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Progressive external ophthalmoplegia (PEO) may originate from a variety of neurological disorders. In 1988, Zeviani et al. clarified that large-scale rearrangements of mitochondrial DNA (mtDNA) occur in sporadic cases. Deletions are mainly confined to a region of mtDNA (Table 71.1). The three main clinical syndromes caused by a large-scale deletion are Kearns-Sayre syndrome with onset of PEO and pigmentary retinitis before age 20 years, PEO with ragged-red fibers, and Pearson syndrome, a marrow-pancreatic disorder. The typical morphological change in the muscle is the presence of ragged-red fibers with Gomori trichrome stain, which may look granular or disrupted and are devoid of cytochrome C oxidase activity. These abnormal fibers also show excessive lipid and glycogen and accumulation of mitochondria with structural abnormalities on electron microscopy. In the following years, cases of PEO due to nuclear gene mutations were described due to a variety of nuclear genes (Table 71.2) that have a role in DNA maintenance and/or replication. Some of these disorders may present with central nervous system and extrapyramidal features.

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

Progressive external ophthalmoplegia (PEO), Kearns–Sayre syndrome (KSS) and Pearson syndrome are the three sporadic clinical syndromes classically associated with single large-scale deletions of mitochondrial DNA (mtDNA). PEO plus is a term frequently utilized in the clinical setting to identify patients with PEO and some degree of multisystem involvement, but a precise definition is not available. The purpose of the present study is to better define the clinical phenotypes associated with a single mtDNA deletion, by a retrospective study on a large cohort of 228 patients from the database of the “Nation-wide Italian Collaborative Network of Mitochondrial Diseases”. In our database, single deletions account for about a third of all patients with mtDNA-related disease, more than previously recognized. We elaborated new criteria for the definition of PEO and “KSS spectrum” (a category of which classic KSS represents the most severe extreme). The criteria for “KSS spectrum” include the resulting multisystem clinical features associated with the KSS features, and which therefore can predict their presence or subsequent development. With the new criteria, we were able to classify nearly all our single-deletion patients: 64.5% PEO, 31.6% KSS spectrum (including classic KSS 6.6%) and 2.6% Pearson syndrome. The deletion length was greater in KSS spectrum than in PEO, whereas heteroplasmy was inversely related with age at onset. We believe that the new phenotype definitions implemented here may contribute to a more homogeneous patient categorization, which will be useful in future cohort studies of natural history and clinical trials. © 2015, Springer-Verlag Berlin Heidelberg.

Pearson marrow‑pancreas syndrome (PS) is a progressive multi‑organ disorder caused by deletions and duplications of mitochondrial DNA (mtDNA). PS is often fatal in infancy, and the majority of patients with PS succumb to the disease before reaching three‑years‑of‑age, due to septicemia, metabolic acidosis or hepatocellular insufficiency. The present report describes the case of a four‑month‑old infant with severe normocytic normochromic anemia, vacuolization of hematopoietic precursors and metabolic acidosis. After extensive clinical investigation, the patient was diagnosed with PS, which was confirmed by molecular analysis of mtDNA. The molecular analysis detected a novel large‑scale (5.712 kb) deletion spanning nucleotides 8,011 to 13,722 of mtDNA, which lacked direct repeats at the deletion boundaries. The present report is, to the best of our knowledge, the first case reported in South Korea.

Pearson syndrome (PS) is a rare mitochondrial disorder that usually presents with transfusion-dependent macrocytic anemia, exocrine pancreatic dysfunction, and lactic acidosis. Typical bone marrow (BM) features are vacuolization in hematopoietic progenitors, hypocellularity, and ringed sideroblasts. At the neonatal age, PS may have a variable clinical onset. Moreover, there is little information about BM features at this age and the timing of their presentation. We report a neonatal case of PS that presented with refractory anemia and atypical BM features. We reviewed the BM findings in neonatal-onset PS cases to stress the importance and limitations of BM evaluation at this age.

The aim of the present review was to summarize and discuss previous findings concerning renal manifestations of primary mitochondrial disorders (MIDs). A literature review was performed using frequently used databases. The study identified that primary MIDs frequently present as mitochondrial multiorgan disorder syndrome (MIMODS) at onset or in the later course of the MID. Occasionally, the kidneys are affected in MIDs. Renal manifestations of MIDs include renal insufficiency, nephrolithiasis, nephrotic syndrome, renal cysts, renal tubular acidosis, Bartter-like syndrome, Fanconi syndrome, focal segmental glomerulosclerosis, tubulointerstitial nephritis, nephrocalcinosis, and benign or malign neoplasms. Among the syndromic MIDs, renal involvement has been most frequently reported in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome, Kearns-Sayre syndrome, Leigh syndrome and mitochondrial depletion syndromes. Only in single cases was renal involvement also reported in chronic progressive external ophthalmoplegia, Pearson syndrome, Leber's hereditary optic neuropathy, coenzyme-Q deficiency, X-linked sideroblastic anemia and ataxia, myopathy, lactic acidosis, and sideroblastic anemia, pyruvate dehydrogenase deficiency, growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death, and hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis syndrome. The present study proposes that the frequency of renal involvement in MIDs is probably underestimated. Diagnosis of renal involvement follows general guidelines and treatment is symptomatic. Thus, renal manifestations of primary MIDs require recognition and appropriate management, as they determine the outcome of MID patients.

