Disorders of tyrosine metabolism http://www-uptodate-com.ezproxy.galter.northwestern.edu/contents/disor...

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Disorders of tyrosine metabolism

Author Section Editors Deputy Editor

Markus Grompe, MD Helen V Firth, DM, FRCP, DCH Elizabeth TePas, MD, MS
Elizabeth B Rand, MD

Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2012. | This topic last updated: Aug 14, 2012.

INTRODUCTION — Tyrosine is an aromatic amino acid important in the synthesis of thyroid hormones,
catecholamines, and melanin. Impaired catabolism of tyrosine is a feature of several acquired and genetic disorders
that may result in elevated plasma tyrosine concentrations [1].

TYROSINE METABOLISM — Tyrosine degradation is catalyzed by a series of five enzymatic reactions that yield
acetoacetate, which is ketogenic, and the Krebs cycle intermediate fumarate, which is glucogenic (figure 1). The
hepatocyte and renal proximal tubules are the only two cell types that express the complete pathway and contain
sufficient quantities of all enzymes required for tyrosine catabolism.

Four autosomal recessive disorders result from deficiencies in specific enzymes in the tyrosine catabolic pathway:
hereditary tyrosinemia (HT) types 1, 2, and 3, and alkaptonuria. Each disorder is assigned a number on the Online
Mendelian Inheritance in Man (OMIM) website located at www.omim.org. Except for alkaptonuria, these disorders
result in elevated blood tyrosine levels.

Hypertyrosinemia — Normal plasma tyrosine concentrations are 30 to 120 micromol/L. Values >200 micromol/L are
considered elevated. However, clinical manifestations typically do not become apparent until plasma levels exceed
500 micromol/L.

Hypertyrosinemia is detected by quantitative measurement of plasma amino acids. This test usually is performed to
evaluate otherwise unexplained liver disease or neurologic abnormalities, such as seizures or developmental delay.
Hypertyrosinemia also may be detected on a plasma specimen obtained to investigate elevated urinary tyrosine,
seen in the renal Fanconi syndrome (which is manifested by impaired proximal tubular function). HT types 1 and 2
may be detected by expanded newborn metabolic screening available in some states.

Hypertyrosinemia is caused by a variety of genetic and acquired disorders (table 1). They include:

Inherited deficiencies of enzymes in the degradation pathway

Transient tyrosinemia of the newborn
Liver disease
Miscellaneous disorders including scurvy and hyperthyroidism

The most important diagnostic consideration in the evaluation of hypertyrosinemia is the presence or absence of
liver disease. If liver disease is present, additional tests must be performed urgently to detect HT type 1, a potentially
lethal disorder that requires immediate treatment.

HEREDITARY TYROSINEMIA TYPE 1 — Hereditary tyrosinemia type 1 (HT1, MIM# 276700), also known as
hepatorenal tyrosinemia, is the most severe disorder of tyrosine metabolism. Hereditary tyrosinemia type 1 occurs in
1 in 12,000 to 1 in 100,000 individuals of northern European descent [2].

HT1 pathophysiology — HT1 is caused by deficiency of fumarylacetoacetate hydrolase (FAH), the last enzyme in
the pathway of tyrosine catabolism (figure 1) [3]. Fumarylacetoacetate (FAA), the substrate for FAH in the tyrosine

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pathway, accumulates in FAH-deficient hepatocytes and proximal renal tubular cells, resulting in liver and kidney
damage.

FAA causes oxidative damage to cells by reacting with glutathione and sulfhydryl groups of proteins [4]. FAA is also
mutagenic [5,6], although it is not known whether it causes direct or indirect damage to DNA. The mutagenicity of
FAA is thought to be the cause of the high rate of hepatocellular carcinoma in HT1.

