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AIM: The diagnosis of drug-induced liver injury (DILI) is challenging. We modified the revised electronic version of the Roussel Uclaf Causality Assessment Method (RUCAM) for the diagnosis of DILI (RECAM), the scoring system developed in US and Spanish cohorts in 2022, and developed RECAM-J 2023 to align with the clinical practice in Japan. In the current study, we introduce RECAM-J 2023 and verify its performance in the context of Japanese patients with DILI. METHODS: After translation of RECAM into Japanese, modifications were made to develop RECAM-J 2023 without any alteration to the scores. To examine the validity and performance of RECAM-J 2023, clinical information on DILI and non-DILI cases in Japan were retrospectively collected. The diagnosis of DILI was made by expert's decision. Then we scored each case using RECAM-J 2023, and calculated area under curve (AUC) values for identification for DILI. RESULTS: We collected data from 538 DILI and 128 non-DILI cases. The sum of highly probable (HP) and probable (PR) cases categorized by RECAM-J 2023 were only 206 (38%) in DILI cases. As the primary cause of low scores was the deduction with missing hepatitis virus markers, which is unlikely to be an issue in prospective applications, we rescored without these deductions. At this time, the sum of HP and PR was raised to 421 (78%). The AUCs of RECAM-J 2023 without deductions were 0.70 and 0.88 for identifying at least HP, and at least PR, respectively. CONCLUSION: RECAM-J 2023, when prospectively used without any missing hepatitis virus markers, provides acceptable performance for identifying at least PR DILI cases in Japanese daily clinical practice.
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Approximately 80% of rare diseases have a genetic cause, and an accurate genetic diagnosis is necessary for disease management, prognosis prediction, and genetic counseling. Whole-exome sequencing (WES) is a cost-effective approach for exploring the genetic cause, but several cases often remain undiagnosed. We combined whole genome sequencing (WGS) and RNA sequencing (RNA-seq) to identify the pathogenic variants in an unsolved case using WES. RNA-seq revealed aberrant exon 4 and exon 6 splicing of ITPA. WGS showed a previously unreported splicing donor variant, c.263+1G>A, and a novel heterozygous deletion, including exon 6. Detailed examination of the breakpoint indicated the deletion caused by recombination between Alu elements in different introns. The proband was found to have developmental and epileptic encephalopathies caused by variants in the ITPA gene. The combination of WGS and RNA-seq may be effective in diagnosing conditions in proband who could not be diagnosed using WES.
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Familia , Pirofosfatasas , Humanos , Secuenciación del Exoma , Secuenciación Completa del Genoma , Exones , Análisis de Secuencia de ARNRESUMEN
We describe a patient presenting with argininosuccinic aciduria and Silver-Russell syndrome (SRS). SRS was caused by maternal uniparental disomy of chromosome 7 (UPD(7)mat). UPD(7)mat also unmasked a maternally inherited splicing variant in ASL on chromosome 7, leading to the onset of argininosuccinic aciduria. The phenotype of the present case was more severe than that of a previous case, demonstrating a phenotypic variation in the combination of argininosuccinic aciduria and SRS.
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Biallelic deletions extending into the ATPase family AAA-domain containing protein 3A (ATAD3A) gene lead to infantile lethality with severe pontocerebellar hypoplasia (PCH). However, only 12 such cases have been reported worldwide to date, and the genotype-phenotype correlations are not well understood. We describe cases associated with the same novel biallelic deletions of the ATAD3A and ATAD3B/3A regions in Japanese siblings with severe spinal cord hypoplasia and multiple malformations, including PCH, leading to neonatal death. The ATAD3A protein is essential for normal interaction between mitochondria and endoplasmic reticulum and is important for mitochondrial biosynthesis. The cases were evaluated using whole-genome sequencing for genetic diagnosis of mitochondrial disease. Spinal cord lesions associated with biallelic compound heterozygous deletion extending into the ATAD3A gene have not been reported. In addition, the ATAD3A deletion was 19 base pairs long, which is short compared with those reported previously. This deletion introduced a frameshift, resulting in a premature termination codon, and was expected to be a null allele. The pathological findings of the atrophic spinal cord showed gliosis and tissue destruction of the gray and white matter. We describe spinal cord lesions as a new central nervous system phenotype associated with a biallelic compound heterozygous deletion extending into the ATAD3A gene. Biallelic ATAD3A deletions should be considered in cases of mitochondrial disease with spinal cord hypoplasia and PCH.
