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Tyrosinemia Type 1

Tyrosinosis

Tyrosinemia type 1 (TT1), also referred to as hepatorenal tryosinosis, is caused by an inborn error of metabolism. This genetic disorder affects the liver, kidney, and central nervous system. Without treatment, patients usually die in childhood.

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Presentation

This metabolic disease may present in infancy, early childhood, or beyond [12] [13] and the symptomology varies from one patient to another. TT1 occurs in one of three forms: acute, subacute, or chronic.

Acute

This type manifests either congenitally or in early infancy, as the more severe cases develop in the first two months [12]. The most common clinical picture includes severe liver disease, which progresses to liver failure and coagulopathy. Infants will typically have a rapid and dramatic onset of fever, emesis, diarrhea, epistaxis, and melena. They also have the failure to thrive and appear lethargic and irritable. Furthermore, these children are also predisposed to developing infections [13]. Patients also exhibit a developmental delay.

On examination, the notable findings may include hepatosplenomegaly, jaundice, ascites, and purpura. Also, they may emit a cabbage-like odor.

Subacute

This less severe type appears in the first year of life. Patients develop failure to thrive, clotting abnormalities, and rickets. The exam is notable for hepatosplenomegaly.

Chronic

Patients with chronic variant are older than the age of one. The onset is more gradual and typically presents with the failure to thrive. The features include cirrhosis, renal disease, and developmental delay. Also, cardiomyopathy is common although it is benign in these patients [14].

Primary manifestations

Acute liver failure is one of the most ominous diseases that occurs in patients with TT1. It evolves into cirrhosis, the formation of liver nodules, and possibly hepatocellular carcinoma. Liver dysfunction leads to hypoglycemia [15], coagulopathy, hypoalbuminemia with the resultant ascites, and jaundice. Liver impairment is nearly always present to some extent.

Another common complication is a renal disease such as Fanconi syndrome. The severity of this disorder is variable and is typically characterized by tubular acidosis, aminoaciduria, glycosuria, and/or phosphaturia. Kidney disease may progress into glomerulosclerosis and eventually chronic failure. Furthermore, patients at risk for rickets due to low serum phosphate levels.

Affected individuals may also experience a neurological crisis, described as a porphyria-like syndrome, after an infection. These episodes feature pain in the abdomen and lower extremities, hypertonia, tachycardia, hypertension, and weakness. This may be life-threatening as it can cause a condition known as ascending motor neuropathy, which is often accompanied by respiratory failure that necessitates assisted ventilation.