The oxidative and DNA damage caused by FAA leads to either cell death or a profound perturbation of gene
expression, especially in the liver [7,8]. As a result, many metabolic processes, including gluconeogenesis,
detoxification of ammonia, and synthesis of secreted proteins, are impaired. Impaired protein synthesis in
FAH-deficient hepatocytes leads to a marked reduction in tyrosine aminotransferase (TAT), the first enzyme in
tyrosine degradation, resulting in the elevated plasma tyrosine levels typical of the disorder. Tyrosine itself is not
toxic to the liver or kidney, but causes dermatologic, ophthalmologic, and possibly neurodevelopmental problems.

FAA has a short intracellular half-life (the mechanism is not known) and thus is not found in body fluids of HT1
patients. The principal metabolites of FAA, succinylacetoacetate (SAA) and succinylacetone (SA) are released into
the circulation and can be measured for diagnosis.

Increased levels of these metabolites can lead to secondary biochemical alterations in HT1. As an example, SA is a
potent inhibitor of aminolevulinate (ALA) dehydratase (porphobilinogen synthase), the first step of heme biosynthesis
[3,9,10]. This can result in neurologic symptoms of ALA dehydratase porphyria [11]. Circulating SA also may impair
proximal ALA reabsorption, which contributes to the increase in ALA excretion [12]. (See "ALA dehydratase
porphyria".)

HT1 genetics — The mode of inheritance for HT1 is autosomal recessive. The gene encoding FAH has been
mapped to human chromosome 15q23-q25, cloned, and sequenced [13,14].

HT1 occurs more commonly in some ethnic groups, most notably in the Saguenay-Lac-St.-Jean region of Quebec.
In that population, the carrier rate and prevalence at birth were estimated at 1 in 20 to 25 inhabitants and 1 in 1846
live births, respectively [15,16]. A splice mutation was identified in the FAH gene in all patients from Saguenay-
Lac-St.-Jean and in 28 percent of patients from other regions [16]. A stop mutation is common in Finnish patients
[17].

HT1 clinical features — HT1 is characterized by severe progressive liver disease and renal tubular dysfunction.
The latter typically is manifest as the Fanconi syndrome with renal tubular acidosis, aminoaciduria, and
hypophosphatemia (due to phosphate wasting) [18]. Features of rickets often are present.

Most patients present in early infancy with failure to thrive and hepatomegaly. Some develop conjugated
hyperbilirubinemia. An often marked elevation in serum alpha fetoprotein (AFP) is common in HT1. Studies in
newborns have shown that cord blood AFP is elevated at a time when tyrosine levels are still normal [19]. This
observation suggests that the liver disease begins prenatally. (See "Causes of neonatal cholestasis".)

Progression of the liver disease can be chronic or acute, with rapid deterioration and early death [1]. Liver
dysfunction commonly results in hypoglycemia and coagulation abnormalities. Serum aminotransferase levels
typically are only mildly elevated and often disproportionately low compared with the marked degree of
coagulopathy. Complications of liver failure, including jaundice, ascites, and hemorrhage often develop.

The chronic form consists of a mixed micronodular and macronodular cirrhosis. The risk of developing hepatocellular
carcinoma is high in survivors, occurring in as many as 37 percent of patients older than two years of age [20,21].
Cancer formation is thought to be caused by the mutagenicity of FAA.

Both the acute and chronic forms can occur in affected siblings or other patients with identical genotypes [22].
Intrafamilial variability in the severity of HT1 may be caused in part by somatic mosaicism. Immunohistologic
analysis of liver in some patients shows enzyme activity in some regenerating nodules [23,24]. In these areas of
regeneration, one of the mutant alleles may revert spontaneously to the normal genotype [23]. Reversion to the
normal allele in some individuals may be associated with milder liver disease, but the risk for liver cancer remains

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[25].

