Disorders of Tyrosine Metabolism
Introduction to Metabolic Disorders of Tyrosine
Tyrosine is a non-essential amino acid that plays a crucial role in the synthesis of neurotransmitters, thyroid hormones, and melanin. Metabolic disorders of tyrosine result from enzymatic defects in its catabolic pathway, leading to the accumulation of toxic metabolites and various clinical manifestations.
The main disorders in this category include:
- Tyrosinemia Type I (Fumarylacetoacetate Hydrolase Deficiency)
- Tyrosinemia Type II (Tyrosine Aminotransferase Deficiency)
- Tyrosinemia Type III (4-Hydroxyphenylpyruvate Dioxygenase Deficiency)
- Alkaptonuria (Homogentisate 1,2-Dioxygenase Deficiency)
- Hawkinsinuria (Hawkinsin-forming Oxygenase Deficiency)
Understanding these disorders is crucial for early diagnosis and appropriate management to prevent severe complications and improve patient outcomes.
Tyrosinemia Type I (Fumarylacetoacetate Hydrolase Deficiency)
Tyrosinemia Type I is the most severe form of tyrosine metabolism disorder, caused by a deficiency of fumarylacetoacetate hydrolase (FAH).
Pathophysiology:
- FAH deficiency leads to accumulation of fumarylacetoacetate and maleylacetoacetate
- These metabolites are converted to succinylacetone, which is highly toxic to the liver and kidneys
- Succinylacetone inhibits δ-aminolevulinic acid dehydratase, disrupting heme synthesis
Clinical Features:
- Acute form: Rapid liver failure in infants
- Chronic form: Progressive liver disease, renal tubular dysfunction, rickets
- Neurological crises: Peripheral neuropathy, paralysis, seizures
- Increased risk of hepatocellular carcinoma
Genetics:
Autosomal recessive inheritance, mutations in the FAH gene on chromosome 15q23-q25
Tyrosinemia Type II (Tyrosine Aminotransferase Deficiency)
Tyrosinemia Type II, also known as Richner-Hanhart syndrome, is caused by a deficiency of tyrosine aminotransferase (TAT).
Pathophysiology:
- TAT deficiency leads to elevated levels of tyrosine in blood and tissues
- Tyrosine crystals deposit in the cornea and skin
Clinical Features:
- Ocular: Photophobia, corneal ulcers, corneal opacities
- Dermatological: Painful palmoplantar hyperkeratosis
- Neurological: Developmental delay, intellectual disability (in some cases)
Genetics:
Autosomal recessive inheritance, mutations in the TAT gene on chromosome 16q22.1-q22.3
Tyrosinemia Type III (4-Hydroxyphenylpyruvate Dioxygenase Deficiency)
Tyrosinemia Type III is the rarest form of tyrosinemia, caused by a deficiency of 4-hydroxyphenylpyruvate dioxygenase (4-HPPD).
Pathophysiology:
- 4-HPPD deficiency results in elevated levels of tyrosine and 4-hydroxyphenylpyruvate
- Less severe than Types I and II due to the absence of toxic metabolite accumulation
Clinical Features:
- Neurological: Intermittent ataxia, seizures, developmental delay
- Mild intellectual disability in some cases
- Generally normal liver and kidney function
Genetics:
Autosomal recessive inheritance, mutations in the HPD gene on chromosome 12q24-qter
Alkaptonuria (Homogentisate 1,2-Dioxygenase Deficiency)
Alkaptonuria is a rare disorder caused by a deficiency of homogentisate 1,2-dioxygenase (HGD).
Pathophysiology:
- HGD deficiency leads to accumulation of homogentisic acid (HGA)
- HGA is excreted in urine, causing it to darken upon exposure to air
- HGA polymers deposit in connective tissues, causing ochronosis
Clinical Features:
- Dark urine (oxidizes to black upon standing)
- Ochronosis: Blue-black pigmentation of cartilage and connective tissues
- Arthritis, particularly of large joints and spine
- Cardiovascular complications: Aortic valve disease, coronary artery calcification
- Renal and prostate stones
Genetics:
Autosomal recessive inheritance, mutations in the HGD gene on chromosome 3q13.33
Hawkinsinuria (Hawkinsin-forming Oxygenase Deficiency)
Hawkinsinuria is a rare disorder of tyrosine metabolism caused by a specific mutation in the HPD gene, leading to the formation of hawkinsin.
