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Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency has been a target of expanded newborn screening (ENBS) using tandem mass spectrometry in Japan. Since the implementation of ENBS, a number of novel ACADVL variants responsible for VLCAD deficiency have been identified. In this study, genotypic differences in Japanese patients with VLCAD deficiency were investigated before and after ENBS. The ACADVL variants in 61 subjects identified through ENBS (ENBS group) and in 40 patients who subsequently developed clinical symptoms without undergoing ENBS (pre-ENBS group) were compared. Subjects in the ENBS group underwent genetic testing and/or VLCAD enzyme activity measurements. Patients in the pre-ENBS group were stratified into three clinical phenotypes and underwent genetic testing. This study revealed that the variants p.K264E, p.K382Q and c.996dupT were found in both groups, but their frequencies were lower in the ENBS group (5.2%, 3.1% and 4.2%, respectively) than in the pre-ENBS group (16.5%, 12.7% and 10.1%, respectively). In addition, p.C607S, p.T409M, p.M478I, p.G289R, p.C237R, p.T260M, and p.R229* were exclusively identified in the ENBS group. Among these variants, p.C607S exhibited the highest frequency (18.8%). The patients who were heterozygous for p.C607S demonstrated 7-42% of control enzyme activity. p.C607S is suspected to be unique to Japanese individuals. According to a comparison of enzyme activity, patients with the p.C607S variant may exhibit higher enzyme activity than those with the p.A416T, p.A180T, p.R450H, and p.K264E variants, which are responsible for the myopathic form of the disease. The VLCAD deficiency genotypes have changed since the initiation of ENBS in Japan.
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Síndrome Congênita de Insuficiência da Medula Óssea , Erros Inatos do Metabolismo Lipídico , Doenças Mitocondriais , Doenças Musculares , Acil-CoA Desidrogenase/genética , Acil-CoA Desidrogenase de Cadeia Longa/genética , Síndrome Congênita de Insuficiência da Medula Óssea/epidemiologia , Humanos , Recém-Nascido , Japão/epidemiologia , Erros Inatos do Metabolismo Lipídico/epidemiologia , Doenças Mitocondriais/epidemiologia , Doenças Musculares/epidemiologia , Triagem Neonatal/métodosRESUMO
Key Clinical Message: This case report describes the clinical course of a juvenile female with FGF23-related hypophosphatemic rickets preceding the onset of SLE. Our study demonstrates the possibility of hypophosphatemic rickets as an early symptom of SLE. Abstract: Fibroblast growth factor 23 (FGF23)-related hypophosphatemic rickets is observed in both genetic and acquired disorders. Various reports describe FGF23-related hypophosphatemia with systemic lupus erythematosus (SLE), although FGF23-related hypophosphatemia preceding the onset of SLE has never been described. Here, we report the case of a 9-year-old female with FGF23-related hypophosphatemic rickets preceding the onset of SLE. The patient presented to us with arthralgia in the lower extremities and abnormality of gait lasting for 8 months. She was diagnosed with FGF23 hypophosphatemic rickets due to the presence of hypophosphatemic rickets symptoms and high serum levels of FGF23. Additional examination excluded hereditary diseases and tumor-induced osteomalacia. Three months after diagnosis of FGF23-related hypophosphatemic rickets, she developed nephritis and was diagnosed with SLE. She was treated with prednisolone, hemodialysis, and disease-modifying drugs, as well as oral sodium phosphate to improve hypophosphatemia. Serum anti-double-stranded DNA antibody (dsDNAab) and plasma tumor necrosis factor-α (TNF-α) were elevated at FGF23-related hypophosphatemic rickets diagnosis. During the clinical course, serum FGF23 correlated with dsDNAab and TNF-α serum levels, which are involved in SLE disease activity. In this case, FGF23-related hypophosphatemic rickets without hereditary diseases or tumor-induced osteomalacia occurred before the appearance of juvenile SLE symptoms, and serum FGF23 represented disease activity in SLE.
