ito tetsuya

症例は5歳女児で、発熱、悪心、胸痛を主訴とした。砂遊びによる両手指の慢性湿疹に対して外用加療中であり、近医受診後も発熱が持続し、入院時には胸骨直上に辺縁不明瞭な発赤、腫脹を認め、CT検査で胸骨体の両側に低吸収帯を認めた。感染症の疑いで抗菌薬治療を開始し、血液培養でメチシリン耐性黄色ブドウ球菌(MRSA)が同定されたため、バンコマイシン(VCM)を併用した。その結果、解熱と胸痛の軽快が得られ、MRSAによる原発性胸骨骨髄炎と診断した。その後はCRP陰性化を確認してリネゾリド内服に変更し、VCMと併せて計6週間の抗MRSA薬による治療を行ったところ、炎症の再燃や血小板減少は認めなかった。本症例では手指の慢性湿疹が感染経路と考えられ、慢性湿疹を背景に持つ患児では薬剤耐性菌による全身性の感染症に留意する必要があると考えられた。

Phenylketonuria (PKU) is an inborn error of metabolism caused by deficiency of phenylalanine hydroxylase, resulting in high blood phenylalanine (Phe) concentrations with potential for impaired neurocognition. Pegvaliase, a pegylated recombinant phenylalanine ammonia lyase that metabolizes Phe, is approved for use in adults with PKU and high blood Phe despite prior management. In the Phase 3 PRISM studies conducted in the United States, pegvaliase induction/titration/maintenance dosing led to clinically meaningful and statistically significant blood Phe reductions versus placebo, with a manageable safety profile. Here we report the primary endpoint, change in blood Phe levels from baseline to Week 52, and 2-year interim efficacy and safety results (to Week 144; data cut-off March 31, 2022) of an ongoing, open-label study in a Japanese PKU population (JapicCTI-194,642). Participants were 12 adults with PKU from Japan aged 18-70 years with blood Phe levels >600 μmol/L. In Part 1, participants received subcutaneous 2.5 mg pegvaliase once weekly for 4 weeks (induction), followed by titration up to 20 mg/day, then dose adjustment to a maximum 40 mg/day to achieve blood Phe efficacy (≤360 μmol/L); this maintenance dose was continued to Week 52. In Part 2, participants continued pegvaliase with dose adjustments up to a maximum 60 mg/day for up to 168 weeks. Among 11 participants evaluable for efficacy, mean (standard deviation) blood Phe concentration decreased from 1025.9 (172.7) μmol/L at baseline to 448.3 (458.8) μmol/L at Week 52 (mean 57.5% decrease). Up to Week 104, all 11 (100%) efficacy-evaluable participants achieved blood Phe levels ≤600 μmol/L, 9 (81.8%) achieved ≤360 μmol/L, and 8 (72.7%) achieved ≤120 μmol/L. All 12 participants reported ≥1 adverse event (AE), most commonly injection site erythema and injection site swelling (n = 10, 83.3% each). The pegvaliase exposure-adjusted AE rate was 23.5 per person-years overall, 41.2 per person-years during induction/titration, and 13.5 per person-years during maintenance. All participants developed pegvaliase-induced antibody responses. There were no AEs leading to discontinuation, no deaths, and no anaphylaxis events. Although interim, these results support the use of pegvaliase in Japanese adults with PKU with elevated blood Phe levels and are consistent with results from the Phase 3 PRISM studies.

BACKGROUND: Glycogen storage disease type Ia (GSDIa) is caused by biallelic pathogenic variants in the glucose-6-phosphatase gene (G6PC) and mainly characterized by hypoglycemia, hepatomegaly, and renal insufficiency. Although its symptoms are reportedly mild in patients carrying the G6PC c.648G>T variant, the predominant variant in Japanese patients, details remain unclear. Therefore, we examined continuous glucose monitoring (CGM) data and daily nutritional intake to clarify their associations in Japanese patients with GSDIa with G6PC c.648G>T. METHODS: This cross-sectional study enrolled 32 patients across 10 hospitals. CGM was performed for 14 days, and nutritional intake was recorded using electronic diaries. Patients were divided according to genotype (homozygous/compound heterozygous) and age. The durations of biochemical hypoglycemia and corresponding nutritional intake were analyzed. Multiple regression analysis was performed to identify factors associated with the duration of biochemical hypoglycemia. RESULTS: Data were analyzed for 30 patients. The mean daily duration of hypoglycemia (<4.0 mmol/L) in the homozygous group increased with age (2-11 years [N = 8]: 79.8 min; 12-18 years [5]: 84.8 min; ≥19 years [10]: 131.5 min). No severe hypoglycemic symptoms were recorded in the patients' diaries. The mean frequency of snack intake was approximately three times greater in patients aged 2-11 years (7.1 times/day) than in those aged 12-18 years (1.9 times/day) or ≥19 years (2.2 times/day). Total cholesterol and lactate were independently associated with the duration of biochemical hypoglycemia. CONCLUSION: Although nutritional therapy prevents severe hypoglycemia in patients with GSDIa with G6PC c.648G>T, patients often experience asymptomatic hypoglycemia.