Anemia is very common in infants. Although its causes are usually not severe and treatable, proper etiologic diagnosis should be established. When anemia is non-regenerative, it can be caused by aplastic anemia, myelodysplastic syndrome, bone marrow infiltration or hematopoietic factors deficiencies. Another possible cause is Pearson's syndrome, a rare mitochondrial disease that causes non-regenerative anemia associated with other cytopenias, pancreatic insufficiency, lactic acidosis and great variability in clinical presentation conditioned by heteroplasmy. It is characteristic to find in bone marrow studies variable vacuolization in erythroblastic progenitors and ring sideroblasts. The diagnosis is established by genetic study of mitochondrial deoxyribonucleic acid performed by Southern blot analysis (complete mitochondrial deoxyribonucleic acid amplification by polymerase chain reaction -long), obtaining 70-80% deletion of 4977 bp (NMD 8343-13459). There is no curative therapy and support treatment is the only available nowadays. Death is frequent in early years of life.

Severe congenital neutropenia is a group of rare diseases, characterized by a severe depletion of absolute neutrophil count which can be isolated or associated to extrahematological features (neurological, endocrine, immunological, renal, etc.). The bone marrow usually shows a block of maturation at promyleocyte stage. ELANE and HAX 1 mutations are then most frequent causative genetic lesions of the disease, but a number of different genes may be involved. Granulocyte colony–stimulating factor (G-CSF) is a lifetime treatment that had radically changed the natural history of the disease. However infections are still the major concern for these subjects who are dependent on G-CSF life time. The therapeutic dose of G-CSF is highly variable and is regarded as the minimal amount to prevent/minimize infections which in turn largely depends on achieving a protective peripheral blood neutrophil count. Transformation into myelodysplasia and/or acute leukemia occurs in around 20% of the population and depends on dose and duration of exposure to G-CSF. Hematopoietic stem cell transplantation is a definitive cure for the disease and in face of 3-year overall survival rate of 80%, it provides a nonnegligible mortality rate related to the procedure of 17%. Not all SCN affected patients have an absolute indication to HSCT, malignant-inherited osteopetrosis is a heterogeneous group of rare disorders characterized by increased bone density due to abnormal osteoclast activity. Consequent impaired bone reabsorption and endochondral formation replaces hematopoietic cells in the medullary cavity, and also increases the incidence of fractures due to bone fragility. The reduction of hematopoietic cells can also cause hematological abnormalities including thrombocytopenia, anemia, susceptibility to infections, and extramedullary hematopoiesis. Neurological manifestations of osteopetrosis can also occur due to narrowing of osseous foramina. Fast recognition and early differential diagnosis is essential prerequisite for the success of HSCT which is the only definitive cure of the disease at least for the severe neonatal form. Pearson syndrome (PS) is a rare sporadic multisystemic disease caused by severe defect in the mitochondrial respiratory chain. Multiple organs/systems may be involved (heart, muscle, liver, eye, kidney, etc.). Exocrine pancreatic deficiency and neurological/neuromuscular signs are present in more than half of the patients. Anemia, very often macrocytic and in a context of pancytopenia, is an early finding and neutropenia, is generally moderate (between 0.5 and 1 × 109 L−1). Treatment is essentially supportive and the outcome is rather dismal.

Background Sideroblastic anemia represents a heterogeneous group of inherited or acquired diseases with disrupted erythroblast iron utilization, ineffective erythropoiesis, and variable systemic iron overload. In a cohort of 421 patients with multisystem mitochondrial diseases, refractory anemia was found in 8 children. Results Five children had sideroblastic anemia with increased numbers of ring sideroblasts >15%. Two of the children had a fatal course of MLASA1 syndrome (mitochondrial myopathy, lactic acidosis, and sideroblastic anemia [SA]) due to a homozygous, 6-kb deletion in the PUS1 gene, part of the six-member family of pseudouridine synthases (pseudouridylases). Large homozygous deletions represent a novel cause of presumed PUS1-loss-of-function phenotype. The other three children with SA had Pearson syndrome (PS) due to mtDNA deletions of 4 to 8 kb; two of these children showed early onset of PS and died due to repeated sepsis; the other child had later onset of PS and survived as the hematological parameters normalized and the disease transitioned to Kearns-Sayre syndrome. In addition, anemia without ring sideroblasts was found in three other patients with mitochondrial disorders, including two children with later onset of PS and one child with failure to thrive, microcephaly, developmental delay, hypertrophic cardiomyopathy, and renal tubular acidosis due to the heterozygous mutations c.610A>G (p.Asn204Asp) and c.674C>T (p.Pro225Leu) in the COX10 gene encoding the cytochrome c oxidase assembly factor. Conclusions Sideroblastic anemia was found in fewer than 1.2% of patients with multisystem mitochondrial disease, and it was usually associated with an unfavorable prognosis.