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Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited metabolic disease caused by a defect in electron transfer flavoprotein alpha (ETFA), ETF beta (ETFB), or ETF dehydrogenase (ETFDH), and riboflavin metabolism disorders have recently been reported to present as mimicking MADD. MADD is roughly classified into neonatal (type 1 or 2) and later-onset (type 3) forms. To identify clinicogenetic characteristics in Japan, we investigated 37 Japanese patients with MADD diagnosed from 1997 to 2020. The causes of MADD were ETFDH deficiency in 26 patients, ETFA deficiency in four, ETFB deficiency in six, and riboflavin metabolism disorder in one. All 15 patients with the neonatal-onset type died by 2 years of age, while five of 22 patients with the later-onset form died by 3 years of age. Furthermore, 8 of 15 patients with the later-onset form of ETFDH deficiency treated with riboflavin were riboflavin non-responders. p.Y507D in ETFDH was identified as the most common variant (9 of 48 alleles, 18.8%). Of two patients with a homozygous p.Y507D variant, one experienced disease onset and died in the neonatal period, while the other experienced disease onset at two months of age and died at two years old, suggesting that the p.Y507D variant results in fatal outcomes. Our study concluded that more than half of Japanese patients with MADD died by three years old, and more than half of patients with the later-onset form had poor responsiveness to riboflavin, partly due to the unique Japanese p.Y507D variant in ETFDH.
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Flow injection analysis−tandem mass spectrometry (FIA-TMS) has been applied in a first-tier test of newborn screening (NBS). Although isovalerylcarnitine (i-C5), which is a diagnostic indicator of isovaleric acidemia (IVA), is isobaric with pivaloylcarnitine (p-C5), 2-methylbutyrylcarnitine, and n-valerylcarnitine, these isomers cannot be distinguished by the FIA-TMS. There are many reports of false positives derived from p-C5 due to the use of pivalate-conjugated antibiotics. In this study, we developed a new FIA-TMS method to distinguish i-C5 and p-C5. We found that the intensity ratio of product ions for i-C5 and p-C5 was different in a certain range even under the same analytical conditions. The product ions with the most distinct differences in ionic intensity between the isomers and the collision energies that produce them were determined to be m/z 246.2 > 187.1 and −15 V, respectively. In addition to the quantification ion, a reference ion was defined, and the similarity of the i-C5 and p-C5 reference ion ratios (i-C5 score and p-C5 score, respectively) were used to estimate which isomer (i-C5 and p-C5) was responsible for elevated C5 acylcarnitine in dried blood spots (DBSs). As a result of analyses of 11 DBS samples derived from pivalate-conjugated antibiotics and four DBS samples from IVA patients using our method, it was found that our method was able to correctly determine the type of C5-acylcarnitine (i-C5 or p-C5) in the DBS samples. Implementation of this new FIA-TMS method into the current NBS protocol will allow for a reduction in false positives in IVA.
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Hyperammonemia is a typical symptom of urea cycle disorders. While early-onset argininosuccinic aciduria (ASA) can often be detected by hyperammonemia, patients with late-onset ASA predominantly present with psychomotor retardation and mental disorders. However, in late-onset ASA that develops during early childhood, hyperammonemia can sometimes be caused by acute infections, stress, and reduced dietary intake. Here, we report the case of a 14-year-old boy with late-onset ASA associated with hyperammonemia that was triggered by an influenza A infection. Due to the infection, he presented with a fever and was unable to eat food or take oral medication. He then experienced restlessness, a disturbance in his level of consciousness, and seizures. Hyperammonemia (3286 µg/dL, reference value ≤100 µg/dL) was detected. He was biochemically diagnosed with ASA based on increased serum and urinary argininosuccinic acid levels. Additionally, genetic testing revealed compound heterozygous mutations in the ASL gene: c.91G > A(p.Asp31Asn) and c.1251-1G > C. This case revealed that in late-onset ASA, hyperammonemia can occur not only in early childhood but also during adolescence. Late-onset ASA may have a very broad clinical spectrum that includes hyperammonemia. We suggest that urea cycle disorders such as ASA must be considered when patients present with hyperammonemic decompensation during adolescence.