Pain
  • The crises resemble those of acute intermittent porphyria, manifesting with painful parasthesias (causing patients to assume ophisthotonic position, self mutilation), autonomic signs (hypertension, tachycardia, ileus) and respiratory decompensation.[orpha.net]
  • These episodes feature pain in the abdomen and lower extremities, hypertonia, tachycardia, hypertension, and weakness.[symptoma.com]
  • Failure to thrive during infancy Diarrhea Vomiting Jaundice Cabbage-like odor Increased risk of bleeding (e.g. nosebleeds) Liver failure Increased risk of liver cancer Kidney dysfunction Weakening of bones (i.e. rickets) Peripheral neuropathy Abdominal pains[evolvegene.com]
  • Other reported manifestations have included hypertrophic cardiomyopathy (8) and inhibition of aminolevulinate dehydratase, resulting in porphyria-like neurologic symptoms, such as pain, ileus, weakness, and even paralysis (1, 2, 7).[path.upmc.edu]
  • Children with this condition can have eye pain, painful skin, and mental disability. Tyrosinemia Type 3: Rarest of the types. Symptoms include intellectual disability, seizures, and intermittent ataxia.[stlouischildrens.org]
Weakness
  • However, study quality was moderate to weak, with high risk of confounding and applicability concerns to the screening context. We conducted post hoc analyses to address these issues.[ncbi.nlm.nih.gov]
  • When nerves are affected, children have severe pain, often in the legs, associated with rigid legs/ body (hypertonia), vomiting, weakness and sometimes paralysis.[childrenliverindia.org]
  • Methodological quality of the studies was moderate to weak. There was evidence of associations between early treatment with nitisinone and lower rates of death, liver disease and transplantations, and renal dysfunction.[jech.bmj.com]
  • Case presentation: A six years old girl presented with difficulty in walking and weakness of muscles so she was admitted in neurology ward in Qaem hospital in Mashhad.[ijp.mums.ac.ir]
  • Other reported manifestations have included hypertrophic cardiomyopathy (8) and inhibition of aminolevulinate dehydratase, resulting in porphyria-like neurologic symptoms, such as pain, ileus, weakness, and even paralysis (1, 2, 7).[path.upmc.edu]
Fever
  • Case 1 was a male infant who presented at 2 months old with fever, vomiting and refusal of feeding. Examination revealed a sick-looking infant with signs of severe dehydration and hypovolemic shock.[ncbi.nlm.nih.gov]
  • Clinical considerations: Fever, diarrhea, vomiting Enlarged liver, jaundice Lethargy or irritability Note: No dietary intervention is needed at this time. Continue to feed the baby as usual. b.[archildrens.org]
  • Infants will typically have a rapid and dramatic onset of fever, emesis, diarrhea, epistaxis, and melena. They also have the failure to thrive and appear lethargic and irritable.[symptoma.com]
  • It is many times precipitated by events like fever or some other infection.[childrenliverindia.org]
  • These include failure to thrive, fever, vomiting, diarrhoea, enlarged liver or liver failure, excessive abdominal fluids (ascites), jaundice, impaired kidney function, rickets, and liver tumours.[socialstyrelsen.se]
Developmental Delay
  • The features include cirrhosis, renal disease, and developmental delay. Also, cardiomyopathy is common although it is benign in these patients.[symptoma.com]
  • Some children with tyrosinemia, type I (TYR I) have developmental delays. If you think that your baby is not meeting their developmental milestones, ask your baby’s doctor about the next steps in accessing a developmental evaluation and care.[babysfirsttest.org]
  • Symptoms may include developmental delay, ataxia, microcephaly, and seizures, whereas other individuals have been identified by newborn screening without any clinical symptoms.[clinicaladvisor.com]
  • These may include: Enlarged spleen Developmental delays Cirrhosis or scarring of liver Swelling of stomach caused by fluid retention Hypoglycemia Conjugated hyperbilirubinemia Coagulation abnormalities Elevated levels of AFP Life-threatening complications[hxbenefit.com]
  • It has been reported that very low phenylalanine levels could have peripheral implications such as eczema and faltering growth, but could also cause developmental delay in HT1 [ 19 ].[ojrd.biomedcentral.com]
Vomiting
  • Case 1 was a male infant who presented at 2 months old with fever, vomiting and refusal of feeding. Examination revealed a sick-looking infant with signs of severe dehydration and hypovolemic shock.[ncbi.nlm.nih.gov]
