伊藤 哲哉

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.

Arginase 1 (ARG1) deficiency is a rare urea cycle disorder (UCD), with an estimated frequency of 1 per 2,200,000 births in Japan. Patients with ARG1 deficiency develop symptoms in late infancy or pre-school age with progressive neurological manifestations and sometimes present with severe hepatic disease. We previously investigated the status of UCDs in Japan; however, only one patient was identified as having ARG1 deficiency. Therefore, we aimed to investigate the current status of patients with ARG1 deficiency in 2018-2021 because almost 10 years have passed since the previous study. We present the disease history, clinical outcome, and treatment of five surviving patients with ARG1 deficiency and discuss the features of ARG1 deficiency in Japan. We found that clinicians often face difficulty in diagnosing ARG1 deficiency at the early stage of onset because of interpatient variability in onset time and clinical manifestations. Blood L-arginine and guanidino compounds were considered to be the major factors causing adverse neurodevelopmental outcomes. Therefore, early detection and intervention of ARG1 deficiency is essential for improved neurodevelopmental outcomes. Liver transplantation has been considered an effective treatment option that can dramatically improve the quality of life of patients, prior to the neurological manifestation of symptoms caused by ARG1 deficiency.

<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.

© 2021 The Authors Urea cycle disorders (UCDs) are inherited metabolic diseases that lead to hyperammonemia. Severe hyperammonemia adversely affects the brain. Therefore, we conducted a nationwide study between January 2000 and March 2018 to understand the present status of UCD patients in Japan regarding diagnosis, treatments, and outcomes. A total of 229 patients with UCDs (126 patients: ornithine transcarbamylase deficiency [OTCD]; 33: carbamoyl phosphate synthetase 1 deficiency [CPS1D]; 48: argininosuccinate synthetase deficiency [ASSD]; 14: argininosuccinate lyase deficiency [ASLD]; and 8: arginase 1 deficiency [ARG1D]) were enrolled in the present study. Although growth impairment is common in patients with UCDs, we discovered that Japanese patients with UCDs were only slightly shorter than the mean height of the general adult population in Japan. Patients with neonatal-onset UCDs are more likely to experience difficulty finding employment and a spouse; however, some patients with late-onset UCDs were employed and married. Additionally, intellectual and developmental disabilities, such as attention deficit hyperactivity disorder (ADHD) and autism, hinder patients with UCDs from achieving a healthy social life. Moreover, we identified that it is vital for patients with UCDs presenting with mild to moderate intellectual disabilities to receive social support. Therefore, we believe the more robust social support system for patients with UCDs may enable them to actively participate in society.

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.

＜文献概要＞先天的にガラクトースの代謝経路が障害されているガラクトース血症は,これまでその酵素障害部位によりI型,II型,III型が知られていたが,東北大学のグループらの検討により新規疾患としてIV型ガラクトース血症が報告された.これらは新生児マススクリーニングにより血中ガラクトース,ガラクトース-1-リン酸の高値を契機に診断されるが,現在,血中ガラクトースを測定している一般の検査機関はなく,マススクリーニング検査施設でのみ対応可能であるため,日常診療で本疾患を発見することは難しい.I型,II型では乳糖制限を継続する必要があり,I型では卵巣機能不全などの慢性期合併症にも注意が必要である.

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.

