Novel CAD gene mutations in a boy with developmental and epileptic encephalopathy 50 with dramatic response to uridine therapy: a case report and a review of the literature.

BACKGROUND: Developmental and epileptic encephalopathy-50 (DEE-50) is a rare clinical condition believed to be caused by a mutation in the CAD gene and is associated with a bleak prognosis. CAD-related diseases have a wide range of clinical manifestations and other symptoms that may be easily overlooked. Like other rare diseases, the clinical manifestations and the treatment of DEE-50 necessitate further investigation. CASE PRESENTATION: A 1-year-old male patient presented with developmental delay, seizures, and anaemia at 3 months of age. He further developed refractory status epilepticus (SE), rapid deterioration of cognitive and motor function, and even became comatose at 5 months of age. Whole-exome sequencing of trios (WES-trios) revealed a compound heterozygous variant in the CAD gene, with one locus inherited from his father (c.1252C>T: p.Q418* nonsense mutation) and one from his mother (c.6628G>A: p.G2210S, missense mutation). This compound heterozygous CAD variant was unreported in the Human Gene Mutation Database. After uridine treatment, his cognitive faculties dramatically improved and he remained seizure-free. Forty two cases with CAD gene mutation reported in the literatures were reviewed. Among them, 90% had onset before 3 years of age, with average of 1.6±1.8 years old. The average age of diagnosis was 7.7 ± 10 years. The mortality rate was approximately 9.5%, with all reported deaths occurring in patients without uridine treatment. The clinical entity could be improved dramatically when the patient treated with uridine. CONCLUSIONS: We present a boy with DEE 50 caused by novel CAD gene mutations and reviewed the clinical features of 42 patients reported previously. DEE 50 has early onset, refractory seizures, even status epilepticus leading to death, with favorable response to treatment with oral uridine. Early uridine treatment is recommended if CAD defect is suspected or genetically diagnosed. This study enhances the knowledge of DEE 50 and expands the spectrum of CAD gene mutations.

Clinical impact of c-KIT and CEBPA mutations in 33 patients with corebinding factor (Non-M3) acute myeloid leukemia.

BACKGROUND: Corebinding factor acute myeloid leukemia (CBF-AML) is the most common cytogenetic subtype of pediatric AML. CBF-AML is associated with a relatively favorable outcome, although the relapse rate of approximately 40% indicates a high degree of clinical heterogeneity. The clinical impact of additional cytogenetic aberrations, including c-KIT and CEBPA mutations, in pediatric CBF-AML has not been well characterized, especially in the multi-ethnic region of Yunnan Province in China. METHODS: In this study, we retrospectively analyzed the clinical features, gene mutations, and prognoses of 72 pediatric patients newly diagnosed with non-M3 AML in Kunming Children's Hospital, China, from January 1, 2015 to May 31, 2020. RESULTS: Of the 72 pediatric patients with AML, 46% (33/72) had CBF-AML. Thirteen patients with CBF-AML (39%) had c-KIT mutations, five (15%) had CEBPA mutations, and eleven (33.3%) had no other cytogenetic aberrations. The c-KIT mutations, resulting from single nucleotide substitutions and small insertions or deletions, occurred in exons 8 and 17. All of the CBF-AML-associated CEBPA mutations were single mutations and occurred in patients with RUNX1-RUNX1T1 fusion. We found no significant differences in the clinical data between CBF-AML patients with c-KIT or CEBPA mutations and CBF-AML patients without other aberrations, and no prognostic significance was established for these mutations. CONCLUSION: Our study is the first to report the clinical impact of c-KIT and CEBPA mutations in pediatric patients with non-M3 CBF-AML from the multi-ethnic Yunnan Province, China. c-KIT and CEBPA mutations occurred at a higher frequency in CBF-AML cases and were associated with unique clinical characteristics; however, no potential molecular prognostic markers were identified.

Effects of TPMT, NUDT15, and ITPA Genetic Variants on 6-Mercaptopurine Toxicity for Pediatric Patients With Acute Lymphoblastic Leukemia in Yunnan of China.

Background: 6-Mercaptopurine (6-MP) is the cornerstone of current antileukemia regimen and contributes greatly to improve the survival of pediatric acute lymphoblastic leukemia (ALL) patients. However, 6-MP dose-related toxicities limit its application. TPMT, NUDT15, and ITPA are pharmacogenetic markers predicting 6-MP-related toxicities, but their genetic polymorphisms differ from those of ethnic populations. In Yunnan province, a multiethnic region of China, we had no genetic data to predict 6-MP toxicities. In this study, we evaluated the most common variants involved in 6-MP metabolism-TPMT *3C (rs1142345), NUDT15 c.415C>T (rs116855232), and ITPA c.94C>A (rs1127354) variants-in our cohort of pediatric ALL patients. Methods: A total of 149 pediatric ALL patients in the Affiliated Children's Hospital of Kunming Medical University (Yunnan Children's Medical Center) from 2017 to 2019 were enrolled in this retrospective study. We assessed the TPMT *3C (rs1142345), NUDT15 c.415C>T (rs116855232), and ITPA c.94C>A (rs1127354) frequencies and evaluated association between genotypes and 6-MP toxicities, 6-MP dose, and event-free survival (EFS) in these ALL patients. Results: The allele frequencies of TPMT *3C (rs1142345), NUDT15 c.415C>T (rs116855232), and ITPA c.94C>A (rs1127354) were 1.34%, 14.43%, and 18.79%, respectively. Only NUDT15 c.415C>T (rs116855232) was strongly associated with 6-MP toxicity and 6-MP tolerable dose. NUDT15 c.415C>T was related to leukopenia, p = 0.008, OR = 2.743 (95% CI: 1.305-5.768). The T allele was significantly correlated with 6-MP tolerable dose, dose of NUDT15 c.415C>T wild genotype CC 39.80 ± 1.32 mg/m2, heterozygotes CT 35.20 ± 2.29 mg/m2, and homozygotes TT 18.95 ± 3.95 mg/m2. 6-MP tolerable dose between CC and TT had a significant difference, p = 0.009. Between CC and CT, and CT and TT, they had no significant difference. EFS showed no significant difference among NUDT15 c.415C>T genotypes. Conclusion: NUDT15 c.415C>T (rs116855232) was an optimal predictor for 6-MP toxicity and tolerable dose in pediatric ALL patients from Yunnan province, a multiethnic region in China, and would play an important role in precise therapy for ALL.