% solution concentration and irradiation dosages of 10-50kGy. The anticoagulant activities of the low molecular weight fragments were additionally evaluated. Notably, anticoagulant activities were reduced with decreasing molecular weights. Compared to the native fCS-Pg, low molecular weight fragments displayed significantly decreased anticoagulant activities. Based on the collective findings, we propose that these fragments are potentially applicable as antithrombotic agents with reduced bleeding risk relative to native fCS-Pg.
2013-04-01 | Sulfation pattern of the fucose branch is important for the anticoagulant and antithrombotic activities of fucosylated chondroitin sulfates
The aim is to compare the structures, anticoagulant and antithrombotic activities of two fucosylated chondroitin sulfates isolated from sea cucumbers Isostichopus badionotus (fCS-Ib) and Pearsonothuria graeffei (fCS-Pg), which were known to have different sulfation patterns on the fucose branches. The structures of fCSs were identified using 2D NMR. Anticoagulant activities were measured by activated partial thromboplastin time (APTT) and thrombin time (TT), and inhibition of factors IIa, Xa and XIIa was assessed in vitro. Antithrombotic activity was determined ex vivo by measuring the length and weight of the thrombus generated. The two fCSs had identical chondroitin sulfate E backbones and similar fucose branches, but different sulfation patterns of the fucose branches. The fucose branch in fCS-Ib was mainly 2,4-O-sulfated whereas that in fCS-Pg was mainly 3,4-O-sulfated. In vitro assay indicated that fCS-Pg possessed much lower potency than fCS-Ib in prolonging APTT/TT and in inhibition of thrombin. However, they both exhibited similar inhibitory effects on factor X activation by intrinsic tenase complex, and on thrombus generation. Furthermore, both fCSs significantly activated factor XII, which has been proved to be associated with adverse clinical events associated with heparin contaminated by oversulfated chondroitin sulfate. The 2,4-O-sulfated fucose branch is the key structural factor of fCSs for prolonged APTT/TT and inhibition of thrombin, whereas the inhibitory effect of fCSs on factor X, XII activation and thrombus generation was attributed to the overall structure of fCS polysaccharide. Both fCSs have well defined structures and can be readily quality-controlled, and therefore may be potential alternatives for heparin as anticoagulant and antithrombotic drugs.
gene therapies
2025-10-11 | Genotype-Phenotype Correlations in Chinese Pediatric Patients With Single Large-Scale Mitochondrial DNA Deletion Disorders.
This study investigated clinical and genetic characteristics of Chinese pediatric patients with single large-scale mitochondrial DNA deletions (SLSMD). We analyzed 28 patients (July 2004-March 2025) using long-range PCR and next-generation sequencing. Spearman correlation and ANOVA assessed genotype-phenotype relationships. Patients (mean age 5.52 ± 3.96 years) exhibited multi-organ involvement (5.43 ± 1.87 organs). Common initial presentations included ocular (29%), neurologic, and endocrine dysfunction. Only 14.3% had the classic 4977 bp deletion, and 23 novel deletions were identified in 25 patients. Larger deletions correlated with more deleted MRC complexes (r = 0.516, p = 0.0123) and more deleted tRNAs (r = 0.534, p = 0.0103). Kearns-Sayre syndrome (KSS) patients had later onset (p = 0.0337), larger deletions (p = 0.0263), and greater tRNA/MRC complex (p = 0.0263, p = 0.0319) involvement than non-KSS patients. SLSMD in Chinese children primarily causes KSS, Pearson syndrome (PS), and progressive ophthalmoplegia with multi-organ involvement. Genotype-phenotype correlations exist, particularly between deletion size, onset age, and disease severity. KSS patients show distinct genetic and clinical profiles, suggesting slower progression. This study expands the known SLSMD spectrum and underscores mitochondrial testing in pediatric multi-organ disorders.
2025-09-17 | Molecular Aspects of Mitochondrial Dysfunction in Diabetes, Pearson and Kearns-Sayre Syndromes, and Neurodegenerative Disorders.
Mitochondrial dysfunction results in complex pathophysiological alterations associated with clinical disease states including cancer, cardiovascular diseases, diabetes mellitus, and anxiety disorders. As a key organelle within mammalian cells, the mitochondrion serves as the energetic source of cellular function which are crucial to cellular homeostasis, and cell death. In this report, we review key molecular causes of mitochondrial dysfunction and discuss how it influences insulin resistance, Pearson Syndrome and Kearns-Sayre syndrome, the latter of which occur due to pathogenic variants in mitochondrial DNA that lead to direct cellular pathology. We discuss the molecular and cellular pathophysiological mechanisms, disease interplays, and clinical considerations related to these diseases influenced by mitochondrial dysfunction.
2025-02-22 | Recognizing the evolution of clinical syndrome spectrum progression in individuals with single large-scale mitochondrial DNA deletion syndromes (SLSMDS).
