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Background Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a mitochondrial fatty acid oxidation disorder that causes episodic attacks, such as general fatigue, hypotonia, myalgia, and rhabdomyolysis accompanied by lack of energy. As yet, there are no preventative drugs for these VLCADD-associated metabolic attacks. Patients and methods We conducted an open-label, non-randomized, multi-center study into the effects of bezafibrate on five patients with VLCADD. Bezafibrate was administered for 4 years, and we analyzed the number of myopathic attacks requiring hospitalization and treatment infusions. Results The number of myopathic attacks requiring infusions of 24 h or longer significantly decreased during the study period. The patients’ ability to conduct everyday activities was also improved by the treatment. Conclusion Our findings show the potential long-term efficacy of bezafibrate in preventing myopathic attacks for patients with VLCADD.

Very long‐chain acyl‐CoA dehydrogenase (VLCAD) deficiency is an autosomal recessive mitochondrial fatty acid oxidation disorder that manifests in three clinical forms: (a) severe, (b) milder, and (c) myopathic. Patients with the myopathic form present intermittent muscular symptoms such as myalgia, muscle weakness, and rhabdomyolysis during adolescence or adulthood. Here, the clinical symptoms and serum creatine kinase (CK) levels of a pregnant 31‐year‐old woman with the myopathic form of VLCAD deficiency were reduced during pregnancy. Clinical symptoms rarely appeared during pregnancy, although she had sometimes suffered from muscular symptoms before pregnancy. When ritodrine was administered for threatened premature labor at 35 weeks of gestation, her CK level was elevated to over 3900 IU/L. She delivered a full‐term baby via cesarean section but suffered from muscle weakness with elevated CK levels soon after delivery. It has been reported that an unaffected placenta and fetus can improve maternal β‐oxidation during pregnancy. However, in our case, the baby was also affected by VLCAD deficiency. These suggest that the clinical symptoms of a woman with VLCAD deficiency might be reduced during pregnancy even if the fetus is affected with VLCAD deficiency.

Introduction: Fatty acid oxidation disorders (FAODs) are rare diseases caused by defects in mitochondrial fatty acid oxidation (FAO) enzymes. While the efficacy of bezafibrate, a peroxisome proliferator-activated receptor agonist, on the in vitro FAO capacity has been reported, the in vivo efficacy remains controversial. Therefore, we conducted a clinical trial of bezafibrate in Japanese patients with FAODs. Materials and methods: This trial was an open-label, non-randomized, and multicenter study of bezafibrate treatment in 6 patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency and 2 patients with carnitine palmitoyltransferase-II (CPT-2) deficiency (median age, 8.2 years; ranging from 5.8 to 26.4 years). Bezafibrate was administered for 6 months following a 6-month observation period. The primary endpoint was the frequency of myopathic attacks, and the secondary endpoints were serum acylcarnitines (ACs, C14:1 or C16 + C18:1), creatine kinase (CK) levels, degree of muscle pain (VAS; visual analog scale) during myopathic attacks, and quality of life (QOL; evaluated using validated questionnaires). Results: The frequency of myopathic attacks after bezafibrate administration decreased in 3 patients, increased in 3, and did not change in 2. The CK, AC, and VAS values during attacks could be estimated in only three or four patients, but a half of the patients did not experience attacks before or after treatment. Changes in CK, AC, and VAS values varied across individuals. In contrast, three components of QOL, namely, physical functioning, role limitation due to physical problems (role physical), and social functioning, were significantly elevated. No adverse drug reactions were observed. Conclusion: In this study, the frequency of myopathic attacks and CK, AC, and VAS values during the attacks could not be evaluated due to several limitations, such as a small trial population. Our findings indicate that bezafibrate improves the QOL of patients with FAODs, but its efficacy must be examined in future investigations. Keywords: Bezafibrate, Fatty acid oxidation disorders (FAODs), Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, Carnitine palmitoyltransferase-II (CPT-2) deficiency, Clinical trial