  • Clinical considerations: Fever, diarrhea, vomiting Enlarged liver, jaundice Lethargy or irritability Note: No dietary intervention is needed at this time. Continue to feed the baby as usual. b.[archildrens.org]
  • Affected infants present with failure to thrive, vomiting and diarrhea and, if undiagnosed, die from liver failure. We present two infants who presented with severe coagulopathy and no other signs of liver failure.[journals.lww.com]
  • Children typically fail to grow appropriately and suffer from fever, vomiting, epistaxis, and other symptoms. The workup is comprised of the patient and family history, physical exam, and the appropriate studies.[symptoma.com]
  • When nerves are affected, children have severe pain, often in the legs, associated with rigid legs/ body (hypertonia), vomiting, weakness and sometimes paralysis.[childrenliverindia.org]
Failure to Thrive
  • Although failure to thrive is one of the typical features in HT1, our proband, similar to the reported Scandinavian patients, had normal growth and development. The results of this study have applications in patient screening and genetic counselling.[ncbi.nlm.nih.gov]
  • Clinical features includes acute or chronic liver disease with increased risk of hepatocellular carcinoma, hypophosphatemic rickets due to renal tubular dysfunction, glomerulosclerosis, failure to thrive, neurological porphyria-like crisis, hypertrophic[ncbi.nlm.nih.gov]
  • Patients develop failure to thrive, clotting abnormalities, and rickets. The exam is notable for hepatosplenomegaly. Chronic Patients with chronic variant are older than the age of one.[symptoma.com]
  • Affected infants present with failure to thrive, vomiting and diarrhea and, if undiagnosed, die from liver failure. We present two infants who presented with severe coagulopathy and no other signs of liver failure.[journals.lww.com]
  • If treatment is begun too late, rickets, failure to thrive, and hypotonia may result.[checkorphan.org]
Diarrhea
  • Clinical considerations: Fever, diarrhea, vomiting Enlarged liver, jaundice Lethargy or irritability Note: No dietary intervention is needed at this time. Continue to feed the baby as usual. b.[archildrens.org]
  • Affected infants present with failure to thrive, vomiting and diarrhea and, if undiagnosed, die from liver failure. We present two infants who presented with severe coagulopathy and no other signs of liver failure.[journals.lww.com]
  • Infants will typically have a rapid and dramatic onset of fever, emesis, diarrhea, epistaxis, and melena. They also have the failure to thrive and appear lethargic and irritable.[symptoma.com]
  • COMMON Features of the Disorder Failure to thrive during infancy Diarrhea Vomiting Jaundice Cabbage-like odor Increased risk of bleeding (e.g. nosebleeds) Liver failure Increased risk of liver cancer Kidney dysfunction Weakening of bones (i.e. rickets[evolvegene.com]
  • Symptoms usually appear in the first few months of life and include failure to thrive , diarrhea, vomiting, jaundice , cabbage-like odor, and increased tendency to bleed (particularly nosebleeds).[rarediseases.info.nih.gov]
Abdominal Pain
  • pains PROGNOSIS Individuals with the disorder have onset of symptoms in the first months of life.[evolvegene.com]
  • This enzyme deficiency causes the same symptoms as acute intermittent porphyria, including abdominal pains, high blood pressure and neurological symptoms.[socialstyrelsen.se]
  • Repeated neurologic crises may occur involving mental status change, abdominal pain, peripheral neuropathy, and/or respiratory failure. These are due to the accumulation of delta amino levulinic acid, whose metabolism inhibited by succinylacetone.[medicalhomeportal.org]
  • Children with tyrosinemia type 1 also have neurologic crises and severe abdominal pain or other neurologic problems.[medicalhomeportal.org]
  • Adults commonly present with abdominal pain related to biliary or pancreatic obstruction, whereas children commonly present with jaundice [9] .[file.scirp.org]
Melena
  • Infants will typically have a rapid and dramatic onset of fever, emesis, diarrhea, epistaxis, and melena. They also have the failure to thrive and appear lethargic and irritable.[symptoma.com]
  • Common features may include: Melena Epistaxis Marked edema Purpuric lesions A distinctive, cabbage-like odor In chronic variants, the symptoms progress slowly and take on less severe forms.[hxbenefit.com]