Pathophysiology:
- Mutation in HPD gene causes the enzyme to produce hawkinsin instead of the normal product
- Hawkinsin is a sulfur-containing amino acid that is excreted in urine
Clinical Features:
- Transient metabolic acidosis in infancy
- Failure to thrive in early childhood
- Generally asymptomatic in adulthood
Genetics:
Autosomal dominant inheritance, specific mutation (A33T) in the HPD gene on chromosome 12q24-qter
Diagnosis of Tyrosine Metabolic Disorders
General Diagnostic Approach:
- Newborn screening: Measures tyrosine levels in dried blood spots
- Plasma amino acid analysis: Reveals elevated tyrosine levels
- Urine organic acid analysis: Detects specific metabolites
- Genetic testing: Confirms the specific gene mutation
Disorder-Specific Diagnostic Tests:
- Tyrosinemia Type I:
- Elevated succinylacetone in urine and blood
- Liver function tests, coagulation studies
- Imaging studies to assess liver and kidneys
- Tyrosinemia Type II:
- Slit-lamp examination of the cornea
- Skin biopsy of hyperkeratotic lesions
- Alkaptonuria:
- Urine darkening test
- Measurement of homogentisic acid in urine
- Radiographic studies to assess joint involvement
Treatment of Tyrosine Metabolic Disorders
General Principles:
- Dietary restriction of tyrosine and phenylalanine
- Supplementation with essential amino acids
- Regular monitoring of plasma amino acid levels
- Management of complications specific to each disorder
Disorder-Specific Treatments:
- Tyrosinemia Type I:
- NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione): Inhibits 4-HPPD
- Liver transplantation in severe cases or NTBC failure
- Tyrosinemia Type II:
- Topical lubricants and corticosteroids for ocular symptoms
- Topical retinoids for skin lesions
- Alkaptonuria:
- Nitisinone (NTBC) - off-label use, under investigation
- Pain management for arthritis
- Cardiac and renal monitoring
- Hawkinsinuria:
- Supportive care during infancy
- Generally, no specific treatment required in adulthood
Future Directions:
Research is ongoing in gene therapy and enzyme replacement therapy for various tyrosine metabolic disorders.
Tyrosinemia Type I (Fumarylacetoacetate Hydrolase Deficiency)
- What enzyme is deficient in Tyrosinemia Type I?
Fumarylacetoacetate hydrolase (FAH) - What is the mode of inheritance for Tyrosinemia Type I?
Autosomal recessive - Which metabolite accumulates in Tyrosinemia Type I?
Fumarylacetoacetate - What is the OMIM number for Tyrosinemia Type I?
276700 - What chromosome is the FAH gene located on?
Chromosome 15 (15q25.1) - What are the three main clinical forms of Tyrosinemia Type I?
Acute, subacute, and chronic - What is the most severe form of Tyrosinemia Type I?
Acute form - At what age does the acute form of Tyrosinemia Type I typically present?
Before 6 months of age - What organ is primarily affected in Tyrosinemia Type I?
Liver - What is the risk of hepatocellular carcinoma in untreated Tyrosinemia Type I patients?
Greater than 90% by age 20 - What amino acid-restricted diet is recommended for Tyrosinemia Type I patients?
Low-phenylalanine and low-tyrosine diet - What medication is the primary treatment for Tyrosinemia Type I?
Nitisinone (NTBC) - How does nitisinone work in treating Tyrosinemia Type I?
It inhibits 4-hydroxyphenylpyruvate dioxygenase, preventing the formation of toxic metabolites - What is the biochemical hallmark of Tyrosinemia Type I in urine?
Elevated succinylacetone - What renal manifestation is common in Tyrosinemia Type I?
Fanconi syndrome - What neurological complication can occur in Tyrosinemia Type I?
Porphyria-like neurological crises - What is the typical age of onset for the chronic form of Tyrosinemia Type I?
After 1 year of age - What blood test is used to screen for Tyrosinemia Type I in newborns?
Elevated tyrosine levels - What confirmatory test is used to diagnose Tyrosinemia Type I?
Genetic testing for FAH gene mutations - What is the long-term prognosis for Tyrosinemia Type I patients treated early with nitisinone?
Generally good, with reduced risk of liver disease and hepatocellular carcinoma - What growth abnormality is common in untreated Tyrosinemia Type I patients?
Failure to thrive - What skeletal manifestation can occur in Tyrosinemia Type I?
Rickets - What is the role of liver transplantation in Tyrosinemia Type I treatment?