20歳男性。新生児期にプロピオン酸血症(PA)を急性発症し、19歳頃から心エコーで拡張型心筋症の所見を認めていたが、心収縮能低下は認めず、経過観察していた。20歳時に感染を契機に心不全を発症し、PAに伴う拡張型心筋症と診断し、入院のうえ心不全治療を開始した。心不全は一時改善したが再度増悪し、カルベジロールとピモベンダンを導入することで改善が得られ、退院となった。退院6週後に高アンモニア血症とC3値の上昇、C0の低下を認め、代謝クライシスの急性期治療を行うとともに、自然タンパク量、総タンパク量を含めた食事療法の再調整を行った。以後5年間の経過は良好で、利尿薬の減量が可能となり、心機能は著明に改善している。

Mutations in transport and Golgi organization 2 homolog (TANGO2) have recently been described as a cause of an autosomal recessive syndrome characterized by episodes of metabolic crisis associated with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration. Herein, we report a case of a one-and-a-half-year-old Japanese girl, born to nonconsanguineous parents, who presented with metabolic crisis characterized by hypoglycemia with hypoketonemia, rhabdomyolysis, lactic acidosis, and prolonged corrected QT interval (QTc) at the age of 6 months. Acylcarnitine analysis during the episode of crisis showed prominent elevation of C14:1, suggesting very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. In addition, worsening rhabdomyolysis was observed after intravenous administration of L-carnitine. VLCAD deficiency was initially suspected; however, the enzyme activity in lymphocytes was only mildly decreased at the gene carrier level, and no mutation in the VLCAD gene (ADADVL) was detected. Subsequently, acylcarnitine analysis was nonspecific at 17-h fasting and almost normal during the stable phase. Eventually, a trio whole-exome sequencing revealed a compound heterozygous variant of two novel variants in the TANGO2 gene, a missense variant, and a deletion of exon 7. This is the first case of TANGO2 deficiency in Asians. Our case suggests that elevated C14:1 may be seen in severe metabolic crises and that the use of L-carnitine should be avoided during metabolic crises.

Maple syrup urine disease (MSUD) is a rare autosomal recessive inherited disorder of branched-chain amino acid metabolism caused by mutations in BCKDHA, BCKDHB, and DBT that encode the E1α, E1β, and E2 subunits of the branched-chain α-ketoacid dehydrogenase (BCKD) complex. Various MSUD-causing variants have been described; however, no structural rearrangements in BCKDHA have been reported to cause the classic MSUD phenotype. Here, we describe the classic patient with MSUD with compound heterozygous pathogenic variants in BCKDHA: a missense variant (NM_000709.3:c.757G > A, NP_000700.1:p.Ala253Thr) and a paracentric inversion disrupting Intron 1 of BCKDHA, which was identified by whole-genome sequencing and validated by fluorescence in situ hybridization. Using the sequence information of the breakpoint junction, we gained mechanistic insight into the development of this structural rearrangement. Furthermore, the establishment of junction-specific polymerase chain reaction could facilitate identification of the variant in case carrier or future prenatal/preimplantation tests are necessary.

