Pharmacokinetics, safety, and tolerability of sodium phenylacetate and sodium benzoate in healthy Japanese volunteers: A phase I, single-center, open-label study.

TAK-123, a combination of sodium phenylacetate (NaPA) and sodium benzoate (NaBZ), is an intravenously administered drug developed for the treatment of acute hyperammonemia in infants, children, and adults with urea cycle enzyme deficiencies. The aim of the current study was to evaluate the pharmacokinetics, safety, and tolerability after intravenous infusion of TAK-123 in Japanese healthy adult volunteers. Ten volunteers received a 3.75 g/m2 loading dose of TAK-123 over a period of 1.5 h followed by a maintenance infusion of the same dose over 24 h. Phenylacetate (PA) and benzoate (BZ) and their respective metabolites, phenylacetylglutamine (PAG) and hippurate (HIP) were measured over a 24-h period using a high-performance liquid chromatography/tandem mass spectrometry method. Non-compartmental analysis was performed using WinNonlin® Professional. During the loading dose, plasma levels of both PA and BZ peaked at 1.5 h. Plasma PA levels plateaued and were maintained up to 6.5 h, whereas plasma BZ levels declined rapidly after switching to maintenance infusion. Urinary excretion ratios of PAG and HIP at 48 h after the administration were 99.3% and 104%, respectively, suggesting that almost all NaPA and NaBZ were metabolized and excreted into urine. Overall, TAK-123 was well-tolerated in healthy Japanese adults.

Newborn screening for Gaucher disease in Japan.

Gaucher disease (GD) is an autosomal recessive inborn metabolic disorder caused by a glucocerebrosidase (GCase) defect. GD is classified into three main types depending on accompanying neurological symptoms. Enzyme replacement therapy and substrate reduction therapy are limited in the treatment of neurological symptoms, and using genotype and GCase activity to discriminate between non-neuronopathic and neuronopathic GD may be challenging as the two sometimes phenotypically overlap. The number of patients exhibiting neurological symptoms in Japan is significantly higher than that in Europe and the United States, and newborn screening (NBS) is still not actively performed in Japan. Definitive determination of the actual frequency and proportion of the type of GD from the results of NBS remains inconclusive. We performed NBS for Fabry disease, Pompe disease, and GD, mainly in the Kyushu area in Japan. Herein, we discuss the results of NBS for GD, as well as, the insights gained from following the clinical course of patients diagnosed through NBS. A total of 155,442 newborns were screened using an enzyme activity assay using dried blood spots. We found four newborns showing lower GCase activity and were definitively diagnosed with GD by GBA gene analysis. The frequency of GD diagnosis through NBS was 1 in 77,720 when limited to the probands. This frequency is higher than that previously estimated in Japan. In the future, NBS for GD is expected to be performed in many regions of Japan and contribute to detecting more patients with GD. Early screening and diagnosis may have a very significant impact on the quality of life and potentially longevity in infants with GD.

Current status of newborn screening for Pompe disease in Japan.

BACKGROUND: Pompe disease is an autosomal recessive inherited metabolic disorder caused by a deficiency of the acid α-glucosidase (GAA). Pompe disease manifests as an accumulation of lysosomal glycogen in the skeletal and heart muscle. We conducted newborn screening (NBS) for Pompe disease in Japan from April 2013 to October 2020 to determine the feasibility and utility of NBS for Pompe disease. RESULTS: From the 296,759 newborns whose enzyme activity was measured, 107 of which underwent GAA analysis, we found one patient with infantile-onset Pompe disease (IOPD) and seven with potential late-onset Pompe disease (LOPD). We identified 34 pseudodeficient individuals and 65 carriers or potential carriers. The frequency of patients with IOPD was similar to that in the United States, but significantly lower than that in Taiwan. One patient with IOPD underwent early enzyme replacement therapy within a month after birth before presenting exacerbated manifestations, whereas those with potential LOPD showed no manifestations during the follow-up period of six years. CONCLUSIONS: The frequency of IOPD in Japan was similar to that in the United States, where NBS for Pompe disease is recommended. This indicates that NBS for Pompe disease may also be useful in Japan. Therefore, it should be used over a wider region in Japan.