Background: Pearson Syndrome (PS) is an ultra-rare disease caused by de-novo mitochondrial DNA (mtDNA) deletions. Patients present at infancy with sideroblastic anemia and later develop a multisystem metabolic disorder, leading to death in early or late childhood. No disease-modifying treatments are available for PS. Ex-vivo enrichment of functional mitochondria into various cells has been previously demonstrated, as has inter-cellular mitochondrial transfer. In preclinical models of mitochondrial and lysosomal disorders, hematopoietic stem and progenitor cells (HSCs) have been shown capable of carrying and transferring normal organelles into diseased tissues, thereby altering disease phenotype. Here, we show enrichment of PS-derived HSCs with wild-type mitochondria, a process termed mitochondrial augmentation. We further report on three patients with PS treated with autologous HSCs following ex-vivo mitochondrial augmentation. Methods: Diagnosis of PS was confirmed by MLPA and deletion-specific dPCR. Colony formation assays were performed on PS patient-derived HSCs, prior to and after mitochondrial augmentation. HSC mobilization was performed with GCSF alone (n=1) or with plerixafor (n=2) prior to leukapheresis. Autologous CD34+ cells were positively-selected using a CliniMACS system, followed by ex-vivo mitochondrial augmentation of the cells with maternal cryopreserved mitochondria carrying normal mtDNA as confirmed by MLPA. Enriched cells were intravenously infused without conditioning. Level of heteroplasmy (relative normal to deleted mtDNA) was determined by deletion-specific dPCR of DNA from peripheral blood. Patients were followed for a period of up to 1 year including clinical and metabolic evaluations. Adverse events were reported as per CTCAE v4.03. Cellular mitochondrial function was studied on peripheral blood mononuclear cells (PBMCs) by ATP content, O2 consumption and flow cytometry for TMRE (tetramethylrhodamine ethyl ester) and MTG (mitotracker green). Results: Three patients were treated with production and safety data available, and in two patients efficacy data is available. PS-patient derived HSCs have a diminished capacity to form colonies in vitro (median, 360 colonies per 5x104 cells vs. 1090 in healthy donors). HSC colony forming capacity increased by an average of 30% after mitochondrial augmentation. Target cell dose (4x106 CD34+ cells/kg) was not reached despite two leukapheresis procedures in patients 1 and 2, who received 1.1 and 1.8 million CD34+ cells/kg recipient, respectively. Patient 3 received 2.8 million cells/kg following a single apheresis. Mitochondrial enrichment in the products was 156%, 162% and 114% for patients 1, 2 and 3. To date, the only treatment-related adverse events noted were leukapheresis related, including anemia, hypocalcemia and alkalosis. In two patients with more than 3 months follow-up, we observed in vivo mitochondrial enrichment starting 3-4 months after cellular therapy, and throughout the follow-up period (Figure). Metabolic function of PBMCs showed improvement at 5 months post-treatment in lymphocyte ATP content, O2 consumption and TMRE:MTG ratio, indicating improved mitochondrial respiratory capacity. Improvement in mitochondrial heteroplasmy and function was in line with clinical findings. Following cell therapy, no events of metabolic crisis occurred, along with normalization of a pre-treatment negative base excess in patient 1 and ongoing improvement in baseline lactate levels in patient 2. Aerobic ability and fine motor functions were superior compared to baseline in both patients. Importantly, quality of life, as measured by the International Pediatric Mitochondrial Disease Score (IPMDS), was greatly improved after treatment. Conclusion: We report a first in human study with a novel form of cellular therapy, mitochondrial augmentation, in which we enrich HSCs with organelles encoding non-mutated version of the mtDNA sequence. We show the ability of mitochondrial augmentation to improve in vitro PS-derived HSC function, and improvement in metabolic determinants, aerobic capacity and quality of life of two patients treated. Together, these preliminary clinical data suggest that mitochondrial augmentation therapy is safe, and may alter the clinical course for patients with mitochondrial deletions/mutations including PS. Figure Figure. Disclosures Jacoby: Novartis Israel: Consultancy. Blumkin:Minovia Therapeutics: Employment. Sher:Minovia Therapeutics: Employment. Yivgi Ohana:Minovia Therapeutics: Employment. Toren:Novartis Israel: Consultancy.

Pearson syndrome (PS) is rare and often fatal multisystemic mitochondrial disorder. Many of those who survive develop signs and symptoms later in life of a related disorder called Kearns-Sayre syndrome (KSS). 13-month-old male child presented with transfusion dependent anemia since the age of 3 months and was initially labeled as a case of Diamond Black fan Anemia. Mitochondrial and pancreatic enzyme replacement therapy. Through this case report, we attempt to address the fact that possibility of PS, which is often labeled as DBA in initial stages, should be considered in cases of congenital anemia of uncertain etiology. Early diagnosis of PS and interventional therapy in the form of mitochondrial and pancreatic replacement can significantly prolong survival and improve quality of life.

Studies in patients have suggested that the clinical phenotypes of some mitochondrial diseases might transit from one disease to another (e.g., Pearson syndrome [PS] to Kearns-Sayre syndrome) in single individuals carrying mitochondrial (mt) DNA with a common deletion (∆mtDNA), but there is no direct experimental evidence for this. To determine whether ∆mtDNA has the pathologic potential to induce multiple mitochondrial disease phenotypes, we used trans-mitochondrial mice with a heteroplasmic state of wild-type mtDNA and ∆mtDNA (mito-mice∆). Late-stage embryos carrying ≥50% ∆mtDNA showed abnormal hematopoiesis and iron metabolism in livers that were partly similar to PS (PS-like phenotypes), although they did not express sideroblastic anemia that is a typical symptom of PS. More than half of the neonates with PS-like phenotypes died by 1 month after birth, whereas the rest showed a decrease of ∆mtDNA load in the affected tissues, peripheral blood and liver, and they recovered from PS-like phenotypes. The proportion of ∆mtDNA in various tissues of the surviving mito-mice∆ increased with time, and Kearns-Sayre syndrome−like phenotypes were expressed when the proportion of ∆mtDNA in various tissues reached >70–80%. Our model mouse study clearly showed that a single ∆mtDNA was responsible for at least two distinct disease phenotypes at different ages and suggested that the level and dynamics of ∆mtDNA load in affected tissues would be important for the onset and transition of mitochondrial disease phenotypes in mice.

