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Orphanet J Rare Dis. 2022; 17: 379. PMCID: PMC9575259

Published online 2022 Oct 17. doi: 10.1186/s13023-022-02538-9 PMID: 36253820

Pearson syndrome: a multisystem mitochondrial disease with bone marrow failure

Ayami Yoshimi, 1 Kaori Ishikawa,3 Charlotte Niemeyer,1 and Sarah C. Grünert2

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.

Keywords: Pearson syndrome, Natural history, Mitochondrial DNA deletion

Background
:
 Pearson Syndrome (PS) was first described in 1979 by Howard Pearson as a disorder of
refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic
dysfunction [1]. Nine years later, Rötig et al. discovered that PS is caused by deletion of
mitochondrial DNA (mtDNA) [2]. The prevalence of PS is approximately 1: 1,000,000 [3]. To
date, less than 150 cases have been reported worldwide [3–7]. PS is a unique primary
mitochondrial disease (PMD), which typically presents with severe hypoproliferative anemia in
early infancy followed by progressive symptoms and multi-organ dysfunctions including lactic
acidosis, pancreatic insufficiency, renal tubulopathy, failure to thrive, muscle hypotonia, and
endocrine disorders [1, 3, 4, 6–8]. Interestingly, about two-thirds of patients with PS experience
spontaneous resolution of anemia and become transfusion dependent during their clinical
course. Therapeutic approaches are so far only symptomatic, and patients with PS have a dismal
prognosis. The majority of patients die before 6 years of age [3–5, 7, 8]. Recently, increasing
attention is being paid to PS due to development of novel therapies for PMDs, which can
potentially be applied in children with this rare disease [9–12].

Main text

Mitochondrial disease and mitochondrial DNA deletion syndrome

PMDs are a clinically and genetically heterogeneous group of disorders characterized by

dysfunction of the mitochondrial respiratory chain and caused by pathologic variants of genes
encoded by either mtDNA or nuclear DNA [13, 14]. mtDNA encodes for 13 polypeptides that
are essential subunits of complexes I, III, IV, and V, as well as 22 tRNAs and 2 rRNAs that are
necessary for translation of these 13 polypeptides. Each cell in the body obtains hundreds and
thousands of copies of mtDNA, depending on the cell type. Many patients with a PMD have a
mixture of both wild-type and mutated mtDNA in the same cell, called heteroplasmy.
Distribution of mutated mtDNA differs in different tissues, possibly by random partitioning
during early cell division. Cellular dysfunction appears only if the level of heteroplasmy exceeds
a certain critical threshold (threshold effect).

PS is caused by single large-scale mtDNA deletions (SLSMDs) of variable size (1.5 to 8.0 kb)
and location [4–6, 15]. About 40–50% of PS patients carry the “common deletion” with a length
of 4977 bp [4, 5, 16]. SLSMDs are also found in children or young adults with chronic
progressive external ophthalmoplegia (CPEO) or Kearns-Sayre syndrome (KSS) characterized
by PEO, pigmentary retinal degeneration, ataxia and cardiac conduction block. PS, CPEO and
KSS form a continuous spectrum of diseases called “mtDNA deletion syndromes” with a
common genetic event [4, 17]. Of note, patients with PS surviving early childhood can develop a
KSS-like phenotype [3, 15, 18].
:
 Pathogenic mechanisms and mouse model of mtDNA deletion syndrome

The unique clinical course of patients with mtDNA deletion syndromes raises interesting
questions about the disease mechanisms: (1) How does the same mtDNA deletion cause diverse
disorders (PS, KSS and CPEO)? (2) What is the mechanism of spontaneous resolution of
anemia in PS? (3) How and why does the clinical phenotype change from PS to KSS? It has
been hypothesized that varied loads of deleted mtDNA in different tissues are the main cause for
different disease phenotypes. Patients with PS may have a higher proportion of deleted mtDNA
in varied tissues overall than those who present in later life with KSS or CPEO [19].
Hematological recovery in PS may be due to a positive selection of hematopoietic stem cells
(HSCs) harboring a low amount of deleted mtDNA (Fig. 1) [15, 20]. In contrast to
hematopoietic cells, deleted mtDNA may accumulate in tissues such as muscles with time,
resulting in the development of neuro- and muscular complications seen in KSS.

Fig. 1

Hypothesis for the phenotypical change in Pearson syndrome. Hematological recovery is hypothesized to be
due to a positive selection of hematopoietic stem cells harboring low load of deleted mitochondrial DNA
(mtDNA). In contrast, deleted mtDNA accumulates in muscle, resulting in the development of Kearns-Sayre
syndrome with muscular complications

Studies in a mouse model of mtDNA deletion syndrome (mito-miceΔ) carrying various levels of
heteroplasmy support the above hypothesis [21, 22]. Neonatal mice with a high proportion of
deleted mtDNA (> 50%) develop a PS-like severe clinical phenotype [22]. Some of them die
soon after birth, and surviving mice can achieve remission from the PS-like phenotype but
develop KSS-like disease later. Mice with a moderate burden of deleted mtDNA (11–49%) are
healthy at birth but develop KSS-like disease later, while mice with a low proportion (up to
10%) remain healthy. It was also shown that the proportion of deleted mtDNA in blood and liver
decreases with age in this mouse model, while time-dependent accumulation of deleted mtDNA
was observed in other tissues including muscle where the amount of deleted mtDNA reaches
approximately 70 to 80% in various tissues when the mice develop KSS-like disease.

In PS patients, the proportion of deleted mtDNA in peripheral blood is very high (usually >
70%) at diagnosis [4–6]. A few autopsy reports of patients with PS provided information on
heteroplasmy status in various tissues and organs, and revealed a high load of deleted mtDNA of
:
 more than 70–80% in all tissues [23–25]. Although some reports have shown that severely
affected tissues tend to contain a higher proportion of deleted mtDNA [26], a clear association
between the proportion of deleted mtDNA in a specific tissue and clinical severity of tissue-
specific symptoms is not always present [23]. Therefore, additional factors such as the energy
demand and reserve of different tissues may contribute to the phenotype [23, 25]. Studies in with
a small number of PS patients have shown that the amount of deleted mtDNA in blood and bone
marrow (BM) cells decreased with improvement of anemia [20, 27]. In contrast, repetitive
muscle biopsy specimens in patients with KSS showed that the proportion of deleted mtDNA
increased with time from 50 to 60% to more than 80%, paralleling the progression of the disease
[15].

