Tyrosinemia Type 1

Tyrosinemia Type 1 – Definition

Tyrosinemia type I (OMIM #276700) is a genetic disease caused by mutations in the FAH gene. If left untreated, it usually leads to acute kidney failure within the first year of life and also to renal tubular dysfunction with growth disorders, rickets, and neurological crises. Without adequate treatment, the progression of the disease is fatal within the first decade of life. If treated with nitisinone and a diet low in tyrosine is maintained, the survival rate is over 90%.

Synonyms:

FAH deficiency, hepatorenal tyrosinemia

Gene:

FAH

Gene product:

FAH (fumarylacetoacetase)

Funktion:

FAH catalyzes the final degradation step of the amino acid tyrosine. FAH deficiency leads to

the accumulation of fumarylacetoacetate (FAA) in hepatocytes and causes cell damage and apoptosis,
the defective degradation of FAA to form succinyl acetoacetate and succinylacetone, which
- leads to reduced hydroxyphenylpyruvate dioxygenase (HPPD) enzyme activity and thus to increased tyrosine levels on the one hand and
- to reduced δ-aminolevulinic acid (δ-ALA) dehydratase activity on the other hand, resulting in the accumulation of δ-ALA, which in turn induces nerve damage.

Pattern of inheritance:

Autosomal recessive

Prevalence:

An estimated 1:100.000-1:120.000
Considerably higher in Scandinavia (1:75.000) and Finland (1:60.000) and also in Quebec, Canada (1:16.000)
The frequency of carriers in the US is around 1:150-1:100.

Genotype-phenotype correlation:

None known

Penetrance:

Unknown

Overview of the Chapters on This Page:

Tyrosinemia Type 1 – Definition (This Section)

Tyrosinemia Type 1 – Diagnosis

Clinical Presentation

Special Features of Treatment

Recommendations for Early Detection in Your Patients

Further Information (e.g., Links to Support Groups)

Tyrosinemia Type 1 – Definition (This Section)

Tyrosinemia Type 1 – Diagnosis

Clinical Presentation

Special Features of Treatment

Recommendations for Early Detection in Your Patients

Further Information (e.g., Links to Support Groups)

Tyrosinemia Type 1 – Diagnosis

Suspected Diagnosis

Tyrosinemia type I is suspected when patients present with the following findings:
- Elevated tyrosine level during newborn screening
- Severe liver disease in early infancy
- Signs of kidney disease, rickets, and/or neurological crises in children > 6 months old

Laboratory Chemical Diagnostics

Elevated succinylacetone concentration in the blood and urine
Elevated concentration of tyrosine, methionine, and phenylalanine in the plasma
Elevated concentration of tyrosine metabolites and δ-aminolevulinic acid in urine
Massively elevated concentration of alpha-fetoprotein (AFP) and prolonged prothrombin and partial thromboplastin time as signs of a hepatic function disorder due to untreated tyrosinemia type I

Genetic Diagnostics

The diagnosis of “tyrosinemia type I” is confirmed by detecting a biallelic germline mutation of the FAH gene by sequence and deletion/duplication analysis.

Differential Diagnoses

Examples of Other Metabolic Diseases Linked with Liver Damage:

Tyrosinämie Typ II
Tyrosinämie Typ III
Galaktosämie
Fruktose-1,6-Bisphosphatase-Mangel
Neonatale Hämochromatose
Morbus Wilson
Angeborene Glykosilierungsstörungen

Other Liver Diseases:

Bacterial infections (sepsis, salmonellosis, tuberculosis)
Viral infections (CMV, hepatitis A/B, herpes)
Side effects of medications

Other Kidney Diseases:

Lowe syndrome
Cystinosis
Renal tubular acidosis
Fanconi anemia

Other Causes of Rickets:

Hypophosphatasia
Vitamin D deficiency

Other Causes of Neurological Crises:

Cerebral hemorrhage/edema
Bacterial/viral meningitis
Hypernatriemic dehydration
Acute intermittent porphyria

Clinical Presentation

Untreated Tyrosinemia Type I

Children with tyrosinemia type I who escaped detection by newborn screening methods are generally identified during early infancy due to severe liver complications or even later during the first year of life due to liver dysfunction, kidney complications, a growth disorder, and rickets. If left untreated, tyrosinemia type I results in death within the first decade of life.

Liver Complications:

If it is not diagnosed or left untreated, tyrosinemia type I typically results in acute liver failure within the first 6 months of life. The first sign is the loss of the synthesis function of the coagulation factors. In contrast, the transaminases are only slightly elevated, and even the bilirubin level may be normal or only slightly elevated. This paradoxical combination distinguishes tyrosinemia type I from other severe liver diseases.

Furthermore, untreated children who have survived acute liver failure have a much higher risk of hepatocellular carcinomas.

Kidney Complications:

Kidney complications in untreated children do not usually become evident until after the age of 6 months, when they manifest in the form of a dysfunction of the renal tubules. This leads to generalized aminoaciduria and phosphate loss, which can cause both rickets as well as renal tubular acidosis.

Neurological Crises:

Untreated, children may exhibit repeated neurological crises that are similar to acute intermittent porphyria, with symptoms such as behavioral changes, abdominal pain, peripheral neuropathy, and respiratory dysfunction, the latter may even require ventilation.

Treated Tyrosinemia Type I

The combination of nitisinone therapy and a tyrosine-reduced diet results in a survival rate > 90%, normal growth, improved liver function, the prevention of cirrhosis, the correction of renal tubular acidosis, and prevention of secondary rickets.

Neurological Crises:

These have only been observed in patients following prolonged interruption of the treatment.

Liver Complications:

Acute liver failure usually improves within the first week after nitisinone therapy is started. The risk of a hepatocellular carcinoma is < 5% at the age of 10 in patients for whom nitisinone therapy was started before the age of 2.

Special Features of Treatment

Nitisinone therapy should be started right after the diagnosis is made. In addition, it is also necessary to maintain a low-tyrosine diet once the diagnosis has been made.

If there is a lack of response to nitisinone or if there are malignant changes in the liver, a liver transplant may be worth considering.

Diagnosis of Tyrosinemia Type 1- What's Next?

Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.