Introduction: Fatty acid oxidation disorders (FAODs) are rare diseases caused by a defective mitochondrial fatty acid oxidation (FAO) enzyme. We recently reported that bezafibrate improved patient quality of life (QOL) based on the SF-36 questionnaire score in patients with FAODs during a 50-week, open-label, clinical trial. Herein we conducted further survey assessments of the trial patients to define the long-term efficacy and safety of bezafibrate. Materials and methods: This trial was an open-label, non-randomized, and multicenter study of bezafibrate treatment in five patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency and one patient with carnitine palmitoyltransferase-II (CPT-2) deficiency (median age, 15.9 years; range, 5.8–26.4 years). The bezafibrate administration was continued for a further 102–174 weeks after the 24-week treatment described in our previous study. QOL was quantitated using the 36-Item Short Form Health Survey (SF-36) questionnaire, which constitutes eight components: physical functioning (PF), role limitation due to physical problems, bodily pain, general health perception, vitality, social functioning, role limitation due to emotional problems, and mental health. Results: PF was elevated in all patients and continued to rise during the study, with the total QOL scores increased from baseline in five of the six cases. In particular, three patients older than 20 years showed treatment efficacy, and all subcategories of QOL were elevated in two of these cases. Conclusion: Our findings supported one of the stated benefits of bezafibrate in improving QOL for patients with FAODs. Keywords: Bezafibrate, Fatty acid oxidation disorders (FAODs), Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, Carnitine palmitoyltransferase-II (CPT-2) deficiency, Clinical trial, Quality of life

Iliopsoas abscess (IPA) is rare in children, particularly in neonates. A male neonate was born at 38 weeks of gestation with a weight of 2915 g. On day 22 after birth, his family noticed that his right thigh was swollen. Abdominal computed tomography showed a mass extending to the right iliopsoas from the right thigh with thick septa. Puncture to the right groin yielded purulent fluid, and so a diagnosis of abscess was made. The puncture was followed by surgical drainage through a small inguinal incision, and the abscess cavity was irrigated thoroughly using normal saline. Culture of abscess fluid was positive for Streptococcus pneumoniae, so intravenous ABPC infusion was continued. The postoperative magnetic resonance imaging indicate that the IPA was derived from arthritis of the hip, and the patients received Riemenbugel for the incomplete hip dislocation. He is doing well at 2 years of age.

Juvenile myelomonocytic leukemia (JMML) is a clonal disease arising from abnormal hematopoietic stem cells, although the involvement of lymphoid lineage differs among reported cases. Here, we present a case of JMML with a KRAS G13D mutation. The mutation was detected in various hematopoietic lineages, including T and B lymphocytes and also in lineage(-) CD34(+) CD38(-) hematopoietic stem cells, showing a different percentage of affected cells in each lineage. Single cell-based analysis of hematopoietic cells revealed the loss of wild-type KRAS in a significant proportion of G13D-harboring cells. The percentage of loss of heterozygosity (LOH)/non-LOH cells showed lineage-dependent skewing in hematopoietic cells. The loss of the wild-type KRAS allele may be a common secondary genetic change in KRAS-related JMML and may affect the differentiation behavior of early JMML progenitors.

Iliopsoas abscess (IPA) is rare in children, particularly in neonates. A male neonate was born at 38 weeks of gestation with a weight of 2915 g. On day 22 after birth, his family noticed that his right thigh was swollen. Abdominal computed tomography showed a mass extending to the right iliopsoas from the right thigh with thick septa. Puncture to the right groin yielded purulent fluid, and so a diagnosis of abscess was made. The puncture was followed by surgical drainage through a small inguinal incision, and the abscess cavity was irrigated thoroughly using normal saline. Culture of abscess fluid was positive for Streptococcus pneumoniae, so intravenous ABPC infusion was continued. The postoperative magnetic resonance imaging indicate that the IPA was derived from arthritis of the hip, and the patients received Riemenbügel for the incomplete hip dislocation. He is doing well at 2 years of age.