No association between mitochondrial disease and pancreatitis has yet been established, although diabetes mellitus and diseases caused by exocrine insufficiency, such as Pearson syndrome, are the commonest pancreatic complications of mitochondrial diseases. Here, we report 2 cases of mitochondrial disease complicated by pancreatitis as an unusual pancreatic exocrine manifestation. One patient was a 10-year-old girl with mild retardation of psychomotor development who had experienced recurrent pancreatitis since the age of 4 years. Chronic progressive external ophthalmoplegia (CPEO) due to m.8344A>G mutation was diagnosed when the patient was 10 years old. The other patient was a 28-year-old woman who was diagnosed with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) due to m.3243A>G mutation at 10 years of age. She had experienced regular recurrent vomiting since the age of 16 and suffered an episode of critical pancreatitis at 23 years. In both cases, no possible etiological, morphological, or genetic factors for pancreatitis were identified, including anomalous pancreaticobiliary duct. A combination therapy of the standard treatment for chronic pancreatitis and supportive therapy for mitochondrial energy production may be beneficial to prevent the recurrence of acute pancreatitis complicating mitochondrial diseases. The pathophysiological mechanism of pancreatitis in mitochondrial disease has not been adequately established; however, our observations suggest that pancreatitis should be included in the list of pancreatic complications of mitochondrial disease.

Pearson syndrome. Clinical spectrum of mitochondrial disorders is broad, so consensus diagnostic criteria for mitochondrial disorders have been proposed for children and adults. Sequence map of human mitochondrial genome with its normal and patho­ genic variants is publicly available. In this review, we will discuss genetic features of mitochondrial myopathies as well as their key findings. Representative syndromes will be described in detail and the less common entities will be summarized in Table 1.

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.

Fusarium species are ubiquitous fungi causing a wide array of infections, including invasive disease in the immunosuppressed. We present a fusarium bone infection in a child with Pearson syndrome and review the literature. Ten cases of fusarium osteomyelitis were reported in the past 40 years, and we review the treatments.

Pearson syndrome was first described in 1979. This is an infantile disorder presenting with early growth failure along with clinical features of sideroblastic anemia, lactic acidosis, and exocrine pancreatic failure. Renal tubular dysfunction is common, and glomerular dysfunction, as well as a hepatopathy, may occur early in the course of the illness in some cases. Early treatment requires repeated blood transfusions, management of the nutritional effects of the illness that can include supplemental feeding and use of pancreatic enzymes, surveillance for iron overload caused by the transfusions, buffering with bicarbonate therapy for the acidosis, and investigation and surveillance of other organ system dysfunction. Large-scale deletion of segment(s) of mtDNA is the most common cause of Pearson syndrome, although complex rearrangements and deletion-duplication of the mtDNA is also seen in some children. Although the common 4977 base-pair (bp) deletion responsible for Kearns-Sayre syndrome can be found in many cases, both larger and smaller deletions have been reported. These deletions involve both protein-encoding segments as well as several tRNA segments of the genome. If children survive early childhood, they go on to develop the clinical manifestations of Kearns-Sayre syndrome. In some cases, the bone marrow failure resolves and blood transfusions are no longer needed. A progressive external ophthalmoplegia, hepatopathy, insulin-dependent diabetes, glomerular disease, myopathy, cardiomyopathy, dementia, seizures, and metabolic strokes may occur early in childhood. Children with this disorder require a comprehensive care management team because there are serious manifestations that span many organ systems. There is no specific therapy for the illness, and early death is common.

Hemophagocytic lymphohistiocytosis (HLH) may develop secondary to infections, malignancies, immune deficiency syndromes, and rheumatologic and metabolic disorders. Associations between HLH and inborn errors of metabolism, including lysinuric protein intolerance, multiple sulfatase deficiency, galactosemia, Gaucher disease, Pearson syndrome, and galactosialidosis, have previously been reported in the literature. In this report the authors present 3 children with disorders of propionate metabolism--1 with methylmalonic acidemia and 2 with propionic acidemia--who developed secondary HLH during their metabolic attacks. All patients fulfilled the 5 HLH criteria of the Histiocyte Society. Familial HLH was ruled out by molecular analysis. Plasma exchange was performed for 2 of them. Unfortunately 1 died of multiorgan failure despite intensive therapy. This is the first report of such an association.

Mitochondrial disorders recognized in the neonatal period usually present as a metabolic crisis combined with one or several organ manifestations. Liver disorder in association with a respiratory chain deficiency may be overlooked since liver dysfunction is common in severely sick newborn infants. Lactacidosis, hypoglycemia, elevated serum transaminases and conjugated bilirubin are common signs of mitochondrial hepatopathy. Hepatosplenomegaly may occur in severe cases. A clinical picture with fetal growth restriction, postnatal lactacidosis, hypoglycemia, coagulopathy, and cholestasis, especially in combination with neurological symptoms or renal tubulopathy, should alert the neonatologist to direct investigations on mitochondrial disorder. A normal lactate level does not exclude respiratory chain defects. The most common liver manifestation caused by mutated mitochondrial DNA (deletion) is Pearson syndrome. Recently, mutations in several nuclear DNA genes have been identified that lead to mitochondrial hepatopathy, e.g. mitochondrial depletion syndrome caused by DGUOK, MPV17, SUCLG1, POLG1, or C10ORF2 mutations. A combination of lactacidosis, liver involvement, and Fanconi type renal tubulopathy is common when the complex III assembly factor BCS1L harbors mutations, the most severe disease with consistent genotype-phenotype correlation being the GRACILE syndrome. Mutations in nuclear translation factor genes (TRMU, EFG1, and EFTu) of the respiratory chain enzyme complexes have recently been identified. Diagnostic work-up of neonatal liver disorder should include assessment of function and structure of the complexes as well as mutation screening for known genes. So far, treatment is mainly symptomatic.