It is curative but generally reserved for cases with liver failure or hepatocellular carcinoma - What is the estimated incidence of Tyrosinemia Type I worldwide?
Approximately 1 in 100,000 live births - In which population is Tyrosinemia Type I more common?
French Canadians in the Saguenay-Lac-Saint-Jean region of Quebec
Tyrosinemia Type II (Tyrosine Aminotransferase Deficiency)
- What enzyme is deficient in Tyrosinemia Type II?
Tyrosine aminotransferase (TAT) - What is the mode of inheritance for Tyrosinemia Type II?
Autosomal recessive - What is the OMIM number for Tyrosinemia Type II?
276600 - On which chromosome is the TAT gene located?
Chromosome 16 (16q22.2) - What are the primary clinical manifestations of Tyrosinemia Type II?
Ocular, dermatological, and neurological symptoms - What ocular symptom is characteristic of Tyrosinemia Type II?
Pseudodendritic keratitis - What dermatological manifestation is common in Tyrosinemia Type II?
Palmoplantar hyperkeratosis - What neurological symptoms can occur in Tyrosinemia Type II?
Developmental delay and intellectual disability - At what age do symptoms of Tyrosinemia Type II typically appear?
Early childhood, often before age 5 - What metabolite accumulates in the blood of Tyrosinemia Type II patients?
Tyrosine - What is the typical range of blood tyrosine levels in Tyrosinemia Type II?
Greater than 500 μmol/L, often exceeding 1000 μmol/L - What dietary treatment is recommended for Tyrosinemia Type II?
Low-tyrosine and low-phenylalanine diet - How does the liver function in Tyrosinemia Type II compared to Type I?
Liver function is typically normal in Tyrosinemia Type II - What is another name for Tyrosinemia Type II?
Richner-Hanhart syndrome - What test is used to confirm the diagnosis of Tyrosinemia Type II?
Genetic testing for mutations in the TAT gene - How does the incidence of Tyrosinemia Type II compare to Type I?
Tyrosinemia Type II is rarer than Type I - What is the role of nitisinone (NTBC) in treating Tyrosinemia Type II?
Nitisinone is not effective in treating Tyrosinemia Type II - What ophthalmological complication can occur if Tyrosinemia Type II is left untreated?
Corneal ulcers - How does dietary treatment affect the dermatological symptoms of Tyrosinemia Type II?
Skin lesions typically improve with dietary tyrosine restriction - What is the long-term prognosis for Tyrosinemia Type II patients with good dietary control?
Generally good, with improvement or prevention of symptoms - What biochemical test can be used to monitor treatment efficacy in Tyrosinemia Type II?
Blood tyrosine levels - How does Tyrosinemia Type II affect pregnancy?
Elevated maternal tyrosine levels can potentially harm fetal development - What is the risk of liver cancer in Tyrosinemia Type II?
There is no increased risk of liver cancer, unlike in Tyrosinemia Type I - What is the typical frequency of ophthalmological examinations recommended for Tyrosinemia Type II patients?
At least annually, or more frequently if symptoms persist - How does the intellectual prognosis of Tyrosinemia Type II compare to Type I?
Intellectual disability is more common in Type II, especially if treatment is delayed
Tyrosinemia Type III (4-Hydroxyphenylpyruvate Dioxygenase Deficiency)
- What enzyme is deficient in Tyrosinemia Type III?
4-Hydroxyphenylpyruvate dioxygenase (HPPD) - What is the mode of inheritance for Tyrosinemia Type III?
Autosomal recessive - What is the OMIM number for Tyrosinemia Type III?
276710 - On which chromosome is the HPD gene (encoding HPPD) located?
Chromosome 12 (12q24.31) - How common is Tyrosinemia Type III compared to Types I and II?
It is the rarest form of tyrosinemia - What are the primary clinical manifestations of Tyrosinemia Type III?
Neurological symptoms, including intellectual disability and seizures - Does Tyrosinemia Type III typically affect liver function?
No, liver function is usually normal - What metabolite accumulates in the blood of Tyrosinemia Type III patients?
Tyrosine - What is the typical range of blood tyrosine levels in Tyrosinemia Type III?
350-700 μmol/L, but can be higher - What dietary treatment is recommended for Tyrosinemia Type III?
Low-tyrosine and low-phenylalanine diet - How does Tyrosinemia Type III differ from Type I in terms of succinylacetone levels?
Succinylacetone is not elevated in Tyrosinemia Type III - What test is used to confirm the diagnosis of Tyrosinemia Type III?
