Hereditary Tyrosinemia Type 1 in Turkey

Aktuğlu-Zeybek, Çiğdem; Kıykım, Ertuğrul; Cansever, Mehmet Şerif

doi:10.1007/978-3-319-55780-9_15

Cited by 9 publications

(12 citation statements)

References 54 publications

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“…With nitisinone therapy, higher rates of 85% and 100% are reported in the Turkish and French series, respectively (21,29), transient interruption of the treatment due to lack of health insurance coverage is common in developing countries (17). Several studies have shown that nitisinone interruption can lead to higher mortality rate in HT1 by HCC (20), in addition to triggering neurological crisis (30), rapid deterioration (31,32) and death. In our series, the difficulty of maintaining nitisinone as a longterm therapy was impeded by the financial burden and not by patients' compliance.…”

Section: Discussionmentioning

confidence: 99%

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Diagnostic and Therapeutic Challenges of Hereditary Tyrosinemia Type 1 in Lebanon: A 12-Year Retrospective Review

et al. 2021

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Background: Hereditary tyrosinemia type 1 is a rare genetic disorder leading to liver cirrhosis and hepatocellular carcinoma. Few decades ago, dietary measures and ultimately liver transplant constituted the only treatment modalities. Nowadays, early diagnosis and therapy with nitisinone can reverse the clinical picture. In developing countries, diagnostic and therapeutic challenges may affect the outcome of this disease. The choice of the treatment modality may depend on the economic status of each country. Few reports on the long-term outcome of hereditary tyrosinemia type 1 are available from developing and Arab countries.Methods: A retrospective study of charts of Lebanese patients diagnosed with tyrosinemia type 1 and followed, at the American University of Beirut, during a 12-year period was performed. Clinical presentation and liver biochemical profile at diagnosis were analyzed, along with therapeutic modalities and long-term outcome.Results: Twenty-two children were diagnosed and followed during the study period. Median age at diagnosis was 7 months (range: one day to 35 months). Most of the patients presented with hepatomegaly and jaundice. Four patients were referred for atypical presentations with developmental delay and seizures, secondary to undiagnosed hypoglycemia episodes. Around half of the patients presented with failure to thrive. Transaminitis, cholestasis and increased α-fetoprotein level were variably present at diagnosis (36% to 50%). All patients had elevated plasma tyrosine and urinary succinylacetone levels. Genetic testing was performed in 9%. Only one third could be treated with nitisinone. Liver transplant was electively performed in 9% of cases, to overcome the long-term cost of nitisinone. One third of the patients died between the age of 1 month and 11 years. Surviving patients are still candidates for liver transplant.Conclusion: Our experience reflects the challenges of diagnosis and treatment of hereditary tyrosinemia type 1 in a developing country. In the absence of specific neonatal screening, early diagnosis relies mostly on the clinical awareness of the physician. Long-term nitisinone use may be deterred by its high cost and liver transplantation carries risks of surgical complications. New, effective, and less expensive treatments are needed, especially for developing countries.

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Section: Discussionmentioning

confidence: 99%

“…Although liver transplantation was privileged in some centers in Turkey to overcome the long-term cost of nitisinone therapy (22)(23)(24), recent reports from Turkey (20,21).…”

Section: Discussionmentioning

confidence: 99%

Diagnostic and Therapeutic Challenges of Hereditary Tyrosinemia Type 1 in Lebanon: A 12-Year Retrospective Review

et al. 2021

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“…The risk of liver cancer (mainly HCC, although hepatoblastoma could occur) decreased tremendously and is estimated to be around 1% if NTBC treatment is initiated early [11, 13, 31, 83, 113]. In line with this, long-term follow-up revealed that NTBC-treated TT1 patients are still at risk for HCC, especially when NTBC is initiated late due to delayed diagnosis or unavailability of NTBC [13, 31, 46, 55, 114–121].…”

Section: Outcome In Tt1 Before and After Introduction Of Ntbcmentioning

confidence: 99%

“…The characteristic renal disease in TT1 patients is a renal tubulopathy with aminoaciduria, glucosuria, phosphaturia, and acidosis (that is difficult to fully correct) and, as a consequence, secondary hypophosphatemic (vitamin D-resistant) rickets may develop. However, the severity of the renal problems varies significantly between patients [45, 50, 55, 132]. Dietary restriction of phenylalanine and tyrosine and supplementation of minerals and vitamins seem to improve renal tubular defects (even without NTBC) in some patients.…”