Current status of surviving patients with arginase 1 deficiency in Japan.

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.

Guide for diagnosis and treatment of hyperphenylalaninemia.

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.

Detection of novel Fabry disease-associated pathogenic variants in Japanese patients by newborn and high-risk screening.

BACKGROUND: In Japan, newborn and high-risk screening for Fabry disease (FD), an inherited X-linked disorder caused by GLA mutations, using dried blood spots was initiated in 2006. In newborn screening, 599,711 newborns were screened by December 2018, and 57 newborns from 54 families with 26 FD-associated variants were detected. In high-risk screening, 18,235 individuals who had symptoms and/or a family history of FD were screened by March 2019, and 236 individuals from 143 families with 101 FD-associated variants were detected. Totally 3, 116 variants were detected; 41 of these were not registered in Fabry-database.org or ClinVar and 33 were definitely novel. Herein, we report the clinical outcomes and discuss the pathogenicity of the 41 variants. METHODS: We traced nine newborns and 46 individuals with the 33 novel variants, and nine newborns and 10 individuals with eight other variants not registered in the FD database, and analyzed the information on symptoms, treatments, and outcomes. RESULTS: Thirty-eight of the 46 individuals with the 33 novel variants showed symptoms and received enzyme-replacement therapy and/or chaperone treatment. CONCLUSION: Delayed diagnosis should be avoided in patients with FD. Our results will help clinicians diagnose FD and determine the appropriate treatment for patients with these variants.

Fabry disease screening in high-risk populations in Japan: a nationwide study.

BACKGROUND: Fabry disease (FD) is a X-linked inherited disorder caused by mutations in the GLA gene, which results in the deficiency of α-galactosidase A (α-Gal A). This leads to the progressive accumulation of metabolites, which can cause multisystemic dysfunction. A recent screening study among neonates reported an increase in the incidence of FD, and numerous FD patients remain undiagnosed or even misdiagnosed. Therefore, this study aimed to identify patients with FD by performing high-risk screening in 18,135 individuals, enrolled from October 2006 to March 2019, with renal, cardiac, or neurological manifestations from all prefectures in Japan. A total of 601 hospitals participated in this study. RESULTS: Low α-Gal A activity was detected in 846 individuals, with 224 of them diagnosed with FD by GLA sequencing. Cases with a family history of FD (n = 64) were also subjected to sequencing, without α-Gal A assay, as per individual request, and 12 of them were diagnosed with a variant of FD. A total of 236 patients with FD (97 males and 139 females) were identified from among 18,199 participants. A total of 101 GLA variants, including 26 novel variants, were detected in the 236 patients with FD from 143 families, with 39 amenable variants (39%) and 79 of the 236 patients (33%) suitable for migalastat treatment. CONCLUSIONS: From among 18,199 participants, 101 GLA variants, including 26 novel variants, were identified in the 236 patients with FD from 143 families. Migalastat was identified as a suitable treatment option in 33% of the patients with FD and 39% of the GLA variants were detected as amenable. Therefore, the simple screening protocol using dried blood spots that was performed in this study could be useful for early diagnosis and selection of appropriate treatments for FD in high-risk and underdiagnosed patients with various renal, cardiac, or neurological manifestations.

Effect of L-Carnitine on Amino Acid Metabolism in Elderly Patients Undergoing Regular Hemodialysis.

