Physical Growth of Patients with Hereditary Tyrosinaemia Type I: A Single-Centre Retrospective Study.

In a retrospective review, we aimed to assess long-term growth in 17 patients (n = 11 males) with hereditary tyrosinaemia type I (HTI). Median age at assessment was 15.6 years (5.7-26.6 years) and median age at diagnosis was 1 month (range: 0-16 months), with 35% (n = 6/17) symptomatic on presentation. From the age of 8 years, there was a noticeable change in median height, weight, and body-mass-index [BMI]-z-scores. Median height-for-age z-scores were consistently ≤ -1 (IQR -1.6, -0.5) during the first 8 years of life but increased with age. Weight-for-age z-scores ranged between -1 to 0 (IQR -1.2, 0.1) in the first 8 years; then increased to > 0.5 (IQR -0.3, 1.3) by age 16 years, and BMI-for-age z-scores ranged from 0 to 1 (IQR -0.7, 1.3) up to 8 years, and >1 (IQR -0.2, 1.9) until 16 years. The percentage of overweight and obesity was lowest in children aged < 5 years, and consistently > 40% in patients aged between 7 to 16 years. The prescribed total protein intake was associated with improved height growth (p < 0.01). Impaired growth in early life improved with age achieving normal population standards. Further studies are needed to investigate factors that influence growth outcome in HTI patients.

Discovery of Hereditary Tyrosinemia in Saguenay- Lac St-Jean.

Given the interest of many people and families directly or indirectly affected by hereditary tyrosinemia (HT1), I have tried to give my view on the history of the disease from 1965 to 2015 (Fig. 1.1).

Clinical and Biochemical Profile of Tyrosinemia Type 1 in Tunisia.

BACKGROUND: Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disease caused by a defect of fumarylacetoacetate hydrolase. This study aimed to estimate the prevalence of HT1 in Tunisia and report its clinical, biochemical and genetic features. METHODS: During the last 25 years, 69 patients were diagnosed with HT1 based on clinical features and increased succinylacetone (SA) in blood and urine. SA was detected by GC-MS after oximation and quantified by a spectrophotometric method. Nine prenatal diagnoses for HT1 have been done and nine unrelated patients were screened for the hotspot IVS6-1(G-T) mutation using PCR. RESULTS: Using the Hardy-Weinberg formula, the incidence of HT1 was estimated at 1/14804 births in Tunisia. According to clinical form, 21 patients (30%) had the acute form and 48 patients (70%) had the chronic form. Mean plasma and urine SA were higher in the acute form (24 and 193 µmol/L vs. 9 and 90 µmol/L, respectively). Diagnosis of HT1 was done for 4 fetuses. The hotspot IVS6-1(G-T) mutation was found in six of nine explored patients. CONCLUSIONS: The incidence of HT1 is relatively high in Tunisia with a predominance of the chronic form. It is important to diagnose the disease as early as possible to prevent unfavorable issues. Prenatal diagnosis should be recommended to minimize the recurrence of the disease.

Diagnosis and treatment of hereditary tyrosinemia in Japan.

Hereditary tyrosinemia is an autosomal recessive inherited disease that manifests as three types (types I-III). We conducted a nationwide survey of this disease in Japan, and here review the results in relation to prevalence, clinical characteristics, and treatment and diagnosis. A definitive diagnosis of tyrosinemia type I is difficult to obtain based only on blood tyrosine level. Detection of succinylacetone using dried blood spots or urinary organic acid analysis, however, is useful for diagnosis. In tyrosinemia type I, dietary therapy and nitisinone (Orfandin®) are effective. Prognosis is greatly affected by the complications of liver cancer and hypophosphatemic rickets; even patients that are treated early with nitisinone may develop liver cancer. Long-term survival can be expected in type I if nitisinone therapy is effective. Prognosis in types II and III is relatively good.

Hereditary tyrosinemia type 1 in Turkey: twenty year single-center experience.

BACKGROUND: Hereditary tyrosinemia type 1(HT1) is a chronic disorder leading to severe hepatic, renal and peripheral nerve damage if left untreated. Despite nitisinone treatment HT1 still carries the risks of hepatocellular carcinoma (HCC) and neuropsychological outcome. METHODS: A retrospective single center study was carried out based on the phenotype, therapy and outcome in 38 Turkish patients with HT1 diagnosed during the last 20 years. RESULTS: None of the patients was diagnosed on newborn screening. The patients were grouped according to acute, subacute and chronic forms of the disorder. The main clinical manifestations were hepatosplenomegaly, liver and renal tubular dysfunction. Thirty-six patients were treated with nitisinone. The mean duration of nitisinone treatment was 64 months and the mean dosage was 1.2 mg/kg/day. Dietary compliance problems were frequent. Eleven patients had cognitive evaluation (mean total IQ, 84 points). Six patients had living donor liver transplantation despite nitisinone treatment: three due to suspected HCC, two for non-compliance to diet, and one for both, at a median age of 90 months. CONCLUSION: Nitisinone treatment is effective and improves both short- and long-term prognosis of HT1. Early diagnosis on newborn screening is needed because delay in treatment increases the risk of the persistence of hepatic disease and HCC. Interruption of the drug can lead to re-occurrence of hepatocellular damage and neurological crisis. Increased α-fetoprotein and new hypoechoic nodule formation are the warning signs for HCC.

