Broadening the phenotypic spectrum of Pearson syndrome: Five new cases and a review of the literature.

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

[Molecular pathophysiology of sideroblastic anemia].

Sideroblastic anemias (SAs) are heterogeneous congenital and acquired disorders characterized by anemia and the presence of ring sideroblasts in bone marrow. Congenital sideroblastic anemia (CSA) is a rare disease caused by mutations in genes that are involved in heme biosynthesis, iron-sulfur [Fe-S] cluster biosynthesis, and mitochondrial protein synthesis. The most common form of CSA is X-linked sideroblastic anemia; it occurs because of mutations in the erythroid-specific δ-aminolevulinate synthase gene (ALAS2), which is the first enzyme of the heme biosynthesis pathway in erythroid cells. Additionally, SAs can occur after exposure to certain drugs or alcohol and with copper deficiency (secondary SA) ; they are also detected in association with myelodysplastic syndrome (idiopathic SA). Among all types of SAs, idiopathic SA is the most common form. This review encompasses the current understanding of the molecular pathophysiology of SA.

Sideroblastic anaemia and primary adrenal insufficiency due to a mitochondrial respiratory chain disorder in the absence of mtDNA deletion.

A fatigued 8-year-old boy was found to have sideroblastic anaemia (haemoglobin 7.8 g/dL) which over time became transfusion dependent. Subtle neurological dysfunction, initially manifesting as mild spastic diplegia, was slowly progressive and ultimately led to wheelchair dependence. Elevated plasma lactate and urinary 3-methylglutaconate led to a muscle biopsy which confirmed partial complex IV deficiency. PCR in leucocytes and muscle was negative for mitochondrial DNA (mtDNA) deletions. Faltering growth prompted an insulin tolerance test which confirmed growth hormone sufficiency and adrenal insufficiency. Plasma renin was elevated and adrenal androgens were low, suggesting primary adrenal insufficiency. Glucocorticoid and mineralocorticoid replacement therapy was initiated. A renal tubular Fanconi syndrome and diabetes mellitus developed subsequently. Sideroblastic anaemia and primary adrenal insufficiency, both individually and collectively, are associated with mtDNA deletion; however, absence of the same does not exclude the possibility that sideroblastic anaemia and primary adrenal insufficiency are of mitochondrial origin.

Pathophysiology and genetic mutations in congenital sideroblastic anemia.

Sideroblastic anemias are heterogeneous congenital and acquired disorders characterized by anemia and the presence of ringed sideroblasts in the bone marrow. Congenital sideroblastic anemia (CSA) is a rare disease caused by mutations of genes involved in heme biosynthesis, iron-sulfur [Fe-S] cluster biosynthesis, and mitochondrial protein synthesis. The most common form is X-linked sideroblastic anemia, due to mutations in the erythroid-specific δ-aminolevulinate synthase (ALAS2), which is the first enzyme of the heme biosynthesis pathway in erythroid cells. Other known etiologies include mutations in the erythroid specific mitochondrial transporter (SLC25A38), adenosine triphosphate (ATP) binding cassette B7 (ABCB7), glutaredoxin 5 (GLRX5), thiamine transporter SLC19A2, the RNA-modifying enzyme pseudouridine synthase (PUS1), and mitochondrial tyrosyl-tRNA synthase (YARS2), as well as mitochondrial DNA deletions. Due to its rarity, however, there have been few systematic pathophysiological and genetic investigations focusing on sideroblastic anemia. Therefore, a nationwide survey of sideroblastic anemia was conducted in Japan to investigate the epidemiology and pathogenesis of this disease. This review will cover the findings of this recent survey and summarize the current understanding of the pathophysiology and genetic mutations involved in CSA.

Hereditary sideroblastic anemia: pathophysiology and gene mutations.