Genetic testing for mutations in the HPD gene - At what age do symptoms of Tyrosinemia Type III typically appear?
Symptoms can appear in infancy or early childhood - What is the role of nitisinone (NTBC) in treating Tyrosinemia Type III?
Nitisinone is not used in treating Tyrosinemia Type III, as it inhibits the already deficient enzyme - How does Tyrosinemia Type III affect pregnancy?
Elevated maternal tyrosine levels may potentially affect fetal development - What is the long-term prognosis for Tyrosinemia Type III patients with good dietary control?
Generally good, with potential improvement or stabilization of neurological symptoms - What biochemical test can be used to monitor treatment efficacy in Tyrosinemia Type III?
Blood tyrosine levels - How does Tyrosinemia Type III differ from Type II in terms of ocular symptoms?
Tyrosinemia Type III does not typically cause ocular symptoms - What is the risk of liver cancer in Tyrosinemia Type III?
There is no increased risk of liver cancer - How does the intellectual prognosis of Tyrosinemia Type III compare to Types I and II?
Intellectual disability can occur but may be less severe than in Type II if treated early - What other neurological symptoms may be present in Tyrosinemia Type III?
Ataxia, tremors, and developmental delay - How is Tyrosinemia Type III typically detected in newborn screening programs?
Through elevated tyrosine levels, similar to other types of tyrosinemia - What is the estimated incidence of Tyrosinemia Type III worldwide?
Unknown due to its rarity, but fewer than 20 cases have been reported in medical literature - How does Tyrosinemia Type III affect the breakdown of tyrosine?
It blocks the second step in tyrosine catabolism, leading to accumulation of 4-hydroxyphenylpyruvate - What is the importance of early diagnosis and treatment in Tyrosinemia Type III?
Early intervention may prevent or minimize neurological complications
Alkaptonuria (Homogentisate 1,2-Dioxygenase Deficiency)
- What enzyme is deficient in Alkaptonuria?
Homogentisate 1,2-dioxygenase (HGD) - What is the mode of inheritance for Alkaptonuria?
Autosomal recessive - What is the OMIM number for Alkaptonuria?
203500 - On which chromosome is the HGD gene located?
Chromosome 3 (3q13.33) - What metabolite accumulates in Alkaptonuria?
Homogentisic acid - What is the characteristic urine color change in Alkaptonuria?
Dark brown or black upon standing or exposure to air - What is the term for the deposition of pigment in connective tissues in Alkaptonuria?
Ochronosis - At what age do the first symptoms of Alkaptonuria typically appear?
Often in adulthood, typically after 30 years of age - What joints are commonly affected in Alkaptonuria?
Large joints such as hips, knees, and shoulders - What cardiovascular complication can occur in Alkaptonuria?
Aortic valve disease - How does Alkaptonuria affect the spine?
It can cause intervertebral disc calcification and fusion - What is the estimated incidence of Alkaptonuria worldwide?
Approximately 1 in 250,000 to 1 in 1,000,000 live births - What test is used to confirm the diagnosis of Alkaptonuria?
Genetic testing for mutations in the HGD gene - How does Alkaptonuria affect the skin?
It can cause bluish-black discoloration, especially in sun-exposed areas - What is the current standard treatment approach for Alkaptonuria?
Symptomatic management and supportive care - What dietary restrictions are sometimes recommended for Alkaptonuria patients?
Low protein diet, particularly limiting phenylalanine and tyrosine intake - What medication has shown promise in clinical trials for treating Alkaptonuria?
Nitisinone (NTBC) - How does nitisinone work in Alkaptonuria?
It inhibits 4-hydroxyphenylpyruvate dioxygenase, reducing homogentisic acid production - What is the name of the diagnostic test that involves adding sodium hydroxide to urine?
Benedict's test - How does Alkaptonuria affect life expectancy?
It generally does not significantly reduce life expectancy but can affect quality of life - What is the characteristic appearance of cartilage in Alkaptonuria patients?
Black or blue-gray discoloration - How does Alkaptonuria affect kidney function?
It can lead to kidney stones and renal impairment - What is the role of antioxidants in managing Alkaptonuria?
They may help reduce oxidative stress and tissue damage - How does Alkaptonuria affect prostate health in men?
It can lead to prostate stones and increased risk of prostate cancer - What imaging technique is commonly used to assess joint damage in Alkaptonuria?
X-rays and MRI