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INTRODUCTION: Various markers, such as C14:1 and the C14:1/C2 ratio, are used as diagnostic markers of very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). However, the levels of these markers in patients with VLCADD overlap with those in heterozygous carriers and even healthy subjects. MATERIALS AND METHODS: In twenty-three affected patients and 15 heterozygous carriers with VLCADD, the accuracies of C14:1, C14:1/C12:1, C14:1/C2, and C14:1/C16 in dried blood spots (DBS) and serum were statistically estimated. RESULTS: Among the serum markers, the sensitivity, specificity, positive predictive value, negative predictive value, false-positive rate, false-negative rate, and validity of C14:1/C12:1 were superior to those of C14:1, C14:1/C2, and C14:1/C16, but C14:1/C2 demonstrated a statistical advantage compared with only C14:1 and C14:1/C16. Elevation in serum C14:1/C12:1 was observed in only one heterozygous carrier, whereas almost half of the carriers displayed false positive results for the other markers. Among the DBS markers, although the accuracy of C14:1/C2 was ostensibly the best, no statistical significance was observed. DISCUSSION: Serum C14:1/C12:1 might be useful for differentiating patients with VLCADD from heterozygous carriers. Although serum C14:1/C2 was significantly useful for the detection of VLCADD, this marker could not distinguish the affected patients from carriers. C14:1/C12:1 might be optimal compared with the other markers.
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STUDY DESIGN: A review of a prospective database. OBJECTIVES: Surgery for elderly patients is increasing yearly due to aging of society and the desire for higher quality of life. The goal of the study was to examine perioperative complications in spine surgery in such patients. METHODS: A multicenter study of surgical details and perioperative complications was performed in 35 patients aged older than 90 years who underwent spinal surgery, based on a review of a prospective database. The frequency and severity of complications were assessed, and the effects of patient-specific and surgical factors were examined. Major complications were defined as those that were life threatening, required reoperation in the perioperative period or left a permanent injury. Ambulatory function before and after surgery was also analyzed. RESULTS: Perioperative complications occurred in 19 of the 35 cases (54%), and included 11 cases of postoperative delirium, most of which occurred after cervical spine surgery. There were 8 major complications (23%), including cerebral infarction (n = 3), coronary heart disease (n = 3), pulmonary embolism (n = 1), and angina (n = 1). Preoperative motor deficit, operative time, estimated blood loss, and instrumented fusion were significantly associated with major complications. An improved postoperative ambulatory status occurred in 61% of cases, with no change in 33%, and worsening in 2 cases (6%). CONCLUSIONS: Timing of surgery before paralysis progression and reduced surgical invasiveness are important considerations in treatment of the very elderly. Improved outcomes can be obtained with better management of spine surgery for patients aged 90 years or older.
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Hypertrophic spinal pachymeningitis (HSP) is a comparatively rare disease characterized by hypertrophic inflammation of the dura mater and clinical symptoms that progress from local pain to myelopathy. The authors report two cases of recurrent HSP and review the English- and Japanese-language literature focusing on the recurrence of HSP. In the first case, a man who presented at 67 years of age with lower-extremity numbness, gait disturbance, and bladder dysfunction experienced two recurrences of HSP during the 11 years of follow up after his initial laminectomy. Both recurrences were successfully treated with laminoplasty and duraplasty. Three years after his last surgical procedure, he was still able to walk with the aid of a walker. In the second case, a man who presented at 62 years of age with lower-extremity numbness and gait disturbance was initially treated successfully with steroid pulse therapy. Approximately 8 months after his initial presentation, his symptoms recurred. He underwent laminoplasty and duraplasty. At the 2.5-year follow-up examination, he had only mild neurological deficits and was still able to walk unaided. To explore possible causes of recurrence, the authors searched the English- and Japanese-language literature for cases of HSP. Of the 96 cases identified, 11 were recurrent. Data on the presence or absence of inflammatory signs were available for 84 patients. A chi-square analysis revealed a significantly increased rate of recurrence for patients who had at least one positive inflammatory sign before surgery (six [20%] recurrent cases of 30) compared with those who had no positive inflammatory signs before surgery (two [3.7%] recurrent cases of 54) (p < 0.05). The authors conclude that HSP recurrence occurs because of active inflammation of the dura before surgery and the influence of chronic inflammation, including residual arachnoiditis.
