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.

• Splenomegaly

  Abdominal CT showed hepatomegaly with multiple hyperdense masses, splenomegaly and ascites. CT brain showed cerebral atrophy. Blood phenylalanine, tyrosine and methionine levels were all high. [adc.bmj.com]

  (A) Abdominal CT of the patient revealed multiple hepatic rounded hyperdense masses and splenomegaly. (B) Brain CT showed bifrontal cerebral atrophy. [ncbi.nlm.nih.gov]

  Portal vein was patent and splenomegaly was also noticed. Signs of portal hypertension were not there. [birpublications.org]

  Eventually infants with the acute form of tyrosinemia type I experience developmental delays, an abnormally enlarged spleen (splenomegaly), and accumulation of fluid (edema) in the abdomen (ascites). [rarediseases.org]

• 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]

  Often, symptoms begin in early childhood and include excessive tearing, photophobia, eye pain and redness, and painful skin lesions on the palms and soles. [ivami.com]

  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 is inhibited by succinylacetone. [thezbfoundation.com]

  These episodes feature pain in the abdomen and lower extremities, hypertonia, tachycardia, hypertension, and weakness. [symptoma.com]

  Symptoms such as abdominal pain, damage to the peripheral nerves and high blood pressure appear. In addition, symptoms common in acute intermittent porphyria can also occur. [centogene.com]

• 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]

  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]

  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]

  […] enlarged liver yellowing of the skin tendency to bleed and bruise easily swelling of the legs and abdomen Kidney problems also happen and can lead to: rickets, a bone thinning condition delays in walking Some babies also have episodes that include: pain or weakness [thezbfoundation.com]

• 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]

  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]

  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 individuals may present with any of a number of signs and symptoms, including failure to thrive, fever, vomiting, diarrhea, hepatomegaly, ascites, jaundice, renal Fanconi syndrome, or conditions such as rickets and hepatocellular carcinoma.1If [pediatrics.aappublications.org]

• Developmental Delay

  The features include cirrhosis, renal disease, and developmental delay. Also, cardiomyopathy is common although it is benign in these patients. [symptoma.com]

  Analyzes chromosomes in newborns and infants for changes that can explain certain birth defects or developmental delays. Multiple testing options providing information on the genetic health of your baby during the first and second trimesters. [integratedgenetics.com]

  delay liver and kidney disease neurological problems TreatmentOpen Treatment for Tyrosinemia Type 1 begins as early as possible and is life long. [newbornscreening.on.ca]

  Additional symptoms include developmental delays and progressive scarring and impaired function (cirrhosis) of the liver resulting in chronic liver failure. [rarediseases.org]

• Death in Childhood

  Without treatment, death in childhood is common. Treatment with nitisinone and dietary restrictions are associated with improved outcomes; some studies suggest better outcomes when treatment begins at an asymptomatic stage. [ncbi.nlm.nih.gov]

  If left untreated, Tyrosinemia Type I leads to death in childhood by age 10. If diagnosed and treated early, the majority of individuals can prevent complications such as liver, kidney, and bone issues associated with the disorder. [evolvegene.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]

  The child has a slow weight gain plus fever, diarrhea, blood in the feces and vomiting. [centogene.com]

  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]

• 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]

  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]

  Skip to Content Screening Results At a Glance Approximate Incidence in Ontario 1 in 100, 000 Marker Measured Tyrosine and succinylacetone Screening can Prevent Liver and kidney damage and sequelae, failure to thrive, coagulopathy Treatment Special diet [newbornscreening.on.ca]

  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]

• Diarrhea

  The child has a slow weight gain plus fever, diarrhea, blood in the feces and vomiting. [centogene.com]

  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]

• Abdominal Pain

  Symptoms such as abdominal pain, damage to the peripheral nerves and high blood pressure appear. In addition, symptoms common in acute intermittent porphyria can also occur. [centogene.com]

  pains PROGNOSIS Individuals with the disorder have onset of symptoms in the first months of life. [evolvegene.com]

  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 is inhibited by succinylacetone. [thezbfoundation.com]

  Children with tyrosinemia type 1 also have neurologic crises and severe abdominal pain or other neurologic problems. [medicalhomeportal.org]

• Melena

  Case report An Saudi 8-month-old male infant presented with complaints of abdominal distension, fever, jaundice, melena and disturbed level of consciousness for 3 days prior to admission to PICU (in King Fahd Hospital, Al-Baha). [adc.bmj.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]