INTRODUCTION: Among patients regularly undergoing hemodialysis, hypocarnitinaemia often develops as a consequence of inadequate dietary intake, reduced synthesis in the body, and considerable losses during hemodialysis. OBJECTIVES: To evaluate the effects of L-carnitine supplementation on patients with end-stage kidney disease (ESKD) who underwent hemodialysis. METHODS: Thirty-one patients with ESKD, comprising 18 men and 13 women, with a median age of 72 (range 58-89) years, who underwent regular hemodialysis received treatment with L-carnitine for 1 year. The total and free carnitine, acylcarnitine, and amino acids (AA) levels before and after L-carnitine treatment were analyzed, and the blood biochemistry results and clinical profiles of the subjects were compared before and after treatment. RESULTS: The median (interquartile range [IQR]) serum total and free carnitine and acylcarnitine levels significantly increased from 34.5 (28.2-44.3), 20.9 (15.8-27.6), and 14.1 (11.2-17.6) µmol/L, respectively to 407.4 (371.6-493.5), 270.2 (228.3-316.0), and 155.0 (136.1-168.5) µmol/L, respectively, after treatment (all p < 0.001). The median (IQR) blood valine, tyrosine, phenylalanine, and citrulline levels increased from 0.94 (0.80-1.09), 0.45 (0.39-0.55), 0.61 (0.56-0.79), and 1.04 (0.79-1.26) mg/dL, respectively to 1.24 (1.13-1.54), 0.76 (0.62-0.85), 0.90 (0.70-1.04), and 1.22 (0.92-1.39) mg/dL, respectively, following L-carnitine treatment (p < 0.001, p < 0.001, p = 0.002, and p = 0.030, respectively); however, the median (IQR) blood arginine level decreased from 0.20 (0.13-0.24) to 0.09 (0.06-0.14) mg/dL after treatment (p < 0.001). The median (IQR) percentage fractional shortening (41.5 vs. 41.9%; p = 0.012) and left ventricular ejection fraction (65.2 vs. 67.3%; p = 0.036) increased significantly following treatment. CONCLUSIONS: L-Carnitine increased the blood acylcarnitine levels, enhanced fatty acid metabolism, and affected AAs metabolism; this may be beneficial for energy production within the cardiac and skeletal muscles.

Newborn screening for Fabry disease in the western region of Japan.

Newborn screening (NBS) for Fabry disease (FD) is the best way to detect FD early prior to presentation of symptoms and is currently implemented in Taiwan and several states such as Illinois, Missouri, and Tennessee in the United States of America. In this report, we provide data from the first large-scale NBS program for FD in Japan. From August 2006 to December 2018, 599,711 newborns were screened; 26 variants, including 15 pathogenic variants and 11 variants of uncertain significance (VOUS; including eight novel variants), were detected in 57 newborns. Twenty-six male and 11 female newborns with pathogenic variants were diagnosed as hemizygous and heterozygous patients, respectively. Thirteen male and seven female newborns with VOUS were diagnosed as potential hemizygous and potential heterozygous patients, respectively. At the most recent follow up, three of 26 hemizygous patients had manifested symptoms and were receiving enzyme replacement therapy. The other patients were being followed up by clinicians. The frequency of FD (pathogenic variants + VOUS) in this study was estimated to be 1:7683, whereas that of patients with pathogenic variants was 1:11,854. In the future, the NBS system for FD may contribute to the detection of newborns not presenting manifestations related to FD and adults who have or have not developed manifestations related to FD.

Rhabdomyolysis in organic acidemia patients manifesting with metabolic decompensation.

Several metabolic disorders are related to rhabdomyolysis, but their association with methylmalonic acidemia (MMA) and propionic acidemia (PA) is unclear. Eleven patients with MMA and four patients with PA were treated and/or followed up in Kumamoto University Hospital between January 2009 and December 2018. Three patients with MMA and one patient with PA developed rhabdomyolysis at 1-2 weeks after onset of metabolic crisis. Cases 1 and 4 initially developed rhabdomyolysis after withdrawal from continuous hemodiafiltration (CHDF), and cases 2 and 3 developed rhabdomyolysis at the time of onset and had recurrent rhabdomyolysis during the recovery phase after withdrawal from CHDF. Mitochondrial dysfunction is associated with rhabdomyolysis. The rhabdomyolysis in patients with MMA and PA may have been attributed to a defect in energy production because of a secondary mitochondrial disorder. Therefore, physicians should closely follow patients with MMA and PA, especially after withdrawal of hemodialysis therapy, and provide supportive care for their mitochondrial function.