Inheritance

Although the vast majority of PS cases are sporadic and caused by a somatic mutational event
during early embryonic development, there are a few reports of mothers with CPEO who had
children with PS [28–30]. mtDNA is inherited exclusively from the mother [13]. Therefore,
deleted mtDNA can be transmitted from the mother to her children. Only a few copies of
maternal mtDNA are transmitted to the offspring (a mitochondrial genetic bottleneck), leading
to markedly different levels of heteroplasmy in offspring and mother. The unpredictable
heteroplasmy status in a child of a mother with mtDNA deletions renders genetic counselling a
challenge. In a large study including 226 families with at least one index patient with a mtDNA
deletion syndrome, clinically unaffected mothers are highly unlikely to have more than one
affected child, while affected women with CPEO had, on average, a one in 24 risk of having a
child affected with a mtDNA deletion syndrome [30].

Diagnosis of Pearson syndrome

Clinical presentation

PMDs can affect virtually any tissue and organ, but typically, organs that are highly dependent
on aerobic metabolism, such as muscle and brain are involved. PS is a clinically unique PMD, in
which anemia is often the sole presenting symptom and other features suggesting PMD are
lacking [3, 6, 31]. Other common initial symptoms are failure to thrive and gastrointestinal
symptoms such as vomiting, diarrhea and feeding difficulties [7, 31]. In our recently published
study on 25 individuals with PS, anemia developed at a median age of 5 months (range 0–
31 months) [6]. Pregnancy and birth are usually uneventful [3, 6]. However, about 10% of
patients have intrauterine growth restriction [31]. Furthermore, Farruggia et al. reported that
27% of newborns of PS are small for gestational age [3]. Some patients present already in the
:
 neonatal period with anemia, lactic acidosis, and/or other organ involvement [3, 6, 8]. In general,
clinical symptoms in early infancy are often nonspecific, such as muscular hypotonia, failure to
thrive, vomiting and chronic diarrhea. In addition, episodic metabolic crises with lactic acidosis
can occur.

Hematological findings at diagnosis

Patients with PS show macrocytic or normocytic hypogenerative anemia [3, 6, 31]. Majority of
patients have neutropenia and thrombocytopenia as well [3–6, 32]. In our German/Austrian
study with 25 patients, additional neutropenia and thrombocytopenia was found in 80% and
72%, respectively [6]. Rötig et al. reported that 16 of 21 patients (76%) with PS had
thrombocytopenia and/or thrombocytopenia [5]. The fetal hemoglobin (HbF) concentration and
the level of erythropoietin are elevated in the majority of patients [3, 6]. BM cellularity is
typically normal or reduced. Dysplastic features in all cell lineages are common (Fig. 2), and the
myeloid lineage often shows disturbed maturation. Vacuolization in myeloid and erythroid
precursors is a unique morphological feature of PS detected in nearly all patients [3, 6, 33]. Iron
staining reveals ring-sideroblasts in 70–85% of these patients [3, 6]. While detection of ring-
sideroblasts is helpful to ensure the diagnosis of PS [3], these typical BM findings can be
lacking in the first months of life [33].

Fig. 2

Bone marrow findings in patients with Pearson syndrome. Bone marrow can be hypocellular A or
normocellular B. C + D: micromegakarocytes, E: dysplastic megakaryocyte with bi-nuclei. F:
proerythroblast and myelocyte with vacuoles. G: proerythroblast with vacuoles, H: myelocyte with
vacuoles, I: promyelocyte with vacuoles and double nuclei, J: macrocytic normoblast with disturbed
hemoglobinization. K: erythroblast with lobulated nuclei. L: ring sideroblast (iron-staining)

Biochemical findings and other laboratory tests

There are no pathognomonic biomarkers for PS. Like in other PMD, elevated serum lactate
concentrations are found in the majority of PS patients [3, 4]. However, in some patients, these
abnormalities are only detected intermittently. The ratio of lactate to pyruvate is usually higher
than 20 in patients [26]. Organic acid analysis in urine by gas-chromatography mass
:
 spectrometry typically reveals elevated concentrations of lactate and the citric cycle
intermediates fumarate and malic acid. In some cases elevated excretion of 3-methylglutaconic
acid can be observed as a marker of mitochondrial dysfunction [3, 34]. Patients can also display
ketonuria with elevated concentrations of 3-hydroxybutyrate in urine [4]. Amino acid analysis
shows elevated concentrations of alanine in most patients, which is explained by interruption of
the citric cycle resulting in accumulation of pyruvate that can be reversibly converted to lactate
or alanine [3, 35]. Additionally, low levels of citrulline and arginine have been reported [35].
Although none of these abnormalities is specific for PS and can also be present in other
mitochondriopathies [4], the metabolite pattern can be helpful for the differential diagnosis from
other non-mitochondrial BM failure disorders [3]. Carnitine levels can be normal or low in PS
and can decrease during the course [36] [37] [38].The diagnostic work-up of a child with PS also
includes endocrinological investigations and evaluation of the exocrine pancreatic function to
rule out pancreas insufficiency, which is often already present at diagnosis.

Diagnostic algorithm

The proposed diagnostic algorithm in PS differs from that of other PMDs (Fig. 3). Metabolic
investigations including lactate measurements, urine organic acid analysis and amino acid
analysis in plasma can be helpful in the diagnostic work-up. In most cases, typical BM findings
with cytoplasmic vacuoles in myeloid and erythroid precursors and ring-sideroblasts will lead to
the suspicion of PS. The diagnosis is to be confirmed by mutation analysis of the mitochondrial
DNA in peripheral blood. There is a high probability that the single large mtDNA deletion will
also be present in other tissues such as buccal swab and/or urinary epithelial cells and the
information of the mutational status in these tissues may influence the patient´s management.
However, it should be noted that the mtDNA deletion may be detectable only in blood and BM
cells in rare cases of PS [4]. Southern blot and long-range polymerase chain reaction analysis
can detect SLSMDs, but analysis by next generation sequencing of the entire mitochondrial
genome has become increasingly common [39–41]. There is usually no need for a skeletal
muscle biopsy with histochemical and biochemical analysis.
:
 Fig. 3

Diagnostic algorithm for suspected Pearson syndrome. Diagnosis of Pearson syndrome is suggested by
patient history, clinical symptoms and laboratory findings. The key diagnostic procedures are genetic
analysis to detect single large-scale mitochondrial DNA (mtDNA) deletions in blood cells and bone marrow
examination. *The single large mtDNA deletion can be also be present in other tissues such as buccal swab
and/or urinary epithelial cells in majority of patients [4]

