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Amino acid disorders and urea cycle disorders
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
Tyrosinaemia is diagnosed on the basis of a range of specialised tests, a clinical evaluation and family history. The diagnosis can be conirmed by demonstrating the presence of succinylacetone in the urine and decreased activity of the enzyme fumarylacetoacetate hydrolase in liver tissue or cultured ibroblasts. Prenatal diagnosis can be made by measuring the activity of this enzyme in amniotic luid cells. Some states in the USA test for tyrosinaemia type 1 in the newborn screening programme. Treatment ofthe disorder includes restricting dietary intake of the amino acids tyrosine and phenylalanine. As these occur in most natural proteins, a low-protein diet is needed. As some protein is essential for normal growth and repair of tissues, specially prepared formulas are required. These contain all of the essential amino acids except tyrosine and phenylalanine. With progression of the condition there may be liver failure that requires a liver transplant. In some cases a transplant can improve the function of the kidneys as well as normalising liver activity. A new drug, NTBC (Nitisinone®), has been developed which blocks the formation of the toxic substances that build up in tyrosinaemia, and improvements in the liver and kidney function of affected individuals have been observed. However, children who are receiving this drug need to be monitored carefully, with frequent follow-up.
Accident and Emergency
Published in Nagi Giumma Barakat, Get Through, 2006
Treatment of tyrosinaemia consists of a low-phenylalanine and low-tyrosine diet (300-500 mg/day), which may produce considerable improvement in clinical, biochemical and histological findings. Additional treatment for Fanconi’s syndrome (e.g. l,25-dihydroxyvitamin-D3 or alkali) and for hepatocellular damage (e.g. vitamin K or dietary restriction of protein) may be required. A competitive inhibitor of pHPPA hydroxylase, known as NTBC, is extremely effective in reversing even severe liver damage and in reducing the level of succinylacetone to normal, but if liver damage is advanced then liver transplantation is indicated and should be performed as early as possible to prevent hepatic carcinoma. After transplantation, patients still excrete succinylacetone but appear to escape toxic damage to the transplanted liver. It is not known whether the drug can permanently prevent cancer.
Inherited Metabolic Disorders
Published in Timothy G Barrett, Anthony D Lander, Vin Diwakar, A Paediatric Vade-Mecum, 2002
Timothy G Barrett, Anthony D Lander, Vin Diwakar
If there is unexplained hypoglycaemia, refer to the investigation protocol (see hypoglycaemia in Chapter 4). If there is unexplained, acute liver failure, consider urinary succinyl acetone and blood for PBG synthase screening test (tyrosinaemia type 1).
Liver-directed gene-based therapies for inborn errors of metabolism
Published in Expert Opinion on Biological Therapy, 2021
Pasquale Piccolo, Alessandro Rossi, Nicola Brunetti-Pierri
Genotoxicity is a concern particularly for IEM with increased cancer risk (e.g., GSDI, GSDIII, GSDIV, HT1, mitochondrial DNA depletion, and citrin deficiency). Three mechanisms are thought to be involved in HCC occurring in IEM: i) direct toxicity of accumulating metabolites, ii) metabolite channeling, and iii) mitochondrial dysfunction predisposing to inflammation. For example, in HT1 the HCC risk is related to accumulation of succinylacetone, fumarylacetoacetate and maleylacetoacetate, in citrin deficiency to unbalanced nucleotide pools, in GSDI, GSDIII and GSDIV to metabolite shunting, and in mitochondrial disorders to the excess of reactive oxygen species [140]. In the context of these disorders, the additional risk of insertional mutagenesis and inflammation induced by AAV vectors is a concern. However, correction of the metabolic defect in at least a subset of the liver cells is also expected to improve the metabolic defect, thus reducing the burden of toxic metabolites associated with increased cancer risk.
Genetic Analysis of Tyrosinemia Type 1 and Fructose-1, 6 Bisphosphatase Deficiency Affected in Pakistani Cohorts
Published in Fetal and Pediatric Pathology, 2020
Muhammad Yasir Zahoor, Huma Arshad Cheema, Sadaqat Ijaz, Zafar Fayyaz
The patient enrolled from family PKTT1F6 was a 1.5-year-old female who had experienced recurrent fevers for over one year. She had also episodes of epistaxis, jaundice, and was failing to thrive during the most recent four months. Her brother had previously died at 19 months of age, though her other siblings were unaffected (Fig. 1). An elevated level of succinyl acetone in the urine was suggestive of tyrosinemia type 1 and the patient was given a controlled diet and a course of Nitisinone was initiated. The patient showed no improvement and died at 2 years of age before a liver transplant could be performed. Genetic analysis of FAH showed that both parents were heterozygous carriers of the IVS12 + 5G > A mutation (Fig. 1).
Bilateral recurrent pseudodendritic keratopathy as the initial manifestation of tyrosinemia type II
Published in Ophthalmic Genetics, 2022
Bruno Avelar Miranda, Anna Christina Higino Rocha, Rodrigo Rezende Arantes, Viviane de Cássia Kanufre, Sabrina Cavaglieri Silva, Daniel Vitor Vasconcelos-Santos
At this time, further workup revealed serum tyrosine level of 1,346.14 µmol/L (normal range, <157.0 µmol/L). Succinylacetone level was normal, excluding tyrosinemia type I. Genetic testing of oral mucosa swab sample identified the variant chr16: 71.571.660 T > C on GRCh38 (or alternatively c.707–2 A > G—ENST00000355962) in homozygosity in TAT gene (tyrosine aminotransferase, OMIM* 613018), which occurs in a canonical site of messenger RNA processing (splicing acceptor site).