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Case Reports
and basophilic stippling. Iron staining showed ring sider- oblasts in 10% of erythroid cells. He went on to develop mild concentric left ventricular hypertrophy, glaucoma, constipation, scoliosis and mixed central/obstructive sleep apnoea requiring non-invasive ventilation therapy. Brain MRI at 16 months of age demonstrated bilateral hyperintensities of caudate nuclei and putamen. Subsequent neuroimaging showed global cerebral and basal ganglia volume loss with bilateral putamina cavita- tion, characteristic of Leigh disease and a small lactate peak on NMR spectroscopy in basal ganglia (Figure 1C). Plasma lactate was intermittently elevated (up to 3.3 mmol/L, normal 0.6-2.4 mmol/L) but biochemical work- up was otherwise normal. He died from central respira- tory failure at the age of 14 years. In patient 3 and 4, whole exome sequencing identified two compound het- erozygous variants in IARS2; a paternally inherited non- sense variant (c.2025dup; p. Asp676*) predicted to result in either NMD or loss of the terminal two thirds of the protein including anticodon binding domain; and a maternally inherited missense variant (c.986T>C; p. Leu329Pro) modifying a mildly conserved residue. Neither of these variants have been reported to date.
Respiratory chain enzyme activities were normal in the liver, skeletal muscle or lymphocytes of patients 1 and 3 (Table). Blue native polyacrylamide gel electrophoresis of respiratory enzyme chain complexes was normal in cul- tured skin fibroblasts of patient 1 (not shown). No mito- chondrial DNA (mtDNA) deletions or rearrangements were found in circulating leukocytes and bone marrow of patients 1 to 3 (Table).
Here, we report on three unrelated patients presenting with sideroblastic anemia, initially suggestive of Pearson Marrow-Pancreas syndrome. The absence of mtDNA deletion or complex rearrangements prompted to recon- sider this diagnosis and to eventually identify biallelic pathogenic IARS2 variants in the three patients. Children with Pearson syndrome usually present with bone mar- row failure and exocrine pancreatic dysfunction in the first year of life. They have macrocytic sideroblastic ane- mia with ringed sideroblasts detected by iron staining of the bone marrow. This transfusion-dependent condition is accompanied by thrombocytopenia and neutropenia. The disease gradually worsens and multisystem involve- ment occurs, including failure to thrive, liver failure, hypotonia and lactic acidosis. Survival and spontaneous recovery from bone marrow dysfunction after several years is possible, with a transition to clinical manifesta- tions of Kearns-Sayre syndrome.9 Pearson syndrome is caused by a single large-scale mitochondrial DNA dele- tion.10
At variance with Pearson syndrome, our patients had a low level of ring sideroblasts in blood marrow aspiration, and presented with an early extra-hematological involve- ment (cardiomyopathy, cataract, and neurological involvement).
Pearson syndrome is not the unique cause of siderob- lastic anemia in respiratory chain deficiency. In fact, sideroblastic anemia has been associated with pathogenic variants in other mitochondrial proteins, namely SLC25A38, PUS1, ABCB7, GLRX5, NDUFB11, COX10, HSPA9, TRNT1 and ATP6.11 Moreover, congenital sider- oblastic anemia has been associated with mutations in two other mitochondrial ARS2 genes, namely YARS2 and LARS2.12-14
IARS2 mutations were first identified in patients with CAGSSS, then in patients with Leigh syndrome, and more recently in patients with cataract. To date, 18 patients have been reported with a broad range of partial-
ly overlapping symptoms (Table 1).3-8
Our report expands the clinical spectrum of IARS2-
related disorders to early-onset sideroblastic anemia mimicking Pearson syndrome. It adds IARS2 to the list of mitochondrial disease genes underlying sideroblastic ane- mia in early childhood. Future studies will hopefully help in identifying the actual impact of respiratory chain defi- ciency on human erythropoiesis and explaining why sideroblastic anemia is a frequent, yet inconstant feature in mitochondrial disorders.
Giulia Barcia,1 Dinusha Pandithan,2 Benedetta Ruzzenente,3 Zahra Assouline,1Alessandra Pennisi,1 Clothilde Ormieres,1 Claude Besmond,4 Charles-Joris Roux,5 Nathalie Boddaert,5 Isabelle Desguerre,6 David R. Thorburn,7,8 Drago Bratkovic,2 Arnold Munnich,1-3 Jean-Paul Bonnefont,1-3 Agnès Rötig3
and Julie Steffann1-3
1Federation of Medical Genetics and Reference Center for Mitochondrial Diseases (CARAMMEL), Hospital Necker - Enfants Malades, Paris, France; 2Metabolic Clinic, Women’s and Children’s Hospital, North Adelaide, South Australia, Australia; 3Laboratory for Genetics of Mitochondrial Disorders, UMR 1163, Université de Paris, Institut Imagine, Paris, France; 4Translational Genetics Laboratory, UMR U1163, Institut Imagine, Université Paris Descartes-Sorbonne Paris Cité, Paris, France; 5Department of Pediatric Radiology, Hospital Necker Enfants Malades, Paris, France; 6Department of Pediatric Neurology, Hospital Necker-Enfants Malades, Paris, France; 7Murdoch Children’s Research Institute and Victorian Clinical Genetics Services, Royal Children’s Hospital, Melbourne, Victoria, Australia and 8Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia
Correspondence: GIULIA BARCIA - giulia.barcia@aphp.fr doi:10.3324/haematol.2020.270710
Disclosures: no conflicts of interest to disclose.
Contributions: GB performed molecular researchs, data analysis and wrote the manuscript; AM supervised this study, performed clinical evaluation, and wrote the manuscript. BR performed data analysis; ZA and CB performed the molecular study; DP, AP, CO, ID performed clinical follow-up; CJR and NB performed neuro-imaging analysis; DRT, DB, JPB, AR, JS performed data analysis and supervised the study.
References
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haematologica | 2021; 106(4)