MicroRNAs (miRNAs) regulate cell proliferation and differentiation by controlling the expression of proteins involved in many signaling pathways. Recent studies have shown that dysregulation of miRNA expression is associated with increased tumorigenicity and a poor prognosis in several types of cancers. The miRNA let-7b is one of the severely downregulated miRNAs in mixed-lineage leukemia (MLL)-rearranged acute lymphoblastic leukemia (ALL) patients. In vitro transfection of leukemogenic MLL fusion genes into human embryonic kidney-293 cells suppressed let-7b expression. In leukemic cells with an MLL fusion gene, the regulatory region for let-7b expression was hypermethylated, and its expression was partially recovered after culturing the cells with the demethylating agent 5-azacitidine. These results suggest that loss of let-7b expression may be one of the consequences of oncogenic MLL fusion proteins, and contributes to leukemogenesis possibly through the upregulation of let-7b-regulated target genes with leukemogenic potential in hematopoietic cells. The enforced expression of let-7b in ALL cell lines with an MLL fusion gene inhibited their growth, indicating the possible use of let-7b as a new therapeutic tool for refractory infant ALL with an MLL fusion gene.

Abstract 986 Poster Board I-8 Introduction: MicroRNAs (miRs) play an important role in leukemogenesis; specific miRs are underexpressed, whereas others are overexpressed in leukemias. In addition, to regulate the leukemogenesis, each specific miRs repress one or many target genes. These findings indicate that some specific miRs can regulate the leukemogenesis also in infant ALL. Recently, the etiology of infant leukemia has been calrified; in utero exposure to topoisomerase-II inhibitors and other factors may affect MLL gene rearrangements, which lead to induction of leukemogenesis. After birth, specific oncogenes and proliferation or differentiation factors will be disrupted via enhanced HoxA9 by the stimulation of MLL fusion genes. In this study, let-7b miR and its regulator lin28 are suppressed, followed by the enhanced expression of HoxA9 and HMGA2 oncogene in MLL-rearranged infant ALL. Materials and methods: Leukemic cells from ALL infants and ALL cell lines with and without MLL gene rearrangements were used. In microarray analysis, miR was extracted and analysis was performed by using the mirVanaTM miRNA Bioarray V2 system. Quadruplicated data were averaged, and all miRs with >2-fold different expression was considered as significant in this study. Then, TaqMan real-time PCR method was used to quantify the expression of each miR. The relative expression of each gene was calculated by setting the control normal B lymphocytes. Finally, the transfection of MLL fusion genes to HEK293 cells was performed to induce let-7b expression in vitro. Results: By the microarray analysis, 13 miRs showed >2-fold lower expression in MLL-rearranged ALLs than MLL-germline ALLs, including miR-124a, miR-153, and let-7b with >5-fold lower expression. When we focused on let-7b, expressions of let-7b, its associated genes lin28 and Dicer were significantly lower in MLL-rearranged ALLs than MLL-germline ALLs. MLL-rearranged ALLs showed high expression of HoxA9 and HMGA2, possible target genes for let-7b. The in vitro transfection of MLL fusion genes to HEK293 cells also induced the suppression of let-7b. Discussion: Our study first demonstrated that the expressions of let-7b is significantly decreased in MLL-rearranged ALL cells. Let-7 family has been reported as tumor-suppressor gene in cancer; the expression level of let-7 family increases during differentiation of cancer cells, while its target genes show a reciprocal expression pattern. However, it remains to be explored whether let-7 might be involved directly or indirectly in the leukemia-related functions. Conclusion: The interaction between HoxA9 disrupted by MLL fusion and HMGA2 oncogene regulated by specific miRs including let-7 could be involved in the pathogenesis of infant ALL with MLL gene rearrangements. These genes might become a target for therapeutic approach in the future. Disclosures: No relevant conflicts of interest to declare.