TYROSINEMIA-I
 
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TYROSINEMIA-1

 

DEFINITION:

A disorder of tyrosine metabolsim characterized by the build-up of tyrosine and its metabolites resulting in hepatic and renal damage.

EPIDEMIOLOGY:

  • incidence: rare (about 100 cases worldwide)
  • age of onset:
    • first 6 months of life (acute form); after 1 year (chronic form)
  • risk factors:
    • familial - autosomal recessive
      • chrom.#: 15q23-q25
      • gene: fumarylacetoacetate hydrolase (FAH)
    • French-Canadian population
      • 146/100,000 live births
    • F = M

PATHOGENESIS:

1. Background

  • FAH is an enzyme consisting of two subunits
  • metabolism of tyrosine to CO2 and H2O occurs in about 6 steps
  • FAH catalyzes the final step where fumarylacetoacetic acid is broken down into fumaric acid and acetoacetic acid
  • a deficiency in FAH will therefore result in the accumulation of fumarylacetoacetic acid which is subsequently metabolized to succinylacetoacetic acid and succinylacetone

2. Genetic Defect

  • mutation in gene coding for FAH -> accumulation of tyrosine and its metabolites (succinylacetoacetate, succinylacetone, and fumarylacetone) in the liver and kidney
  • succinylacetone is structurally similar to maleic acid which is a known inhibitor of renal tubular function and may cause the renal tubular abnormality (i.e., Fanconi Syndrome)
  • succinylacetone may also inhibit porphobilinogen synthetase which results in the accumulation of aminolevulinic acid and symptoms of acute intermittent porphyria
  • two forms exist and it appears that the degree of residual FAH activity determines whether or not the disease will be acute or chronic:

1. Acute Form

  • no FAH activity
  • most common and severe form

2. Chronic Form

  • variable residual FAH activity
  • less severe form with later onset

CLINICAL FEATURES:

1. Acute Form

1. General

  • diarrhea, fever, failure to thrive, irritability, lethargy, vomiting
  • cabbage-like odour (methionine metabolites)

2. Hepatic Manifestations

  • hepatomegaly +/- abdominal distension
  • jaundice
  • hepatic failure:
    • ascites, edema, hypoglycemia
    • bleeding tendencies
      • ecchymoses, epistaxis, hematuria, melena
    • death from fulminant hepatic failure by 2 years

2. Chronic Form

1. General

  • developmental delay, failure to thrive (FTT)

2. Hepatic Manifestations

  • progressive cirrhosis
  • hepatocellular carcinoma (hepatoma) in 37% of cases
  • death from liver failure or hepatoma within first decade

3. Renal Manifestations (Fanconi Syndrome)

  • episodes of vomiting, dehydration, weakness, & unexplained fever
  • anorexia, constipation, polydipsia, polyuria, growth failure, rickets

4. Neurological Manifestations (in 40% of patients)

  • episodes of acute polyneuropathy resembling acute porphyria
    • severe leg +/- abdominal pain
    • hypertonia
    • vomiting and paralytic ileus
    • self-mutilation

5. Cardiovascular Manifestations

  • hypertrophic obstructive cardiomyopathy
  • hypertension

INVESTIGATIONS:

1. Tyrosinemia

1. Diagnostic

  • decreased activity of FAH in liver biopsy specimens or cultured fibroblasts
  • presence of succinylacetoacetate and succinylacetone in the serum or urine
  • prenatal:
    • decreased FAH activity in chorionic villus biopsy
    • elevated succinylacetone in amniotic fluid

2. Serum

  • elevated tyrosine and methionine
  • unconjugated and conjugated hyperbilirubinemia
  • hypoglycemia
  • elevated transaminases, prolonged PT
  • elevated alpha-fetoprotein
  • normocytic anemia, leukocytosis, thrombocytosis

3. Urine

  • elevated excretion of tyrosine and metabolites
  • aminoaciduria, hematuria

4. Liver Biopsy

  • consistent with chronic active hepatitis

2. Fanconi Syndrome

1. Serum

  • normal anion gap hyperchloremic metabolic acidosis (with low serum bicarbonate)
  • normal or low amino acids, normal glucose
  • hypophosphatemia, hypokalemia, hypouricemia
  • elevated alkaline phosphatase

2. Urine

  • generalized (non-specific) hyperaminoaciduria
  • glycosuria, phosphaturia
  • pH <5.5 with a low specific gravity
  • bicarbonaturia, hyperkaliuria, uricosuria, tubular proteinuria, hyposthenuria, carnitinuria, low urinary ammonia

3. Skeletal X-Ray

  • rickets, osteopenia, or osteoporosis

MANAGEMENT:

1. Diet

  • low phenylalanine, tyrosine, and methionine diet
    • progression of disease not halted but delayed
    • may get a phenylalanine-tyrosine deficiency syndrome
      • growth failure, anorexia, lethargy, hypotonia

2. Surgery

  • liver transplantation:
    • for end stage liver failure and prevents hepatoma
    • may not affect Fanconi Syndrome

3. Fanconi Syndrome

  • oral phosphate, bicarbonate, and Vit D supplements

4. Supportive

  • genetic counselling

 

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