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Pathogenic mitochondrial DNA heteroplasmy has mainly been assessed with bulk sequencing in individuals with mitochondrial disease. However, the distribution of heteroplasmy at the single-cell level in skin fibroblasts obtained from individuals, together with detailed clinical and biochemical information, remains to be investigated. We used the mitochondrial DNA single-cell assay for the transposase-accessible chromatin sequencing method. Skin fibroblasts were obtained from six individuals with mitochondrial disease and pathogenic m.3243A>G variants of differing severity. Different distributions of heteroplasmy at the single-cell level were identified in skin fibroblasts from all six individuals. Four individuals with different outcomes showed similar averaged heteroplasmy rates with normal mitochondrial respiratory chain enzyme activity, while the distribution of single-cell heteroplasmy patterns differed among the individuals. This study showed different heteroplasmy distribution patterns at the single-cell level in individuals with the m.3243A>G variant, who had a similar averaged heteroplasmy rates with normal mitochondrial respiratory chain enzyme activity. Whether such different heteroplasmy distribution patterns explain the different clinical outcomes should be assessed further in future studies. Measuring heteroplasmy of pathogenic mitochondrial DNA variants at the single-cell level could be important in individuals with mitochondrial disease.
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ADN Mitocondrial , Enfermedades Mitocondriales , Humanos , ADN Mitocondrial/genética , Heteroplasmia , Enfermedades Mitocondriales/genética , Mitocondrias/genéticaRESUMEN
BACKGROUND: Hypophosphatasia (HPP) is a rare inherited metabolic disorder caused by mutations in the ALPL gene, which encodes tissue nonspecific alkaline phosphatase. The severity of HPP is widely diverse from the perinatal form to the adult mild form. The former represents the most severe form and was earlier associated with high mortality due to pneumonia which was caused by severe hypomineralization of the bones-such as chest deformity and fractured ribs-and muscle weakness. Enzyme replacement therapy using asfotase alfa (AA) was approved in 2015 in Japan for treating patients with HPP and has improved their pulmonary function and life prognosis. There are several practical and ethical challenges related to using orphan drugs for a rare disorder in a publicly funded healthcare system. Sharing experiences about their application is essential towards formulating guidelines to assist clinicians with decisions about their initiation and withdrawal. We report the details of AA experience in ten cases of pediatric-onset HPP in nine families from January 2015 to November 2019 (median [interquartile range] age 11.0 [7.6-12.5] years; 60% male). This is a study of a single-center cohort describing the clinical course of patients with HPP, mainly consisting of the mild childhood form of HPP, treated with AA in Japan. RESULTS: One case of perinatal form of HPP, two cases of benign prenatal form, and seven cases of childhood form were observed. The most common symptom at onset was pain. All patients had low serum alkaline phosphatase levels as compared to the age-matched reference range before the commencement of AA. All HPP patients seem to have responded to AA treatment, as evidenced by pain alleviation, increased height standard deviation, improvement in respiratory condition and 6-min walk test result improvement, disappearance of kidney calcification, alleviation of fatigue, and/or increases in bone mineralization. There were no serious adverse events, but all patients had an injection site reaction and skin changes at the injection sites. Genetic analysis showed that eight out of ten patients had compound heterozygosity. CONCLUSIONS: AA may be effective in patients with mild to severe pediatric-onset forms of HPP.
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Hipofosfatasia , Adulto , Fosfatasa Alcalina/genética , Niño , Femenino , Humanos , Hipofosfatasia/complicaciones , Hipofosfatasia/tratamiento farmacológico , Inmunoglobulina G , Japón , Masculino , Dolor/tratamiento farmacológico , Enfermedades Raras/tratamiento farmacológico , Proteínas Recombinantes de FusiónRESUMEN
The m.14453G > A mutation in MT-ND6 has been described in a few patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes or Leigh syndrome.However, the clinical spectrum and molecular characteristics are unclear.Here, we present four infantile-onset patients with m.14453G > A-associated Leigh syndrome. All four patients had brainstem lesions with basal ganglia lesions, and two patients had cardiac manifestations. Decreased ND6 protein expression and immunoreactivity were observed in patient-derived samples. There was no clear correlation between heteroplasmy levels and onset age or between heteroplasmy levels and phenotype; however, infantile onset was associated with Leigh syndrome.