High-risk screening for Anderson-Fabry disease in patients with cardiac, renal, or neurological manifestations.

Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by abnormalities in the α-galactosidase (Gal) A gene (GLA; MIM:300644). The reduced activity of the lysosomal enzyme, α-galactosidase A (α-Gal A) leads to classic early manifestations and vascular disease of the heart, kidneys, and brain. As a high-risk screening for symptomatic AFD using an enzymatic assay on dried blood spot samples, we enrolled 2325 individuals (803 females and 1522 males; median age: 66 years) with cardiac, renal, or neurological manifestations that met at least one of the following criteria: (a) family history of early-onset cardiovascular diseases; (b) typical classic manifestations, such as acroparesthesias, clustered angiokeratoma, cornea verticillata, and hypo-anhidrosis; (c) proteinuria; (d) receiving dialysis; (e) left ventricular hypertrophy on electrocardiography or echocardiography; or (f) history of stroke. Ninety-two patients displayed low α-Gal A activity. Four males and two females had different pathogenic GLA mutations (0.26%) including a novel mutation c.908-928del21. Four males (0.17%) harbored the GLA c.196G>C (p.E66Q) variant. This simple screening protocol using dried blood spot samples is useful for early diagnosis of AFD in high-risk and underdiagnosed patients suffering from various cardiac, renal, or neurological manifestations.

Urea cycle disorders-update.

The urea cycle is a metabolic pathway for the disposal of excess nitrogen, which arises primarily as ammonia. Nitrogen is essential for growth and life-maintenance, but excessive ammonia leads to life-threatening conditions. The urea cycle disorders (UCDs) comprise diseases presenting with hyperammonemia that arise in either the neonatal period (about 50% of cases) or later. Congenital defects of the enzymes or transporters of the urea cycle cause the disease. This cycle utilizes five enzymes, two of which, carbamoylphosphate synthetase 1 and ornithine transcarbamylase are present in the mitochondrial matrix, whereas the others (argininosuccinate synthetase, argininosuccinate lyase and arginase 1) are present in the cytoplasm. In addition, N-acetylglutamate synthase and at least two transporter proteins are essential to urea cycle function. Severity and age of onset depend on residual enzyme or transporter function and are related to the respective gene mutations. The strategy for therapy is to prevent the irreversible toxicity of high-ammonia exposure to the brain. The pathogenesis and natural course are poorly understood because of the rarity of the disease, so an international registry system and novel clinical trials are much needed. We review here the current concepts of the pathogenesis, diagnostics, including genetics and treatment of UCDs.

Newborn screening for Pompe disease in Japan: report and literature review of mutations in the GAA gene in Japanese and Asian patients.

A newborn screening program for Pompe disease using dried blood spots (DBSs) was initiated in Japan. Here, we summarized this screening program and described the results of the GAA gene analysis. From April 2013 to November 2016, 103,204 newborns were screened; 71 had low acid alpha-glucosidase (AαGlu) activity. GAA sequencing showed that 32 (45.1%) and 37 (52.1%) of these newborns were homozygous and heterozygous for pseudodeficiency alleles c.[1726G>A; 2965G>A], respectively. Moreover, 24 of 32 newborns with homozygous c.[1726G>A; 2965G>A] alleles had no mutations, and the other eight had one mutation each. Thirty-five of 37 newborns with heterozygous c.[1726G>A; 2965G>A] alleles had one mutation, and the other two had two mutations each. Only one newborn who had two mutations did not harbor c.[1726G>A; 2965G>A] alleles. Thus, it was difficult to distinguish newborns with c.[1726G>A; 2965G>A] alleles from newborns with pre-symptomatic Pompe disease using AαGlu assays in DBSs or fibroblasts; GAA gene sequencing was necessary. Seventy-one newborns had 50 variants, including 21 mutations or predictably pathogenic variants, and 29 polymorphisms or predictably non-pathogenic variants. Four of 21 mutations or predictably pathogenic variants and four of 29 polymorphisms or predictably non-pathogenic variants were novel. No infantile-onset Pompe disease was detected, and three newborns were diagnosed with potential late-onset Pompe disease. In the literature, 156 variants have been reported for 296 patients from 277 families in 41 articles from Japan, Korea, Taiwan, and China. Our results provide insights into GAA gene mutation profiles and the relationship between GAA and Pompe disease in Asian populations.

Unexpectedly High Prevalence of Coronary Spastic Angina in Patients With Anderson-Fabry Disease.

BACKGROUND: Although we and others have reported cases of patients with Anderson-Fabry disease (AFD) complicated by coronary spastic angina (CSA), the prevalence of CSA in these patients remains unknown. Methods and Results: We performed the acetylcholine-induced provocation test, according to the Japanese guidelines for the diagnosis and treatment of patients with CSA, in 9 consecutive patients having 5 independent AFD pedigrees. Coronary spasms were provoked in conjunction with symptoms and ECG ischemic changes in 8 of 9 (89%) patients with AFD. CONCLUSIONS: We found an unexpectedly high prevalence of CSA in patients with AFD.

Early liver transplantation in neonatal-onset and moderate urea cycle disorders may lead to normal neurodevelopment.

Urea cycle disorders (UCDs) are inherited metabolic diseases that lead to hyperammonemia. Neurodevelopmental outcomes of patients with UCDs depend on the maximum ammonia concentration (MAC) in the blood during onset. MAC ≥360 µM is a marker of poor neurodevelopmental outcomes. We investigated the neurodevelopmental outcomes and MAC at onset for 177 patients with UCDs in Japan (median age, 8 years and 2 months; range, 10 days-72 years), including 57 patients with male ornithine transcarbamylase (OTCD), 59 patients with female OTCD, 23 patients with carbamoyl-phosphate synthetase 1 deficiency (CPSD), 28 patients with arginosuccinate synthetase deficiency, 9 patients with arginosuccinate lyase deficiency (ALD), and 1 patient with arginase 1 deficiency. Neurodevelopmental outcomes of patients with CPSD and ALD were poor because most had neonatal onset with blood MAC ≥300 µM at onset. Although OTCD, particularly female late-onset OTCD, has good neurodevelopmental outcomes among those with UCDs, it is not necessarily a mild disease with good long-term outcomes. Patients with severe UCDs and MAC ≥300 µM at onset should undergo liver transplantation (LT). Moreover, this study suggested that if the onset of UCD began during the neonatal period, then even UCD patients with MAC <300 µM at onset should undergo LT to protect the brain.

LSD1 mediates metabolic reprogramming by glucocorticoids during myogenic differentiation.

The metabolic properties of cells are formed under the influence of environmental factors such as nutrients and hormones. Although such a metabolic program is likely initiated through epigenetic mechanisms, the direct links between metabolic cues and activities of chromatin modifiers remain largely unknown. In this study, we show that lysine-specific demethylase-1 (LSD1) controls the metabolic program in myogenic differentiation, under the action of catabolic hormone, glucocorticoids. By using transcriptomic and epigenomic approaches, we revealed that LSD1 bound to oxidative metabolism and slow-twitch myosin genes, and repressed their expression. Consistent with this, loss of LSD1 activity during differentiation enhanced the oxidative capacity of myotubes. By testing the effects of various hormones, we found that LSD1 levels were decreased by treatment with the glucocorticoid dexamethasone (Dex) in cultured myoblasts and in skeletal muscle from mice. Mechanistically, glucocorticoid signaling induced expression of a ubiquitin E3 ligase, JADE-2, which was responsible for proteasomal degradation of LSD1. Consequently, in differentiating myoblasts, chemical inhibition of LSD1, in combination with Dex treatment, synergistically de-repressed oxidative metabolism genes, concomitant with increased histone H3 lysine 4 methylation at these loci. These findings demonstrated that LSD1 serves as an epigenetic regulator linking glucocorticoid action to metabolic programming during myogenic differentiation.