Differential diagnosis

Hematological features of PS, such as pancytopenia, elevated HbF and mean corpuscular
volume, marrow hypoplasia and dysplasia resemble those of other inherited BM failure
disorders. Diamond- Blackfan anemia (DBA) shares the common feature of hypogenerative
anemia in infancy [3, 42], noted in about half of the patients with PS [6]. Patients with
Shwachman-Diamond syndrome (SDS) present with exocrine pancreatic insufficiency, failure to
thrive, and neutropenia in infancy, features also noted in PS [43]. However, in clinical practice,
DBA or SDS can be well distinguished from PS by BM cytology, because vacuolization in
marrow precursors and ring-sideroblasts are neither observed in DBA nor SDS. Moreover, most
infants with PS have bi- or pancytopenia, while infants with DBA and SDS generally have
isolated anemia or neutropenia, respectively. Interestingly, normal reticulocyte counts are
frequently reported in patients with PS [3], while DBA patients usually have reticulocytopenia.
Erythrocyte adenosine deaminase (eADA) levels are typically elevated in DBA and have been
used in the diagnosis of DBA. However, the measurement of eADA is not useful for the
differential diagnosis between DBA and PS, because elevated eADA levels were reported in
some patients with PS as well [3, 44]. Pediatric hematologists should be aware of the
hematological findings in PS, because current standard next generation sequencing panels for
congenital anemia or inherited BM failures syndromes usually do not include the analysis of
mtDNA. Vacuolization of hematopoietic precursors with or without ring-sideroblasts is a typical
finding for PS, but can be seen in other conditions such as copper deficiency, zinc toxicity,
riboflavin deficiency, riboflavin transporter deficiency, acute alcoholism, phenylketonuria,
chloramphenicol- and linezolid- toxicity as well as other PMDs [45–54].

Hematological course
:
 Spontaneous resolution of anemia and clonal evolution

Patients with PS are usually red blood cell transfusion dependent, and often require platelet
transfusions during infancy and early childhood as well. The frequency of spontaneous
resolution of anemia with transfusion independency was 66% in our German/Austrian study [6].
Hematological recovery usually occurred at the age of 1 to 3 years [6, 7]. Presence of
hematological recovery does, however, not imply a better outcome with lower severity of other
organ complications [6]. Unfortunately, no predictive factors for spontaneous resolution of
anemia have been reported so far. Serial evaluations of heteroplasmy status in peripheral blood
cells may possibly be useful to predict hematological remission in the future. Recent reports
have suggested that PS patients have a risk of clonal evolution with chromosome 7 aberration
similar to other congenital BM failure syndromes: Hoyoux et al. reported on a PS patient who
developed a 7q deletion at the age of 2 years [55]. Gagne et al. detected transient monosomy 7
during the course in a child with PS [42]. Nishimura et al. reported a PS patient who developed
myelodysplastic syndrome with excess blasts, monosomy 7 and a somatic RUNX1 mutation in
BM cells [56]. Son, et al. reported a patient with PS, who developed myelodysplastic syndrome
with excess blasts (13% blasts in BM) at the age of 9 months and received allogeneic HSCT at
the age of 10 months [57]. Reynolds et al. reported that 9% of patient with PS developed
myeloid malignancies [7]. These reports suggest that PS predisposes to myeloid malignancies.

Non-hematological complications

Various non-hematological complications generally develop during the course in patients with
PS and are generally irreversible. Figure 4 displays complications observed in 25 patients with
PS included in our previous retrospective study [6], Table 1 summarizes the incidences and the
age at onset for major complications in a most recent review of 139 cases of PS by Ying et al.
and 3 largest cohorts of PS in the literatures [5–7, 31]. The majority of patients suffer from
failure to thrive resulting in growth retardation and small stature [3–7, 31]. Muscular hypotonia
appears early in the clinical course. Dysfunction of the exocrine pancreas is one of the most
common non-hematological complications; the incidence ranged from 27 to 62% of patients
with PS in the literatures [3, 5–7]. Liver diseases with elevated serum transaminases, bilirubin
and/or abnormal sonographic findings are early complications, usually diagnosed before 2 years
of age [4–7]. Hepatomegaly is observed in 30–70% of PS patients, while splenomegaly is seen
less frequently [3, 7]. Renal involvement with tubulopathy is also common and usually
diagnosed at the age of 2–4 years; some patients develop chronic renal failure [3–7]. Endocrine
disorders, such as insulin-dependent diabetes, growth hormone deficiency, hypothyroidism,
hypoparathyroidism, and adrenal insufficiency can develop at any age [3–7, 44].
Ophthalmological complications including ptosis, retinitis pigmentosa and cataract and cardiac
conduction defects are relatively late complications (Table 1) [6, 7]. Some patients have mild
:
 delay in motor and speech development in infancy and childhood, while ataxia and tremor
appears at a later age [6, 18]. Cognitive impairment is no typical feature of PS. Reynolds et al.
reported that 69% of patients had psychiatric problems including anger or rage outbursts,
distractibility, and perseveration [6]. Surviving patients typically develop a KSS phenotype
(ophthalmoplegia, retinitis pigmentosa, cardiac conduction block and ataxia) [18, 19].
Development of Leigh syndrome has been reported as well [18, 58, 59]. Severe infections are
frequent in PS and can result in a fatal course [3, 7].

Fig. 4

Initial presentation and complications during the clinical course in 25 patients with Pearson syndrome. Signs
and symptoms at first presentation (blue), at time of diagnosis (red) or manifesting itself during the clinical
course (green) are shown. The left axis provides the number of patients for each item. [6]

Table 1

Frequency and time of presentation of varied non-hematological complications

:
 Ying, 2022 (n Reynolds, 2021 (n Yoshimi, 2021 (n Rötig, 1995 (n =
= 139*) = 42**) = 25) 21)

Symptoms/organ % % average % median % median

dysfunctions age age age

(months) (range, (range,

months) months)

Failure to thrive 49 89 – 72 12 (3–92) – –

Muscle hypotonia 12 71 – 52 24 (7–77) – –

Pancreatic insufficiency 40 47 20 56 12 (3–31) 57 12 (5–

42)

Liver dysfunction - 66 8 16 18 (10– 33 23 (7–

30) 36)

Renal disorders 43 80 – – – – –

(tubulopathy/Fanconi - 37 48 32 41 (21– 24 30 (23–

syndrome) 121) 45)

Cardiac 20 66 20 66 (31– – –
abnormality/arrhythmia 183)

(cardiac conduction – (17) (107) – – – –

diseases)

Adrenal insufficiency – 30 57 8 66 (65–

67)