Single large-scale mtDNA deletions (SLSMD) result in single large-scale deletion syndromes (SLSMDS). SLSMDS presentations have classically been recognized to encompass at least 3 distinct clinical phenotypes: Pearson syndrome (PS), Kearns-Sayre syndrome (KSS), and chronic progressive ophthalmoplegia. A facilitated review of electronic medical records, manual charts, and Research Electronic Data Capture research databases was performed to complete a retrospective natural history study of 30 participants with SLSMDS in a single health system between 2002 and 2020. The evaluated characteristics included genetic and clinical laboratory test values, growth parameters, signs and symptoms, demographics, and patient-reported outcome measures of fatigue, quality of life, and overall function. Detailed cohort characterization highlighted that a recurrent deleted region involving MT-ND5 (HGNC:7641) occurs in 96% of participants with SLSMDS regardless of the clinical phenotype, which tends to evolve over time. Higher blood heteroplasmy correlated with an earlier age of onset. Growth differentiation factor 15 levels were elevated in all participants with SLSMDS. A history of PS was associated with poor survival prognosis. Furthermore, increased fatigue and decreased quality of life have been reported in patients with SLSMD with advanced age. A retrospective natural history study of patients with SLSMDS demonstrated the evolution of classically considered PS, Kearns-Sayre syndrome, and chronic progressive ophthalmoplegia clinical presentations in affected individuals, which may inform future clinical trial developments.
2024-01-01 | Rare disease reported in a pediatric patient: Pearson syndrome
Pearson Syndrome (PS) is a congenital multisystem disorder caused by mitochondrial DNA deletions. The main clinical manifestations are: Sideroblastic anemia, neutropenia, thrombocytopenia and exocrine pancreatic insufficiency. Organs such as the heart, kidneys, eyes, ears and brain are the most affected due to the greater energy demand they need. Diagnosis is often challenging due to phenotypic heterogeneity and should always be suspected in multisystemic manifestations. It is confirmed by genetic testing, through mitochondrial DNA sequencing. It is a disease that has no cure, however, there is treatment with co-factors that reduce the signs and symptoms, in addition to ongoing research in gene therapy. Supportive measures aim to avoid physiological stressors. It is a syndrome that is usually fatal in childhood, and those who survive develop signs and symptoms of Kearns-Sayre Syndrome. This case report aims to guide and favor the diagnosis of similar clinical conditions, since PS is probably underdiagnosed, as few physicians are aware of the existence of the disease, much less of its signs and symptoms.
2014-10-06 | Pearson syndrome in a Diamond-Blackfan anemia cohort.
In this issue of Blood, Gagne et al describe a cohort of 362 patients clinically classified as having Diamond-Blackfan anemia (DBA), in which 175 (48%) were found to have mutations and deletions in ribosomal protein genes or GATA1, and 8 of the remaining patients (2.2% overall) had mitochondrial gene deletions consistent with Pearson marrow-pancreas syndrome (PS). The authors propose that all patients with presumptive DBA should be tested for mitochondrial DNA (mtDNA) deletion during their initial genetic evaluation.
cell therapies
2026-01-30 | Outcomes of kidney transplantation in three patients with single large-scale mitochondrial DNA deletion syndromes.
Single large-scale mitochondrial DNA deletion syndromes (SLSMDS) are a clinical continuum of three classic discrete clinical syndromes: Pearson marrow-pancreas syndrome, Kearns-Sayre syndrome, and chronic progressive ophthalmoplegia. Kidney manifestations, including chronic kidney disease with progression kidney failure has emerged as significant cause of morbidity and mortality in SLSMDS. Despite this recognition, reports of kidney transplantation in this population are limited. Here, we describe outcomes of kidney transplantation in three patients with SLSMDS and kidney failure over a 1-2.5-year follow-up period. All three patients had multisystem involvement at the time of transplantation. In all three patients, surgery was uncomplicated without evidence of acute metabolic decompensation in the perioperative period and standard immunosuppressive protocols were well tolerated. One patient developed post-transplant lymphoproliferative disease at 9 months status-post transplant which was ultimately fatal. The two surviving patients remain with stable graft function and functional quality of life at 1- and 3.5-years post-transplant.