Section: Outcome In Tt1 Before and After Introduction Of Ntbcmentioning

confidence: 99%

Long-Term Outcomes and Practical Considerations in the Pharmacological Management of Tyrosinemia Type 1

et al. 2019

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Tyrosinemia type 1 (TT1) is a rare metabolic disease caused by a defect in tyrosine catabolism. TT1 is clinically characterized by acute liver failure, development of hepatocellular carcinoma, renal and neurological problems, and consequently an extremely poor outcome. This review showed that the introduction of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) in 1992 has revolutionized the outcome of TT1 patients, especially when started pre-clinically. If started early, NTBC can prevent liver failure, renal problems, and neurological attacks and decrease the risk for hepatocellular carcinoma. NTBC has been shown to be safe and well tolerated, although the long-term effectiveness of treatment with NTBC needs to be awaited. The high tyrosine concentrations caused by treatment with NTBC could result in ophthalmological and skin problems and requires lifelong dietary restriction of tyrosine and its precursor phenylalanine, which could be strenuous to adhere to. In addition, neurocognitive problems have been reported since the introduction of NTBC, with hypothesized but as yet unproven pathophysiological mechanisms. Further research should be done to investigate the possible relationship between important clinical outcomes and blood concentrations of biochemical parameters such as phenylalanine, tyrosine, succinylacetone, and NTBC, and to develop clear guidelines for treatment and follow-up with reliable measurements. This all in order to ultimately improve the combined NTBC and dietary treatment and limit possible complications such as hepatocellular carcinoma development, neurocognitive problems, and impaired quality of life. Key Points Treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) has been found to be generally safe and has clearly improved treatment and outcomes for patients with tyrosinemia type 1.

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“…In the present study, the patient in whom HT1 was detected at an early stage was promptly treated with nitisinone and showed a positive 1‐year outcome, which is consistent with the successful experiences reported worldwide (Alvarez & Mitchell ). Nevertheless, the development of hepatocellular carcinoma remains a risk in all HT1 patients, thereby indicating the need for promising novel or complementary therapeutic strategies (Aktuglu‐Zeybek, Kiykim, & Cansever, ; VanLith et al, ).…”

Section: Discussionmentioning

confidence: 99%

Mutational spectrum of Mexican patients with tyrosinemia type 1: In silico modeling and predicted pathogenic effect of a novel missense FAH variant

Ibarra-González

Fernández-Lainez

Alcántara-Ortigoza

et al. 2019

Molec Gen & Gen Med

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BackgroundTyrosinemia type 1 (HT1, MIM#276700) is caused by a deficiency in fumarylacetoacetate hydrolase (FAH) and it is associated with severe liver and renal disfunction. At present, the mutational FAH (15q25.1, MIM*613871) spectrum underlying HT1 in the Mexican population is unknown. The objective of this study was to determine the FAH genotypes in eight nonrelated Mexican patients with HT1, who were diagnosed clinically.MethodsSequencing of FAH and their exon–intron boundaries and in silico protein modeling based on the crystallographic structure of mouse FAH.ResultsWe identified pathogenic variants in 15/16 studied alleles (93.8%). Nine different variants were found. The most commonly detected HT1‐causing allele was NM_000137.2(FAH):c.3G > A or p.(?) [rs766882348] (25%, n = 4/16). We also identified a novel missense variant NM_000137.2(FAH):c.36C > A or p.(Phe12Leu) in a homozygous patient with an early and fatal acute form. The latter was classified as a likely pathogenic variant and in silico protein modeling showed that Phe‐12 residue substitution for Leu, produces a repulsion in all possible Leu rotamers, which in turn would lead to a destabilization of the protein structure and possible loss‐of‐function.ConclusionHT1 patients had a heterogeneous mutational and clinical spectrum and no genotype–phenotype correlation could be established.

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Hereditary Tyrosinemia Type 1 in Turkey

Cited by 9 publications

References 54 publications

Diagnostic and Therapeutic Challenges of Hereditary Tyrosinemia Type 1 in Lebanon: A 12-Year Retrospective Review

Diagnostic and Therapeutic Challenges of Hereditary Tyrosinemia Type 1 in Lebanon: A 12-Year Retrospective Review

Long-Term Outcomes and Practical Considerations in the Pharmacological Management of Tyrosinemia Type 1

Mutational spectrum of Mexican patients with tyrosinemia type 1: In silico modeling and predicted pathogenic effect of a novel missense FAH variant

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