Diabetes mellitus 18 22 111 4 19 10 30 (24–

36)

Ophthalmological 24 86 – 20 39 (19– – –
problem 92)

Hearing impairment 3 31 100 4 115

Data of the most recent review by Ying et al. and 3 largest cohorts of patients with Pearson syndrome (PS)
in literatures are displayed (5–7, 31).*The cohort from Ying et al. includes the cases reported by Rötig et al.
**The study by Reynolds et al. is based on patient reported outcomes, and the cohort includes 34 cases with
PS and 8 pediatric cases with Kearns-Sayre syndrome

Therapy for patients with Pearson syndrome

:
 Like for the vast majority of PMD patients, there is no cure for children with PS. Therapy is
largely supportive to prevent metabolic decompensations during catabolic episodes (eg. fasting,
fever, surgery, injury and dehydration) and to treat organ-specific complications [13, 39, 60].
Most PMD patients receive supplements such as coenzyme Q10, L-carnitine and/or various
vitamins (vitamin B1, B2, C, E) despite limited evidence for efficacy. Other supportive therapies
include sodium bicarbonate substitutions to treat persistent metabolic acidosis, correction of
electrolyte abnormalities, fluid infusions and antibiotics. Some medications (eg. valproic acid,
statins, and aminoglycosides) should be avoided in PMD because of their effects on
mitochondrial function and increased side effects [60]. Patients with PMD also require special
attention in case of anesthesia and surgical intervention [39]. We direct the reader to several
recent excellent reviews and recommendations of expert panels for management and treatment
as well as emerging new therapies of patients with PMDs, because these issues are beyond the
scope of this paper [11, 39, 60, 61]. Disease-specific therapies for PS are not available, but
awareness of natural history, common complications, and age of their onsets in PS may optimize
monitoring and care of patients, and minimize morbidity. Regular monitoring of pancreatic
function, renal tubular function, multiple endocrine functions, cardiac function, and follow-up
by a multidisciplinary team is necessary to provide optimal care for patients and families (Table
2). PS patients often require pancreatic enzyme replacement and hormone substitution [3, 6].
Tube feeding including placement of percutaneous endoscopic gastrostomy and/or parenteral
nutrition is often considered because of severe loss of appetite, dysphagia, feeding difficulty and
failure to thrive [7]. Because febrile infections can induce catabolism and trigger metabolic,
potentially life-threatening decompensations, the prevention of infections including vaccinations
and early antipyretic as well as antibiotic therapy is crucial to minimize the risk. PS patients who
developed cardiac conduction defects may require intervention such as ablation and pacemaker
implantations [62]. It is recommended that patients with PS carry an emergency protocol, which
provides the necessary information for evaluation and optimal care in acute settings.

Table 2

Initial and follow-up work-ups for patients with Pearson syndrome

:
 Basic check-ups At diagnosis and every visit

Physical examination including height/weight, neurological

and developmental evaluation

CBC with manual differentiation, MCV and reticulocyte count

Clinical chemistries with electrolytes including calcium and

magnesium, transaminases, BUN, creatinine, glucose, ferritin
and phosphate, serum lactate

Blood gas analysis

Urine analysis for tubulopathy

Bone marrow examination with cytogenetic analysis* At diagnosis and every 12 months until
hematological recovery

Endocrine screening tests such as growth chart, pubertal At diagnosis and every 12 months
staging, pancreatic function (serum amylase/lipase, stool
elastase), thyroid function (TSH, free thyroxine) and
hemoglobin A1c
Cardiac evaluation including echocardiography and ultrasound At diagnosis and every 12 months

Abdominal ultrasound (pancreas, liver, kidney, spleen) At diagnosis and every 12 months

Ophthalmologic examination At diagnosis and every 12 months

Hearing examination At diagnosis and every 12 months

Provide emergency protocol

CBC Complete blood count, MCV Mean corpuscular volume, BUN Blood urea nitrogen, TSH Thyroid
stimulating hormone, *risk of anesthesia should considered

Therapy of hematological complications

Granulocyte-colony-stimulating factor (G-CSF) may correct neutropenia, but erythropoietin and

elthrombopag have limited effect on anemia [6, 63]. Multiple transfusions may cause iron
overload in patients with PS. Indication for iron-chelation therapy need to be carefully weighed
:
 against the high incidence of spontaneous resolution of anemia, short life expectancy as well as
potential toxicities of chelating drugs in PS. Whether iron-chelating therapy in PS could delay
progression of organ dysfunctions is unknown.

The indication for hematopoietic stem cell transplantation (HSCT) is often discussed in clinical
practice due to persistent transfusion dependency or severe neutropenia. Due to the high rate of
spontaneous resolution of anemia, which often occurs in early infancy, it is generally not
recommended to consider HSCT before the age of 3–4 years [6, 16]. Although hematological
remission can be achieved after HSCT, the potential role of HSCT as therapy for non-
hematological complications in PS is unclear. A study in mito-miceΔ carrying mtDNA deletion
demonstrated prolonged survival, delayed development of renal failure and suppression of
apoptosis of renal cells after BM transplantation [64]. Interestingly, recent studies have
demonstrated horizontal mitochondrial transfer between varied cells both in physiological and
pathological conditions and mitochondrial transplantation is considered as a potential therapy
for varied conditions with mitochondrial dysfunction [12, 65, 66]. The most common donor
cells studied for the mitochondrial transcellular transfer are mesenchymal stem cells (MSCs)
[65], which can infuse mitochondria into a variety of cells and rescue aerobic respiration of
acceptor cells. Moreover, a mitochondrial transfer from donor derived HSCs to damaged
recipient MSCs and the metabolic recovery of the recipient MSCs after allogeneic HSCT was
recently demonstrated in a mouse model [67]. This study suggests the potential therapeutic role
of transplanted HSCs for the recovery of mitochondrial function in some tissues with
mitochondrial dysfunction.

Nevertheless, there is no sufficient evidence that HSCT can prolong the survival and correct or
prevent the progressive multi-organ dysfunction in patients with PS so far. Moreover, risk for
irreversible damage from conditioning with chemotherapy prior to HSCT and greater than
expected transplant-related complications should be considered. Six PS patients who received
HSCT are reported in the literature [42, 55, 57, 68, 69]. Four of them died following HSCT; one
patient died of pulmonary hemorrhage and metabolic acidosis soon after HSCT [57], one patient
developed acute myeloid leukemia of recipient origin with 7q deletion and trisomy 8 after
second HSCT and died. The causes of death is not reported in two cases. Two patients, who both
had an aberration of chromosome 7 prior to HSCT, were alive 3 years and 20 months after cord
blood transplantation, respectively. HSCT is currently the only curative treatment for PS patients
who developed myeloid malignancy.

