Initial presentation, management and follow-up data of 33 treated patients with hereditary tyrosinemia type 1 in the absence of newborn screening

Hela Hajji; Apolline Imbard; Anne Spraul; Ludmia Taibi; Valérie Barbier; Dalila Habes; Anaïs Brassier; Jean-Baptiste Arnoux; Juliette Bouchereau; Samia Pichard; Samira Sissaoui; Florence Lacaille; Muriel Girard; Dominique Debray; Pascale de Lonlay; Manuel Schiff

doi:10.1016/j.ymgmr.2022.100933

Initial presentation, management and follow-up data of 33 treated patients with hereditary tyrosinemia type 1 in the absence of newborn screening

Mol Genet Metab Rep. 2022 Nov 8:33:100933. doi: 10.1016/j.ymgmr.2022.100933. eCollection 2022 Dec.

Authors

Hela Hajji¹, Apolline Imbard^{2

3}, Anne Spraul⁴, Ludmia Taibi⁵, Valérie Barbier¹, Dalila Habes⁶, Anaïs Brassier¹, Jean-Baptiste Arnoux¹, Juliette Bouchereau¹, Samia Pichard¹, Samira Sissaoui⁷, Florence Lacaille⁷, Muriel Girard⁷, Dominique Debray⁷, Pascale de Lonlay^{1

8}, Manuel Schiff^{1

9}

Affiliations

¹ Reference Center for Inborn Error of Metabolism, Department of Pediatrics, Necker-Enfants Malades Hospital, APHP, Université Paris Cité, Filière G2M, Paris, France.
² Metabolic Biochemistry Laboratory, Necker-Enfants Malades Hospital, APHP, Paris, France.
³ LYPSIS, Pharmacy University, Paris-Saclay University, Chatenay-Malabry,France.
⁴ Biochemistry Laboratory, Bicêtre Hosiptal, APHP, Le Kremlin-Bicêtre, France.
⁵ Biochemistry Laboratory, Robert Debré Hospital, APHP, Paris, France.
⁶ Pediatric Hepatology, Bicêtre Hospital, APHP, Le Kremlin-Bicêtre, France.
⁷ Pediatric Gastroenterology-Nutrition and Hepatology, Necker-Enfants Malades Hospital, APHP, Paris, France.
⁸ Inserm UMR 1151, Institut Necker-Enfants Malades, Université Paris Cité, Paris, France.
⁹ Inserm UMR_S1163, Institut Imagine, Université Paris Cité, Paris, France.

Abstract

Hereditary tyrosinemia type 1 (HT1) is a rare autosomal recessive disorder of phenylalanine and tyrosine catabolism due to a deficiency of fumarylacetoacetate hydrolase. HT1 has a large clinical spectrum with acute forms presenting before six months of age, subacute forms with initial symptoms occurring between age 6 and 12 months, and chronic forms after 12 months of age. Without treatment, HT1 results in the accumulation of toxic metabolites leading to liver disease, proximal tubular dysfunction, and porphyria-like neurological crises. Since the early nineties, the outcome of HT1 has dramatically changed due to its treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC, nitisinone). In some countries, HT1 is included in the newborn screening program based on the analysis of succinylacetone concentration on dried blood spots. In the present study, we report clinical and laboratory parameters data on 33 HT1 patients focusing on clinical presentation and therapeutic management at the time of diagnosis. Eighteen patients were diagnosed with the acute form (median age at presentation 2.5 months), 6 with the subacute form (median age at presentation 10 months), and 5 with the chronic form of HT1 (median age at presentation 15 months). Four patients were diagnosed pre-symptomatically in the setting of a family history of HT1. Among the 29 symptomatic patients, hepatomegaly was found in 83% of patients and prolonged coagulation times due to hepatocellular insufficiency was observed in 93% of patients. HT1 diagnosis was confirmed by increased urine succinylacetone in all patients. All patients but 2 were treated with nitisinone immediately at diagnosis. During follow-up, 2 patients received liver transplant for high grade dysplasia or hepatocellular carcinoma, 10 patients exhibited some form of neurocognitive impairments. Our data confirm that HT1 is a severe treatable liver disease that should be detected at the earliest, ideally by newborn screening and appropriately treated.

Keywords: Hepatocellular carcinoma; NTBC; Neurocognitive outcome; Newborn screening; Nitisinone; Succinylacetone; Tyrosinemia type 1.