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Sideroblastic anemias (SA) are a group of hematological disorders that are characterized by inadequate levels of hemoglobin and ringed sideroblasts in the bone marrow. They can be acquired or congenital. Acquired SA are part of the myelodysplastic syndromes with onset in adulthood. Congenital SA show both early onset in infancy or childhood and in adulthood, and they are the result of germline mutations (inherited or de novo). Several genes have been associated with SA, and these are involved in mitochondrial pathways, such as for heme synthesis, iron-sulfur cluster biogenesis, and mitochondrial metabolism. Point mutations in the ALAS2, SLC25A38, GLRX5, and HSPA9 genes have been reported for the nonsyndromic SA. Point mutations in the ABCB7, PUS1, YARS2, LARS2, TRNT1, SLC19A2, and MT-ATP6 genes, and deletion of mitochondrial DNA and the NDUFB11 gene are causal for the syndromic forms of SA. We report here on a case of an infant with microcytic anemia and paternal isodisomy at the SLC25A38 locus (Figure 1A). We revealed uniparental isodisomy (UPD) in the proband, which carried a homozygous recessive mutation, with only one parent heterozygous for the same variant (excluding a de novo mutation), and in the absence of parental consanguineity. UPD is characterized by the presence of two identical copies of a complete or partial chromosome from one of the parents. This results in homozygosity for an autosomal recessive gene, and thus the clinical expression of a recessive disease. To date, UPD has never been described as a pathogenic mechanism of SA. The patient considered here was a newborn male of nonconsanguineous parents from Italy (Figure 1A). At 21 days old, he was admitted to the pediatric Emergency Department due to deep asthenia. He showed mucocutaneous pallor, hypospadia, and micropenis, without any jaundice, fever, or other clinical signs and symptoms. Peripheral blood tests showed severe hypochromic and microcytic anemia, normal white blood cells and platelet counts, and reticulocytopenia (Table 1). A peripheral blood smear showed marked anisopoichylocytosis, with some dacrocytes, microcytes, and spherocytes. His ferritin level was high (747 mg/L), with serum iron and transferrin in the normal range (Table 1); his bilirubin, haptoglobin, and lactate dehydrogenase levels were normal; and his serum erythropoietin (EPO) level was high (114 mUI/mL) (Table 1). Bone marrow smear evaluation was not performed. He received one blood transfusion (10 cm/kg), and reached a hemoglobin (Hb) of 11.3 g/dL at 23 days old. After the first transfusion, he showed a slow and progressive reduction in Hb (Figure 1B). The first suspected condition was the sequelae of fetal maternal hemolytic diseases, but the immune-hematological tests were negative. Due to the early onset of the condition, the patient was suspected of having a hereditary anemia. Accordingly, a first level of investigation was performed on the parents. Both parents showed normal red blood cell parameters without abnormal hemoglobins. Thus, a second level of investigation was performed, as genetic testing, using a targeted next-generation sequencing (t-NGS) 86-gene custom panel for hereditary anemias. This panel is an updated version of a similar previously published one. The genetic analysis of the proband revealed the presence of the rare nonsense variant c.832C>T, p.Arg278* (rs147431446, alternative allele frequency <0.0001 in GnomAD_exome database;

Apparent recessive inheritance of sideroblastic anemia type 2 due to uniparental isodisomy at the SLC25A38 locus