Background

Type-1-hereditary-tyrosinemia is a rare genetic disorder that affects tyrosine breakdown due to mutation. It is a metabolic disorder of autosomal recessive inheritance. 

Fumarylacetoacetate hydrolase enzyme deficiency causes tyrosine degradation pathway disruption. 

Autosomal recessive disorder inherited when individual receives defective gene copies from both parents. 

Hepatocellular carcinoma commonly seen in chronic disorder form. 

It is classified as: 

Acute 

Chronic  

Epidemiology

It has global incidence estimated about 1 in 100000 to 120000 live births. 

In the French-Canadian community the incidence of HT1 is significantly higher, estimated about 1 in 1,846 live births.  

FAH gene mutations have low carrier frequency in this rare disease. HT1 impacts diverse ethnicities with distribution differences linked to genetic factors and founder mutations. 

Families with HT1 history can use prenatal genetic testing and counselling to assess future pregnancy risks. 

Anatomy

Pathophysiology

Enzymes break down tyrosine through multiple steps. Fumarylacetoacetate hydrolase converts fumarylacetoacetate to fumarate and acetoacetate. 

Toxic build-up of fumarylacetoacetate damages cells in liver and kidneys due to high reactivity. 

Fumarylacetoacetate converts to succinyl acetone, it is a toxic compound that accumulates and inhibits heme synthesis enzyme. 

HT1 damages the liver with accumulated fumarylacetoacetate and succinyl acetone causes cell death, fibrosis, and cirrhosis. 

Etiology

HT1 is caused by mutations in the FAH gene, which is located on chromosome 15q25.1.  

Various types of mutations occur in the FAH gene including missense mutations, nonsense mutations, insertions, deletions, and splice site mutations.  

Individuals who have one mutated copy and one normal copy of the FAH gene are carriers. Carriers do not show symptoms of the disease but can pass the mutated gene. 

Genetics

Prognostic Factors

Early identification through newborn screening or clinical diagnosis improves outcomes significantly. Early treatment with NTBC and diet helps prevent organ damage. 

NTBC treatment improves prognosis to block toxic metabolite formation in patients. It inhibits an enzyme in the tyrosine degradation pathway. 

Hepatocellular carcinoma is a serious complication with a poor prognosis in untreated or late-diagnosed patients. 

Clinical History

The clinical history of a patient with Type 1 Hereditary Tyrosinemia involves onset and severity of symptoms with some patients present in the neonatal period and others later in infancy or early childhood.  

Physical Examination

• Neurological Examination 
• Musculoskeletal Examination 
• Cardiovascular Examination 
• Renal Examination 

Age group

Associated comorbidity

Associated activity

Acuity of presentation

Acute symptoms are: 

• Acute Liver Failure 
• Metabolic Crisis 
• Gastrointestinal Symptoms 
• Chronic symptoms are: 
• Renal Tubulopathy 
• Progressive Liver Disease 
• Neurological Symptoms 

Differential Diagnoses

• Neonatal Hemochromatosis 
• Galactosemia 
• Biliary Atresia 
• Alpha-1 Antitrypsin Deficiency 

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

Avoid the accumulation of succinyl acetone and toxic metabolites that cause liver and kidney damage. 

Nitisinone blocks 4-hydroxyphenylpyruvate dioxygenase in tyrosine degradation pathway. 

Reduce the substrate load on the tyrosine degradation pathway and prevent the buildup of tyrosine and its derivatives. 

Inhibition of harmful metabolites stops such as maleylacetoacetate and fumarylacetoacetate to prevent succinyl acetone buildup and organ damage. 

Monitoring blood and urine succinyl acetone levels to gauge the effectiveness of nitisinone therapy. 

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

use-of-non-pharmacological-approach-for-type-1-hereditary-tyrosinemia

Food items should meet dietary restrictions for HT1 to use specialized low tyrosine/phenylalanine medical formulas and foods. 

Regular metabolic follow-ups for monitoring succinyl acetone levels, liver/kidney function, and health. 

Store medical foods and formulas according to their specific requirements to maintain efficacy. 

Proper awareness about HT-1 should be provided and its related causes with management strategies. 

Appointments with a physician and preventing recurrence of disorder is an ongoing life-long effort. 

Use of HPPD inhibitors

Nitisinone: 

It inhibits the 4-hydroxyphenylpyruvate dioxygenase enzyme, which is involved in the tyrosine degradation pathway. 

use-of-intervention-with-a-procedure-in-treating-type-1-hereditary-tyrosinemia

Use of Intervention with a procedure in treating Type-1 hereditary tyrosinemia

use-of-phases-in-type-1-hereditary-tyrosinemia

In the initial assessment phase, rapid identification and management to prevent severe complications and stabilize the patient. 

Biochemical testing was conducted to confirm diagnosis through elevated succinyl acetone levels in blood or urine. 

Pharmacologic therapy is effective in the treatment phase as it includes use of HPPD inhibitors. 

In supportive care and management phase, patients should receive required attention such as lifestyle modification and intervention therapies. 

The regular follow-up visits with the physician are scheduled to check the improvement of patients along with treatment response. 

Medication

Future Trends

Media Gallary

References

The pathophysiology and treatment of hereditary tyrosinemia type 1 – PubMed (nih.gov) 

Hereditary tyrosinemia type I–an overview – PubMed (nih.gov)