Pearson syndrome (PS) is a multisystem disease including refractory anemia, vacuolization of marrow precursors and pancreatic fibrosis. The disease starts during infancy and affects various tissues and organs, and most affected children die before the age of 3years. Pearson syndrome is caused by de novo large-scale deletions or, more rarely, duplications in the mitochondrial genome. In the present report, we described a Pearson syndrome patient harboring multiple mitochondrial deletions which is, in our knowledge, the first case described and studied in Tunisia. In fact, we reported the common 4.977kb deletion and two novel heteroplasmic deletions (5.030 and 5.234kb) of the mtDNA. These deletions affect several protein-coding and tRNAs genes and could strongly lead to defects in mitochondrial polypeptides synthesis, and impair oxidative phosphorylation and energy metabolism in the respiratory chain in the studied patient.

Mitochondria are the source of cellular energy. Genetically they depend on mitochondrial genes (mtDNA) as well as nuclear genes. MtDNA inheritance differs from Mendalian inheritance in many respects. As mitochondria are found in all cells, mitochondrial disease has an exceptionally wide clinical spectrum. This review summarizes the features of the classical mitochondrial disorders including the classical syndromes. The investigation and management is also discussed.

There are published reports stating that some of the congenital metabolic diseases, such as lysinuric protein intolerance, multiple sulphatase deficiency, galactosemia, Gaucher disease, Pearson syndrome, and galactosialidosis, might lead to secondary hemophagocytic lymphohistiocytosis (HLH). However, to date, to our knowledge, the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency has never been investigated among patients with HLH. Here, we report on a patient who was referred to our institution for a differential diagnosis of pancytopenia, liver failure, and rhabdomyolysis. The patient was diagnosed with HLH. Further investigation revealed an underlying diagnosis of the LCHAD deficiency. Our case was reported to contribute to the literature, as well as the HLH clinic, emphasizing the consideration of LCHAD deficiency, especially in 1 to 6 months' old infants with laboratory findings of hypoglycemia, metabolic acidosis, and elevated creatine kinase.

A number of tests of exocrine pancreatic function have been devised over the years, but the search for a simple and yet sensitive and specific test has been elusive until recently. We will discuss the evidence that determination of the faecal concentration of pancreatic elastase 1 with an enzyme-linked immunosorbent assay method fulfils these criteria and thus provides an ideal tool to assess exocrine pancreatic function. Approximately 90% of the pancreas is made up of exocrine tissue comprising acinar cells, which secrete pancreatic enzymes, and ductal cells, which secrete bicarbonate rich fluid. About 1% of the pancreas is endocrine tissue, the remainder being stromal tissue. The exocrine pancreas has a large functional capacity. More than 98% of function is usually lost before symptoms and signs of fat malabsorption are manifest. The most common disease causing exocrine pancreatic insufficiency in children is cystic fibrosis (CF). Other conditions are rare but include chronic and familial pancreatitis, Shwachman–Diamond syndrome, Johanson–Blizzard syndrome, Pearson syndrome and isolated specific enzyme deficiencies—for example, lipase. A secondary pancreatic insufficiency may be seen in small bowel enteropathies, significant protein-energy malnutrition or short gut syndrome.1 There is increasing recognition of exocrine pancreatic dysfunction in children with diabetes.2 The clinical consequences of inadequate exocrine pancreatic output are mainly due to maldigestion of protein and fat rather than carbohydrate. With protein maldigestion, hypoproteinaemia and oedema may occur, and in fat maldigestion, overt malnutrition with steatorrhoea and wasting is more prominent. In practice, both tend to occur together and the signs and symptoms associated with the fat maldigestion are more obvious. Fat-soluble vitamin deficiencies also develop quickly. ### Previously available pancreatic function tests #### Direct tests These tests measure the enzyme activities, the bicarbonate levels and the pancreatic juice flow rates in the duodenal juice after exogenous hormonal stimulation of the pancreas, usually with secretin and cholecystokinin or, occasionally, after …

Among the etiologies of anemia in the newborn, those related to mitochondrial cytopathies are rare. Pearson syndrome is mostly diagnosed during infancy and characterized by refractory sideroblastic anemia with vacuolization of marrow progenitor cells and exocrine pancreatic dysfunction. We describe two diagnosed cases of Pearson syndrome in the early neonatal period caused by severe macrocytic aregenerative anemia. Bone marrow aspiration revealed sideroblastic anemia and vacuolization of erythroblastic precursors. The diagnosis was confirmed by genetic analysis revealing a deletion in the mitochondrial DNA. These two newborns received monthly transfusions. Five other newborns suffering from Pearson syndrome with various clinical symptoms were found in literature. Pearson syndrome, rarely diagnosed in newborns, should be suspected in the presence of macrocytic aregenerative anemia and requires a bone marrow aspirate followed by a genetic analysis from a blood sample.