Severe neurologic manifestations are common in poorly controlled HT1 and contribute to morbidity and mortality. In
one study of 48 children with tyrosinemia identified with neonatal screening, neurologic crises resembling the crises
of the neuropathic porphyrias occurred in 20 (42 percent) [11]. These acute episodes of peripheral neuropathy were
characterized by severe pain with extensor hypertonia (in 75 percent), vomiting or paralytic ileus (69 percent),
muscle weakness (29 percent), and self-mutilation (8 percent). Eight children required mechanical ventilation
because of paralysis. Between crises, most patients regained normal function. Electrophysiologic studies in seven
patients and neuromuscular biopsies in three patients showed axonal degeneration and secondary demyelination.
Intellectual disability (mental retardation) is not a feature.

About 30 percent of patients display cardiomyopathy at the time of diagnosis with interventricular septal hypertrophy
being the most common finding. This disease manifestation is reversible with nitisinone therapy [26,27].

If untreated, patients with HT1 have a significantly shortened lifespan. Patients may die of acute liver failure before
the second year after birth, or from chronic liver failure or hepatocellular carcinoma before the end of the second
decade.

HT1 laboratory diagnosis — The most important diagnostic test for HT1 is the measurement of urine organic acids.
The presence of succinylacetone in urine is pathognomonic for the disorder. The diagnosis is confirmed by
measurement of FAH enzyme activity in cultured skin fibroblasts. Molecular testing for disease causing mutations is
available through multiple laboratories. Affected patients also have elevated plasma concentrations of tyrosine and
methionine and excrete tyrosyl compounds in the urine.

Newborn screening for HT1 is available in regions with high prevalence, including Quebec, and in some states in the
United States. Tandem mass spectrometry can reliably detect diagnostic quantities of succinylacetone [28]. (See
"Newborn screening".)

HT1 management — Dietary treatment, consisting of foods with low or absent phenylalanine, tyrosine, and
methionine and restriction of natural protein, results in decreased tyrosine levels. However, this approach does not
stop the production of SA, prevent the progression of liver or renal disease, or reduce the risk of developing
hepatocellular carcinoma or neurologic abnormalities.

Nitisinone — The treatment of choice is nitisinone (Orfadin), formerly known as NTBC, which inhibits 4-OH
phenylpyruvate dioxygenase (HPD), an early step in the tyrosine degradation pathway [29]. This treatment reduces
metabolic flow through the pathway and limits formation of the toxic compounds FAA and SA (figure 1).

Since the first nitisinone trial in 1991, approximately 90 percent of treated patients have improved clinically [30,31].
Treatment started at an early age decreases the risk of early development of hepatocellular carcinoma, although
longer follow-up is needed to determine if the effect persists throughout life. In addition, the long-term risk of
developing neurologic problems is unknown; this is a concern because neurologic complications develop in some
patients with inherited HPD deficiency, the same enzyme affected by nitisinone [32,33]. A study of long-term
outcomes of NTBC treatment in France showed cognitive impairment in 35 percent of patients [31]. It is not known
whether this phenotype is related to elevated tyrosine or caused by other factors.

A typical starting dose of nitisinone is 1 mg/kg per day, divided into a morning and evening dose and given orally.
Because nitisinone increases plasma tyrosine levels, patients should have a protein-restricted diet that is low in
phenylalanine and tyrosine. The dietary protein intake is varied to keep the plasma tyrosine level <500 micromol/L.
Monitoring includes the measurement of plasma amino acids, blood and urinary succinylacetone (SA), liver function
tests, complete blood count (CBC) and differential, and serum alpha fetoprotein (which increases further with
hepatocellular carcinoma).

If the biochemical parameters (except plasma SA) have not normalized within one month of starting therapy, the
dose should be increased to 1.5 mg/kg per day. The dose of nitisinone should be adjusted to completely suppress
excretion of SA. However, it may take as long as three months for complete suppression of SA to occur. A dose of 2

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mg/kg per day may be needed, especially in infants. However, this dose should be considered maximal.