Cell therapy and future direction

:
 There has been great progress in development of novel pharmacological and non-
pharmacological treatments including cell and gene therapies for patients with PMDs over the
past decade [11, 13, 61]. The first clinical trial of mitochondrial augmentation therapy (MAT)
was opened (ClinicalTrials.gov Identifier: NCT03384420) and offered patients and families new
hope. In this trial, G-CSF mobilized HSCs of PS patients are subjected to ex-vivo mitochondrial
augmentation with maternal mitochondria carrying normal mtDNA [9–12]. These autologous
HSCs containing normal maternal mtDNA are reinfused in the patient. The advantage of this
therapy compared to allogeneic HSCT is that cytotoxic conditioning and transplant-associated
complications can be waived. In very preliminary results, improvement of some laboratory
findings, neurological complications and quality of life have been described, although how the
MAT led to clinical improvement is not fully understood [10]. Further results are awaited to
evaluate whether this therapy can prevent or delay the progression of non-hematological
complications in PS.

Prognosis

The prognosis of patients with PS is dismal. About half of patients in the literatures died until
the age of 3 years [31] In the German/Austria study including 25 patients with PS, the overall
survival at 5 years of age was 58% without demonstrating a plateau [6]. The median age of death
was 49 months. Similar survival rates have been reported in other 2 studies [3, 4]. Only few
patients with PS have been reported to reach the age of 15 years [5–7, 27], and there is currently
no prognostic factor to predict the prognosis of PS patients. The most common cause of death is
metabolic crisis with severe and uncontrollable lactic acidosis, followed by infections and multi-
organ failures such as liver and kidney failure. Arrhythmia is an important cause of death in
older patients.

Conclusion

A diagnosis of PS needs to be excluded in all infants with hypogenerative anemia. Pediatricians

need to be aware of the typical hematological findings, the wide spectrum of complications and
a dynamic change in clinical phenotypes during the course in patients with PS. Early diagnosis
is crucial for implementation of symptomatic therapy and genetic counseling of families. While
curative treatment is currently not available for this dismal disorder, development of cell and
gene therapy is expected to offer a new treatment paradigm and hope for affected patients and
their families.

Acknowledgements
:
 We appreciate the support of the FZSE (Freiburg Zentrum für Seltene Erkrankungen/Freiburg
Center for Rare Diseases) in University of Freiburg, the European Reference Network for
Paediatric Oncology (ERN PaedCan), the European Reference Network for Hereditary
Metabolic Disorders (MetabERN), and the German Federal Ministry of Education and Research
(BMBF) 01GM1911A "MyPred—Network for young individuals with syndromes predisposing
to myeloid malignancies".

Abbreviations

PS Pearson syndrome

mtDNA Mitochondrial DNA

PMD Primary mitochondrial disease

SLSMD Single large-scale mtDNA deletions

CPEO Chronic progressive external ophthalmoplegia

KSS Kearns-Sayre syndrome

HSCT Hematopoietic stem cell

BM Bone marrow

HbF Fetal hemoglobin

DBA Diamond- Blackfan anemia

SDS Shwachman-Diamond syndrome

G-CSF Granulocyte-colony-stimulating factor

:
 Author contributions

AY and SG drafted the manuscript. All authors read, revised and the final manuscript.

Funding

Open Access funding enabled and organized by Projekt DEAL.

Availability of data and materials

The data of the German/Australian cohort used and/or analysed for this review is published [6]
and datasets are available from the corresponding author on reasonable request.

Declarations
Ethics approval and consent to participate

The study of the German/Australian cohort was approved by the institutional ethics committee
(University of Freiburg, 325/20).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional
affiliations.

References
:
 1. Pearson HA, Lobel JS, Kocoshis SA, Naiman JL, Windmiller J, Lammi AT, et al. A new syndrome of refractory
sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction. J Pediatr.
1979;95(6):976–984. doi: 10.1016/S0022-3476(79)80286-3. [PubMed] [CrossRef] [Google Scholar]

2. Rotig A, Colonna M, Blanche S, Fischer A, Le Deist F, Frezal J, et al. Deletion of blood mitochondrial DNA in
pancytopenia. Lancet. 1988;2(8610):567–568. doi: 10.1016/S0140-6736(88)92687-6. [PubMed] [CrossRef] [Google
Scholar]

3. Farruggia P, Di Cataldo A, Pinto RM, Palmisani E, Macaluso A, Valvo LL, et al. Pearson syndrome: a retrospective
cohort study from the marrow failure study group of A.I.E.O. (Associazione Italiana Emato-Oncologia Pediatrica).
JIMD Reports. 2016;26:37–43. [PMC free article] [PubMed]

4. Broomfield A, Sweeney MG, Woodward CE, Fratter C, Morris AM, Leonard JV, et al. Paediatric single
mitochondrial DNA deletion disorders: an overlapping spectrum of disease. J Inherit Metab Dis. 2015;38(3):445–457.
doi: 10.1007/s10545-014-9778-4. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

5. Rotig A, Bourgeron T, Chretien D, Rustin P, Munnich A. Spectrum of mitochondrial DNA rearrangements in the
Pearson marrow-pancreas syndrome. Hum Mol Genet. 1995;4(8):1327–1330. doi: 10.1093/hmg/4.8.1327. [PubMed]
[CrossRef] [Google Scholar]

6. Yoshimi A, Grünert SC, Cario H, Fisch A, Gross-Wieltsch U, Timmermann K, et al. Haematological characteristics
and spontaneous haematological recovery in Pearson syndrome. British J Haematol. 2021;193(6):1283–1287.
[PubMed]

7. Reynolds E, Byrne M, Ganetzky R, Parikh S. Pediatric single large-scale mtDNA deletion syndromes: the power of
patient reported outcomes. Mol Genet Metab. 2021;134(4):301–308. doi: 10.1016/j.ymgme.2021.11.004. [PubMed]
[CrossRef] [Google Scholar]

8. Manea EM, Leverger G, Bellmann F, Stanescu PA, Mircea A, Lebre AS, et al. Pearson syndrome in the neonatal
period: two case reports and review of the literature. J Pediatr Hematol Oncol. 2009;31(12):947–951.
doi: 10.1097/MPH.0b013e3181bbc4ef. [PubMed] [CrossRef] [Google Scholar]

9. Jacoby E, Ben Yakir-Blumkin M, Blumenfeld-Kan S, Brody Y, Meir A, Melamed-Book N, et al. Mitochondrial

augmentation of CD34(+) cells from healthy donors and patients with mitochondrial DNA disorders confers
functional benefit. NPJ Regen Med. 2021;6(1):58. doi: 10.1038/s41536-021-00167-7. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]

10. Jacoby E, Blumkin M, Anikster Y, Varda-Bloom N, Pansheen J, Bar Yoseph O, et al. First-in-human mitochondrial
augmentation of hematopoietic stem cells in pearson syndrome. Blood. 2018;132(Supplement 1):1024.