  • Clinical Manifestations Type I Type I tyrosinemia in the acute form is characterized by failure to thrive, vomiting, diarrhea, a cabbage-like odor, hepatomegaly, fever, jaundice, edema, melena, and progressive liver disease.[wvdhhr.org]
Hypertension
  • Under conditions of low-dose NTBC, FAH-/- pigs developed liver fibrosis and portal hypertension, and thus may serve as a large-animal model of chronic liver disease.[ncbi.nlm.nih.gov]
  • The crises resemble those of acute intermittent porphyria, manifesting with painful parasthesias (causing patients to assume ophisthotonic position, self mutilation), autonomic signs (hypertension, tachycardia, ileus) and respiratory decompensation.[orpha.net]
  • These episodes feature pain in the abdomen and lower extremities, hypertonia, tachycardia, hypertension, and weakness.[symptoma.com]
  • Other features have included hypertrophic obstructive cardiomyopathy, abdominal crises, polyneuropathy, hypertension, and hepatoma (a late complication in one third of patients). Death occurs during the first decade of life.[wvdhhr.org]
  • Augenbeteiligung Familiäre hyperphosphatämische tumorale Kalzinose/Hyperphosphatämische Hyperostose-Syndrom Familiäre primäre Hypomagnesiämie mit Hyperkalziurie und Nephrokalzinose Farber-Lipogranulomatose Fatale infantile Enzephalopathie-pulmomale Hypertension-Syndrom[se-atlas.de]
Tachycardia
  • The crises resemble those of acute intermittent porphyria, manifesting with painful parasthesias (causing patients to assume ophisthotonic position, self mutilation), autonomic signs (hypertension, tachycardia, ileus) and respiratory decompensation.[orpha.net]
  • These episodes feature pain in the abdomen and lower extremities, hypertonia, tachycardia, hypertension, and weakness.[symptoma.com]
Jaundice
  • 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.[ncbi.nlm.nih.gov]
  • The current patient presented with jaundice; as two causes for cholestases coexisted, it was difficult to specify whether jaundice was secondary to both of these conditions or tyrosinemia only.[file.scirp.org]
  • Clinical considerations: Fever, diarrhea, vomiting Enlarged liver, jaundice Lethargy or irritability Note: No dietary intervention is needed at this time. Continue to feed the baby as usual. b.[archildrens.org]
  • On examination, the notable findings may include hepatosplenomegaly, jaundice, ascites, and purpura. Also, they may emit a cabbage-like odor. Subacute This less severe type appears in the first year of life.[symptoma.com]
  • COMMON Features of the Disorder Failure to thrive during infancy Diarrhea Vomiting Jaundice Cabbage-like odor Increased risk of bleeding (e.g. nosebleeds) Liver failure Increased risk of liver cancer Kidney dysfunction Weakening of bones (i.e. rickets[evolvegene.com]
Hepatomegaly
  • 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.[ncbi.nlm.nih.gov]
  • Subacute type manifests a similar but less severe clinical picture presenting usually with hepatomegaly or hypophosphatemic rickets (due to tubular dysfunction). Intercurrent illness may precipitate hepatic crisis.[orpha.net]
  • Infants with focal hepatic lesions and hepatomegaly (n 13) were younger at diagnosis than those with rickets (n 5) (median age: 3.25 vs. 10 months; P 0.05). Alpha fetoprotein was highly elevated in all children.[ncbi.nlm.nih.gov]
  • 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.[ncbi.nlm.nih.gov]
  • The disease typically manifests as early onset type in early infancy with acute hepatic crisis with hepatomegaly and bleeding tendency. The acute crisis may resolve spontaneously but hepatomegaly and failure to thrive persist ( 10 ).[ijp.mums.ac.ir]
Hepatosplenomegaly
  • 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.[ncbi.nlm.nih.gov]
  • The exam is notable for hepatosplenomegaly. Chronic Patients with chronic variant are older than the age of one. The onset is more gradual and typically presents with the failure to thrive.[symptoma.com]
  • Coagulopathy, failure to thrive, hepatosplenomegaly, rickets, neurological problems, Cirrhosis or other liver problems and cardiomyopathy are some of its clinical presentations ( 2 ).[ijp.mums.ac.ir]
  • A sub-acute form manifests between 6 months and 1 year of age with liver disease, hypoglycemia, failure to thrive, coagulopathy, hepatosplenomegaly, renal Fanconi syndrome that may lead to rickets, and hypotonia.[genedx.com]
Muscle Weakness
  • In this study, we report a 6-year-old patient with tyrosinemia type 1 who was admitted due to muscle weakness and difficulty walking and finally after treatment significant remission was achieved.[ijp.mums.ac.ir]