Thrombotic microangiopathy (TMA) is a disease that causes organ damage due to microvascular hemolytic anemia, thrombocytopenia, and microvascular platelet thrombosis. Streptococcus pneumoniae-associated TMA (spTMA) is a rare complication of invasive pneumococcal infection. In addition, atypical hemolytic uremic syndrome (aHUS) is TMA associated with congenital or acquired dysregulation of complement activation. We report the case of a nine-month-old boy with refractory nephrotic syndrome complicated by spTMA in the setting of heterozygous complement factor-I (CFI) gene mutation and CFHR3-CFHR1 deletion. He repeatedly developed thrombocytopenia, anemia with schistocytes, hypocomplementemia, and abnormal coagulation triggered by infection, which manifested clinically with convulsions and an intraperitoneal hematoma. Eculizumab (a monoclonal humanized anti-C5 antibody) provided transient symptomatic benefit including improvement in thrombocytopenia; however, he developed unexplained cardiac arrest and was declared brain dead a few days later. In this report, we highlight the diagnostic challenges of this case and the causal relationship between spTMA and complement abnormalities and consider the contribution of heterozygous mutation of CFI and CFHR3-CFHR1 deletion.

全国の小児科診療施設へのアンケート調査を行いメチルマロン酸血症(MMA)の治療内容について検討した。大学病院小児科、小児病院、地域の主要病院等368施設に対して一次アンケートを実施し、症例ありと回答されたのは35施設で、メチルマロニルCoAムターゼ(MCM)欠損症75例、ビタミンB12反応性のコバラミン代謝異常症29例、病型不明7例であった。さらに二次アンケートを行い、計82例のMMA患者の臨床情報を得ることができた。平均発症月齢はMCM欠損症3.7±7.2ヵ月、コバラミン代謝異常症3.5±4.7ヵ月、病型不明1.6±3.2ヵ月といずれも乳児期早期の発症割合が高いことが示唆された。最も施行されていた治療はカルニチン内服で、MCM欠損症で54例(91%)、コバラミン代謝異常症で15例(83%)、次に自然タンパク制限で、MCM欠損症で50例(84%)、コバラミン代謝異常症で6例(33%)に行われていた。また、MCM欠損症では39例(85%)で食事のタンパク制限を施行していた。

Maturity-onset diabetes of the young (MODY) is a form of diabetes mellitus characterized by autosomal dominant inheritance, early onset, and the absence of pancreatic autoimmune markers. MODY-causing mutations have been identified in 14 genes, and carboxyl ester lipase (CEL) has been implicated in MODY8. We report a Japanese patient with MODY who harbored a heterogeneous mutation in CEL exon 2 (NM_001807.4:c.146_147delCT; NP_001798.2:p.Ser49CysfsTer52). A 13-year-old girl experienced her first episode of diabetic ketoacidosis, during which her endogenous insulin secretion was poor. However, her insulin secretion had apparently recovered 2 months after the commencement of insulin treatment, and no further treatment was required for the following 2 years. Diabetic ketoacidosis recurred when the patient was 15 years old, when her insulin secretion was again poor. Since that time, the patient, who is now 18 years old, has been undergoing continuous insulin treatment. The large fluctuations in her insulin secretory capacity led us to suspect MODY. MODY8 patients that carry a mutation in the variable number of tandem repeats in the last exon of the CEL gene typically show pancreatic exocrine dysfunction. However, in the present case, which features premature termination, there is no involvement of exocrine dysfunction, potentially demonstrating a genotype-phenotype correlation.

<title>Abstract</title>We report a case of a 13-year<bold>-</bold>old boy with arginase 1 deficiency carrying a new variant in <italic>ARG1</italic>. Sanger sequencing identified the compound heterozygous variants: NM_000045.4: c.365G&gt;A (p.Trp122*)/c.820G&gt;A (p.Asp274Asn). Although not previously reported, the p.Asp274Asn variant is predicted to have strong pathogenicity because it is located in a highly conserved domain in the protein core and arginase activity in the patient was below measurement sensitivity.

IMPORTANCE: Sapropterin hydrochloride, a natural coenzyme (6R-tetrahydrobiopterin) of phenylalanine hydroxylase, was first approved as a treatment for tetrahydrobiopterin deficiency in 1992 in Japan, and was then approved as a treatment for a tetrahydrobiopterin-responsive hyperphenylalaninemia in 2007 and 2008, in the USA and Japan, respectively. Guidelines are required on the proper use of sapropterin hydrochloride for tetrahydrobiopterin-responsive hyperphenylalaninemia. OBSERVATIONS: It is recommended that tetrahydrobiopterin-responsive hyperphenylalaninemia should be diagnosed in all cases of hyperphenylalaninemia, including phenylketonuria, by tetrahydrobiopterin administration tests rather than by phenotype or blood phenylalanine levels. CONCLUSIONS AND RELEVANCE: If tetrahydrobiopterin-responsive hyperphenylalaninemia is diagnosed, all ages can be treated with sapropterin hydrochloride. Although there are reports that sapropterin hydrochloride is effective and safe for the prevention of maternal phenylketonuria, further investigation is required.