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Dura-Máter/patologia , Meningite/patologia , Meningite/cirurgia , Idoso , Humanos , Hipertrofia/etiologia , Hipertrofia/patologia , Hipertrofia/cirurgia , Masculino , Meningite/etiologia , Pessoa de Meia-Idade , RecidivaRESUMO
STUDY DESIGN: Prospective comparative study. PURPOSE: To compare the incidence and severity of adverse reactions associated with myelography performed in outpatients vs. in inpatients and report the safety and usefulness of outpatient myelography in Japanese patients. OVERVIEW OF LITERATURE: Myelography is normally performed as an inpatient procedure in most hospitals in Japan. No studies have reported the usefulness and adverse effects of outpatient myelography in Japanese patients. METHODS: We performed 221 myelography procedures. Eighty-five of the 221 patients underwent outpatient myelography using our new protocol. The incidence and severity of adverse reactions were compared with the other 136 patients, who underwent conventional inpatient myelography. We further compared the cost of outpatient and inpatient myelography. RESULTS: The overall rate of adverse effects was 9.4% in outpatients, as compared with 7.4% in inpatients. Overall, 1.2% of outpatients and 0.74% inpatients experienced "severe" adverse effects (requiring hospitalization). There were no significant differences between the 2 groups in either the overall rate of adverse effects or the rate of "severe" adverse effects. Moreover, the average outpatient procedure cost was only one-third to one-half that of the inpatient procedure. CONCLUSIONS: This was the first study to address the safety and usefulness of outpatient myelography in Japanese patients. If selected according to proper inclusion criteria for outpatient procedure, no significant differences were observed in the adverse effects between inpatients and outpatients. The outpatient procedure is more economical and has the added benefit of being more convenient and time-efficient for the patient.
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STUDY DESIGN: Prospective, multicenter study. OBJECTIVE: To conduct peripheral arterial disease (PAD) screening on intermittent claudication (IC) in patients with lumbar spinal canal stenosis (LSCS) to examine the relationships among combined LSCS and PAD, symptoms, and physical findings. SUMMARY OF BACKGROUND DATA: IC occurs due to two underlying diseases, LSCS and PAD, and has an increasing prevalence with the aging of society. Reliable diagnosis of PAD is critical for appropriate conservative management of IC patients with LSCS in an Orthopedic Surgery Outpatient Department (OSOPD). METHODS: PAD tests were prospectively conducted in 201 patients with IC and LSCS who initially visited an OSOPD at a hospital affiliated with the Nogoya Spine Group. Occurrence of PAD as a complication was assessed using ankle brachial pressure index (ABI) and toe brachial pressure index (TBI) tests. PAD was diagnosed in patients with ABI ≤ 0.9 or TBI ≤ 0.6, and the relationship of the occurrence of PAD with symptoms and physical findings such as abnormal arterial pulses was investigated. RESULTS: Combined LSCS and PAD was found in 52 patients (26%), with 45 cases (22%) diagnosed on the basis of TBI test in patients with a normal ABI. Of the patients with PAD, many suffered from risk factors for PAD, with a significantly higher frequency of PAD in patients with hyperlipidemia (P < 0.05). PAD also occurred significantly more frequently in patients with abnormal pulses in the popliteal (P < 0.05), posterior tibial (P < 0.0001), and dorsal pedis (P < 0.0001) arteries; however, the sensitivity of these tests for PAD diagnosis was relatively low, at 34%, 60% and 68%, respectively. CONCLUSION: The results of the prospective study define the rate of occurrence of combined LSCS and PAD using ABI and TBI tests for the first time, and the findings suggest that screening for PAD should be conducted in LSCS patients. ABI and TBI tests are necessary for PAD screening in outpatients, whereas observation of the arterial pulse in the lower extremities is necessary but not sufficient for PAD diagnosis.