  • Prevention of Secondary Complications Because carnitine deficiency secondary to the renal tubular Fanconi syndrome can cause skeletal muscle weakness, serum concentration of carnitine should be measured so that carnitine deficiency, if identified, can[ncbi.nlm.nih.gov]
Purpura
  • On examination, the notable findings may include hepatosplenomegaly, jaundice, ascites, and purpura. Also, they may emit a cabbage-like odor. Subacute This less severe type appears in the first year of life.[symptoma.com]
Epistaxis
  • Infants will typically have a rapid and dramatic onset of fever, emesis, diarrhea, epistaxis, and melena. They also have the failure to thrive and appear lethargic and irritable.[symptoma.com]
  • Common features may include: Melena Epistaxis Marked edema Purpuric lesions A distinctive, cabbage-like odor In chronic variants, the symptoms progress slowly and take on less severe forms.[hxbenefit.com]
Kidney Failure
  • The disease can cause severe liver damage, kidney failure and neurological manifestations. Nitisinone is used to treat hereditary tyrosinemia type 1 in combination with adherence to a reduced tyrosine dietary regime.[mendelikabs.com]
  • Tyrosinemia type I can lead to liver and kidney failure, softening and weakening of the bones, problems affecting the nervous system, and an increased risk of liver cancer .[rarediseases.info.nih.gov]
  • In untreated children, TT1 progresses to liver and kidney failure, and other complications that ultimately lead to death. Furthermore, patients are at risk for developing hepatocellular carcinoma.[symptoma.com]
  • Tyrosinemia type I can lead to liver and kidney failure, softening and weakening of the bones ( rickets ), and an increased risk of liver cancer (hepatocellular carcinoma).[ghr.nlm.nih.gov]
Irritability
  • Clinical considerations: Fever, diarrhea, vomiting Enlarged liver, jaundice Lethargy or irritability Note: No dietary intervention is needed at this time. Continue to feed the baby as usual. b.[archildrens.org]
  • They also have the failure to thrive and appear lethargic and irritable. Furthermore, these children are also predisposed to developing infections. Patients also exhibit a developmental delay.[symptoma.com]
  • Most commonly, the children present with liver problems and acute liver failure like fever, irritability vomiting, jaundice, bleeding from skin leading to bluish spots on the skin, black stool(malena).[childrenliverindia.org]
  • […] treatment of choice considering the risk of recurrent cholangitis, acute biliary colic, pancreatitis [7] ; as well as malignant degeneration [9] , the degenerated mucosa of a choledochal cyst increases the risk for carcinomatous development due to chronic irritation[file.scirp.org]
  • Babies with TYR I may show signs such as: Diarrhea Bloody stool Vomiting Poor weight gain Sleeping longer and more often Tiredness Irritability “Cabbage-like” odor Yellowing skin (known as jaundice) Increased bleeding or bruising Swollen legs or abdomen[babysfirsttest.org]
Polyneuropathy
  • In such cases children experience abdominal pain, polyneuropathy (a disease causing peripheral nerve damage), high blood pressure and sometimes paralysis of the respiratory musculature.[socialstyrelsen.se]
  • Due to the inhibitory influence of succinylacetone on heme biosynthetic pathway, infants with the chronic form might develop polyneuropathy along with painful abdominal crises, much like in cases of acute intermittent porphyria .[hxbenefit.com]
  • Other features have included hypertrophic obstructive cardiomyopathy, abdominal crises, polyneuropathy, hypertension, and hepatoma (a late complication in one third of patients). Death occurs during the first decade of life.[wvdhhr.org]
  • Phosphoribosylpyrophosphat-Synthetase-Überaktivität Phosphoribosylpyrophosphat-Synthetase-Überaktivität, milde Phosphoribosylpyrophosphat-Synthetase-Überaktivität, schwere Phosphoserin-Aminotransferase-Mangel Polyglucosan-Körper-Myopathie Typ 1 Polyglukosankörper-Krankheit, adulte Polyneuropathie[se-atlas.de]
Lethargy
  • Clinical considerations: Fever, diarrhea, vomiting Enlarged liver, jaundice Lethargy or irritability Note: No dietary intervention is needed at this time. Continue to feed the baby as usual. b.[archildrens.org]
  • Patients are affected with: Failure to grow and gain weight Fever Diarrhea Vomiting Nosebleeds Bruising easily Lethargy and irritability Developmental delay Enlarged liver Yellowing of the skin and the eyes Severe liver diseases such as cirrhosis Severe[symptoma.com]

