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Anemia is the most prevalent nutrition-related disorder worldwide. Zinc is an essential trace element for various biological processes in the body, and zinc deficiency has been associated with anemia in humans. However, the molecular mechanisms by which zinc availability alters red blood cell development remain uncertain. The present study identifies the essentiality of zinc during erythroid development, particularly for normal heme biosynthesis. G1E-ER4 mouse cells were used as an in vitro model of terminal erythroid differentiation, which featured elevated cellular zinc content by development. Restriction of zinc import compromised the rate of heme and α-globin production and, thus, the hemoglobinization of the erythroid progenitors. Heme is synthesized by the incorporation of iron into protoporphyrin. The lower heme production under zinc restriction was not due to changes in iron but was attributable to less porphyrin synthesis. The requirement of adequate zinc for erythroid heme metabolism was confirmed in another erythropoietic cell model, MEL-DS19. Additionally, we found that a conventional marker of iron deficiency anemia, the ZnPP-to-heme ratio, responded to zinc restriction differently from iron deficiency. Collectively, our findings define zinc as an essential nutrient integral to erythroid heme biosynthesis and, thus, a potential therapeutic target for treating anemia and other erythrocyte-related disorders.

The management of tyrosinaemia type 1 (HT1, fumarylacetoacetase deficiency) has been revolutionised by the introduction of nitisinone but dietary treatment remains essential and the management is not easy. In this review detailed recommendations for the management are made based on expert opinion, published case reports and investigational studies as the evidence base is limited and there are no prospective controlled studies. The added value of this paper is that it summarises in detail current clinical knowledge about HT1 and makes recommendations for the management.

The third known case in the country of Tyrosinemia type 1 is presented, a 10-month-old male infant who was referred to the emergency room due to hepatomegaly, compromised liver function, neurological deterioration, and abnormal urinary amino acids findings. Given the persistence of hepatic deterioration and focal hepatic lesions, a high clinical suspicion of Tyrosinemia type 1 was considered, and targeted treatment with Nitisinone and a restrictive diet was initiated, resulting in an appropriate clinical and tests response. However, there was an abrupt discontinuation of the medication without any medical indication, added to the fact that elevated succinylacetone levels were later reviewed, the main diagnosis was confirmed. The medication was continued, but the patient experienced adverse events related to it, requiring multiple dose adjustments provided by the medical team. Tyrosinemia type I is a rare disease and therefore difficult to diagnose, requiring extensive knowledge for timely and accurate treatment. Hence, the importance of acknowledging the management of these adverse events is crucial. The aim of this article is to present a rare clinical case and propose a desensitization protocol for Nitisinone for those cases that present adverse reactions to the medication.

Undiagnosed and untreated tyrosinemia type 1 (TT1) individuals carry a significant risk for developing liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Elevated succinylacetone (SA) is pathognomonic for TT1 and therefore often used as marker for TT1 newborn screening (NBS). While SA was long considered to be elevated in every TT1 patient, here we present a recent false-negative SA TT1 screen. A nine-year-old boy presented with HCC in a cirrhotic liver. Additional tests for the underlying cause unexpectedly revealed TT1. Nine years prior, the patient was screened for TT1 via SA NBS with a negative result: SA 1.08 µmol/L, NBS cut-off 1.20 µmol/L. To our knowledge, this report is the first to describe a false-negative result from the TT1 NBS using SA. False-negative TT1 NBS results may be caused by milder TT1 variants with lower SA excretion. Such patients are more likely to be missed in NBS programs and can be asymptomatic for years. Based on our case, we advise TT1 to be considered in patients with otherwise unexplained liver pathology, including fibrosis, cirrhosis and HCC, despite a previous negative TT1 NBS status. Moreover, because the NBS SA concentration of this patient fell below the Dutch cut-off value (1.20 µmol/L at that time), as well as below the range of cut-off values used in other countries (1.29–10 µmol/L), it is likely that false-negative screening results for TT1 may also be occurring internationally. This underscores the need to re-evaluate TT1 SA NBS programs.

