Figure 1. The tyrosine catabolic pathway
 |
|
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. Tyrosinemia type I results from deficiency of the enzyme fumarylacetoacetate hydrolase (FAH), encoded by FAH. Typical biochemical findings include increased succinylacetone concentration in the blood and urine, elevated plasma concentrations of tyrosine; methionine, and phenylalanine; and elevated urinary concentration of tyrosine metabolites and the compound δ-ALA. Assay of FAH enzyme activity in skin fibroblasts is possible but not readily available. Molecular genetic testing by targeted mutation analysis for the four common FAH mutations and sequence analysis of the entire coding region are clinically available and can detect mutations in greater than 95% of affected individuals.
Management. Treatment of manifestations: Nitisinone (Orfadin®), 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC), which blocks parahydroxyphenylpyruvic acid dioxygenase (p-HPPD), the second step in the tyrosine degradation pathway, prevents the accumulation of fumarylacetoacetate and its conversion to succinylacetone. Nitisinone treatment should begin as soon as the diagnosis of tyrosinemia type I is confirmed. Because nitisinone increases the blood concentration of tyrosine, dietary management with controlled intake of phenylalanine and tyrosine should be started immediately upon diagnosis to prevent tyrosine crystals from forming in the cornea. If the blood concentration of phenylalanine becomes too low (<20 μmol/L), additional protein should be added to the diet. Prior to the availability of nitisinone, the only definitive therapy for tyrosinemia type I was liver transplantation, which now should be reserved for those children who have severe liver failure at presentation and fail to respond to nitisinone therapy or have documented evidence of malignant changes in hepatic tissue. Prevention of primary manifestations: Treatment with nitisinone should begin as soon as the diagnosis is confirmed. Prevention of secondary complications: treatment of early signs of carnitine deficiency, osteoporosis, and rickets that are secondary to renal tubular Fanconi syndrome. Surveillance: Guidelines for routine surveillance of individuals with tyrosinemia type I have been established. Testing of relatives at risk: All subsequent children of the parents of a child with tyrosinemia type I should have urine succinylacetone analyzed as soon as possible after birth to enable the earliest possible diagnosis and initiation of therapy.
Genetic counseling. Tyrosinemia type I is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if both disease-causing alleles in a family are known.
Tyrosinemia type I, a disorder of tyrosine metabolism, classically presents as severe liver disease in young infants. Children older than age six months may come to medical attention with signs of renal disease, rickets, or neurologic crises.
Figure 1. The tyrosine catabolic pathway
). In FAH deficiency, the immediate precursor, fumarylacetoacetate (FAA):
Appears to accumulate in hepatocytes, causing cellular damage and apoptosis (identified in an animal model by Endo & Sun [2002]);
Is diverted into succinylacetoacetate and succinylacetone. Succinylacetone interferes with the activity of the following hepatic enzymes:
Parahydroxyphenylpyruvic acid dioxygenase (p-HPPD), resulting in elevation of plasma tyrosine concentration
PBG synthase, resulting in (1) reduced activity of the enzyme δ-ALA dehydratase in liver and circulating red blood cells; (2) reduced heme synthesis; (3) increased δ-aminolevulinic acid (δ-ALA), which may induce acute neurologic episodes; and (4) increased urinary excretion of δ-ALA
Tyrosinemia type I is characterized by the following biochemical findings:
Increased succinylacetone concentration in the blood and excretion in the urine
Note: (1) Increased excretion of succinylacetone in the urine of a child with liver failure or severe renal disease is pathognomonic of tyrosinemia type I. (2) Many laboratories require that measurement of succinylacetone be specifically requested when ordering urine organic acids.
Elevated plasma concentration of tyrosine, methionine, and phenylalanine
Note: (1) Plasma tyrosine concentration in affected infants can be normal in cord blood and during the newborn period. (2) Elevated plasma tyrosine concentration can also be a nonspecific indicator of liver damage or immaturity; for example, in infants taking a high-protein formula [Techakittiroj et al 2005], including undiluted goat's milk [Hendriksz & Walter 2004].