Metabolic monitoring is performed monthly for the first year, then every three months throughout childhood. The
CBC should be monitored because some patients develop hematologic abnormalities [34], especially leukopenia
and thrombocytopenia. Ophthalmologic examination and hepatic imaging (magnetic resonance imaging is preferred)
should be performed annually. Some patients treated with nitisinone have reduced levels of blood
phenylalanine levels, raising concerns about negative effects on growth and neurologic development from lack of
this essential amino acid [35]. The clinical significance of this observation is unclear, but some centers chose to
supplement phenylalanine in the diet when two independent measurements show phenylalanine levels of <30
micromoles/L [35].

Serum alpha fetoprotein (AFP) can take many months to normalize after Nitisinone therapy is started. It is important
to monitor the trend of the decline, which should be continuously downward. If AFP levels off in a range above
normal or begins to increase, an evaluation of possible hepatocarcinoma should be initiated. In one study, AFP
levels did not normalize in about one-third of patients, even after one year of NTBC treatment [31].

Liver transplantation — Orthotopic liver transplantation (OLT) is performed in patients with persistent liver
failure who do not respond to nitisinone therapy or have hepatic malignancy [36,37]. In one series of eight patients
transplanted at a median age of 64 months, plasma tyrosine and alpha fetoprotein returned to normal, urinary SA
decreased, and, if present, hypertrophic cardiomyopathy resolved [36]. Two children died, one from a nonfunctioning
graft and one from chronic rejection. Late complications in the six survivors included renal dysfunction in three and
lymphoproliferative disease of the iris in one. Renal tubular function remains abnormal in many transplanted patients
and careful monitoring of kidney function is therefore recommended [34]. Plasma and urinary SA levels are not
completely normalized after transplantation [38], but the clinical significance of this finding is unknown. OLT is not
predicted to prevent the accumulation of mutagenic and toxic FAA in renal tubules. More extensive long-term studies
are needed to determine whether renal pathology (progressive tubular disease or renal cancer) can be prevented by
OLT in the absence of nitisinone treatment.

HEREDITARY TYROSINEMIA TYPE 2 — Hereditary tyrosinemia type 2 (HT2, MIM# 276600), also known as
oculocutaneous tyrosinemia or Richner-Hanhart syndrome, is characterized by early development of eye and skin
abnormalities.

HT2 pathophysiology — HT2 is caused by deficiency of tyrosine aminotransferase (TAT), the first enzyme in the
tyrosine degradation pathway (figure 1). As a result, plasma tyrosine and its metabolites are elevated. These
elevated levels are thought to be responsible for the clinical manifestations of the disorder. In animal models, a diet
high in tyrosine can induce the ocular findings of HT2 [39].

HT2 genetics — HT2 is inherited in an autosomal recessive pattern. The gene encoding for TAT has been mapped
to chromosome 16q22 and cloned [40]. Mutations in this gene are responsible for HT2 [41].

HT2 clinical features — The ophthalmologic and dermatologic features of HT2 usually become apparent in the first
year after birth, although some patients present as adults. The characteristic ocular findings are corneal ulcers or
dendritic keratitis (table 2). These result in photophobia, pain, excessive lacrimation, and redness.

The skin lesions consist of painful hyperkeratotic plaques, primarily on the palms and soles. Plaques also may
develop on elbows, knees, and ankles. Some patients have erythematous papular lesions.

Approximately 50 percent of patients with HT2 have intellectual disability (mental retardation) [42]. However, it is
unclear whether the neurologic problems are due to elevated tyrosine or caused by other factors such as
consanguinity. Unlike HT1, the liver and kidney are not affected in this disorder; as a result, liver function tests, the
plasma creatinine concentration, and acid -base balance are normal.

HT2 laboratory diagnosis — HT2 should be suspected if patients present with typical signs or if elevated
tyrosine levels are detected on newborn metabolic screening. The plasma tyrosine concentration in this disorder
typically is >1000 micromol/L, substantially higher than in other forms of tyrosinemia. The urine contains large

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amounts of tyrosine metabolites (eg, 4-hydroxyphenylacetate, 4-hydroxyphenylactate, and

4-hydroxyphenylpyruvate).