Liver Transplant for Children With Hepatocellular Carcinoma and Hereditary Tyrosinemia Type 1.

OBJECTIVES: This study sought to determine the prevalence of hepatocellular carcinoma and other premalignant lesions in children with hereditary tyrosinemia type 1 who had undergone an orthotopic liver transplant at the Shiraz Transplant Center, in Shiraz, Iran. MATERIALS AND METHODS: Between September 2006, and June 2011, thirty-six patients with hereditary tyrosinemia type 1 received a liver transplant from a deceased (whole or split) or a living-related donor. Clinical records and pathologic specimens, before and after surgery, for each case were reviewed. In addition, ultrasound, abdominal computed tomographic imaging scan findings, and levels of alpha-fetoprotein were recorded. RESULTS: Twenty-two patients with hepatic nodules larger than 10 mm underwent a Tru-Cut needle biopsy before their liver transplant. In 2 patients, a diagnosis of hepatocellular carcinoma was made by pathologic examination; in the other 20, cirrhosis was confirmed with no evidence of malignancy. After pathologic examination of the explanted livers, the largest nodules in the 36 patients were 35 mm. Five cases had at least 1 nodule of hepatocellular carcinoma. Three of the other patients had small cell dysplasia in some of nodules. All 5 cases with hepatocellular carcinoma were patients older than 2 years of age (19 patients were older than 2 years of age). All patients with hepatocellular carcinoma received pretransplant nitisinone treatment. All patients with hepatocellular carcinoma after their liver transplant are alive at the time of this writing. CONCLUSIONS: The prevalence of cell dysplasia and hepatocellular carcinoma in children with hereditary tyrosinemia type 1 in our study is not as high as that reported previously, so it appears that patients older than 2 years of age require a liver transplant.

Tyrosinemia type I: clinical and biochemical analysis of patients in Mexico.

INTRODUCTION: Hepatorenal tyrosinemia (HT1) is a treatable, inherited, metabolic disease characterized by progressive liver failure with pronounced coagulopathy. The aim of this study is to describe the clinical, biochemical, and histopathological findings in a group of Mexican HT1 patients and their outcome. MATERIAL AND METHODS: Medical records of HT1 patients diagnosed between 1995 and 2011 were analyzed. The diagnosis of HT1 was confirmed by detection of succinylacetone in urine or blood. RESULTS: Sixteen nonrelated HT1 cases were analyzed. Mean age at clinical onset was 9 months, and the mean age at diagnosis was 16.3 months. Main clinical findings were hepatomegaly, splenomegaly, cirrhosis, liver failure, tubulopathy, nephromegaly, Fanconi syndrome, seizures and failure to thrive. Histopathological findings were cirrhosis, fibrosis and steatosis. The HT1 group had a mortality rate of 78%. Patients who received supportive care or nutritional treatment had a 3-year survival rate of 10%. For those who underwent liver transplantation, the 6-year survival rate was 60%. In most cases pharmacological treatment with nitisinone and special dietary products were not available. The leading causes of death were fulminant liver failure, metastatic hepatocellular carcinoma, and porphyria-like neurologic crisis. Newborn screening programs in combination with the availability of orphan drugs, proper monitoring, genetic counseling, and clinical practice guidelines are needed to enable physicians to identify the disease, delay its progression, and improve patients' quality of life. CONCLUSION: The devastating natural history of HT1 is still observed in Mexican patients because they are not diagnosed and treated during the early stages of the disease.

Hereditary tyrosinaemia type I in Norway: incidence and three novel small deletions in the fumarylacetoacetase gene.

A total of 28 Norwegians have been diagnosed with hereditary tyrosinaemia type I (HT1) over the last 30 years. In this study, 19 of these patients were investigated. Three novel small deletions were found (NM_000137.1(FAH): c.615delT, p.Phe205LeufsX2, NM_000137.1(FAH): c.744delG, p.Pro249HisfsX55 and NM_000137.1(FAH):c835delC) pGln279ArgfsX25, all of them leading to a change in the reading frame and a premature stop codon. We hereby genetically characterized 51 of the 56 disease-causing alleles, identifying nine different disease-causing mutations in the Norwegian population. We found that 65% of the Norwegian HT1 patients are compound heterozygous for different mutations. Thus, the relatively high incidence of HT1 in Norway of 1 in 74,800 live births is not due to single founder effects or high incidence of parental consanguinity.

Tyrosinemia type 1 in Spain: mutational analysis, treatment and long-term outcome.