Sideroblastic anemia is characterized by anemia with the emergence of ring sideroblasts in the bone marrow. Ring sideroblasts are erythroblasts characterized by iron accumulation in perinuclear mitochondria due to impaired iron utilization. There are two forms of sideroblastic anemia, i.e., inherited and acquired sideroblastic anemia. Inherited sideroblastic anemia is a rare and heterogeneous disease caused by mutations of genes involved in heme biosynthesis, iron-sulfur (Fe-S) cluster biogenesis, or Fe-S cluster transport, and mitochondrial metabolism. The most common inherited sideroblastic anemia is X-linked sideroblastic anemia (XLSA) caused by mutations of the erythroid-specific δ-aminolevulinate synthase gene (ALAS2), which is the first enzyme of heme biosynthesis in erythroid cells. Sideroblastic anemia due to SLC25A38 gene mutations, which is a mitochondrial transporter, is the next most common inherited sideroblastic anemia. Other forms of inherited sideroblastic anemia are very rare, and accompanied by impaired function of organs other than hematopoietic tissue, such as the nervous system, muscle, or exocrine glands due to impaired mitochondrial metabolism. Moreover, there are still significant numbers of cases with genetically undefined inherited sideroblastic anemia. Molecular analysis of these cases will contribute not only to the development of effective treatment, but also to the understanding of mitochondrial iron metabolism.

Iron-sulfur proteins in health and disease.

Iron-sulfur (Fe/S) proteins are a class of ubiquitous components that assist in vital and diverse biochemical tasks in virtually every living cell. These tasks include respiration, iron homeostasis and gene expression. The past decade has led to the discovery of novel Fe/S proteins and insights into how their Fe/S cofactors are formed and incorporated into apoproteins. This review summarizes our current knowledge of mammalian Fe/S proteins, diseases related to deficiencies in these proteins and on disorders stemming from their defective biogenesis. Understanding both the physiological functions of Fe/S proteins and how Fe/S clusters are formed will undoubtedly enhance our ability to identify and treat known disorders of Fe/S cluster biogenesis and to recognize hitherto undescribed Fe/S cluster-related diseases.

Hereditary sideroblastic anemias: pathophysiology, diagnosis, and treatment.

Inherited sideroblastic anemia comprises several rare anemias due to heterogeneous genetic lesions, all characterized by the presence of ringed sideroblasts in the bone marrow. This morphological aspect reflects abnormal mitochondrial iron utilization by the erythroid precursors. The most common X-linked sideroblastic anemia (XLSA), due to mutations of the first enzyme of the heme synthetic pathway, delta-aminolevulinic acid synthase 2 (ALAS2), has linked heme deficiency to mitochondrial iron accumulation. The identification of other genes, such as adenosine triphosphate (ATP) binding cassette B7 (ABCB7) and glutaredoxin 5 (GLRX5), has strengthened the role of iron sulfur cluster biogenesis in sideroblast formation and revealed a complex interplay between pathways of mitochondrial iron utilization and cytosolic iron sensing by the iron-regulatory proteins (IRPs). As recently occurred with the discovery of the SLC25A38-related sideroblastic anemia, the identification of the genes responsible for as yet uncharacterized forms will provide further insights into mitochondrial iron metabolism of erythroid cells and the pathophysiology of sideroblastic anemia.

Primary myelodysplastic syndrome in Jordan: a single-centre experience.

OBJECTIVE: Study of the disease patterns and clinical evaluation of myelodysplastic syndrome (MDS). SUBJECTS AND METHODS: A retrospective analysis was carried out on 85 patients, with MDS who were followed up over a period of 23 years at Jordan University Hospital, Amman, Jordan. Cases were analyzed according to the French, American and British Classification. RESULTS: Of the 85 patients, 42 (49.4%) were females and 43 (50%) males; mean age was 59 +/- 19 years (range 18-88). Most subtypes found in patients were refractory anemia (RA) in 27 (31.8%) and RA with excess blasts (RAEB) in 28 (32.9%). Adverse prognostic indicators were RAEB subtype and requirement for blood transfusion. CONCLUSION: Our findings showed that MDSs appeared at a younger age and tended to be of the aggressive subtype. Chronic myelomonocytic leukemia subtype seemed to appear dominantly in men.

Benzene exposure and refractory sideroblastic erythropoiesis: is there an association?

