Tyrosinemia type I is an autosomal recessive metabolic disorder, in which fumarylacetoacetate hydrolase (FAH), a key enzyme in the metabolism of tyrosine is missing. This defect leads to accumulation of tyrosine and its metabolites in the body, especially within the liver, causing complications. The acute form of the condition is characterized by diarrhea, vomiting, poor appetite, lethargy, jaundice, and a swollen liver, whereas the chronic form may present with polyneuropathy, kidney problems, intense abdominal pain, heart muscle weakness, and liver cirrhosis. If left untreated, the condition can lead to liver failure, growth failure, rickets, neurological crisis, and/or hepatocellular carcinoma, all in childhood. Although the incidence of this condition is generally less worldwide, some populations, like the French Canadian, may show an increased incidence.
Since the metabolic defect presents itself from birth, it is very important to diagnose it as early as possible, in order to prevent any damage. Increased excretion of succinylacetone in the urine is a major indicator of Type I Tyrosinemia. Other indications include elevated plasma concentrations of tyrosine, methionine and phenylalanine, and elevated urinary levels of other tyrosine metabolites. Diagnosis can also be made on the basis of assay of FAH enzyme activity from muscle fibroblasts, as well as molecular genetic testing of the FAH gene. Prenatal testing for succinylacetone or fumarylacetoacetate in the amniotic fluid is also possible. Once diagnosed, early intervention is imperative, to prevent any complications. Intervention is primarily in the form of dietary restrictions of tyrosine and phenylalanine. In addition, a drug called NTBC (Nitisinone) is also administered, which blocks the metabolic step that leads to the accumulation of fumarylacetotate and its conversion to succinylacetone. For severe cases, where the conditon has proceeded to liver cancer or severe liver damage, liver transplantation may be required.
[See: Saudi Arabia > Imtiaz et al., 2011].
Yadav and Reavey (1988) reviewed the results of quantitative amino acid analysis in 800 subjects over a three-year period in Al-Sabah Hospital, Kuwait. A total of 35 patients were diagnosed with aminoacidopathy, all but two of whom were the offspring of first-degree consanguineous marriages. The patients included nine cases of phenylketonuria, one benign hyperphenylalaninemia, seven non-ketotic hyperglycinemia, five tyrosinemia, five homocystinuria, four citrullinemia, two cystinuria, one hyperprolinemia, and one with maple syrup urine disease.
In a retrospective analysis of IEMs diagnosed over a 12-year period (1998-2010) in a hospital in Lebanon, Karam et al. (2013) found 13 patients diagnosed with tyrosinemia, type I. The median age of diagnosis was 7-months.
Joshi et al. (2002) carried out a retrospective analysis of all patients born with inborn errors of metabolism in Oman between June 1998 and December 2000. Among the 82 patients, two were diagnosed with tyrosinemia type I [CTGA Database Editor's note: Computed annual incidence rate is 1.6/100,000].
Two years later, Joshi and Venugopalan (2004) reported the use of NTBC [2-(2-nitro-4-trifluoromethylbenzoyl)-1, 2-cyclohexanodione] in five children diagnosed with tyrosinemia type 1. At presentation, all patients were clinically evaluated and investigated by complete blood count, renal and liver function tests, coagulation profile, bone profile, alpha fetoprotein, urine analysis and urine gas chromatography linked to mass spectrometer for succinyl acetone analysis, blood tandem mass spectrometry for plasma tyrosine and phenylalanine levels, and abdominal ultrasound. After confirmation of the disease, patients were managed by tyrosine and phenyalanine restricted diets (monitered by tyrosine and phenyalanine levels) and were started on NTBC at a dose of 0.6 - 1 mg/kg/day divided into two to three doses before meals by one hour. They were followed up with clinical and biochemical evaluation, as well as evaluation of NTBC side effects. Case one, who had consanguineous parents and two normal siblings, presented at the age of five months with liver cirrhosis, hepatic encephalopathy, Fanconi syndrome and rickets, and was started on NTBC at the age of nine months, and was followed up for four and a half years. Case two, who had a positive family history, presented at the age of 11 months with liver cirrhosis, Fanconi syndrome, and rickets, and initiation of NTBC was delayed until he was 30 months (parents were looking into liver transplantation), and was followed up for seven months. At the age of 11 months, case three who was a sibling of case two, presented with mild hepatosplenomegaly without cirrhosis, deranged coagulation and biochemical rickets. Within a month, he was started on NTBC, and was followed up for seven months. Liver cirrhosis, deranged coagulation and chronic diarrhea were the findings in case four (six months) who had positive family history with one sibling having died with liver disease. He was immediately started on NTBC and was followed up for two and a half years during which he had two episodes of lower motor neuron facial palsy. Case five was diagnosed at the age of eight months when he presented with liver cirrhosis, deranged coagulation, Fanconi syndrome, and rickets. There was a positive family history with one sibling having died from liver disease. After two months of follow up, this patient died from hepatocellular failure, uncontrolled coagulopathy and septicemia. All these patients had high levels of plasma tyrosine and urine succinyl acetone levels at presentation. Clinical and biochemical improvement was noticed after two months of therapy and after six months, all patients were asymptomatic with normalization of biochemical profiles, healing of rickets and reversal of the radiological signs of liver cirrhosis and portal hypertension. No side effects of NTBC were detected and none of these patients developed liver carcinoma or needed liver transplantation. Three years later, Joshi and Venugopalan (2007) reported their observations for over a seven year period (1998- 2005) in which the clinical profiles of 166 neonates at high risk of having inborn errors of metabolism were evaluated by Tandem Mass Spectrometry (TMS). Out of a total of 38 neonates with positive TMS results, one baby, aged 21 days was diagnosed with tyrosenemia type I. The baby was born to consanguineous parents, but did not have any family history of the condition.