Workup

Newborns who screen positive for TT1 and symptomatic individuals suspected to have this disorder warrant a thorough assessment of the personal and family history, a physical exam, and the pertinent studies.

Laboratory studies

The diagnosis is established by measurement of the biomarker SA in the plasma, urine, or DBS (through mass spectrometry). This demonstrates high specificity and sensitivity. Note that plasma testing offers more accuracy since urine organic acid analyses may not detect SA or the levels of the metabolite may be too low.

A comprehensive evaluation includes coagulation studies, complete blood count (CBC), electrolyte and mineral panel, renal function tests, liver function tests (LFTs), alpha-fetoprotein (AFP), quantitative serum analysis of amino acids, organic acid analysis, urinalysis, and other pertinent tools to understand the clinical picture.

Notable findings include coagulation abnormalities and features indicating liver failure. Also, plasma levels of tyrosine and methionine are increased.

Imaging

The liver and kidneys should be promptly evaluated by ultrasonography at initial presentation and periodically afterward. Specifically, this tool can identify nodular lesions and provide details regarding the liver parenchyma. Additionally, the color doppler mode will help assess the vasculature. Nodules warrant further investigation with magnetic resonance imaging (MRI) or computed tomography (CT).

Also, wrist x-rays are used for diagnosing rickets.

Newborn screening

Early detection of TT1 followed by immediate treatment is paramount [16]. Newborn screening should be done with SA, although screening for this disease is not widely available.

Glycosuria
  • Before starting NTBC therapy, all children manifested signs of renal dysfunction which included hypophosphatemia, acidosis, reduced phosphate reabsorption, aminoaciduria, glycosuria (Fanconi syndrome), and variable degree of proteinuria.[ncbi.nlm.nih.gov]
  • The severity of this disorder is variable and is typically characterized by tubular acidosis, aminoaciduria, glycosuria, and/or phosphaturia. Kidney disease may progress into glomerulosclerosis and eventually chronic failure.[symptoma.com]
  • The characteristic renal disease is a tubular disorder with a Fanconi syndrome; the typical features include aminoaciduria, glycosuria, phosphaturia, renal tubular acidosis and hypophosphataemic rickets [5] .[file.scirp.org]
  • Renal Fanconi syndrome is an important feature that may initially be mild but may progress and lead to significant concerns with aminoaciduria, renal tubular acidosis, and glycosuria.[clinicaladvisor.com]
Methionine Increased
  • Other abnormalities include elevated α -fetoprotein (especially in acutely ill infants), increased plasma levels of tyrosine, phenylalanine and methionine, increased urinary δ-ALA excretion and features of Fanconi tubulopathy.[orpha.net]

Treatment

Therapy should be initiated as soon as a patient is diagnosed with TT1. Additionally, asymptomatic infants identified through newborn screening should be treated before they even develop a clinical picture. There are two main components of treatment which include the use of medication and dietary modification. Patients should be managed by a team of pediatricians, hepatologists, nephrologists, specialized nutritionists, and other professionals.

Emergent management

The treatment of critically ill patients should include stabilization with respiratory support, fluid resuscitation, and blood transfusions as needed.

Medical therapy

The Food and Drug Administration (FDA) approved Nitisinone for the treatment of this disease in 2002 [17]. This agent inhibits parahydroxyphenylpyruvic acid dioxygenase (p-HPPD), which is an enzyme that participates in tyrosine degradation. Blocking this enzyme thereby prevents the production of FAA and SA [1]. This medication should be given promptly after confirmation of the diagnosis. The standard dose is 1.0 mg/kg/day, which is adjusted to attain the therapeutic range as measured by blood concentration. Adverse reactions are rare and may include transient thrombocytopenia and photophobia.