The myelodysplastic syndromes (MDS) consist of a group of diverse hematological disorders that carry an increased risk of transforming into acute myeloid leukemia. They may appear de novo and without obvious cause (primary or de novo MDS) or be induced by certain mutagenic environmental or therapeutic toxins (secondary MDS). Excessive exposures to benzene are generally considered to be a potential environmental risk factor for both MDS and acute myeloid leukemia. However, such risk is unproven for each disease component within the MDS classification. A critical review of the refractory sideroblastic disorders strongly suggests that benzene exposure is not a potential cause of this distinct and still-evolving subset of MDS. The widely disparate nature of MDS suggests that epidemiologic studies can only provide meaningful data on associations and potential causation of its component syndromes by a disease-specific analysis, as is currently advocated for other hematological malignancies.

Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation.

The human protein ABC7 belongs to the adenosine triphosphate-binding cassette transporter superfamily, and its yeast orthologue, Atm1p, plays a central role in the maturation of cytosolic iron-sulfur (Fe/S) cluster-containing proteins. Previously, a missense mutation in the human ABC7 gene was shown to be the defect in members of a family affected with X-linked sideroblastic anemia with cerebellar ataxia (XLSA/A). Here, the promoter region and the intron/exon structure of the human ABC7 gene were characterized, and the function of wild-type and mutant ABC7 in cytosolic Fe/S protein maturation was analyzed. The gene contains 16 exons, all with intron/exon boundaries following the AG/GT rule. A single missense mutation was found in exon 10 of the ABC7 gene in 2 affected brothers with XLSA/A. The mutation was a G-to-A transition at nucleotide 1305 of the full-length cDNA, resulting in a charge inversion caused by the substitution of lysine for glutamate at residue 433 C-terminal to the putative sixth transmembrane domain of ABC7. Expression of normal ABC7 almost fully complemented the defect in the maturation of cytosolic Fe/S proteins in a yeast strain in which the ATM1 gene had been deleted (Deltaatm1 cells). Thus, ABC7 is a functional orthologue of Atm1p. In contrast, the expression of mutated ABC7 (E433K) or Atm1p (D398K) proteins in Deltaatm1 cells led to a low efficiency of cytosolic Fe/S protein maturation. These data demonstrate that both the molecular defect in XLSA/A and the impaired maturation of a cytosolic Fe/S protein result from an ABC7 mutation in the reported family.

[Pathogenic gene linkage analysis and hemopoietic characteristics in a kindred with sideroblastic anemia].

OBJECTIVE: Analysis of pathogenic gene linkage and hemopoietic characteristics in a kindred with sideroblastic anemia. METHODS: PCR amplification of the microsatellites DXS991,DXS1199 in chromosome Xp11.22 linked gene ALAS2 and of the microsatellite DXS1226 in Xp22. 13 linked another irrelevant gene and analysis of gene linkage in a kindred with 2 patients and 7 normal persons. The bone marrow hemopoietic cells from 2 patients were cultured in condition culture matrix with various cytokines added in and the CFU-E, CFU-GM and CFU-Meg formations were observed at different times. RESULTS: The kindred study revealed that pathogenic gene linked with DXS991 and DXS1199 but did not link with DXS1226.Hemopoietic cell culture showed that erythroid colonies of the two patients grew more vigorously than controls and they could grew in the absence of Epo except in common condition matrix. The erythroid colonies withered after a week and were smaller than the controls after 13 days. CONCLUSION: The kindred is subject to an X-linked sideroblastic anemia(XLSA) with the pathogenic gene ALAS2 involved. In XLSA,the function of stem cells is primarily normal before erythropoiesis, then the erythroid progenitors become dysplasia.

[Myelodysplasia in children and mitochondrial cytopathies]. / Myélodysplasies de l'enfant et cytopathies mitochondriales.

Sideroblastic anemia associated with vacuolization of haemopoietic precursors can be observed in some constitutional diseases associated with mitochondrial DNA deletion. In this condition, it is the haematological expression of a multi-tissue disorder. Haemopoiesis is polyclonal, without abnormality of nuclear DNA differing from the acquired idiopathic sideroblastic anemias which arise from a clonal transformed stem cell. This model of childhood polyclonal myelodysplasia can be observed in others myelodysplasias associated with constitutional polymalformative syndromes.

[The morphofunctional characteristics of the bone marrow erythroid cells in some forms of the myelodysplastic syndrome]. / Morfofunktsional'naia kharakteristika éritroidnykh kletok kostnogo mozga pri nekotorykh formakh mielodisplasticheskogo sindroma.