BACKGROUND: Tyrosinemia type 1 (HT1) is a rare but treatable disease. The aim of the present study was to review the efficacy of long-term treatment of HT1 with nitisinone, expand knowledge about the clinical spectrum of the disease and assess a possible genotype-phenotype correlation. METHODS: A retrospective multicenter study was carried out based on questionnaires on genotype, phenotype, therapy and outcome in 34 Spanish patients with HT1. RESULTS: The main manifestations that led to the diagnosis were acute liver failure (55.8%), asymptomatic hepatomegaly (44.1%) and renal tubular dysfunction (29.4%). Laboratory analysis indicated a marked increase of α-fetoprotein and coagulopathy. The most common mutation was IVS6-1(G > T; 66.6% of 24/34 patients for whom mutation analysis was available) and these patients presented less nephrocalcinosis and more hepatomegaly at diagnosis; two novel mutations (c.974C>T, c.398A>T) were found. The mean duration of treatment was 6.73 years. Dietary compliance was very good in 47.1% and good in 20.6%; nitisinone treatment adherence was very good in 85.2% of cases. Mean dose of nitisinone was 0.87 mg/kg per day with average plasma levels of 45.67 µmol/L. Only one patient required liver transplantation after nitisinone and none had hepatocellular carcinoma. CONCLUSIONS: Treatment with nitisinone has improved the prognosis of HT1, and compliance is good. In Spain, screening for HT1 by plasma tyrosine and urine succinylacetone determination may be implemented with IVS6-1(G > T) mutational analysis. A correlation between low frequency of nephrocalcinosis and IVS6-1(G > T) mutation was observed.

Quantitative determination of succinylacetone in dried blood spots for newborn screening of tyrosinemia type I.

BACKGROUND: Tyrosinemia type I (TYR 1) is a severe disorder causing early death if left untreated. While tyrosine can be determined in dried blood spots (DBS), it is not a specific marker for TYR 1 and most often associated with benign transient tyrosinemia of the newborn. Succinylacetone (SUAC) is a specific marker for TYR 1 but not detectable by routine newborn screening. We developed a new assay that determines SUAC in DBS by liquid-chromatography tandem mass spectrometry (LC-MS/MS). METHODS: Whole blood is eluted from a 3/16-in. DBS by an aqueous solution containing deuterium labeled SUAC as internal standard (IS). SUAC and IS are oximated, then extracted, butylated, and analyzed by LC-MS/MS. Quantitation is from SUAC spiked calibrator DBS over the range 0-200 microM using selected reaction monitoring of transitions m/z 212 to 156 and m/z 214 to 140 for SUAC and IS, respectively. Analysis time is 5 min. To assess the effectiveness of a two-tier screening approach for TYR 1 we applied this assay to our newborn screening program over the last 15 months. RESULTS: The intra-assay precision was determined for three different levels of SUAC (5, 20, and 50 micromol/L) and the CV calculated to be 4.7, 2.6, and 3.1%, respectively (n=5). Inter-assay precision CVs were 12.7, 8.2, and 7.8%, respectively on the same samples. SUAC levels in DBS from 10 confirmed TYR 1 cases not treated with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) were clearly abnormal (16-150 micromol/L; mean: 61 micromol/L; controls: <5 micromol/L). Over a 15-month period, SUAC was determined in newborn screening samples with elevated tyrosine concentrations when applying different cut off values until it was settled at 150 micromol/L. No case of TYR 1 was detected in 124,780 newborns tested. CONCLUSION: We have developed a new LC-MS/MS based method for the determination of SUAC in DBS. This assay has the potential to significantly reduce the number of false positive results in newborn screening for TYR 1 and can also be used for the laboratory follow up of patients treated for TYR 1.

Selective screening of amino acid disorders in the south-west of Iran, Shiraz.

A diagnostic study of amino acid concentrations in dried blood spot samples from 1044 symptomatic children revealed high incidences of phenylketonuria, tyrosinaemias, and maple syrup urine disease in the Shiraz region of Iran. Minimum incidences, based on babies born between 1996 and 2001 inclusive, and diagnosed by the end of 2001, are 1:3672, 1:10651 and 1:21 303, respectively.

Mutation analysis of the FAH gene in Israeli patients with tyrosinemia type I.

Thirteen Israeli patients with type I tyrosinemia were studied. To the best of our knowledge, this group represents all of the patients that were diagnosed in Israel during the years 1987-1997. Their age of onset was variable but all the patients suffered from liver disease at presentation. Six died at 3 to 36 months of age, whereas the remaining 7, in whom NTBC was started at 5 to 30 months, are alive and well at 4 to 11 years. Three mutations were identified: a mis-splicing IVS8-1G>C mutation in a large Moslem kindred, Pro261Leu mutation in all Jewish patients, and the IVS12+5G>A mutation, commonly found in French Canadian patients.