Background: Pearson syndrome is a rare mitochondrial disorder characterized by sideroblastic anemia, liver disease, renal tubulopathy and exocrine pancreas deficiency. Observations: We describe a female infant suffering from anemia since birth who gradually developed the complete picture of Pearson syndrome by 13 months. Iron overload was disproportionate to blood transfusions. The patient was heterozygous for HFE gene C282Y mutation (type I hemochromatosis). After an initial response to deferoxamine she presented with cutaneous zygomycosis and died after metabolic derangement and Pneumocystis jiroveci pneumonia. Conclusion: This is the second case of a Pearson syndrome individual who was also heterozygous for HFE gene mutation C282Y published. It is also the second case report of a Pearson patient suffering from severe iron overload and liver disease that responded to therapy with deferoxamine.

BACKGROUND: We report a patient with a highly unusual presentation of a mitochondrial disorder. HISTORY AND SIGNS: An 8-year old girl presented with muscular cramps as well as height and weight deceleration. Investigations revealed lactic acidosis, electrolytic imbalance and urinary loss of glucose and electrolytes secondary to proximal renal tubulopathy consistent with Fanconi syndrome (FS). Ophthalmic examination revealed asymptomatic retinitis pigmentosa (RP) with no other ocular manifestations. A mitochondriopathy was suspected and genetic analysis performed. THERAPY AND OUTCOME: Southern blotting documented a heteroplasmic mutation of mtDNA with deletion/duplication. Three discrete mitochondrial genomes were detected: normal; deletion of 6.7 kb and a deletion/duplication consisting of 1 normal and 1 deleted genome. The relative proportions varied considerably between tissues. CONCLUSIONS: The association of FS and RP combines features of Kearns-Sayre syndrome and Pearson marrow-pancreas syndrome, without being typical of either. This highly unusual clinical presentation emphasises the need for systemic investigation of patients with FS and further underlines the importance of mtDNA analysis in patients with unexpected associations of affected tissues.

Pearson syndrome (PS) is a very rare and often fatal multisystemic mitochondrial disorder involving the liver, kidney, pancreas, and hematopoietic and central nervous system. It is characterized principally by a transfusion-dependent anemia that usually improves over time, a tendency to develop severe infections, and a high mortality rate. We describe a group of 11 PS patients diagnosed in Italy in the period 1993-2014. The analysis of this reasonably sized cohort of patients contributes to the clinical profile of the disease and highlights a rough incidence of 1 case/million newborns. Furthermore, it seems that some biochemical parameters like increased serum alanine and urinary fumaric acid can help to address an early diagnosis.

Purpose To describe the occurrence of bilateral parafoveolar intraretinal crystals in a patient with Pearson syndrome (bone marrow-pancreas syndrome). Methods A patient with an established diagnosis of Pearson syndrome underwent complete ophthalmic examination and optical coherence tomography. Results Fine, refractile, crystalline, parafoveolar intraretinal deposits were seen bilaterally. There was no evidence of pigmentary retinopathy or ophthalmoplegia. Conclusions Intraretinal crystals in the macula may be seen in Pearson syndrome and may not cause a substantial decrease in visual acuity. Pearson syndrome should be considered in the differential diagnosis of parafoveolar crystalline retinopathy.

To study the clinical manifestations and occurrence of mtDNA depletion and deletions in paediatric patients with neuromuscular diseases and to identify novel clinical phenotypes associated with mtDNA depletion or deletions.Muscle DNA samples from patients presenting with undefined encephalomyopathies or myopathies were analysed for mtDNA content by quantitative real-time PCR and for deletions by long-range PCR. Direct sequencing of mtDNA maintenance genes and whole-exome sequencing were used to study the genetic aetiologies of the diseases. Clinical and laboratory findings were collected.Muscle samples were obtained from 104 paediatric patients with neuromuscular diseases. mtDNA depletion was found in three patients with severe early-onset encephalomyopathy or myopathy. Two of these patients presented with novel types of mitochondrial DNA depletion syndromes associated with increased serum creatine kinase (CK) and multiorgan disease without mutations in any of the known mtDNA maintenance genes; one patient had pathologic endoplasmic reticulum (ER) membranes in muscle. The third patient with mtDNA depletion was diagnosed with merosine-deficient muscular dystrophy caused by a homozygous mutation in the LAMA2 gene. Two patients with an early-onset Kearns-Sayre/Pearson-like phenotype harboured a large-scale mtDNA deletion, minor multiple deletions and high mtDNA content.Novel encephalomyopathic mtDNA depletion syndrome with structural alterations in muscle ER was identified. mtDNA depletion may also refer to secondary mitochondrial changes related to muscular dystrophy. We suggest that a large-scale mtDNA deletion, minor multiple deletions and high mtDNA content associated with Kearns-Sayre/Pearson syndromes may be secondary changes caused by mutations in an unknown nuclear gene.

We studied renal involvement in 42 children with mitochondrial diseases (MDs). The diagnosis of MD was established by morphological, biochemical, and molecular genetic criteria. Renal disease was considered when patients had renal failure, nephrotic syndrome, Fanconi's syndrome or any symptomatic renal alteration. Mild tubular disorder was established if they had abnormal laboratory findings with no apparent clinical symptom. Renal involvement was found in 21 children (50%), of whom 8 had an apparent clinical picture and 13 a mild tubular disorder. Five patients with renal disease showed Debré-Toni-Fanconi's syndrome, 2 of them with decreased glomerular filtration rate (GFR). One case had nephrotic syndrome, another one presented decreased GFR, and the last one had a neurogenic bladder and bilateral hydronephrosis. Patients with mild renal disease showed tubular dysfunction with normal GFR. Renal involvement is frequent and present in about half of the children with MD. Thus, studies for evaluating kidney function should be performed on children with MD. Conversely, patients with tubulopathy of unknown origin or progressive renal disease should be investigated for the existence of MD, especially if associated with involvement of other organs or tissues. Southern blot analysis to search for large-scale mitochondrial DNA (mtDNA) rearrangements should be performed for patients with MD and kidney involvement.