Background Hepatorenal tyrosinaemia (Tyr 1) is a rare inborn error of tyrosine metabolism. Without treatment, patients are at high risk of developing acute liver failure, renal dysfunction and in the long run hepatocellular carcinoma. The aim of our study was to collect cross-sectional data. Methods Via questionnaires we collected retrospective data of 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel) about diagnosis, treatment, monitoring and outcome. In a subsequent consensus workshop, we discussed data and clinical implications. Results Early treatment by NTBC accompanied by diet is essential to prevent serious complications such as liver failure, hepatocellular carcinoma and renal disease. As patients may remain initially asymptomatic or develop uncharacteristic clinical symptoms in the first months of life newborn mass screening using succinylacetone (SA) as a screening parameter in dried blood is mandatory for early diagnosis. NTBC-treatment has to be combined with natural protein restriction supplemented with essential amino acids. NTBC dosage should be reduced to the minimal dose allowing metabolic control, once daily dosing may be an option in older children and adults in order to increase compliance. Metabolic control is judged by SA (below detection limit) in dried blood or urine, plasma tyrosine (<400 μM) and NTBC-levels in the therapeutic range (20–40 μM). Side effects of NTBC are mild and often transient. Indications for liver transplantation are hepatocellular carcinoma or failure to respond to NTBC. Follow-up procedures should include liver and kidney function tests, tumor markers and imaging, ophthalmological examination, blood count, psychomotor and intelligence testing as well as therapeutic monitoring (SA, tyrosine, NTBC in blood). Conclusion Based on the data from 21 centres treating 168 patients we were able to characterize current practice and clinical experience in Tyr 1. This information could form the basis for clinical practice recommendations, however further prospective data are required to underpin some of the recommendations.

Background Introduction of nitisinone and newborn screening (NBS) have transformed the treatment of type 1 tyrosinemia, but the effects of these changes on the long-term outcomes remain obscure. Also, the predictors for later complications, the significance of drug levels and the normalization of laboratory and imaging findings are poorly known. We investigated these issues in a nationwide study. Results Type 1 tyrosinemia was diagnosed in 22 children in 1978–2019 in Finland. Incidence was 1/90,102, with a significant enrichment in South Ostrobothnia (1/9990). Median age at diagnosis was 5 (range 0.5–36) months, 55% were girls and 13 had homozygotic Trp262X mutation. Four patients were detected through screening and 18 clinically, their main findings being liver failure (50% vs. 100%, respectively, p = 0.026), ascites (0% vs. 53%, p = 0.104), renal tubulopathy (0% vs. 65%, p = 0.035), rickets (25% vs. 65%, p = 0.272), growth failure (0% vs. 66%, p = 0.029), thrombocytopenia (25% vs. 88%, p = 0.028) and anaemia (0% vs. 47%, p = 0.131). One patient was treated with diet, seven with transplantation and 14 with nitisinone. Three late-diagnosed (6–33 months) nitisinone treated patients needed transplantation later. Kidney dysfunction (86% vs. 7%, p = 0.001), hypertension (57% vs. 7%, p = 0.025) and osteopenia/osteoporosis (71% vs. 14%, p = 0.017) were more frequent in transplanted than nitisinone-treated patients. Blood/serum alpha-fetoprotein decreased rapidly on nitisinone in all but one patient, who later developed intrahepatic hepatocellular carcinoma. Liver values normalized in 31 months and other laboratory values except thrombocytopenia within 18 months. Imaging findings normalized in 3–56 months excluding five patients with liver or splenic abnormalities. Low mean nitisinone concentration was associated with higher risk of severe complications (r = 0.758, p = 0.003) despite undetectable urine succinylacetone. Conclusions Prognosis of type 1 tyrosinemia has improved in the era of nitisinone, and NBS seems to provide further benefits. Nevertheless, the long-term risk for complications remains, particularly in the case of late diagnosis and/or insufficient nitisinone levels.

Introduction: Elevated succinylacetone (SA) is the hallmark of tyrosinemia type 1, which requires immediate treatment. Mild SA elevation has also been recently reported in maleylacetoacetate isomerase deficiency (MAAID). Methods: We report on two cases of MAAID, review clinical features of MAAID and discuss its management. Results: Both cases displayed elevated SA and normal Tyrosine levels at newborn screening. Case 1 showed intermittent SA elevation; Nitisinone and dietary treatment were started, then discontinued after the identification of two variants in the GSTZ1 gene and the definitive diagnosis of MAAID. Case 2, showing no SA elevation at the confirmatory tests and two variants in the GSTZ1 gene, did not start treatment. mRNA analysis confirmed the pathogenicity of the c.68-12G>A variant, found in both patients. Discussion: MAAID should be considered in newborns showing elevated SA and no variants in the FAH gene. Our study reports for the first time the course of SA in a patient affected by MAAID. Furthermore, it expands the molecular epidemiology of this rare disease, also investigating the pathogenicity of a novel splicing mutation. Although our data argue against medical treatment in MAAID, longer follow-up data are warranted.