  Additional early symptoms include fever, diarrhea, bloody stools (melena), and vomiting. Affected infants may also exhibit an abnormally enlarged liver (hepatomegaly), a tendency to bruise easily, jaundice, lethargy, and/or irritability. [rarediseases.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. Copyright 2017 American Society for Investigative Pathology. [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]

  Signs of portal hypertension were not there. [birpublications.org]

  These episodes feature pain in the abdomen and lower extremities, hypertonia, tachycardia, hypertension, and weakness. [symptoma.com]

• 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]

  These episodes, which may be referred to as neurological crises, are associated with severe pains in the legs and stomach, increased muscle tone (hypertonia), vomiting, obstruction of the intestines (ileus), an irregular heartbeat (tachycardia), and high [rarediseases.org]

• 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 physical examination patient looked sick, pale, jaundiced and drowsy. He had rachitic signs. There was mild lower limb edema. Fine crackles were audible bilaterally on the chest. Abdomen was distended. [adc.bmj.com]

• Hepatomegaly

  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. [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]

  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]

  Abdomen ultrasonography revealed hepatosplenomegaly with moderate ascites. Liver examination showed multiple hyperechoic masses. Abdominal CT showed hepatomegaly with multiple hyperdense masses, splenomegaly and ascites. [adc.bmj.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]

  At examination, she presented hepatosplenomegaly. Laboratory tests revealed hypochromic anemia (due to iron deficiency), leucocytosis, low platelet count and altered hepatic functions. Innate metabolic error was suspected. [scielo.br]

• 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]

• Petechiae

  Serdar Ceylaner Pages 50 - 53 Deficiency of mitochondrial sulfur dioxygenase (ETHE1) causes a rare inborn errors of metabolism, ethylmalonic encephalopathy, which is characterized by early-onset encephalopathy, chronic hemorrhagic diarrhea, recurrent petechiae [abstractagent.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]

  […] sk Zoznam menovaných výrobkov en To begin with, when their first child, Michelle, was two, Braam and Ann learned that she had a chronic hereditary disease that causes debilitating muscle weakness. sk Náklady na bežnú údržbu sú z nich vylúčené en 52 The [sk.glosbe.com]

  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]

• 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 child can suffer from enlarged liver, distended abdomen (due to enlarged liver and spleen, ascites and excessive fluids), changes in skeleton, and liver and kidney failure. [centogene.com]

  The child can suffer from enlarged liver, distended abdomen (due to enlarged liver and spleen, acites and excessive fluids), changes in skeleton, and liver and kidney failure. [sobi-northamerica.com]

  Additionally, it can lead to liver and kidney failure, problems affecting the nervous system, and increased risk of liver cancer. Tyrosinemia type 2, is caused by a deficiency of the enzyme tyrosine aminotransferasa-. [ivami.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]

• 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]

  One day after admission, the infant developed repeated daily attacks of neurological crises in bouts of irritability, crying with increased tone and deep tendon reflexes in the lower limbs. [adc.bmj.com]

  poor feeding, vomiting, lethargy, excessive sleepiness, irritability) and treated appropriately. Mode of inheritance Tyrosinemia type 1 is inherited in an autosomal recessive pattern. [my46.org]

• 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]

  poor feeding, vomiting, lethargy, excessive sleepiness, irritability) and treated appropriately. Mode of inheritance Tyrosinemia type 1 is inherited in an autosomal recessive pattern. [my46.org]

  Signs and SymptomsOpen While most babies with Tyrosinemia appear normal at birth, early signs of the disease can include: poor weight gain (failure to thrive) feeding problems irritability extreme sleepiness (lethargy) yellowing of the whites of the eyes [newbornscreening.on.ca]

  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]

• Polyneuropathy

  Approximately 40 percent of affected infants also experience episodes of disease affecting many nerves (polyneuropathy) often following a minor infection. [rarediseases.org]

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

  RESULTS: 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]

  Although the typical features include aminoaciduria, glycosuria, phosphaturia and renal tubular acidosis, they may not all be present. Patients may develop hypophosphataemic rickets, which can be severe. [ojrd.biomedcentral.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]

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.

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].

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.

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.

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.

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.

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].

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:

• 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 kidney disease
• Rickets
• Episodes with peripheral nerve pain

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.

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