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) deficiency is a metabolic disorder caused by mutations in the HMGCS2 gene. The present study describes the identification of four cases of HMGCS2 deficiency in Japan. Hepatomegaly and severe metabolic acidosis were observed in all cases. Fatty liver was identified in three cases, which suggested the unavailability of fatty acids. All patients presented with a high C2/C0 ratio, suggesting that the fatty acid oxidation pathway was normal during metabolic crisis. Genetic analyses revealed five rare, novel variants (p.G219E, p.M235T, p.V253A, p.S392L and p.R500C) in HMGCS2. To confirm their pathogenicity, a eukaryotic expression system and a bacterial expression system was adopted that was successfully used to obtain affinity-purified HMGCS2 protein with measurable activity. Purified M235T, S392L and R500C proteins did not retain any residual activity, whilst the V253A variant showed some residual enzymatic activity. Judging from the transient expression experiment in 293T cells, the G219E variant appeared to be unstable. In conclusion, the present study identified five novel variants of HMGCS2 that were indicated to be pathogenic in four patients affected by HMGCS2 deficiency.

BACKGROUND: Mitochondrial DNA depletion syndrome (MTDPS) is part of a group of mitochondrial diseases characterized by a reduction in mitochondrial DNA copy number. Most MTDPS is caused by mutations in genes that disrupt deoxyribonucleotide metabolism. METHODS: We performed the whole-exome sequencing of a hepato-encephalopathy patient with MTDPS and functional analyses to determine the clinical significance of the identified variant. RESULTS: Here, whole-exome sequencing of a patient presenting with hepato-encephalopathy and MTDPS identified a novel homozygous frameshift variant, c.13_29del (p.Trp6Profs*71) in MICOS13. MICOS13 (also known as QIL1, MIC13, or C19orf70) is a component of the MICOS complex, which plays crucial roles in the maintenance of cristae junctions at the mitochondrial inner membrane. We found loss of MICOS13 protein and fewer cristae structures in the mitochondria of fibroblasts derived from the patient. Stable expression of a wild-type MICOS13 cDNA in the patients fibroblasts using a lentivirus system rescued mitochondrial respiratory chain complex deficiencies. CONCLUSION: Our findings suggest that the novel c.13_29del (p.Trp6Profs*71) MICOS13 variant causes hepato-encephalopathy with MTDPS. We propose that MICOS13 is classified as the cause of MTDPS.

Cancer treatment with a fluoropyrimidine (FP) is often accompanied by severe toxicity that may be dependent on the activity of catalytic enzymes encoded by the DPYD, DPYS, and UPB1 genes. Genotype-guided dose individualization of FP therapy has been proposed in western countries, but our knowledge of the relevant genetic variants in East Asian populations is presently limited. To investigate the association between these genetic variations and FP-related high toxicity in a Japanese population, we obtained blood samples from 301 patients who received this chemotherapy and sequenced the coding exons and flanking intron regions of their DPYD, DPYS, and UPB1 genes. In total, 24 single nucleotide variants (15 in DPYD, 7 in DPYS and 2 in UPB1) were identified including 3 novel variants in DPYD and 1 novel variant in DPYS. We did not find a significant association between FP-related high toxicity and each of these individual variants, although a certain trend toward significance was observed for p.Arg181Trp and p.Gln334Arg in DPYS (P = .0813 and .087). When we focused on 7 DPYD rare variants (p.Ser199Asn, p.IIe245Phe, p.Thr305Lys, p.Glu386Ter, p.Ser556Arg, p.Ala571Asp, p.Trp621Cys) which have an allele frequency of less than 0.01% in the Japanese population and are predicted to be loss-of-function mutations by in silico analysis, the group of patients who were heterozygous carriers of at least one these rare variants showed a strong association with FP-related high toxicity (P = .003). Although the availability of screening of these rare loss-of-function variants is still unknown, our data provide useful information that may help to alleviate FP-related toxicity in Japanese patients with cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.