11. Tinker RJ, Lim AZ, Stefanetti RJ, McFarland R. Current and emerging clinical treatment in mitochondrial disease.
Mol Diagn Ther. 2021;25(2):181–206. doi: 10.1007/s40291-020-00510-6. [PMC free article] [PubMed] [CrossRef]
[Google Scholar]
:
 12. Lightowlers RN, Chrzanowska-Lightowlers ZM, Russell OM. Mitochondrial transplantation-a possible therapeutic
for mitochondrial dysfunction?: Mitochondrial transfer is a potential cure for many diseases but proof of efficacy and
safety is still lacking. EMBO Rep. 2020;21(9):e50964. doi: 10.15252/embr.202050964. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]

13. Gorman GS, Chinnery PF, DiMauro S, Hirano M, Koga Y, McFarland R, et al. Mitochondrial diseases. Nat Rev
Dis Primers. 2016;2:16080. doi: 10.1038/nrdp.2016.80. [PubMed] [CrossRef] [Google Scholar]

14. Alston CL, Rocha MC, Lax NZ, Turnbull DM, Taylor RW. The genetics and pathology of mitochondrial disease. J
Pathol. 2017;241(2):236–250. doi: 10.1002/path.4809. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

15. Larsson NG, Holme E, Kristiansson B, Oldfors A, Tulinius M. Progressive increase of the mutated mitochondrial
DNA fraction in kearns-sayre syndrome. Pediatr Res. 1990;28(2):131–136. doi: 10.1203/00006450-199008000-
00011. [PubMed] [CrossRef] [Google Scholar]

16. Farruggia P, Di Marco F, Dufour C. Pearson syndrome. Expert Rev Hematol. 2018;11(3):239–246.
doi: 10.1080/17474086.2018.1426454. [PubMed] [CrossRef] [Google Scholar]

17. Mancuso M, Orsucci D, Angelini C, Bertini E, Carelli V, Comi GP, et al. Redefining phenotypes associated with
mitochondrial DNA single deletion. J Neurol. 2015;262(5):1301–1309. doi: 10.1007/s00415-015-7710-y. [PubMed]
[CrossRef] [Google Scholar]

18. Lee HF, Lee HJ, Chi CS, Tsai CR, Chang TK, Wang CJ. The neurological evolution of Pearson syndrome: case
report and literature review. Off J European Paediatric Neurol Soc. 2007;11(4):208–214.
doi: 10.1016/j.ejpn.2006.12.008. [PubMed] [CrossRef] [Google Scholar]

19. McShane MA, Hammans SR, Sweeney M, Holt IJ, Beattie TJ, Brett EM, et al. Pearson syndrome and
mitochondrial encephalomyopathy in a patient with a deletion of mtDNA. Am J Hum Genet. 1991;48(1):39–42. [PMC
free article] [PubMed] [Google Scholar]

20. Yanagihara I, Inui K, Yanagihara K, Park YD, Tanaka J, Ozono K, et al. Fluorescence in situ hybridization analysis
of peripheral blood cells in Pearson marrow-pancreas syndrome. J Pediatr. 2001;139(3):452–455.
doi: 10.1067/mpd.2001.116296. [PubMed] [CrossRef] [Google Scholar]

21. Inoue K, Nakada K, Ogura A, Isobe K, Goto Y, Nonaka I, et al. Generation of mice with mitochondrial
dysfunction by introducing mouse mtDNA carrying a deletion into zygotes. Nat Genet. 2000;26(2):176–181.
doi: 10.1038/82826. [PubMed] [CrossRef] [Google Scholar]

22. Katada S, Mito T, Ogasawara E, Hayashi J, Nakada K. Mitochondrial DNA with a large-scale deletion causes two
distinct mitochondrial disease phenotypes in mice. G3. 2013;3(9):1545–52. [PMC free article] [PubMed]

23. de Vries DD, Buzing CJ, Ruitenbeek W, van der Wouw MP, Sperl W, Sengers RC, et al. Myopathology and a
mitochondrial DNA deletion in the Pearson marrow and pancreas syndrome. Neuromuscul Disord. 1992;2(3):185–
195. doi: 10.1016/0960-8966(92)90005-Q. [PubMed] [CrossRef] [Google Scholar]
:
 24. Cormier V, Rotig A, Quartino AR, Forni GL, Cerone R, Maier M, et al. Widespread multi-tissue deletions of the
mitochondrial genome in the Pearson marrow-pancreas syndrome. J Pediatr. 1990;117(4):599–602.
doi: 10.1016/S0022-3476(05)80698-5. [PubMed] [CrossRef] [Google Scholar]

25. Sano T, Ban K, Ichiki T, Kobayashi M, Tanaka M, Ohno K, et al. Molecular and genetic analyses of two patients
with Pearson's marrow-pancreas syndrome. Pediatr Res. 1993;34(1):105–110. doi: 10.1203/00006450-199307000-
00024. [PubMed] [CrossRef] [Google Scholar]

26. Rotig A, Cormier V, Blanche S, Bonnefont JP, Ledeist F, Romero N, et al. Pearson marrow Pancreas syndrome - a
multisystem mitochondrial disorder in infancy. J Clin Invest. 1990;86(5):1601–1608. doi: 10.1172/JCI114881. [PMC
free article] [PubMed] [CrossRef] [Google Scholar]

27. Muraki K, Nishimura S, Goto Y, Nonaka I, Sakura N, Ueda K. The association between haematological
manifestation and mtDNA deletions in Pearson syndrome. J Inherit Metab Dis. 1997;20(5):697–703.
doi: 10.1023/A:1005378527077. [PubMed] [CrossRef] [Google Scholar]

28. Bernes SM, Bacino C, Prezant TR, Pearson MA, Wood TS, Fournier P, et al. Identical mitochondrial DNA
deletion in mother with progressive external ophthalmoplegia and son with Pearson marrow-pancreas syndrome. J
Pediatr. 1993;123(4):598–602. doi: 10.1016/S0022-3476(05)80962-X. [PubMed] [CrossRef] [Google Scholar]

