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ObjectiveNeonatal-onset mitochondrial disease has not been fully characterised owing to its heterogeneity. We analysed neonatal-onset mitochondrial disease in Japan to clarify its clinical features, molecular diagnosis and prognosis.DesignRetrospective observational study from January 2004 to March 2020.SettingPopulation based.PatientsPatients (281) with neonatal-onset mitochondrial disease diagnosed by biochemical and genetic approaches.InterventionsNone.Main outcome measuresDisease types, initial symptoms, biochemical findings, molecular diagnosis and prognosis.ResultsOf the 281 patients, multisystem mitochondrial disease was found in 194, Leigh syndrome in 26, cardiomyopathy in 38 and hepatopathy in 23 patients. Of the 321 initial symptoms, 236 occurred within 2 days of birth. Using biochemical approaches, 182 patients were diagnosed by mitochondrial respiratory chain enzyme activity rate and 89 by oxygen consumption rate. The remaining 10 patients were diagnosed using a genetic approach. Genetic analysis revealed 69 patients had nuclear DNA variants in 36 genes, 11 of 15 patients had mitochondrial DNA variants in five genes and four patients had single large deletion. The Cox proportional hazards regression analysis showed the effects of Leigh syndrome (HR=0.15, 95% CI 0.04 to 0.63, p=0.010) and molecular diagnosis (HR=1.87, 95% CI 1.18 to 2.96, p=0.008) on survival.ConclusionsNeonatal-onset mitochondrial disease has a heterogenous aetiology. The number of diagnoses can be increased, and clarity regarding prognosis can be achieved by comprehensive biochemical and molecular analyses using appropriate tissue samples.

Introduction: Over 40,000 cancer patients have taken comprehensive genomic profiling (CGP) tests under health insurance coverage in Japan since June 2019. However, the indication is limited only to cancer patients who have finished (or are expected to finish) standard treatments. The aim of this study is to evaluate patients’ outcomes, levels of understanding, and satisfaction of the patients who received CGP tests. Methods: We performed a nationwide surveillance of 933 cancer patients who examined CGP tests at 80 institutions in Japan under the approval of the institutional ethics committee. The responses to the questionnaire (either web-based or paper-based) were from patients (81.6%) or their families (18.4%). Results: The range of patients’ age was 70s at 29.6%, followed by 60s at 26.8%, and 50s at 20.8%. The level of understanding during informed consent for the CGP tests {11 scales from 0 (lowest) to 10 (highest)} were 7 or higher in 70.8%, and those about their test results were 7 or higher in 75.2 %. The information was predominantly provided by attending physicians (78.0%) or physicians specialized in genomic medicine (19.6%), and limitedly from cancer genome medical coordinators (11.4%) and nurses (10.4%). The patients underwent FoundationOne CDx® (56.3%), FoundationOne Liquid CDx® (11.6%), or a domestic tumor/normal paired panel (OncoGuideTM NCC Oncopanel System, 14.4%). 16.2% of the patients could not recall which CGP test they received. New treatments based on the CGP testing were suggested in 46.8%, and 20.8% of them were treated with a suggested treatment by an expert panel (i.e., molecular tumor board). The treatment type was (i) approved drugs, 70.3%, (ii) clinical trials, 16.5%, (iii) patient-proposed national basket trial, 3.2%, and (iv) off-label use, 1.1%. 77.4% of the patients requested disclosure of germline findings, 10.5% declined, and 11.4% did not remember their decision. Overall satisfaction scores (11 scales) were found to be 7 or higher at 64.6%. The reasons for satisfaction included having the opportunity to learn about cancer risks of relatives (21.0%), having received detailed explanation (19.7%), having received information on new therapies (18.4%), and having the opportunity to learn about their cancer in detail (15.9%). The reason for lower scores (6 or lower) was mainly due to not receiving recommendations to a genome-matched therapy (58.3%). Conclusion: Our surveillance highlighted the significance of drug accessibility, information from interdisciplinary collaboration team, and appropriate information about the test results. The opportunity to learn about their cancer in detail was valuable for the patients as well, even when the results of CGP testing did not lead to a novel therapy. Citation Format: Katsutoshi Oda, Hidenori Kage, Manabu Muto, Katsuya Tsuchihara, Natsuko Okita, Yusuke Okuma, Junko Kikuchi, Hidekazu Shirota, Hideyuki Hayashi, Toshio Kokuryo, Daisuke Sakai, Akira Hirasawa, Makoto Kubo, Hirotsugu Kenmotsu, Nana Akiyama, Hyangri Chang, Aya Shinozaki-Ushiku, Masahiko Tanabe, Tetsuo Ushiku, Kaori Muto, Kiyoshi Miyagawa, Yasuyuki Seto. Real-world surveillance from cancer patients about their experience of comprehensive genomic profiling tests in Japan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3225.

Background: Prenatal diagnoses of mitochondrial diseases caused by defects in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) have been reported in several countries except for Japan. The present study aimed to clarify the status of prenatal genetic diagnosis of mitochondrial diseases caused by nDNA defects in Japan. A comprehensive genomic analysis was performed to diagnose more than 400 patients, of which, 13 families (18 cases) had requested prenatal diagnoses. Results: Eight cases diagnosed with wild homozygous or heterozygous variants same as either of the heterozygous parents continued the pregnancy and delivered healthy babies. Another eight cases were diagnosed with homozygous, compound heterozygous, or hemizygous variants same as the proband. Of these, seven families chose to terminate the pregnancy, while one decided to continue the pregnancy.Conclusions: Neonatal- or infantile-onset mitochondrial diseases show severe phenotypes and lead to lethality. Therefore, such diseases could be candidates for prenatal diagnosis with careful genetic counseling, and prenatal testing could be a viable option for families.