Diet

Upon diagnosis, all children should be immediately placed on a low protein diet with a limited intake of phenylalanine and tyrosine. The patient's nutritional requirements should be carefully managed and adjusted as needed for growth and overall well-being. Specialized food products may be needed to ensure that essential requirements are fulfilled.

Surgery

Liver transplantation is considered for patients with severe liver failure that is refractory to treatment with Nitisinone, or those who have liver malignancy [18] [19]. There is at least a 10% mortality rate in children who undergo transplantation.

Prognosis

Prior to current therapy, untreated patients exhibited a poor prognosis that typically resulted in childhood death. Treatment has profoundly improved the survival and the quality of life in affected children [11]. Furthermore, medical therapy may also prevent manifestations from emerging. However, complications such as hepatocellular carcinoma pose a lifelong risk for these patients despite treatment [11].

Etiology

This autosomal recessive disorder results from mutations in the FAH gene, which is located on chromosome 15 [3]. FAH codes for the FAH enzyme which plays a key role in the final step of the tyrosine degradation pathway. Hence, a deficiency in FAH leads to an accumulation of tyrosine and numerous toxic products such as SA in the tissues of the liver, kidney, and the CNS.

Epidemiology

The estimated global incidence of TT1 is 1 in 100,000 to 120,000 births [4]. With regards to patient demographics, this metabolic disorder is more prevalent in the Canadian province, Quebec [4] [5]. Additionally, cases have been identified in the Middle East where there are high rates of consanguinity [6]. As for gender, there is no preference.

Sex distribution
Age distribution

Pathophysiology

Children with TT1 develop this disorder as a result of a defect in the tyrosine catabolic pathway. Specifically, the FAH enzyme is absent or insufficient to catalyze tyrosine degradation. As a result, the buildup of tyrosine causes its conversion to upstream products such as SA, succinylacetoacetate (SAA), fumarylacetoacetate (FAA), and maleylacetoacetate (MAA). The accumulation of these toxic metabolites is responsible for the diseases to occur [7].

These substances are implicated in the pathological features of TT1. SA inhibits heme synthesis, which leads to neurotoxicity [8] while FAA and MAA are damaging to hepatocytes and can cause hepatocellular carcinoma open link [9]. Additionally, MAA causes damage to the tubules and results in kidney disease [10]. These toxic products are considered to be carcinogenic.

Prevention

This disease is inherited and therefore cannot be prevented. However, newborn screening can identify affected children earlier, thereby introducing treatment prior to manifestation.

Genetic counseling is offered to affected individuals and their family members to provide them with education about what the disease entails, its mode of inheritance, expectations, and other specific details. Carrier and prenatal testing are available to relatives at risk if the mutation has been identified. Additionally, a fetus can be diagnosed by the presence of SA in the amniotic fluid.

Summary

Tyrosinemia type 1 (TT1) is a rare metabolic disorder that results from a mutation in the gene that codes for fumarylacetoacetate hydrolase (FAH), which is an enzyme that catalyzes the final step of the tyrosine catabolism pathway. This deficiency leads to an accumulation of tyrosine and tyrosine-derived compounds which cause damage to sites such as the liver, kidneys, and central nervous system.

The devastating condition features liver and renal disease, coagulopathy, possibly rickets [1], and neuropathy. In untreated children, TT1 progresses to liver and kidney failure, and other complications that ultimately lead to death. Furthermore, patients are at risk for developing hepatocellular carcinoma. TT1 manifests as either acute, subacute, or chronic in which earlier presentations are associated with greater severity. Children typically fail to grow appropriately and suffer from fever, vomiting, epistaxis, and other symptoms.

The workup is comprised of the patient and family history, physical exam, and the appropriate studies. The confirmatory diagnostic tool for TT1 is the measurement of the pathognomonic marker succinylacetone (SA) in blood, urine, or dried blood spot (DBS). To clarify the complete clinical picture, further laboratory tests are indicated. There are various biochemical abnormalities that are typically observed in these patients. Moreover, imaging is required for the evaluation of the liver and kidney pathologies.