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Enfermedad de Leigh , Encefalomiopatías Mitocondriales , ADN Mitocondrial/genética , Heteroplasmia , Humanos , Enfermedad de Leigh/genética , Mutación , ProbabilidadAsunto(s)
Trasplante de Hígado , Errores Innatos del Metabolismo , Enfermedades Mitocondriales , Niño , ADN Mitocondrial/genética , Humanos , Hígado/cirugía , Proteínas de la Membrana/genética , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/genética , Proteínas Mitocondriales/genética , MutaciónRESUMEN
OBJECTIVE: Neonatal-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. DESIGN: Retrospective observational study from January 2004 to March 2020. SETTING: Population based. PATIENTS: Patients (281) with neonatal-onset mitochondrial disease diagnosed by biochemical and genetic approaches. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Disease types, initial symptoms, biochemical findings, molecular diagnosis and prognosis. RESULTS: Of 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. CONCLUSIONS: Neonatal-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.
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Enfermedad de Leigh , Enfermedades Mitocondriales , ADN Mitocondrial/genética , Humanos , Recién Nacido , Enfermedad de Leigh/diagnóstico , Enfermedad de Leigh/genética , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Mutación , PronósticoRESUMEN
Short-chain enoyl-CoA hydratase (ECHS1) is involved in amino acid and fatty acid catabolism in mitochondria and its deficiency causes Leigh syndrome or exercise-induced dystonia. More than 60 patients with this condition have been reported till date. The accumulation of intermediate metabolites of valine is assumed to be responsible for the cytotoxicity. Since protein restriction, including valine reportedly improves neurological symptoms, it is essential to consider the possible incidence of and diagnose ECHS1 syndrome in the earlier stages. This study reported the liquid chromatography with tandem mass spectrometry (LC-MS/MS) urine and plasma metabolite analysis in six cases, including four new cases with ECHS1 deficiency. The values of urine cysteine/cysteamine conjugates from valine metabolites, S-(2-carboxypropyl) cysteine/cysteamine from methacrylyl-CoA, and S-(2-carboxyethyl) cysteine/cysteamine from acryloyl-CoA were separated between six patients and six normal controls. The LC-MS/MS analysis revealed that these metabolites can be used for the early diagnosis and evaluation of diet therapy.
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BACKGROUND: Cardiomyopathy is a risk factor for poor prognosis in pediatric patients with mitochondrial disease. However, other risk factors including genetic factors related to poor prognosis in mitochondrial disease has yet to be fully elucidated. METHODS AND RESULTS: Between January 2004 and September 2019, we enrolled 223 consecutive pediatric mitochondrial disease patients aged <18 years with a confirmed genetic diagnosis, including 114 with nuclear gene mutations, 89 patients with mitochondrial DNA (mtDNA) point mutations, 11 with mtDNA single large-scale deletions and 9 with chromosomal aberrations. Cardiomyopathy at baseline was observed in 46 patients (21%). Hazard ratios (HR) and 95% confidence intervals (CI) were calculated for all-cause mortality. Over a median follow-up of 36 months (12-77), there were 85 deaths (38%). The overall survival rate was significantly lower in patients with cardiomyopathy than in those without (p < 0.001, log-rank test). By multivariable analysis, left ventricular (LV) hypertrophy (HR = 4.6; 95% CI: 2.8-7.3), neonatal onset (HR = 2.9; 95% CI: 1.8-4.5) and chromosomal aberrations (HR = 2.9; 95% CI: 1.3-6.5) were independent predictors of all-cause mortality. Patients with LV hypertrophy with neonatal onset and/or chromosomal aberrations had higher mortality (100% in 21 patients) than those with LV hypertrophy alone (71% in 14 patients). CONCLUSION: In pediatric patients with mitochondrial disease, cardiomyopathy was common (21%) and was associated with increased mortality. LV hypertrophy, neonatal onset and chromosomal aberrations were independent predictors of all-cause mortality. Prognosis is particularly unfavorable if LV hypertrophy is combined with neonatal onset and/or chromosomal aberrations.
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Cardiomiopatías , Enfermedades Mitocondriales , Cardiomiopatías/diagnóstico , Cardiomiopatías/genética , Niño , Antecedentes Genéticos , Humanos , Hipertrofia Ventricular Izquierda , Recién Nacido , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/epidemiología , Enfermedades Mitocondriales/genética , Pronóstico , Factores de RiesgoRESUMEN
Prenatal diagnoses of mitochondrial diseases caused by defects in nuclear DNA (nDNA) or mitochondrial DNA 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 (16 cases) had requested prenatal diagnoses. Eight cases diagnosed with wild type 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. 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.