Newborn screening in England is a national program with laboratories adhering to common screening algorithms. Until recently, screening for inherited metabolic disorders was provided by ten laboratories using laboratory-developed tests (LDTs) and three using commercial assays: harmonization of results proved challenging. Introduction of hereditary tyrosinemia type 1 screening meant LDTs required modification to include the measurement of succinylacetone, and subsequent re-validation. This provided an opportunity to implement a single commercial reagent kit in all laboratories. It was anticipated that this would improve analytical performance and harmonization. This study aimed to determine whether these goals were achieved. Verification across the 13 laboratories revealed that the commercial kit reduced inter-laboratory variation for all analytes demonstrating improved harmonization. However, this was achieved by applying instrument-specific correction factors to all analytes, the magnitude of which were significant, indicating a lack of standardization. Performance of succinylacetone was limited by instrument-dependent background interference from the methionine stable isotope label, underscoring the need to establish evidence-based screening cut-off values (COV) rather than adopting published thresholds. This study emphasizes the need for traceable reference materials to improve laboratory quality and the value of screening outcome data.

Medical therapy for hereditary hepatorenal tyrosinemia (hereditary tyrosinemia type 1, HT-1) with nitisinone was discovered incidentally, and is a by-product of agrochemistry. It blocks the catabolic pathway of tyrosine, thereby leading to a reduction in the accumulation of toxic metabolites in HT-1. It has to be combined with a low-protein diet supplemented with amino acid mixtures devoid of tyrosine and phenylalanine. This treatment option has completely changed the clinical course of patients suffering from HT-1 who used to die in the first few months to years of life from liver failure, renal dysfunction, and/or hepatocellular carcinoma (HCC). It is essential to start nitisinone therapy early in life to avoid sequelae; beginning treatment in the newborn period is ideal. As initial clinical symptoms of HT-1 are often atypical and because there is a clinically latent phase during the first few months of life in many patients, newborn screening is required to secure early diagnosis. Succinylacetone in blood is a reliable screening parameter whereas tyrosine is neither specific nor sensitive. Especially HCC, but also liver and kidney dysfunction, rickets, and neurological crises can be prevented in most patients if nitisinone therapy is started in the newborn period. It is essential to adhere to a low-protein diet to avoid tyrosine toxicity. Reversible eye symptoms may occur as a side-effect of nitisinone, but other side effects are rare. Neurocognitive development is impaired in some patients, and the reason for this is unclear. Metabolic monitoring includes measurement of tyrosine, succinylacetone, and nitisinone concentrations in blood.

Tyrosinemia type 1 (HT1), due to deficient activity of fumarylacetoacetate hydrolase, causes accumulation of succinylacetone (SA). SA concentrations in urine and plasma of untreated HT1 patients are typically several thousand‐fold higher than normal, hence are readily recognized by traditional diagnostic methods in most cases. However, quantitation of SA in the nanomolar range is important for monitoring patients treated with nitisinone, for identifying attenuated or atypical forms of HT1, and for confirmation or refutation of the diagnosis of HT1 following a positive newborn screen. Our laboratory, a reference centre for diagnosis and monitoring of HT1, previously assayed SA by gas chromatography–mass spectrometry (GC–MS). Three years ago, we upgraded this method by transferring it to a new triple quadrupole technology (GC–MS/MS). A stable isotope dilution process is used, with sample treatment consisting of an oximation step followed by a single liquid–liquid extraction then trimethylsilyl derivatization. Quantitation is based on intensities of the ion transitions m/z 620 → 181 for SA and 625 → 186 for the internal standard. Method validation demonstrated enhanced analytical specificity and sensitivity, with good precision and accuracy. Using GC–MS/MS instead of GC–MS allowed a limit of quantitation of 1 nmol/L while decreasing the required specimen volumes, as well as reducing the number of sample processing steps, chromatographic run time, and instrument maintenance. This assay facilitates laboratory diagnosis and monitoring of HT1, permits identification and characterization of other hypersuccinylacetonemias including maleylacetoacetate isomerase deficiency, and is also a valuable tool for research studies using animal models and cellular models of HT1. Key Points A novel method for succinylacetone quantitation, using gas chromatography–tandem mass spectrometry, was developed and validated. The main advantages of this method, compared to other existing succinylacetone assay methods, are enhanced sensitivity and specificity. Data from three years' routine application in a clinical laboratory demonstrates the method's utility in diagnosis and monitoring of tyrosinemia type 1.