Measurement of urine organic acids and serum alpha fetoprotein should be performed to exclude a mild form of
HT1. The diagnosis is confirmed by detection of mutations in the TAT gene in cultured skin fibroblasts or blood [41].

HT2 management — Management of HT2 consists of a diet low in tyrosine and phenylalanine. Plasma tyrosine
levels should be kept below 500 micromol/L. This approach usually results in resolution of the skin and eye lesions.
Early dietary intervention may prevent cognitive impairment [42].

HEREDITARY TYROSINEMIA TYPE 3 — Type 3 tyrosinemia (MIM# 276710) is a rare autosomal recessive disorder
caused by deficiency of 4-hydroxyphenylpyruvate dioxygenase (HPD), the second step in the tyrosine catabolism
pathway (figure 1) [33,43]. Numerous mutations have been identified in the HPD gene on chromosome 12q24 [44].
Most affected patients have neurologic dysfunction, including ataxia, seizures, and mild psychomotor retardation, but
no other systemic involvement (table 2). The majority of reported cases have mental retardation, but a causative
relationship between HPD deficiency and neurologic problems has not been conclusively demonstrated.
Ascertainment bias may account for the apparent correlation.

The diagnosis is confirmed by detection of mutations in the HPD gene in cultured skin fibroblasts or blood. Prenatal
detection is available using this technique.

Plasma tyrosine levels are elevated in this disorder, but typically remain below 500 micromol/L and therefore usually
do not cause corneal ulcers or hyperkeratosis. Treatment consists of a diet low in tyrosine and phenylalanine,
although whether this diet can prevent or reverse the neurologic symptoms is uncertain.

ALKAPTONURIA — Alkaptonuria (AKU, MIM# 203500) is an autosomal recessive disorder that results from
deficient activity of homogentisic acid dioxygenase (HGD, HGO), the third enzyme in tyrosine degradation [45]. The
description of alkaptonuria by Garrod in 1902 led to recognition of the concept of a single enzyme deficiency
resulting in lifelong disease [46]. The gene encoding HGD has been mapped to chromosome 3q21-q23 and
mutations identified in patients with AKU [47,48].

Clinical features — HGD deficiency results in elevated levels of homogentisic acid (HGA), which polymerizes,
forming a pigment that is deposited in connective tissue throughout the body (ochronosis) (picture 1). Affected
patients usually are asymptomatic in childhood.

During the third decade, deposits of the brownish or bluish pigment become apparent, typically first in the ear
cartilage and sclerae. Additional pigment is deposited in the large joints and the spine, especially the lumbosacral
region. Calcification of multiple intervertebral discs is a characteristic radiographic finding. The development of
ochronotic arthritis results in limitation of motion and often complete ankylosis, resembling rheumatoid arthritis or
osteoarthritis (table 2). Axillary and inguinal areas may have a brownish discoloration [21]. Perspiration can stain
clothing in affected patients.

The natural history of alkaptonuria was evaluated in a study of 58 patients, ages 4 to 80 years [49]. Arthropathy was
common, and one-half of the patients had replacement of one knee, hip, or shoulder before 55 years of age. Renal
stones developed in 16 patients (27 percent), at a mean age of 64 years. The mean ages for detection of cardiac
valve involvement and coronary artery calcification were 54 and 59 years, respectively. In another series, aortic valve
disease was common in patients over 40 years of age [50].

Diagnosis — The disorder is characterized by the excretion of urine that appears normal when fresh, but turns dark
brown or black if left standing or after alkalinization. The dark color is caused by oxidation of homogentisic acid, and
alkaptonuria has also been called black urine disease. Cloth diapers that are washed in alkaline solutions will have
dark brown staining.