MR imaging features of mitochondrial encephalomyopathies, lactic acidosis, and stroke-like episodes, Kearns-Sayre/Pearson syndrome have been described in the literature. We describe extensive white matter changes with abnormal signal intensity lesions involving the deep gray nuclei and myelinated white matter tracts in an 18-year-old female with a large-scale 7.4 kb mitochondrial DNA deletion and a atypical presentation of Kearns-Sayre syndrome. Restricted diffusion due to status spongiosus at the involved sites is also discussed.

Although non-specific gastrointestinal and hepatic symptoms are commonly found in most mitochondrial disorders, they are among the cardinal manifestations of several primary mitochondrial diseases, such as: mitochondrial neurogastrointestinal encephalomyopathy; mitochondrial DNA depletion syndrome; Alpers syndrome; and Pearson syndrome. Management of these heterogeneous disorders includes the empiric supplementation with various "mitochondrial cocktails," supportive therapies, and avoidance of drugs and conditions known to have a detrimental effect on the respiratory chain. There is a great need for improved methods of treatment and controlled clinical trials of existing therapies. Liver transplantation is successful in acquired cases; however neuromuscular involvement in primary mitochondrial disorders should be a contraindication for liver transplantation.

Single deletions of mitochondrial DNA (mtDNA) are associated with three major clinical conditions: Kearns-Sayre syndrome, a multisystem disorder; Pearson syndrome (PS), a disorder of the hematopoietic system; and progressive external ophthalmoplegia (PEO), primarily affecting the ocular muscles. Typically, single mtDNA deletions are sporadic events, since the mothers, siblings, and offspring of affected individuals are unaffected. We studied a woman who presented with PEO, ptosis, and weakness of pharyngeal, facial, neck, and limb muscles. She had two unaffected children, but another of her children, an infant son, had sideroblastic anemia, was diagnosed with PS, and died at age 1 year. Morphological analysis of a muscle biopsy sample from the mother showed cytochrome c oxidase–negative ragged-red fibers—a typical pattern in patients with mtDNA deletions. Southern blot analysis using multiple restriction endonucleases and probed with multiple mtDNA fragments showed that both the mother and her infant son harbored an identical 5,355-bp single deletion in mtDNA, without flanking direct repeats. The deletion was the only abnormal species of mtDNA identified in both patients, and there was no evidence for duplications. We conclude that, although the vast majority of single large-scale deletions in mtDNA are sporadic, in rare cases, single deletions can be transmitted through the germline.

Pearson marrow-pancreas syndrome is a usually fatal disorder that involves the hematopoietic system, exocrine pancreas, liver, kidneys, and often presents clinically with failure to thrive. We report a 5-year-old patient who developed, in addition to the typical features of Pearson syndrome, worsening cardiac function, mainly affecting the left ventricle. The latter finding is particularly interesting because cardiac involvement has not yet been regarded as a major feature of Pearson syndrome. The diagnosis was proved by the finding of so far undescribed pleioplasmatic rearrangement of mitochondrial (mt)DNA (loss of 5,630 bp, 70% deleted and duplicated mtDNA) in blood cells. Our report demonstrates that patients with Pearson syndrome may also have impaired cardiac function. Thus, Pearson syndrome should be considered in the differential diagnosis of patients with left ventricular dysfunction of unknown origin and other clinical findings suggestive of a mitochondrial disease.

Mitochondrial dysfunction should be considered in the differential diagnosis of any progressive multisystem disorder. The diagnosis is most challenging when only one symptom is present. In contrast, the diagnosis is easier to consider when two or more seemingly unrelated symptoms are present, involving more than one organ system. It is important to consider the diagnosis of a mitochondrial disorder when dealing with an unexplained association of symptoms, with an early onset and progressive course involving seemingly unrelated organs. The investigation can be relatively straightforward if a person has a recognizable phenotype and if it is possible to identify a known pathogenic mtDNA mutation. The difficulty arises when no known mtDNA defect can be found or when the clinical abnormalities are complex and not easily matched to those of more common mitochondrial disorders. In summary: A full mitochondrial evaluation often is warranted in children with a complex neurologic picture or a single neurologic symptom and other system involvement. When the presentation is classic for a maternally inherited mitochondrial syndrome, such as MELAS, MERRF, or Leber's hereditary optic neuropathy, appropriate mtDNA studies should be obtained first. When the clinical picture is classic for a nuclear DNA inherited syndrome and the gene or linkage is known, such as MNGIE, the clinician should proceed with genetic studies. When the clinical picture is nonspecific but highly suggestive of a mitochondrial disorder, the clinician should start with plasma or CSF lactic acid, ketone bodies, plasma acylcarnitines, and urinary organic acids. If these studies are abnormal, the clinician should proceed with muscle biopsy and assessment of the respiratory chain enzymes. Normal plasma or CSF lactic acid does not rule out a mitochondrial disorder.