Al-Riyami et al. (2012) reported on the types and patterns of IEMs encountered in a sample of 1100 high-risk neonates referred to SQU Hospital in Oman over a 10-year period (1998-2002). MS/MS was used to analyze blood samples from heel pricks. A total of 119 of these neonates were found to test positive for an IEM. Tyrosinemia-I was detected in seven neonates (five males, two females), belonging to five families. All seven patients had a family history of the condition, and were born to consanguineous parents.
Moammar et al. (2010) reviewed all patients diagnosed with inborn errors of metabolism (IEM) from 1983 to 2008 at Saudi Aramco medical facilities in the Eastern province of Saudi Arabia. During the study period, 165530 Saudi infants were born, of whom a total of 248 newborns were diagnosed with 55 IEM. Affected patients were evaluated based on clinical manifestations or family history of similar illness and/or unexplained neonatal deaths. Almost all patients were born to consanguineous parents. Aminoacidopathies were diagnosed in 38 out of 248 cases (16%). Among them, five cases from a single family were found to have Tyrosinemia. One case of Tyrosinemia out of five was confirmed enzymatically. The estimated incidence is 3 in 100,000 live births. The authors concluded that data obtained from this study underestimate the true figures of various IEM in the region. Therefore, there is an urgent need for centralized newborn screening program that utilizes tandem mass spectrometry, and offers genetic counseling for these families.
Imtiaz et al. (2011) investigated mutations in the FAH gene among 43 patients from 37 families affected with Hereditary Tyrosinemia Type 1. The patients in this study included Saudi Arabian and Egyptian patients. All were born to consanguineous parents, and were clinically classified with acute HT1.
Mohamed et al. (2013) reported two Saudi siblings with tyrosinemia type 1. Case 1 was a male infant who presented at two months of age with fever, vomiting and refusal of feeding. Examination revealed a sick-looking infant with signs of severe dehydration and hypovolemic shock. He was jaundiced, and had hepatomegaly and elevated liver enzymes. Echocardiography was performed in light of a lack of response to inotropes, and revealed biventricular and interventricular septal hypertrophies. The ventricular ejection fraction was 65%. Urine organic acid analysis showed elevated succinylacetone, consistent with a diagnosis of tyrosinemia type 1. An FAH gene study identified a c.1 A?>?G homozygous mutation. This patient responded well to intensive cardiorespiratory therapy, tyrosine-free formula, and oral 2-nitro-4- trifluoromethylbenzyl 1, 3 cyclohexanedione (NTBC). Echocardiographic findings reverted to normal after four weeks. Case 2 was the younger brother of Case 1, and was born six months after his brother had been confirmed with tyrosinemia. Pregnancy and delivery were uneventful. Serum amino acid and organic acid analyses four days after birth confirmed tyrosinemia. DNA analysis identified a c.1 A?>?G homozygous mutation, as in his brother. Echocardiography was normal. Special formula and NTBC were commenced on day seven of life. The infant remained asymptomatic after nine months of follow-up.
Al-Shamsi et al. (2014) undertook a study to calculate the birth prevalence of IEMs among Emiratis in the UAE by taking into consideration all neonates born with an inherited metabolic condition at Tawam Hospital between 1995 and 2012. A total of 37 distinct IEMs were found in Emirati neonates in this study, providing an estimated IEM birth prevalence of 75.24 per 100,000 live births. Type I Tyrosinemia was found to be one of the most prevalent IEMs identified in this study, with a birth prevalence of 2.2-4.9 per 100,000. Two different mutations were identified in the FAH gene among the affected patients.