Glycogen storage disease type IV (GSD IV) is a rare inborn metabolic disorder characterized by the accumulation of amylopectin-like glycogen in the liver or other organs. The hepatic subtype may appear normal at birth but rapidly develops to liver cirrhosis in infancy. Liver pathological findings help diagnose the hepatic form of the disease, supported by analyses of enzyme activity and GBE1 gene variants. Pathology usually shows periodic acid-Schiff (PAS) positive hepatocytes resistant to diastase. We report two cases of hepatic GSD IV with pathology showing PAS positive hepatocytes that were mostly digested by diastase, which differ from past cases. Gene analysis was critical for the diagnosis. Both cases were found to have the same variants c.288delA (p.Gly97GlufsTer46) and c.1825G > A (p.Glu609Lys). These findings suggest that c.1825G > A variant might be a common variant in the non-progressive hepatic form of GSD IV., Highlights • GSD IV is caused by homozygous/compound heterozygous mutations in GBE1. • Pathological features of GSDIV are PAS positive hepatocytes digested by PAS-D. • Some non-progressive hepatic GSD IV cases had hepatocytes mostly digested by PAS-D. • Gene analysis was used for diagnosis and prognosis prediction. • Both cases had c.1825G > A GBE1, indicating a role in non-progressive hepatic GSD IV.

Background Hepatocerebral mitochondrial DNA depletion syndrome (MTDPS) is a disease caused by defects in mitochondrial DNA maintenance and leads to liver failure and neurological complications during infancy. Liver transplantation (LT) remains controversial due to poor outcomes associated with extrahepatic symptoms. The purposes of this study were to clarify the current clinical and molecular features of hepatocerebral MTDPS and to evaluate the outcomes of LT in MTDPS patients in Japan. Results We retrospectively assessed the clinical and genetic findings, as well as the clinical courses, of 23 hepatocerebral MTDPS patients from a pool of 999 patients who were diagnosed with mitochondrial diseases between 2007 and 2019. Causative genes were identified in 18 of 23 patients: MPV17 (n = 13), DGUOK (n = 3), POLG (n = 1), and MICOS13 (n = 1). Eight MPV17-deficient patients harbored c.451dupC and all three DGUOK-deficient patients harbored c.143-307_170del335. The most common initial manifestation was failure to thrive (n = 13, 56.5%). The most frequent liver symptom was cholestasis (n = 21, 91.3%). LT was performed on 12 patients, including nine MPV17-deficient and two DGUOK-deficient patients. Among the 12 transplanted patients, five, including one with mild intellectual disability, survived; while seven who had remarkable neurological symptoms before LT died. Five of the MPV17-deficient survivors had either c.149G > A or c.293C > T. Conclusions MPV17 was the most common genetic cause of hepatocerebral MTDPS. The outcome of LT for MTDPS was not favorable, as previously reported, however, patients harboring MPV17 mutations associated with mild phenotypes such as c.149G > A or c.293C > T, and exhibiting no marked neurologic manifestations before LT, had a better prognosis after LT.

1551 Background: Cancer genomic profiling (CGP) tests have been approved in Japan since June 2019, with the requisite that all test results be discussed by molecular tumor boards (MTBs). More than 20,000 patients in over 200 designated hospitals have taken CGP tests by December 2021. As CGP tests have entered clinical practice, streamlining decision making by MTBs and standardizing interpretation of test results and treatment recommendations have become urgent issues. Here, we evaluated the utility of Chrovis, an annotation algorithm for reporting CGP tests to support MTBs make their recommendations. Methods: We retrospectively reviewed the reporting process of all approved CGP tests done at The University of Tokyo Hospital between December 2019 and November 2021. Chrovis provided annotation for each genetic variant by incorporating biologic, clinical, and therapeutic information by referencing several public knowledge databases and using natural language processing, and generated reports using the automated program. The MTB reviewed and made any necessary changes before finalizing the report. Changes in disclosure of germline findings were made according to the recommendations of a national guideline with consideration of past and family history. Results: Of the 243 tests, 91 changes in 81 Chrovis reports (33% of all reports) were made by the MTB. The most common type of change was germline disclosure with 26 changes (29%), followed by clinical trial information in Japan (18 changes, 20%) and recommendation of the patient-proposed national basket trial with multiple targeted agents (17 changes, 19%). Changes in germline disclosure increased from June 2021, when an update to a national guideline was released, while the proportion of changes in the latter two types remained unchanged. Gene alterations that led to the highest number of changes was TP53, with 13 changes. Changes in therapeutic recommendations were frequently observed in the RAS/MAPK pathway ( BRAF, KRAS, NF1, NRAS) with 12 changes. More changes were required with a tumor-only tissue CGP panel (57 of 149) compared with a matched tumor/normal tissue CGP panel (24 of 94, p = 0.04), mostly due to germline disclosure (24 vs. 2 changes). Conclusions: We observed that automated algorithm-based reporting was sufficient in 67% of reports. Recommendation for germline disclosure still requires manual supervision, particularly with tumor-only tissue CGP panels if algorithms do not incorporate medical history. The process of recommending clinical trials needs improvement, e.g., standardizing database formats for inclusion and exclusion criteria.