[Figure][1] A 3-month-old boy presented with decreased appetite, fatigue, and a nosebleed. Initial workup revealed hemoglobin 2.6 g/dL (10.2-12.7), hematocrit 7.7% (30.9-37.9), mean corpuscular volume 104 fL (71.3-82.6), white blood cell count 4200/μL (240 absolute neutrophil count)

Mitochondrial disorders are associated with well recognized ocular manifestations. Pearson syndrome is an often fatal, multisystem, mitochondrial disorder that causes variable bone marrow, hepatic, renal and pancreatic exocrine dysfunction. Phenotypic progression of ocular disease in a 12-year-old male with Pearson syndrome is described. This case illustrates phenotypic drift from Pearson syndrome to Kearns-Sayre syndrome given the patient's longevity. Persistent corneal endothelial failure was noted in addition to ptosis, chronic external ophthalmoplegia and mid-peripheral pigmentary retinopathy. We propose that corneal edema resulting from corneal endothelial metabolic pump failure occurs within a spectrum of mitochondrial disorders.

A 6-year-old boy presented with pancytopenia. Bone marrow morphology showed dyspoiesis and cytoplasmic vacuolation in myeloid precursor cells. Cytoplasmic vacuoles are described in erythroid cells in myelodysplastic syndrome (MDS) but are extremely rare in myeloid precursor cells. We ruled out viral and autoimmune etiology, hypocupremia, Pearson syndrome, and chromosomal abnormalities. Finally, a diagnosis of MDS of refractory cytopenia of childhood subtype was made. The patient then underwent an allogenic stem cell transplant that resulted in normalization of the complete blood counts and bone marrow morphology. However, he later developed late graft failure; this was followed by a second transplant after which he died of sepsis and multiorgan failure. The case is presented here for the rare morphologic features, hitherto not earlier described in pediatric MDS.

Pearson marrow-pancreas syndrome is a multisystem mitochondrial disorder characterized by bone marrow failure and pancreatic insufficiency. Children who survive the severe bone marrow dysfunction in childhood develop Kearns-Sayre syndrome later in life. Here we report on four new cases with this condition and define their biochemical abnormalities. Three out of four patients presented with failure to thrive, with most of them having normal development and head size. All patients had evidence of bone marrow involvement that spontaneously improved in three out of four patients. Unique findings in our patients were acute pancreatitis (one out of four), renal Fanconi syndrome (present in all patients, but symptomatic only in one), and an unusual organic aciduria with 3-hydroxyisobutyric aciduria in one patient. Biochemical analysis indicated low levels of plasma citrulline and arginine, despite low-normal ammonia levels. Regression analysis indicated a significant correlation between each intermediate of the urea cycle and the next, except between ornithine and citrulline. This suggested that the reaction catalyzed by ornithine transcarbamylase (that converts ornithine to citrulline) might not be very efficient in patients with Pearson syndrome. In view of low-normal ammonia levels, we hypothesize that ammonia and carbamylphosphate could be diverted from the urea cycle to the synthesis of nucleotides in patients with Pearson syndrome and possibly other mitochondrial disorders.

Pearson marrow pancreas syndrome (PS) is a multisystem disorder caused by mitochondrial DNA (mtDNA) deletions. Diamond-Blackfan anemia (DBA) is a congenital hypoproliferative anemia in which mutations in ribosomal protein genes and GATA1 have been implicated. Both syndromes share several features including early onset of severe anemia, variable nonhematologic manifestations, sporadic genetic occurrence, and occasional spontaneous hematologic improvement. Because of the overlapping features and relative rarity of PS, we hypothesized that some patients in whom the leading clinical diagnosis is DBA actually have PS. Here, we evaluated patient DNA samples submitted for DBA genetic studies and found that 8 (4.6%) of 173 genetically uncharacterized patients contained large mtDNA deletions. Only 2 (25%) of the patients had been diagnosed with PS on clinical grounds subsequent to sample submission. We conclude that PS can be overlooked, and that mtDNA deletion testing should be performed in the diagnostic evaluation of patients with congenital anemia.

Purpose: To correlate the molecular characteristics of the mtDNA deletions with clinical phenotypes. Methods: Southern analysis and polymerase chain reaction (PCR)/DNA sequencing were used to determine the size and location of deletions in 16 patients with mtDNA deletion syndrome. An additional 48 reported cases from the literature were also included in the statistical analysis. Results: The common 5-kb deletion is found in eight of nine patients with Kearns-Sayre syndrome (KSS), mitochondrial myopathies (MM), or progressive external ophthalmoplegia (PEO). The rare/novel deletions were found in six of seven patients with extra-neuromuscular multisystemic manifestations and infantile/early childhood onset. Conclusions: Patients with mtDNA deletion syndrome who manifest non-neuromuscular multisystemic disorders at a very young age usually harbor mutant mtDNA with novel or rare deletions in every tissue analyzed. For this group of patients, it is possible to use the less invasive blood specimens instead of muscle biopsies for molecular diagnosis. Overwhelmingly, the common 5-kb deletion is mostly seen in the muscle specimens of patients with KSS and age of onset after the second decade of life.

Pearson syndrome (PS) is a rare mitochondrial disorder characterized by sideroblastic anemia and exocrine pancreas deficiency as a result of mitochondrial DNA deletion or deletion-duplication. A 21-year-old woman and 11-year-old brother who had been diagnosed as PS at the age of 18 and 8, respectively, were admitted to our hospital with the complaints of chronic diarrhea while using exogenous pancreas enzymes. Diarrhea was present in both for a long time and attributed to existing PS. Endoscopic and laboratory examinations revealed celiac disease (CD). After gluten-free diet, their symptoms were resolved. Detailed family investigation revealed that parents and the sister of the siblings were free of both PS and CD. To our knowledge, there has been no previous report of the presence of these 2 disorders, PS and CD, in the same patient. CD should be screened and treated appropriately in cases with PS.