Type 1 Tyrosinaemia
MA Mannion, A Smith, P Mayne, AA Monavari
National Centre of Inherited Metabolic Disease, Temple Street Children’s University Hospital, Dublin 1.
Tyrosinaemia type 1 (TYR1, OMIM# 276700) is a rare autosomal recessive disease that results from an enzyme defect that leads to a deficiency in fumarylacetoacetase (FAH)1. We present 3 cases of TYR1 in the Irish population over a 9 year period, the only cases known to have been diagnosed in Ireland since 1989. The common presenting symptom was hypoglycaemia and the diagnosis was made by the identification of the pathognomonic biomarker succinylacetone on urine organic acid analysis. We discuss the clinical presentation, biochemical and genetic results including one novel mutation. We also highlight the importance of early initiation of Nitisinone (NTBC), which reduces the complications of TYR1 and the incidence of liver transplantation in this population2.
TYR1 is a rare autosomal recessive disorder of tyrosine degradation, typically presenting during the first year of life with failure to thrive, hypoglycaemia, conjugated hyperbilirubinaemia and jaundice, Fanconi syndrome, rickets and/or hepatocellular carcinoma3. At least 95 mutations have been identified in the FAH gene, located on chromosome 15q25.14. This results in the accumulation of 4-fumarylacetoacetate and its metabolite succinylacetone. The prevalence has been estimated to be between 1/100,000 to 1/120,000 births, however, this varies greatly, for example in Finland, the birth prevalence is approximately 1/60,000 births but 1/5,000 in the Finnish population of Ostrobothnia.5
Patient One, a male infant born to non-consanguineous Irish parents, presented on day 12 with E-coli sepsis. His glucose was 2.1mmol/L (3.5-5.5mmol/L) and as part of a hypoglycaemic work up, urine organic acids showed a marked increase in excretion of tyrosine metabolites, succinylacetone and succinylacetoacetate. He was coagulopathic with markedly raised plasma tyrosine, threonine and lysine concentrations; plasma alpha fetoprotein was 219,000kU/l (873-34,743kU/l). Genetic testing showed IVS12+5g and a novel missense mutation c.1210G>A resulting in p.gly404ser.
Patient two, a male infant born to non-consanguineous Irish parents, was hypoglycaemic 2.4mmol/L (3.5-5.5mmol/L) at 12 hours of age. Urine organic acids showed a marked excretion of tyrosine metabolites, succinylacetone and succinylacetoacetate. Amino acids showed raised plasma tyrosine and threonine; alpha fetoprotein was 264,457kU/l (5,381-112,422kU/l). FAH showed heterozygous mutation c.554-1G>T and c.1069G>T pGlu357.
Patient three was born at 36/40 gestation to non-consanguineous Irish parents. He was referred at two weeks of age with failure to thrive and was hypoglycaemic 2.2mmol/L (3.5-5.5mmol/L) on admission. Urine organic acids showed marked increase in tyrosine metabolites and succinylacetone. Plasma threonine and tyrosine were elevated. He was coagulaopathic with hypoalbuminaemia. Genetics show homozygous pathogenic variant c.1062+5G>A.
Following initial diagnosis, all three patients had raised plasma delta-aminolevulinate (δ-ALA) levels; succinylacetone and succinylacetoacetate inhibits porphobilinogen synthesis and can participate a porphyria-like crises. All three patients were commenced on low tyrosine diets and Nitisinone. They are currently aged nine years, one year and five months old respectively and are all clinically well with no evidence of hepatic or renal-tubular dysfunction and normal alpha fetoprotein levels.
In this case series, all three patients presented with hypoglycaemia but other reported symptoms of TYR1 include: failure to thrive, abdominal distension, liver failure with coagulopathy, renal proximal tubular defects and hypophosphataemic rickets6. The most common causes of death are liver failure with recurrent bleeding, hepatocelluar carcinoma and the porphyria-like crisis with respiratory failure3.
Patient one showed two heterozygous mutations: IVS12 +5g>a (OMIM 613871.003), the most common pathological fumarylacetoacetase gene mutation7, and a novel missense mutation c.1210G>A resulting in p.gly404ser. Patient two has a heterozygous mutation in intron 6 of the FAH gene (c.554-1G>T) which was previously described by Rootwell as disease-causing for TYR16. Patient three revealed a homozygous pathogenic variant in intron 12 of the FAH gene, c.1062+5G>A previously described in the literature8.
Nitisinone, 2-(2-nitro-4trifluoromethylbenzoyl–1,3-cyclohexaneione), is the pharmacological treatment for TYR1 by inhibiting the enzyme 4-OH phenylpyruvate dioxygenase and thus the conversion of 4-OH phenylpyruvate to homogentisic acid, the second step in the tyrosine degradation pathway. Therefore, the accumulation of fumarylacetoacetate and its hepatotoxic metabolite, succinylacetone, is prevented9. Pharmacological properties were first discovered in Sweden in rats in 199010. A retrospective analysis in Birmingham showed that prior to 1992, before Nitisinone was available, 6/7 (85.7%) underwent liver transplant compared to 7/31 (22.6%) when the drug was available. Liver transplant is ultimately curative, however, it includes lifelong immunosuppression and a mortality rate of up to 14%. With NTBC treatment, the incidence of hepatocellular carcinoma is less than 10% and early transplant is not supported.2
TYR1 is rare in the Irish population. Early identification and introduction of Nitisinone treatment has had a significant effect on these patients and has positively altered the natural history of this condition in childhood.
Conflict of Interest:
None of the authors have any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Maria Mannion, National Centre of Inherited Metabolic Disease, Children's University Hospital, Temple St, Dublin 1
Email: [email protected]
1. Kvittingen EA: Hereditary tyrosinemia type I-an overview. Scand J Clin Lab Invest Suppl. 1986;184:27-34.
2.DC Bartlett, C Lloyd, PJ McKiernan: Early nitisinone treatment reduces the need for liver transplantation in children with tyrosinaemia type 1 and improves post-transplant renal function. J Inherit Metab Dis. 2014 Sep:37(5):745-52.
3. Van Spronsen F.J., Thomasse Y: Hereditary Tyrosinaemia Type I: A new clinical classification with difference in prognosis on dietary treatment. Hepatology, Volume 20, Issue 5, Pages 1187-1191, November 1994.
4. Arranz JA, Piñol F: Splicing mutations, mainly IVS6-1(G>T), account for 70% of fumarylacetoacetate hydrolase (FAH) gene alterations, including 7 novel mutations, in a survey of 29 tyrosinemia type I patients. Hum Mutat. 2002 Sep;20(3):180-8.
5. St-Louis M, Tanguay RM: Mutations in the fumarylacetoacetate hydrolase gene causing hereditary tyrosinemia type I: overview. Hum Mutat. 1997:9(4):291-9
6. Couce ML, Dalmau J, del Toro M: Tyrosinaemia type I in Spain: mutational analysis, treatment and long-term outcome. Pediatr Int 2011 Dec;53(6):985-9
7. Helge Rootwelt, Ruud Berger: Novel Splice, Missense, and Nonsense Mutations in the Fumarylacetoacetase Gene Causing Tyrosinemia Type I. American Journal of Human Genetics. 55:653-658, 1994
8. Grompe M: The pathophysiology and treatment of hereditary tyrosinaemia type 1. europepmc.org
10. Lock E, Ellis M, Gaskin P: From toxicological problem to therapeutic use: The discovery of the mode of action of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), its toxicology and development as a drug. J Inherit Metab Dis. Aug 1998, Vol 21, Issue 5, pp 498-506.