Although the discoloration of urine in AKU is apparent in infancy, the diagnosis usually is made in adults during
routine urinalysis or investigation of arthritis [51]. In the natural history study cited above, AKU was diagnosed before
one year of age in 12 of 58 patients (21 percent) [49]. In the remaining patients, the mean age at diagnosis was 29

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years.

Levels of HGA are increased in blood, urine, and tissue samples. The diagnosis is confirmed by quantitative
measurement of HGA in urine. Tyrosine levels are normal.

Management — No effective therapy is available for AKU. Dietary restriction of tyrosine and phenylalanine will
reduce the excretion of HGA, although the clinical effect is limited [52]. The arthropathy mostly is not reversible,
although diet may prevent further progression. Ascorbic acid, which inhibits the enzyme that catalyses the oxidation
of HGA to the polymer with affinity for collagen, is given, but its efficacy has not been demonstrated for ochronosis
[52]. Nitisinone, which inhibits the second enzyme in the tyrosine catabolic pathway, decreased urinary HGA levels
by 95 percent in one short-term study [53]. However, no clinical benefits (hip total range of motion and other
measures of musculoskeletal function) were demonstrated in a randomized trial of AKU patients who already had
significant arthritis [54]. It is currently unknown whether early treatment prior to the development of musculoskeletal
symptoms would be beneficial.

ACQUIRED TYROSINEMIA — The most common causes of elevated plasma tyrosine levels are acquired rather
than inherited (table 1).

Transient tyrosinemia of the newborn — Transient tyrosinemia of the newborn is the most common acquired
cause of increased plasma tyrosine levels [1,55]. The etiology of this disorder is immaturity of HPD, which is involved
in an early step of tyrosine degradation (figure 1). Transient immaturity of this enzyme, the gene for which is mutated
in HT3, occurs in approximately 10 percent of preterm infants and some term infants.

This disorder rarely is a problem with modern neonatal management. In the past, affected patients could develop
lethargy, poor feeding, metabolic acidosis, and prolonged jaundice. Symptoms responded rapidly to ascorbic acid, a
cofactor of HPD, and decreased protein intake.

Hepatocellular dysfunction — Hepatocellular dysfunction of any etiology can result in elevated plasma
tyrosine levels and excretion of increased amounts of tyrosine metabolites in urine. The tyrosine levels usually are
<500 micromol/L; as a result, symptoms of hypertyrosinemia are not seen. However, the association can cause
diagnostic confusion in a child who presents with unexplained liver disease in whom elevated plasma tyrosine could
reflect HT1.

SUMMARY

Four autosomal recessive disorders result from deficiencies in specific enzymes in the tyrosine catabolic
pathway: hereditary tyrosinemia (HT) types 1, 2, and 3, and alkaptonuria (figure 1). Except for alkaptonuria,
these disorders result in elevated blood tyrosine levels (table 2). (See 'Tyrosine metabolism' above.)

Hypertyrosinemia is caused by a variety of genetic and acquired disorders; acquired disorders are more
common (table 1). (See 'Hypertyrosinemia' above.)

HT type 1 (HT1, hepatorenal tyrosinemia) is characterized by severe progressive liver disease and renal
tubular dysfunction (table 2). Most patients present in early infancy with failure to thrive and hepatomegaly.
Nitisinone is the treatment of choice. (See 'Hereditary tyrosinemia type 1' above.)

HT 2 (HT2, oculocutaneous tyrosinemia), is characterized by early development of eye and skin abnormalities
that usually become apparent in the first year of life (table 2). HT2 should be suspected in patients with typical
signs or elevated tyrosine levels on newborn metabolic screening. Management consists of a diet low in
tyrosine and phenylalanine. (See 'Hereditary tyrosinemia type 2' above.)

HT 3 (HT3) is a rare disorder. Affected patients often have neurologic dysfunction (ataxia, seizures, mild
psychomotor retardation), but no other systemic involvement (table 2). Treatment consists of a diet low in
tyrosine and phenylalanine. (See 'Hereditary tyrosinemia type 3' above.)