2024-11-05 | T-Lymphoblastic Lymphoma in a Patient with Pearson Syndrome Following Mitochondrial Augmentation
Pearson syndrome (PS) is an ultra-rare childhood disease caused by a deletion in the mitochondrial DNA (mtDNA). PS is associated with bone marrow dysfunction at young age, with later progression to multisystem dysfunction. A few events of myelodysplasia were reported in PS patients. Recently, mitochondrial-augmentation therapy (MAT), a process in which autologous mobilized hematopoietic CD34+ cells are infused after ex-vivo enrichment with healthy mitochondria, has been studied in patients with PS (NCT03384420 and NCT06017869). We report on a patient diagnosed with PS at the age of 12 months, harboring a 6.7kB mtDNA deletion (m.9102-m.15815) with a 69% heteroplasmy. Her disease manifestations included anemia, thrombocytopenia, pancreatic insufficiency, hypoparathyroidism, failure to thrive and recurrent metabolic crisis events. She was treated with mitochondrial augmentation therapy at 2 years of age through a compassionate use program. Following MAT, weight gain and motor improvement were observed. Despite this, one year post MAT she had declining renal function and worsening pancytopenia. Repeated bone marrow biopsies demonstrated low cellularity per age (30-50%), with a decreased number of neutrophils and occasional small and slightly atypical megakaryocytes. Fluorescent in situ hybridization assays did not detect aberrations in chromosomes 5 or 7. The patient was diagnosed with a mediastinal mass 26 months after MAT. A core needle biopsy was diagnostic of T-lymphoblastic lymphoma, positive for CD3, CD5, CD2, CD7, CD4, CD8, CD1a and TdT on immunohistochemistry. A polymerase-chain reaction for T-cell receptor gamma rearrangement demonstrated a monoclonal peak. An additional bone marrow biopsy confirmed low cellularity per age without evidence of leukemic involvement. mtDNA fragments were reported to integrate into the genomic DNA, a process termed numtogenesis, occurring throughout evolution as well as in cancer. We performed long-read NGS PacBio sequencing to the tumor sample as well as pre-MAT peripheral blood DNA. The reads were mapped against the genome and the mitochondrial sequences to identify mtDNA regions inserted in the nuclear genome. The 6.7kb mtDNA deletion was confirmed in both samples, with similar heteroplasmy of ~70%. We identified 8 areas in which mtDNA-specific sequences were integrated within the nuclear genomic DNA. All regions were identical between the tumor sample and the pre-MAT peripheral blood, four were known NUMT sites, and the longer sites were confirmed to have a different haplotype from the patients (and maternal) mitochondria. In addition, somatic mutations in T-cell malignancy associated genes were found in the tumor itself, including mutations in NRAS, FBXW7, PHF6, SUZ12, PTEN and BCOR. The patient was treated with a combination of corticosteroids, vincristine, ARA-C, 6-mercaptopurine and methotrexate, and is currently in remission for more than 18 months. Events of T-cell malignancies were never reported in PS patients. Despite no direct genomic integration involved in MAT, the concern of T-cell malignancies in genetically-engineered cell products initiated our investigation. We could not prove novel disruptive tumor-specific numtogenesis events. The contribution of the MAT to tumor development cannot be ruled out.
2022-12-23 | Mitochondrial augmentation of hematopoietic stem cells in children with single large-scale mitochondrial DNA deletion syndromes.
Patients with single large-scale mitochondrial DNA (mtDNA) deletion syndromes (SLSMDs) usually present with multisystemic disease, either as Pearson syndrome in early childhood or as Kearns-Sayre syndrome later in life. No disease-modifying therapies exist for SLSMDs. We have developed a method to enrich hematopoietic cells with exogenous mitochondria, and we treated six patients with SLSMDs through a compassionate use program. Autologous CD34+ hematopoietic cells were augmented with maternally derived healthy mitochondria, a technology termed mitochondrial augmentation therapy (MAT). All patients had substantial multisystemic disease involvement at baseline, including neurologic, endocrine, or renal impairment. We first assessed safety, finding that the procedure was well tolerated and that all study-related severe adverse events were either leukapheresis-related or related to the baseline disorder. After MAT, heteroplasmy decreased in the peripheral blood in four of the six patients. An increase in mtDNA content of peripheral blood cells was measured in all six patients 6 to 12 months after MAT as compared baseline. We noted some clinical improvement in aerobic function, measured in patients 2 and 3 by sit-to-stand or 6-min walk testing, and an increase in the body weight of five of the six patients suffering from very low body weight before treatment. Quality-of-life measurements as per caregiver assessment and physical examination showed improvement in some parameters. Together, this work lays the ground for clinical trials of MAT for the treatment of patients with mtDNA disorders.
2022-03-31 | 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.
2022-02-21 | Clinical and genetic features of four patients with Pearson syndrome: An observational study.
Pearson syndrome (PS) is a multisystem mitochondrial cytopathy arising from deletions in mitochondrial DNA. Pearson syndrome is a sporadic disease that affects the hematopoietic system, pancreas, eyes, liver, and heart and the prognosis is poor. Causes of morbidity include metabolic crisis, bone marrow dysfunction, sepsis, and liver failure in early infancy or childhood. Early diagnosis may minimize complications, but suspicion of the disease is difficult and only mitochondrial DNA gene testing can identify mutations. There is no specific treatment for PS, which remains supportive care according to symptoms; however, hematopoietic stem cell transplantation may be considered in cases of bone marrow failure.We herein describe the clinical and genetic characteristics of four patients with PS. One patient presented with hypoglycemia, two developed pancytopenia, and the final patient had hypoglycemia and acute hepatitis as the primary manifestation. All patients had lactic acidosis. Additionally, all patients showed a variety of clinical features including coagulation disorder, pancreatic, adrenal, and renal tubular insufficiencies. Two patients with pancytopenia died in their early childhood. Our experience expands the phenotypic spectrum associated with PS and its clinical understanding.
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Drug Discovery Landscape
1 orphan drug designation for Pearson syndrome.
1 orphan drug designation for Pearson syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
autologous CD34+ Cells Enriched with Blood Derived Mitochondria | cell therapies | FDA | 2019-02-26 | — | Minovia Therapeutics Ltd. |
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