Treatment consists of a diet restricted in protein, tyrosine, and phenylalanine in conjunction with nitisinone. The latter is a drug that inhibits the formation of the toxic metabolites such as SA and others [1]. The therapeutic regimen along with the implementation of modified newborn screening programs have profoundly improved survival and reduced most effects of TT1 [2].

Patient Information

What is Tyrosinemia Type 1?

This a rare metabolic disorder in which the patient has a high level of tyrosine. This is an essential amino acid that is very important for the function of cells.

What are the causes?

Tyrosinemia type 1 is caused by a mutation in a gene that normally produces an enzyme known as fumarylacetoacetate hydrolase. This enzyme breaks tyrosine down. When this enzyme is absent, tyrosine and other toxic substances build up. Therefore, these products go on to cause liver disease, kidney disease, and even nerve damage.

This disease is inherited in an autosomal recessive pattern. This means that affected individuals inherit a bad copy from each parent. In other words, each parent is a carrier.

What are the signs and symptoms?

This disease presents in early infancy or childhood. Patients are affected with:

Patients are also at high risk of developing liver cancer known as hepatocarcinoma.

How is it diagnosed?

Patients presenting with symptoms suggestive of this disease or newborns with positive screening should be assessed immediately for this disease. The clinician will obtain the patient and family history, perform a physical exam, and conduct the appropriate studies such as:

  • Measurement of succinylacetone (SA) in the blood or urine
  • Measurement of amino acids in the blood
  • Complete blood count
  • Liver function tests
  • Kidney function tests
  • Blood clotting studies
  • Electrolyte levels
  • Numerous other tests

Additionally, the liver and kidneys should be evaluated with imaging techniques such as ultrasonography.

How is it treated?

There are two main components that are used for treatment and management of patients with this disorder:

  • Diet that is low in protein and limited in tyrosine and phenylalanine
  • Treatment with a drug called nitisinone

These patients should be treated by a team of pediatricians, liver and kidney specialists, and a specialized nutritionist.

Can it be prevented?

This disease is inherited and therefore cannot be prevented. However, newborn screening can identify affected children earlier and therefore these infants can be treated before the effects of the disease emerge.

Also, genetic counseling is offered to patients and relatives at risk. A geneticist can educate the patients, parents, at-risk relatives about the disease, how it is inherited, and many other details. Genetic testing is available for relatives at risk in cases where the genetic mutation is known.

What is the prognosis?

The current treatment has significantly improved the prognosis of patients with this disease. It has increased survival and the quality of life. Also, it can prevent many of the diseases that develop in these patients. The earlier the diagnosis, the sooner the patients receives treatment. Hence, newborn screening is very crucial because this can diagnose patients before they develop symptoms.

References

Article

  1. Scott CR. The genetic tyrosinemias: Part C, Seminars in Medical Genetics. Am J Med Genet. 2006;142C(2):121-6.
  2. Nobili V, Jenkner A, Francalanci P, et al. Tyrosinemia type 1: Metastatic hepatoblastoma with a favorable outcome. Pediatrics. 2010; 126(1):e235-e238.
  3. Paradis K. Tyrosinemia: The Quebec experience. Clin Invest Med. 1996; 19(5):311-316.
  4. Mitchell GA, Grompe M, Lambert M, et al. In: Hypertyrosinemia : the metabolic and molecular bases of inherited disease. Scriver CR, Beaudet A, Sly WS, Valle D, eds. New York: McGraw Hill; 2001:1777–1806.
  5. De Braekeleer M, Larochelle J. Genetic epidemiology of hereditary tyrosinemia in Quebec and in Saguenary-Lac-St-Jean. Am J Hum Genet. 1990; 47(2):302–307.
  6. Imtiaz F, Rashed M, Al Mubarak B, Allam R, et al. Identification of mutation causing hereditary TyrosinemiaType 1 in patients of Middle Eastern origin. Mol Gen Genet . 2011; 104(4):688–690.
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