29. Shanske S, Tang Y, Hirano M, Nishigaki Y, Tanji K, Bonilla E, et al. Identical mitochondrial DNA deletion in a
woman with ocular myopathy and in her son with pearson syndrome. Am J Hum Genet. 2002;71(3):679–683.
doi: 10.1086/342482. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

30. Chinnery PF, DiMauro S, Shanske S, Schon EA, Zeviani M, Mariotti C, et al. Risk of developing a mitochondrial
DNA deletion disorder. Lancet. 2004;364(9434):592–596. doi: 10.1016/S0140-6736(04)16851-7. [PubMed]
[CrossRef] [Google Scholar]

31. Ying Y, Liang Y, Luo X, Wei M. Case report: clinical and genetic characteristics of pearson syndrome in a chinese
boy and 139 patients. Front Genet. 2022;13:802402. doi: 10.3389/fgene.2022.802402. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]

32. Pronman L, Rondinelli M, Burkardt DD, Velayuthan S, Khalili AS, Bedoyan JK. Pearson syndrome: a rare cause
of failure to thrive in infants. Clin Pediatr. 2019;58(7):819–824. doi: 10.1177/0009922819834285. [PubMed]
[CrossRef] [Google Scholar]

33. Tadiotto E, Maines E, Degani D, Balter R, Bordugo A, Cesaro S. Bone marrow features in Pearson syndrome with
neonatal onset: a case report and review of the literature. Pediatr Blood Cancer. 2018;65(4):26939.
doi: 10.1002/ajmg.a.36939. [PubMed] [CrossRef] [Google Scholar]

34. Gibson KM, Bennett MJ, Mize CE, Jakobs C, Rotig A, Munnich A, et al. 3-Methylglutaconic aciduria associated
with Pearson syndrome and respiratory chain defects. J Pediatr. 1992;121(6):940–942. doi: 10.1016/S0022-
3476(05)80348-8. [PubMed] [CrossRef] [Google Scholar]
:
 35. Crippa BL, Leon E, Calhoun A, Lowichik A, Pasquali M, Longo N. Biochemical abnormalities in Pearson
syndrome. Am J Med Genetic Part A. 2015;167 (3):621–8. [PubMed]

36. Seneca S, De Meirleir L, De Schepper J, Balduck N, Jochmans K, Liebaers I, et al. Pearson marrow pancreas
syndrome: a molecular study and clinical management. Clin Genet. 1997;51(5):338–342. doi: 10.1111/j.1399-
0004.1997.tb02484.x. [PubMed] [CrossRef] [Google Scholar]

37. Sato T, Muroya K, Hanakawa J, Iwano R, Asakura Y, Tanaka Y, et al. Clinical manifestations and enzymatic
activities of mitochondrial respiratory chain complexes in Pearson marrow-pancreas syndrome with 3-
methylglutaconic aciduria: a case report and literature review. Eur J Pediatr. 2015;174(12):1593–1602.
doi: 10.1007/s00431-015-2576-7. [PubMed] [CrossRef] [Google Scholar]

38. Williams TB, Daniels M, Puthenveetil G, Chang R, Wang RY, Abdenur JE. Pearson syndrome: unique endocrine
manifestations including neonatal diabetes and adrenal insufficiency. Mol Genet Metab. 2012;106(1):104–107.
doi: 10.1016/j.ymgme.2012.01.018. [PubMed] [CrossRef] [Google Scholar]

39. Parikh S, Goldstein A, Koenig MK, Scaglia F, Enns GM, Saneto R, et al. Diagnosis and management of
mitochondrial disease: a consensus statement from the mitochondrial medicine society. Genet Med. 2015;17(9):689–
701. doi: 10.1038/gim.2014.177. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

40. Cui H, Li F, Chen D, Wang G, Truong CK, Enns GM, et al. Comprehensive next-generation sequence analyses of
the entire mitochondrial genome reveal new insights into the molecular diagnosis of mitochondrial DNA disorders.
Genet Med. 2013;15(5):388–394. doi: 10.1038/gim.2012.144. [PubMed] [CrossRef] [Google Scholar]

41. Wong LJ. Next generation molecular diagnosis of mitochondrial disorders. Mitochondrion. 2013;13(4):379–387.
doi: 10.1016/j.mito.2013.02.001. [PubMed] [CrossRef] [Google Scholar]

42. Gagne KE, Ghazvinian R, Yuan D, Zon RL, Storm K, Mazur-Popinska M, et al. Pearson marrow pancreas
syndrome in patients suspected to have diamond-blackfan anemia. Blood. 2014;124(3):437–440. doi: 10.1182/blood-
2014-01-545830. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

43. Bezzerri V, Cipolli M. Shwachman-diamond syndrome: molecular mechanisms and current perspectives. Mol
Diagn Ther. 2019;23(2):281–290. doi: 10.1007/s40291-018-0368-2. [PubMed] [CrossRef] [Google Scholar]

44. Superti-Furga A, Schoenle E, Tuchschmid P, Caduff R, Sabato V, DeMattia D, et al. Pearson bone marrow-
pancreas syndrome with insulin-dependent diabetes, progressive renal tubulopathy, organic aciduria and elevated fetal
haemoglobin caused by deletion and duplication of mitochondrial DNA. Eur J Pediatr. 1993;152(1):44–50.
doi: 10.1007/BF02072515. [PubMed] [CrossRef] [Google Scholar]

45. Lazarchick J. Update on anemia and neutropenia in copper deficiency. Curr Opin Hematol. 2012;19(1):58–60.
doi: 10.1097/MOH.0b013e32834da9d2. [PubMed] [CrossRef] [Google Scholar]

46. Sheqwara J, Alkhatib Y. Sideroblastic anemia secondary to zinc toxicity. Blood 2013;122(3):311. [PubMed]
:
 47. Lane M, Alfrey CP. The anemia of human riboflavin deficiency. Blood. 1965;25:432–442.
doi: 10.1182/blood.V25.4.432.432. [PubMed] [CrossRef] [Google Scholar]

48. Pillai NR, Amin H, Gijavanekar C, Liu N, Issaq N, Broniowska KA, et al. Hematologic presentation and the role of
untargeted metabolomics analysis in monitoring treatment for riboflavin transporter deficiency. Am J Med Genet A.
2020;182(11):2781–2787. doi: 10.1002/ajmg.a.61851. [PubMed] [CrossRef] [Google Scholar]