高安動脈炎は大動脈とその主要分枝などに病変を生じる大型血管炎で、若年女性に好発する。疾患特異的なマーカーがなく、微熱や全身倦怠感が数週間〜数ヵ月続き、不明熱の鑑別の中で診断されることが多い。我々はけいれん重積で搬送された児が精査の結果、高安動脈炎による腎動脈狭窄が原因の高血圧性脳症だったことが判明した症例を経験したので報告する。症例は13歳、女児。生来健康で、既往歴、家族歴に特記すべきことなし。受診の1ヵ月ほど前から頭痛・嘔気を度々訴えていたが、登校できていた。受診前日の夜より眠れない程の強い頭痛を訴え、翌日朝に児がけいれんしているところを家族が発見し当院へ救急搬送された。けいれん重積および収縮期200mmHg以上の高血圧を認め、それぞれ抗けいれん薬および降圧薬の投与を開始した。頭部MRIの所見より高血圧性脳症と診断した。身体所見では腹部の収縮期血管雑音を認め、四肢の血圧の左右差は認めなかった。またCRPを含めた血液検査は正常であった。後に判明したRA系の亢進と、入院2日目に実施した胸腹部の造影CTで広範囲にわたる大動脈ならびに腎動脈を含む主要分枝の狭窄所見から、高血圧の原因は高安動脈炎による腎血管性高血圧と診断した。バイパス術など専門的な治療を要すると判断し入院4日目に他院に転院となった。本症例はけいれん重積で搬送され診断に至った比較的稀な例である。発熱の病歴はなく、受診時のCRPなどの炎症マーカーも陰性であり、さらにPET-CTにおいても病変部位の炎症反応を検出できず、すでに高度に狭窄した血管病変がみられた。本疾患では一般にCRPや赤沈値などの非特異的な炎症性蛋白の上昇を伴うことが多いが、慢性の経過を辿る症例では炎症所見に乏しい症例も存在する。高学年〜思春期の特に女児に原因不明の重度高血圧を認める場合は本症の可能性を考える必要がある。(著者抄録)

ビタミンB12(VitB12)は代謝産物であるアデノシルコバラミン(AdoCbl)がメチルマロニルCoAムターゼ(MCM)の補酵素であるため、VitB12摂取・腸管での吸収・輸送の諸段階の障害でMCMの活性低下をきたし、メチルマロン酸血症(MMA)を来す。また、母体疾患に伴うVitB12欠乏症では、新生児マススクリーニング(NBS)で児のプロピオニルカルニチン(C3)およびそのアセチルカルニチンに対する比(C3/C2比)高値が検出されることがある。我々はNBSでC3高値、C3/C2比高値を認め、母体からの移行抗内因子抗体により児の尿中メチルマロン酸排泄増加を来たした2例を経験したため報告する。2例とも精査時の血中VitB12は正常範囲であったが、尿中メチルマロン酸・メチルクエン酸の排泄増加、血漿中総ホモシステイン高値を認め、精査受診時にVitB12の内服を開始した。その後、母への詳細な問診の結果、両症例の母はともに悪性貧血の既往がある事が判明した。いずれの母もVitB12投与による治療歴を認めたが、治療中止後も貧血とVitB12低下を認めないことから、妊娠期に治療は継続されていなかった。両症例の母と児の抗内因子抗体を確認したところ陽性であった。両児のメチルマロン酸血症関連遺伝子検査では変異は検出されなかった。2例はそれぞれ生後1.5歳時、6ヵ月時に抗内因子抗体の陰性化を確認し、これらの結果より抗内因子抗体は母体由来の移行抗体であったと考えられた。血中ビタミンB12濃度が正常であっても、母体由来の抗内因子抗体による潜在的なVitB12欠乏の可能性を念頭に置く必要がある。我々はNBSにてC3・C3/C2比高値を示す児の母への詳細な問診の重要性を再認識した。(著者抄録)

有機酸代謝異常症の新生児マススクリーニングは血中アシルカルニチンをフローインジェクション-タンデムマス(FI-MS/MS)法によって分析するため、イソ吉草酸血症の指標であるイソバレリルカルニチン(C5-1)と、ピボキシル基を含む薬剤の服用で生成するピバロイルカルニチン(C5-P)の様な異性体は区別できない。従って、C5アシルカルニチン(C5)高値の場合には、尿中有機酸分析などの特殊検査が必要となる。アシルカルニチンエステラーゼ(ACE、カイノス社)はアシルカルニチンを加水分解し遊離カルニチンを生成する酵素であるが、C5-Pの様に嵩高いアシル基を有するアシルカルニチンに対する活性が低い。この酵素活性の違いを利用し、イソ吉草酸血症の偽陽性の原因となるC5-Pの判別法を検討した。C5-1にACEを反応させると99%以上が加水分解されたが、C5-Pは全く加水分解されなかった。以上から、C5高値の検体をACEで処理後FI-MS/MS法によって分析し、C5のピークが消失した場合はイソ吉草酸血症の可能性が高く、ピーク強度に変化がない場合には薬剤の影響によるC5-Pの蓄積であると判定できる。この方法はスクリーニングで用いた検体を再利用しFI-MS/MS法で分析できるため、C5高値における2次検査法として有用である。(著者抄録)