Refractory anemia (RA) and RA with blast excess (RABE) showed inhibited proliferation of bone marrow erythroid cells (EC), the lowest values being in RABE. The latter, however, was accompanied with the highest count of PAS-positive EC, uneffective erythropoiesis being present in both RA and RABE. In sideroblast anemia the above proliferation was also inhibited, but uneffective erythropoiesis played much more pronounced role in pathogenesis of this anemia than in RA and RABE. The percentage of PAS-positive EC averaged 39.0%. The findings contribute to more profound understanding of anemia arising in myelodysplasia syndrome, to more accurate evaluation of therapeutic effect and prognosis in the above disease.

Ringed sideroblasts in primary myelodysplasia. Leukemic propensity and prognostic factors.

Among 123 patients with ringed sideroblasts on bone marrow aspirates, 85 had acquired ringed sideroblasts with primary myelodysplasia. The patients were placed in categories modified from the French-American-British classification based on percentages of ringed sideroblasts and myeloblasts in the initial bone marrow. Overall, 48% (41/85) of patients with myelodysplasia developed acute leukemia. Primary acquired sideroblastic anemia was the most favorable category with longer survival and 13.8% (4/29) leukemic conversions. Variables correlating with leukemic transformation included male sex, thrombocytopenia, neutropenia, and pseudo-Pelger-Huët neutrophils. Only two variables had independent predictive value by multivariate regression analysis: a high percentage of myeloblasts and a low percentage of ringed sideroblasts. Numerous ringed sideroblasts strongly predicts a more favorable course in myelodysplastic patients.

Natural history of idiopathic refractory sideroblastic anemia.

We analyzed the natural history of idiopathic refractory sideroblastic anemia (IRSA) in 37 patients studied between 1969 and 1986. Although erythroid abnormalities were prominent in all, 12 patients also showed involvement of the granulocytic and/or megakaryocytic cell lines, and nonrandom chromosomal aberrations were observed in five of 23 patients studied for such defects. Measurements of erythroid marrow function showed in most cases erythroid expansion with ineffective erythropoiesis. In seven patients, however, the erythroid activity was found to be inappropriately low for the degree of anemia. Transfusion dependence occurred in 26 of 37 cases. Iron overload was a common feature at presentation but produced clinical manifestations of hemochromatosis only in those patients who subsequently had a regular need for blood transfusions. Five patients progressed to bone marrow failure, and another five patients (two of whom had monosomy 7) evolved into acute nonlymphocytic leukemia (ANLL). The median survival was 72 months, with a high transfusion requirement, multilineage defects, and inappropriately low erythroid proliferation being associated with a poor prognosis. The most common causes of death were complications of iron overload and evolution into ANLL. We conclude that (a) the natural history of IRSA is characterized by an initial phase of erythroid hyperplasia and ineffective erythropoiesis, which is usually stable for many years but in a subset of patients may be followed by a phase of marrow failure with or without the later emergence of leukemic blasts; (b) peripheral blood counts, measurement of erythroid marrow function, and chromosomal analysis are useful for identifying subjects at risk of evolution into marrow failure or ANLL; and (c) IRSA patients with no need for blood transfusions are very likely to be long survivors, whereas those who become transfusion dependent are at risk of death from the complications of secondary hemochromatosis.

[Acquired idiopathic sideroblastic anemia (author's transl)]. / Les anémies sidéroblastiques acquises idiopathiques.

The authors consider the clinical and biological data of Acquired Idiopathic Sideroblastic Anemia (AISA). The physiopathology of the syndrome is discussed; the relationships between pathologic sideroblastosis, dyserythropoiesis and ferrokinetic modifications are pointed out. The associated abnormalities of granulocytic and megacaryocytic series linked AISA to other myelodysplasia.

[Acquired idiopathic sideroblastic anemia (author's transl)]. / Les anémies sidéroblastiques acquises idiopathiques.

The authors consider the clinical and biological data of Acquired Idiopathic Sideroblastic Anemia (AISA). The physiopathology of the syndrome is discussed; the relationships between pathologic sideroblastosis, dyserythropoiesis and ferrokinetic modifications are pointed out. The associated abnormalities of granulocytic and megacaryocytic series linked AISA to other myelodysplasia.