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Conexinas/genética , Enfermedades Mitocondriales/diagnóstico , Diagnóstico Prenatal , Femenino , Asesoramiento Genético/tendencias , Pruebas Genéticas/tendencias , Heterocigoto , Homocigoto , Humanos , Masculino , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/patología , Mutación/genética , Linaje , Embarazo , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: ECHS1 is a key enzyme of the valine catabolic pathway and oxidation of fatty acids. In ECHS1 deficiency (ECHS1D), accumulation of toxic intermediates from the valine induces neurodegeneration, which presents Leigh syndrome (LS). Therefore, valine restriction is suggested as an effective therapy. Further, cysteamine may detoxify the toxic metabolites themselves and N-acetylcysteine (NAC) is a potent antioxidant preventing neurological affect. Herein, we report the therapeutic effects of dietary therapy, cysteamine, and NAC in two siblings with ECHS1D, including their clinical, neuroradiological, and chemical aspects. CASE REPORT: The elder sister was the proband and was diagnosed as LS at 13 months of age. Gene analysis identified compound heterozygous ECHS1 mutations. Her psychomotor development was regressed, and she became bedridden. At 4 years old she started a low protein diet (LPD), but with no obvious neurological change. The younger brother was confirmed early with ECHS1D and received cysteamine and NAC treatment from 5 months of age, which could not prevent him developing LS at 7 months of age. Thus, we started a LPD at 14 months of age, with which he regained his ability to roll over, then we proceeded to a valine-restricted diet. The brain magnetic resonance image hyperintensity was diminished, and the lactate peak on magnetic resonance spectroscopy decreased. His neurological outcome is better than his elder sister. In both cases, excretion of valine metabolites decreased after dietary therapy without obvious adverse effects. CONCLUSION: Early initiation of dietary therapy may reduce neurological sequelae in patients with ECHS1D.
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Enoil-CoA Hidratasa/deficiencia , Valina/metabolismo , Acetilcisteína/farmacología , Cisteamina/farmacología , Dietoterapia/métodos , Enoil-CoA Hidratasa/genética , Enoil-CoA Hidratasa/metabolismo , Enoil-CoA Hidratasa/fisiología , Familia , Femenino , Pruebas Genéticas/métodos , Humanos , Lactante , Japón , Enfermedad de Leigh/genética , Enfermedad de Leigh/prevención & control , Imagen por Resonancia Magnética/métodos , Masculino , Mutación/genética , Linaje , Hermanos , Resultado del Tratamiento , Valina/deficiencia , Valina/genéticaRESUMEN
We report a case of a 7-month-old boy with Short-chain enoyl-CoA hydratase (ECHS1) deficiency concomitant with prominent ketoacidosis, and no elevation in plasma lactate levels. He suddenly became unconscious, after he had a lot of defecation. He was referred to our hospital by a local doctor because of a right conjugate deviation and hypotonia. Initial investigations revealed severe anion gap metabolic acidosis, hyperuricemia, hyperketonemia, and normal lactate levels in the blood and cerebrospinal fluid. Magnetic resonance imaging of the brain showed abnormal signals in the bilateral caudate nucleus and globus pallidus, suggesting the possibility of inborn errors of metabolism. Thus, analysis of acylcarnitine analysis and urine organic acid was performed but could not help diagnose his condition. We then performed mutation analysis using a DNA panel. We found the following heterozygous mutations in ECHS1: c.5C > T (p. Ala2Val) and c.176 A > G (p. Asn59Ser), leading to the diagnosis of Leigh encephalopathy. This case report expands our understanding of the multiple symptoms of ECHS1 deficiency and emphasizes the importance of genetic testing for inborn errors of metabolism, such as ECHS1 deficiency, to initiate early treatment.