49. Yeung KY, Klug PP, Lessin LS. Alcohol-induced vacuolization in bone marrow cells: ultrastructure and
mechanism of formation. Blood Cells. 1988;13(3):487–502. [PubMed] [Google Scholar]

50. Sherman JD, Greenfield JB, Ingall D. reversible bone-marrow vacuolizations in phenylketonuria. N Engl J Med.
1964;270:810–814. doi: 10.1056/NEJM196404162701602. [PubMed] [CrossRef] [Google Scholar]

51. Rosenbach LM, Caviles AP, Mitus WJ. Chloramphenicol toxicity Reversible vacuolization of erythroid cells. N
Engl J Med. 1960;263:724–728. [PubMed]

52. Bernstein WB, Trotta RF, Rector JT, Tjaden JA, Barile AJ. Mechanisms for linezolid-induced anemia and
thrombocytopenia. Ann Pharmacother. 2003;37(4):517–520. doi: 10.1345/aph.1C361. [PubMed] [CrossRef] [Google
Scholar]

53. Bader-Meunier B, Mielot F, Breton-Gorius J, Cramer E, Guichard J, Landrieu P, et al. Hematologic involvement in
mitochondrial cytopathies in childhood: a retrospective study of bone marrow smears. Pediatr Res. 1999;46(2):158–
162. doi: 10.1203/00006450-199908000-00005. [PubMed] [CrossRef] [Google Scholar]

54. Riley LG, Heeney MM, Rudinger-Thirion J, Frugier M, Campagna DR, Zhou R, et al. The phenotypic spectrum of
germline YARS2 variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and
sideroblastic anemia 2. Haematologica. 2018;103(12):2008–2015. doi: 10.3324/haematol.2017.182659. [PMC free
article] [PubMed] [CrossRef] [Google Scholar]

55. Hoyoux C, Dresse MF, Robinet S, Forget P, Pieltain C, Ketelslegers O, et al. Cord blood transplantation in a child
with Pearson's disease. Pediatr Blood Cancer. 2008;51(4):566. doi: 10.1002/pbc.21615. [PubMed] [CrossRef]
[Google Scholar]

56. Hasegawa DH, S.; Nishimura, A.; Aiga, A.; Yamamoto, A.; Hosoya.Y.; Fujiwara, T.; Harigae,H.; Manabe, A. .
Clonal evolution with monosomy 7 in Pearson syndrome. International meeting on childhood MDS and SAA, abstract
book. 2017.

57. Son JS, Seo GH, Kim YM, Kim GH, Jin HK, Bae JS, et al. Clinical and genetic features of four patients with
Pearson syndrome: an observational study. Medicine (Baltimore) 2022;101(5):e28793.
doi: 10.1097/MD.0000000000028793. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

58. Santorelli FM, Barmada MA, Pons R, Zhang LL, DiMauro S. Leigh-type neuropathology in Pearson syndrome
associated with impaired ATP production and a novel mtDNA deletion. Neurology. 1996;47(5):1320–1323.
doi: 10.1212/WNL.47.5.1320. [PubMed] [CrossRef] [Google Scholar]
:
 59. Yamadori I, Kurose A, Kobayashi S, Ohmori M, Imai T. Brain lesions of the Leigh-type distribution associated
with a mitochondriopathy of Pearson's syndrome: light and electron microscopic study. Acta Neuropathol.
1992;84(3):337–341. doi: 10.1007/BF00227830. [PubMed] [CrossRef] [Google Scholar]

60. Parikh S, Goldstein A, Karaa A, Koenig MK, Anselm I, Brunel-Guitton C, et al. Patient care standards for primary
mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med.
2017;19(12):1380. [PMC free article] [PubMed]

61. Hirano M, Emmanuele V, Quinzii CM. Emerging therapies for mitochondrial diseases. Essays Biochem.
2018;62(3):467–481. doi: 10.1042/EBC20170114. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

62. Jennifer MS, Cortez D. Pearson marrow-pancreas syndrome with cardiac conduction abnormality necessitating
prophylactic pacemaker implantation. annals of noninvasive electrocardiology the official journal of the International
Society for Holter and Noninvasive Electrocardiology, Inc. 2019:e12681. [PMC free article] [PubMed]

63. Frączkiewicz J, Sęga-Pondel D, Kazanowska B, Ussowicz M. Eltrombopag therapy in children with rare disorders
associated with thrombocytopenia. J Pediatr Hematol Oncol. 2020;42(2):113–117.
doi: 10.1097/MPH.0000000000001528. [PubMed] [CrossRef] [Google Scholar]

64. Inoue S, Ishikawa K, Nakada K, Sato A, Miyoshi H, Hayashi J. Suppression of disease phenotypes of adult mito-
mice carrying pathogenic mtDNA by bone marrow transplantation. Hum Mol Genet. 2006;15(11):1801–1807.
doi: 10.1093/hmg/ddl102. [PubMed] [CrossRef] [Google Scholar]

65. Qin Y, Jiang X, Yang Q, Zhao J, Zhou Q, Zhou Y. The functions, methods, and mobility of mitochondrial transfer
between cells. Front Oncol. 2021;11:672781. doi: 10.3389/fonc.2021.672781. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]

66. Valenti D, Vacca RA, Moro L, Atlante A. Mitochondria can cross cell boundaries: an overview of the biological
relevance pathophysiological implications and therapeutic perspectives of intercellular mitochondrial transfer. Int J
Mol Sci. 2021;22(15):8312. doi: 10.3390/ijms22158312. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

67. Golan K, Singh AK, Kollet O, Bertagna M, Althoff MJ, Khatib-Massalha E, et al. Bone marrow regeneration
requires mitochondrial transfer from donor Cx43-expressing hematopoietic progenitors to stroma. Blood.
2020;136(23):2607–2619. doi: 10.1182/blood.2020005399. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

68. Tumino M, Meli C, Farruggia P, La Spina M, Faraci M, Castana C, et al. Clinical manifestations and management
of four children with Pearson syndrome. Am J Med Genet A. 2011;155A(12):3063–3066. doi: 10.1002/ajmg.a.34288.
[PubMed] [CrossRef] [Google Scholar]

69. Nishimura A, Hirabayashi S, Hasegawa D, Yoshida K, Shiraishi Y, Ashiarai M, et al. Acquisition of monosomy 7
and a RUNX1 mutation in Pearson syndrome. Pediatr Blood Cancer. 2021;68(2):e28799. doi: 10.1002/pbc.28799.
[PubMed] [CrossRef] [Google Scholar]
:
: