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Dried blood spot succinylacetone (SA) is often used as a biomarker for newborn screening (NBS) for tyrosinemia type 1 (TT1). However, false‐positive SA results are often observed. Elevated SA may also be due to maleylacetoacetate isomerase deficiency (MAAI‐D), which appears to be clinically insignificant. This study investigated whether urine organic acid (uOA) and quantitative urine maleic acid (Q‐uMA) analyses can distinguish between TT1 and MAAI‐D. We reevaluated/measured uOA (GC–MS) and/or Q‐uMA (LC–MS/MS) in available urine samples of nine referred newborns (2 TT1, 7 false‐positive), eight genetically confirmed MAAI‐D children, and 66 controls. Maleic acid was elevated in uOA of 5/7 false‐positive newborns and in the three available samples of confirmed MAAI‐D children, but not in TT1 patients. Q‐uMA ranged from not detectable to 1.16 mmol/mol creatinine in controls (n = 66) and from 0.95 to 192.06 mmol/mol creatinine in false‐positive newborns and MAAI‐D children (n = 10). MAAI‐D was genetically confirmed in 4/7 false‐positive newborns, all with elevated Q‐uMA, and rejected in the two newborns with normal Q‐uMA. No sample was available for genetic analysis of the last false‐positive infant with elevated Q‐uMA. Our study shows that MAAI‐D is a recognizable cause of false‐positive TT1 NBS results. Elevated urine maleic acid excretion seems highly effective in discriminating MAAI‐D from TT1. [ABSTRACT FROM AUTHOR]

Tyrosinemia type 1 (TT1) is caused by fumarylacetoacetate hydrolase activity deficiency, resulting in tissue accumulation of upstream metabolites, including succinylacetone (SA), the pathognomonic compound of this disease. Since the pathogenesis of liver and kidney damage observed in the TT1-affected patients is practically unknown, this study assessed the effects of SA on important biomarkers of redox homeostasis in the liver and kidney of adolescent rats, as well as in hepatic (HepG2) and renal (HEK-293) cultured cells. SA significantly increased nitrate and nitrite levels and decreased the concentrations of reduced glutathione (GSH) in the liver and kidney, indicating induction of reactive nitrogen species (RNS) generation and disruption of antioxidant defenses. Additionally, SA decreased the GSH levels and the activities of glutathione peroxidase, glutathione S-transferase, glutathione reductase, and superoxide dismutase in hepatic and renal cells. Noteworthy, melatonin prevented the SA-induced increase of nitrate and nitrite levels in the liver. Therefore, SA-induced increase of RNS generation and impairment of enzymatic and nonenzymatic antioxidant defenses may contribute to hepatopathy and renal disease in TT1., (© 2024 John Wiley & Sons Ltd.)

The article presents a case study of a newborn with hereditary tyrosinemia type 1 (HT1) who, despite negative urinary succinylacetone (SA) levels, experienced liver failure and died. Topics discussed include the challenges of diagnosing HT1 in Japan, where mass screening does not include blood SA, the potential decrease in SA levels as liver failure progresses, and the importance of genetic testing for both proband and prenatal diagnosis in affected families.

Summary: Fumarylacetoacetate hydrolase (FAH) catalyses the final step of the tyrosine degradation pathway, which is essential to animals but was of unknown importance in plants until we found that mutation of Short‐day Sensitive Cell Death1 (SSCD1), encoding Arabidopsis FAH, results in cell death under short‐day conditions. The sscd1 mutant accumulates succinylacetone (SUAC), an abnormal metabolite caused by loss of FAH. Succinylacetone is an inhibitor of δ‐aminolevulinic acid (ALA) dehydratase (ALAD), which is involved in chlorophyll (Chl) biosynthesis. In this study, we investigated whether sscd1 cell death is mediated by Chl biosynthesis and found that ALAD activity is repressed in sscd1 and that protochlorophyllide (Pchlide), an intermediate of Chl biosynthesis, accumulates at lower levels in etiolated sscd1 seedlings. However, it was interesting that Pchlide in sscd1 might increase after transfer from light to dark and that HEMA1 and CHLH are upregulated in the light–dark transition before Pchlide levels increased. Upon re‐illumination after Pchlide levels had increased, reactive oxygen species marker genes, including singlet oxygen‐induced genes, are upregulated, and the sscd1 cell death phenotype appears. In addition, Arabidopsis WT seedlings treated with SUAC mimic sscd1 in decline of ALAD activity and accumulation of Pchlide as well as cell death. These results demonstrate that increase in Pchlide causes cell death in sscd1 upon re‐illumination and suggest that a decline in the Pchlide pool due to inhibition of ALAD activity by SUAC impairs the repression of ALA synthesis from the light–dark transition by feedback control, resulting in activation of the Chl biosynthesis pathway and accumulation of Pchlide in the dark. Significance Statement: The role of the tyrosine degradation pathway in plants is not well understood. This study revealed a relation between the Tyr degradation pathway and the Chl biosynthetic pathway in mediating sscd1 cell death, which provides insight into the biological function of the Tyr degradation pathway in plants and the regulation of the Chl biosynthesis pathway and cell death. [ABSTRACT FROM AUTHOR]

Introduction In hereditary tyrosinemia type 1 (HT1) patients, the dose of NTBC that leads to the absence of toxic metabolites such as succinylacetone (SA) is still unknown. Therefore, the aims of this study were to investigate the variation and concentrations of 2-(2-nitro-4-trifluormethyl-benzyl)- 1,3-cyclohexanedione (NTBC) during the day in relation to the detection of SA, while comparing different dosing regimens. Methods All patients were treated with NTBC (mean 1.08 ± 0.34 mg/kg/day) and a low phenylalanine-tyrosine diet. Thirteen patients received a single dose of NTBC and five patients twice daily. Home bloodspots were collected four times daily for three consecutive days measuring NTBC and SA concentrations. Statistical analyses were performed by using mixed model analyses and generalized linear mixed model analyses to study variation and differences in NTBC concentrations and the correlation with SA, respectively. Results NTBC concentrations varied significantly during the day especially if NTBC was taken at breakfast only (p = 0.026), although no significant difference in NTBC concentrations between different dosing regimens could be found (p = 0.289). Momentary NTBC concentrations were negatively correlated with SA (p < 0.001). Quantitatively detectable SAwas only found in subjects with once daily administration of NTBC and associated with momentary NTBC concentrations <44.3μmol/l. Discussion NTBC could be less stable than previously considered, thus dosing NTBC once daily and lower concentrations may be less adequate. Further research including more data is necessary to establish the optimal dosing of NTBC. [ABSTRACT FROM AUTHOR]

Hereditary tyrosinemia is an autosomal recessive inherited disease that manifests as three types (types I- III). We conducted a nationwide survey of this disease in Japan, and here review the results in relation to prevalence, clinical characteristics, and treatment and diagnosis. A definitive diagnosis of tyrosinemia type I is difficult to obtain based only on blood tyrosine level. Detection of succinylacetone using dried blood spots or urinary organic acid analysis, however, is useful for diagnosis. In tyrosinemia type I, dietary therapy and nitisinone ( Orfandin®) are effective. Prognosis is greatly affected by the complications of liver cancer and hypophosphatemic rickets; even patients that are treated early with nitisinone may develop liver cancer. Long-term survival can be expected in type I if nitisinone therapy is effective. Prognosis in types II and III is relatively good. [ABSTRACT FROM AUTHOR]

We report the case of a 17-year-old girl with Tyrosinemia type 1a who carried a planned pregnancy to term while being under 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC, nitisinone) treatment and a tyrosine- and phenylalanine-restricted diet. She was on treatment since 2 months of age with poor metabolic control prior to her pregnancy (tyrosine 838 ± 106 umol/L). NTBC and a low tyrosine and phenylalanine diet were continued during her pregnancy. She unfortunately suffered from urinary tract infection and anemia during her pregnancy, with median plasma tyrosine and phenylalanine levels of 613 ± 106 umol/L (200-400 umol/L) and 40.2 ± 8 umol/L (35-90 umol/L), respectively. After 40 weeks of gestation, the patient gave birth to a healthy boy, with no adverse effects related to the use of NTBC. The newborn presented with a transitory elevation of plasma tyrosine levels and normal phenylalanine, methionine, and succinylacetone levels. By 12 months of age, the child was determined to have normal psychomotor development. At 20 months old, he was diagnosed with a mild developmental delay; however, global cognitive evaluation with the Wechsler Intelligence Scale for Children (WISC) test at 5 years old showed normal performance. Here, we discuss one of the few reported cases of nitisinone treatment during pregnancy and demonstrate a lack of teratogenicity and long-term cognitive disabilities., (© 2020 Wiley Periodicals LLC.)

The IGF1R signaling is important in the malignant progression of cancer. However, overexpression of IGF1R has not been properly assessed in HCC. Here, we revealed that GSTZ1‐1, the enzyme in phenylalanine/tyrosine catabolism, is downregulated in HCC, and its expression was negatively correlated with IGF1R. Mechanistically, GSTZ1‐1 deficiency led to succinylacetone accumulation, alkylation modification of KEAP1, and NRF2 activation, thus promoting IGF1R transcription by recruiting SP1 to its promoter. Moreover, inhibition of IGF1R or NRF2 significantly inhibited tumor‐promoting effects of GSTZ1 knockout in vivo. These findings establish succinylacetone as an oncometabolite, and GSTZ1‐1 as an important tumor suppressor by inhibiting NRF2/IGF1R axis in HCC. Targeting NRF2 or IGF1R may be a promising treatment approach for this subset HCC. Synopsis: The phenylalanine/tyrosine catabolism enzyme glutathione S‐transferase zeta 1 (GSTZ1‐1) is downregulated in hepatocellular carcinoma (HCC), but its mechanistic involvement remains unclear. Here, GSTZ1‐1 is shown to suppress tumor growth via controlling levels of the metabolite succinylacetone, and dependent KEAP1/NRF2/IGF‐1R signaling. GSTZ1‐1 expression is decreased in HCC and correlates with poor prognosis.GSTZ1‐1 suppresses hepatoma cell proliferation in vitro and in vivo.Depletion of GSTZ1‐1 results in accumulation of succinylacetone.Increased succinylacetone stabilizes NRF2 by alkylating cysteine residues of KEAP1.Gstz1−/− mice show increased HCC, rescued by targeting the NRF2‐IGF1R anti‐apoptotic pathway. [ABSTRACT FROM AUTHOR]