Alkaptonuria (AKU) should be suspected in patients whose urine appears normal when fresh, but turns dark

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brown or black if left standing after alkalinization. Patients with AKU usually are asymptomatic in childhood;
during the third decade, deposits of brownish or bluish pigment become apparent in the ear cartilage and
sclerae (picture 1). Tyrosine levels are normal. No effective therapy is available; dietary restriction of tyrosine
and phenylalanine reduce the excretion of homogentisic acid, although the clinical effect is limited. Clinical
trials with nitisinone are ongoing and have shown early promise. (See 'Alkaptonuria' above.)

Transient tyrosinemia of the newborn is the most common acquired cause of hypertyrosinemia. It is caused
by immaturity of 4-OH phenylpyruvate dioxygenase (HPD) (figure 1) and occurs in approximately 10 percent
of preterm infants and in some term infants. (See 'Transient tyrosinemia of the newborn' above.)

Hepatocellular dysfunction of any etiology can result in elevated plasma tyrosine levels and excretion of
increased amounts of tyrosine metabolites in urine. The tyrosine levels usually are <500 micromol/L. (See
'Hepatocellular dysfunction' above.)

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Topic 2935 Version 5.0

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GRAPHICS

Tyrosine degradation

(1) Tyrosinemia type II - corneal ulcers, hyperkeratosis,

occasional mental retardation
(2) Tyrosinemia type III - possible mental retardation
(3) Alkaptonuria - ochronosis, black urine
(4) Maleylacetoacetate isomerase deficiency - phenotype?
(5) Tyrosinemia type I - liver failure, renal damage TAT: tyrosine
aminotransferase; 4-OHPPD: 4-OH phenylpyruvate dioxygenase; HGD:
homogentisic acid dioxygenase; MAI: Maleylacetoacetate isomerase; FAH:
fumarylacetoacetate hydrolase. Courtesy of Markus Grompe, MD.

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Etiology of elevated blood tyrosine levels

1. Hepatocellular dysfunction

2. Transient tryosinemia of the newborn

3. Genetic enzyme deficiencies in tyrosine degradation

Hepatorenal tyrosinemia (HT1)

Oculocutaneous tyrosinemia (HT2)

4-OH-phenylpyruvate dioxygenase deficiency (HT3)

4. Miscellaneous
Scurvy

Hyperthyroidism

Postprandial sample

NTBC therapy

Courtesy of Markus Grompe, MD.

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Clinical manifestations of enzyme deficiencies in tyrosine catabolism

Tyrosine 4-OH-phenylpyruvate Homogentisate Maleylaceto- Fumarylaceto-

Defective aminotransferase dioxygenase dioxygenase acetate acetate
enzyme isomerase hydrolase

Tyrosinemia type III Alkaptonuria No human

Tyrosinemia type patients Tyrosinemia
II described type I

Oculocutaneous Hepatorenal
Disease tyrosinemia tyrosinemia
name(s)
Richner-
Hanhardt
syndrome

Elevated +++ ++ ? ++
blood
tyrosine

Corneal +++ +/- ?

ulcers

Hyper- ++ +/- ?
keratosis

Mental +/- +/- ?

retardation

Arthritis +++ ?

Liver ? +++
failure

Renal ? ++
Fanconi
syndrome

Courtesy of Markus Grompe, MD.

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Ochronotic pigmentation of ear cartilage and sclera

A) Bluish-gray auricular cartilage in a patient with alkaptonuria.

B) Ocular ochronosis with scleral pigmentation. Reproduced with
permission from: Gold DH, MD, and Weingeist TA, MD, PhD. Color Atlas of
the Eye in Systemic Disease. Baltimore: Lippincott Williams & Wilkins,
2001. Copyright © 2001 Lippincott Williams & Wilkins.

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