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The detoxification of ammonia to urea requires a functional hepatic urea cycle, which consists of six enzymes and two mitochondrial membrane transporters. The initial step of the urea cycle is catalyzed by carbamyl phosphate synthetase 1 (CPS1). CPS1 deficiency (CPS1D) is a rare autosomal recessive disorder. N-Carbamylglutamate (NCG), a deacylase-resistant analogue of N-acetylglutamate, can activate CPS1. We describe the therapeutic course of a patient suffering from neonatal onset CPS1D with compound heterozygosity for the c.2359C > T (p.Arg787*) and c.3559G > T (p.Val1187Phe) variants in CPS1, treated with NCG. She presented with hyperammonemia, which reached 944 µmol/L at the age of 2 days. The ammonia concentration decreased after treatment with continuous hemodiafiltration, NCG, sodium benzoate, sodium phenylbutyrate, L-arginine, vitamin cocktail (vitamin B1, vitamin B12, vitamin C, vitamin E, biotin), l-carnitine, coenzyme Q10, and parenteral nutrition. Her ammonia and glutamine levels remained low; thus, protein intake was increased to 1.2 g/kg/day. Furthermore, the amount of sodium benzoate and sodium phenylbutyrate were reduced. She remained metabolically stable and experienced no metabolic crisis following treatment with oral NCG, sodium benzoate, sodium phenylbutyrate, citrulline, vitamin cocktail, l-carnitine, and coenzyme Q10 until she underwent liver transplantation at 207 days of age. She had no neurological complications at the age of 15 months. Ammonia and glutamine levels of the patient were successfully maintained at a low level via NCG treatment with increased protein intake, which led to normal neurological development. Thus, undiagnosed urea cycle disorders should be treated rapidly with acute therapy including NCG, which should be maintained until a genetic diagnosis is reached. It is essential to prevent metabolic crises in patients with CPS1D until liver transplantation to improve their prognoses.
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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.
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Trasplante de Hígado , Enfermedades Mitocondriales , ADN Mitocondrial/genética , Humanos , Japón , Enfermedades Mitocondriales/genética , Mutación/genética , Estudios RetrospectivosRESUMEN
Mitochondrial trifunctional protein (TFP) deficiency is a rare inherited metabolic disorder caused by defects in fatty acid ß-oxidation (FAO) of long-chain fatty acids, leading to impaired energy production. Fasting avoidance, fatty acid-restricted diets, and supplementation with medium-chain triglycerides are recommended as a treatment, but there are no pharmaceutical treatments available with strong evidence of efficacy. Bezafibrate, which enhances the transcription of FAO enzymes, is a promising therapeutic option for FAO disorders (FAODs). The effectiveness of bezafibrate for FAODs has been reported in some clinical trials, but few clinical studies have investigated its in vivo efficacy toward TFP deficiency. Herein, we describe two Japanese patients with TFP deficiency. Patient 1 presented with recurrent myalgia since the age of 5 years. Laboratory findings showed increased serum levels of long-chain fatty acids and reduced expression of TFPα and TFPß in his skin fibroblasts. Based on these findings, he was diagnosed with the myopathic type of TFP deficiency. Patient 2 suddenly exhibited cardiopulmonary arrest one day after birth. Elevated levels of creatine kinase and long-chain acylcarnitines were observed. Genetic analysis identified compound heterozygous variants in HADHB (c.1175C>T/c.1364T>G). He was diagnosed with the lethal type of TFP deficiency. Although both patients were treated with dietary therapy and l-carnitine supplementation, they experienced frequent myopathic attacks associated with respiratory infections and exercise. After the initiation of bezafibrate, their myopathic manifestations were markedly reduced, leading to an improvement in quality of life without any side effects. Our clinical findings indicate that bezafibrate combined with other treatments such as dietary therapy may be effective in improving myopathic manifestations in TFP deficiency.
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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.
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Leigh syndrome is a major phenotype of mitochondrial diseases in children. With new therapeutic options being proposed, assessing the mortality and clinical condition of Leigh syndrome patients is crucial for evaluating therapeutics. As data are scarce in Japan, we analysed the mortality rate and clinical condition of Japanese Leigh syndrome patients that we diagnosed since 2007. Data from 166 Japanese patients diagnosed with Leigh syndrome from 2007 to 2017 were reviewed. Patients' present status, method of ventilation and feeding, and degree of disability as of April 2018 was analysed. Overall, 124 (74.7%) were living, 40 (24.1%) were deceased, and 2 (1.2%) were lost to follow-up. Median age of living patients was 8 years (1-39 years). Median length of disease course was 91 months for living patients and 23.5 months for deceased patients. Nearly 90% of deaths occurred by age 6. Mortality rate of patients with onset before 6 months of age was significantly higher than that of onset after 6 months. All patients with neonatal onset were either deceased or bedridden. MT-ATP6 deficiency caused by m.8993T>G mutation and MT-ND5 deficiency induced a severe form of Leigh syndrome. Patients with NDUFAF6, ECHS1, and SURF1 deficiency had relatively mild symptoms and better survival. The impact of onset age on prognosis varied across the genetic diagnoses. The clinical condition of many patients was poor; however, few did not require mechanical ventilation or tube-feeding and were not physically dependent. Early disease onset and genetic diagnosis may have prognostic value.