Sideroblastic anemia associated with multisystem mitochondrial disorders

Abstract

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.

Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures

“…Even though both siblings described here did not have hematological features and chromosome breakage studies consistent with Fanconi anemia, other hematological disorders such as sideroblastic anemia have been well described in multisystemic mitochondrial disorders such as Pearson syndrome, MLASA syndrome (mitochondrial myopathy, lactic acidosis, and SA) and complex I deficiency associated with a hemizygous change in NDUFB11 (Falcon & Howard, ; Lichtenstein et al, ; Riley et al, ; Tesarova et al, ). However, it was not until recently that defective oxidative metabolism and mitochondrial localization along with spontaneous mitochondrial fragmentation have been described in Fanconi anemia cells (Bottega et al, ; Cappelli et al, ; Pagano, Shyamsunder, Verma, & Lyakhovich, ).…”

Reply to Comment on: Sideroblastic anemia associated with multisystem mitochondrial disorders

“…3), can be found in the published research article. 1 In addition, easily available tissues obtained from maternal relatives of P4 (blood, buccal swab, and urinary cells from the mother, and blood from the brother) and P7 (blood, buccal swab, and urinary cells from the mother) were negative for the 5.5 kb and 5 kb mtDNA deletions, respectively. These results do not exclude the presence of the mtDNA deletion in other tissues of maternal relatives.…”

“…We thank J. Finsterer for his interest in our study focused on hematologic complications in patients with mitochondrial diseases and his request for a more extensive description of phenotypes in our patients with mutations in the COX10 gene, MLASA1 (mitochondrial myopathy, lactic acidosis, and sideroblastic anemia), and Pearson/Kearns‐Sayre syndrome (KSS) . J. Finsterer points out the well‐known heterogeneity of phenotypes described in patients with multisystem mitochondrial diseases (MD), including the broad spectrum of common, rare, and ultra‐rare symptoms.…”

“…With respect to the characteristics of patients in our study, descriptions of clinical, hematologic, biochemical, and molecular data, including an age‐related reference range where applicable (e.g., table 3), can be found in the published research article . Some additional details are given below.…”

“…Two children with a fatal course of MLASA1 syndrome due to a homozygous 6‐kb deletion in the PUS1 gene had transfusion‐dependent sideroblastic anemia with increased numbers of ring sideroblasts (18‐28%), microcephaly, short stature, hypotony, developmental delay, and intellectual disability . Both patients died due to pneumonia with respiratory failure at the age of 5 and 24 years, respectively.…”