High-risk screening for Gaucher disease in patients with neurological symptoms.

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by the deficiency of glucocerebrosidase enzyme activity. Clinical phenotypes of GD are categorized into three groups: (i) non-neuronopathic GD (type 1), (ii) acute neuronopathic GD (type 2) and (iii) subacute neuronopathic GD (type 3). The high-risk screening of neuronopathic GD has been performed using an enzymatic assay on the dried blood spot (DBS) samples. We enrolled a total of 102 individuals (47 females, 55 males; 0-57 years old; median age 10.5 years) with various neurological symptoms. We detected two patients with very low enzyme activity and they were diagnosed with the disease by using glucocerebrosidase gene analysis. Patient 1 was found to be compound heterozygous for the p.R159W/p.R170C locus and patient 2 was found to harbor two mutations at the IVS7+1G>T (c.999+1G>T) and p.L483P sites. This simple screening protocol using DBS samples is useful for early diagnosis of GD in high-risk and underdiagnosed patients suffering from various neurological symptoms.

A Significant Difference in the Blood Carnitine Values Obtained by the Enzymatic Cycling and Tandem Mass Spectrometry Methods.

BACKGROUND: There are no reports in the literature of blood samples obtained from the same individual being subjected to analysis at the same time using the enzymatic cycling (EC) method along with electrospray tandem mass spectrometry (ESI/MS/MS) before and after carnitine treatment. METHODS: Blood samples from 29 patients (median age: 73 years old, age range: 41 - 89 years) receiving regular hemodialysis for chronic renal failure before and after carnitine treatment for 3 months were measured by the EC method, and using a dried blood spot (DBS) and ESI/MS/MS. RESULTS: Before the carnitine treatment, the rate of increase or decrease in the free and acyl-carnitine levels of the DBS using the ESI/MS/MS method to those measured by the EC methods was a median of -28.6% (-36.0 to -14.1%) and -20.8% (-30.0 to 1.5%), respectively. After carnitine treatment, the rate of increase or decrease in the free and acyl-carnitine levels of the DBS with the ESI/MS/MS method compared to the EC method was a median of 52.0% (28.4 to 66.7%) and -31.9% (-47.2 to -21.1%), respectively. CONCLUSIONS: There were significant differences in the blood carnitine values using the ESI/MS/MS and EC methods. Caution should be exercised when evaluating DBS values measured by the ESI/MS/MS method.

Tyrosinemia Type I in Japan: A Report of Five Cases.

Tyrosinemia type I in Japan was reported for the first time in 1957 by Sakai et al. (Jikei Med J 2:1-10, 1957) and Kitagawa et al. (Proc Jpn Acad Ser B 88:192-200, 1957). Five cases of patients with tyrosinemia type I were reported to be definitively diagnosed in Japan. The first case was reported by Sakai et al. and Kitagawa et al. To the best of our knowledge, this was the first definite report in the world. The second and third cases were those of a brother and a sister who underwent liver transplantation and who were the children of a Japanese-descent migrant worker; the fourth case was that of a girl who underwent liver transplantation after 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) treatment, which was reported by Hata et al.; and the fifth case was that of a patient who was administered NTBC, which was reported by Ito et al. These were of the subacute type, wherein residual activity was considerably present. When combined therapy with a low phenylalanine and tyrosine diet and NTBC administration is started after early diagnosis, patients can survive without liver transplantation. Development of liver cancer is not found in the cases in Japan, but performing liver transplantation without delay is necessary when liver cancer is found.

Clinical manifestations in two patients with pyruvate dehydrogenase deficiency and long-term survival.

Pyruvate dehydrogenase E1-alpha deficiency (PDHAD) results in lactic acidosis and hyperpyruvatemia. Two patients with PDHAD, a man with a p.R263Q mutation, and a girl with a p.C145del mutation in PDHE1α, presented with lactic acidosis with neurological disorder. These patients were able to survive for a long period under careful nursing care. Herein, we discuss the factors contributing to their relatively stable clinical course, albeit with intellectual disability.