Elevated urinary concentration of tyrosine metabolites p-hydroxyphenylpyruvate, p-hydroxyphenyllactate, and p-hydroxyphenylacetate detected on urine organic acid testing
Increased urinary excretion of the compound δ-ALA secondary to inhibition of the enzyme δ-ALA dehydratase by succinylacetone in liver and circulating red blood cells [Sassa & Kappas 1983]
Untreated tyrosinemia type I is characterized by the following changes in liver function:
Markedly elevated serum concentration of alpha-fetoprotein (average 160,000 ng/mL) (normal: <1000 ng/mL for infants age 1 to 3 months and <12 ng/mL for children age 3 months to 18 years)
Prolonged prothrombin and partial thromboplastin times
Note: (1) Changes in serum concentration of alpha-fetoprotein (AFP) and prothrombin time/partial thromboplastin time (PT/PTT) are more severe in tyrosinemia type I than in nonspecific liver disease and are often the presenting findings in tyrosinemia type I. (2) Transaminases and bilirubin are only modestly elevated, if at all. (3) Presence of normal serum concentration of AFP and normal PT/PTT in an individual with liver disease has a low probability of being from tyrosinemia type I.
Fumarylaceteoacetic acid hydrolase (FAH) enzyme activity. Assay of FAH enzyme activity is possible in skin fibroblasts but is not readily available. Affected individuals have very low or undetectable FAH enzyme activity; specific reference ranges vary among laboratories.
For laboratories offering biochemical testing, see
.
Blood tyrosine or methionine concentration. Elevated concentration of tyrosine or methionine in the blood suggests tyrosinemia type I and should be further evaluated by quantification of plasma or urinary succinylacetone.
Note: (1) Infants with tyrosinemia type I may have only modestly elevated or normal blood concentrations of tyrosine and methionine when the first newborn screening sample is collected. (2) Elevated tyrosine concentration on newborn screening can be the result of transient tyrosinemia of the newborn, tyrosinemia type II or III, or other liver disease. (3) Elevated methionine concentration can indicate liver dysfunction, defects in methionine metabolism, or homocystinuria (see Homocystinuria Caused by Cystathionine Beta-Synthetase Deficiency).
More sensitive and specific indicators of tyrosinemia type I:
Succinylacetone, measured directly from the newborn blood spot by tandem mass spectroscopy [Allard et al 2004, Rashed et al 2005]
Note: Succinylacetone is now being introduced as a biomarker for tyrosinemia-1 in newborn screening laboratories.
Delta-ALA-dehydratase (PBG synthase) enzyme activity, measured in the newborn screening program in Quebec, Canada [Giguère et al 2005]. Succinylacetone is then measured in the urine of infants with apparent δ-ALA dehydratase deficiency [Schulze et al 2001].
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. FAH is the only gene known to be associated with tyrosinemia type I.
Clinical testing
The four common FAH mutations – c.1062+5G>A (IVS12+5 G>A), c.554-1G>T (IVS6-1 G>T), c.607-6T>G (IVS7-6 T>G), and p.Pro261Leu (P261L) – account for approximately 60% of mutations in tyrosinemia type I in the general US population [CR Scott, unpublished data].
The p.Pro261Leu (P261L) mutation accounts for nearly 100% of mutations responsible for tyrosinemia type I in the Ashkenazi Jewish population [Elpeleg et al 2002].
The c.1062+5G>A (IVS12+5 G>A) mutation accounts for 87.9% of mutations in the French Canadian population [Poudrier et al 1996].
Sequence analysis. If neither or only one disease-causing allele is detected by targeted mutation analysis and if biochemical testing has confirmed the diagnosis of tyrosinemia type I, sequence analysis may be performed on FAH to identify rare mutations. Sequence analysis is available on a clinical basis for affected individuals only.
Deletion/duplication analysis. No deletions or duplications involving FAH as causative of tyrosinemia type I have been reported. Therefore, the mutation detection rate is unknown and may be very low.
| Gene Symbol | Test Method | Mutations Detected | Mutation Detection Frequency by Gene and Test Method | Test Availability |
|---|---|---|---|---|
| FAH | Targeted mutation analysis | Mutations 3 c.1062+5G>A (IVS12+5 G>A), c.554-1G>T (IVS6-1 G>T), c.607-6T>G (IVS7-6 T>G), p.Pro261Leu (P261L) | 50% in general US population 1,2 | Clinical
|
| Sequence analysis | Sequence variants | >95% | ||
| Deletion/ duplication analysis | Partial or whole-gene deletions | Unknown 4 |
1. p.Pro261Leu (P261L) accounts for >99% of the mutations in the Ashkenazi Jewish population [Elpeleg et al 2002].
2. c.1062+5G>A (IVS12+5 G>A) accounts for 87.9% of mutations in the French Canadian population [Poudrier et al 1996].
3. Mutations assayed may vary by laboratory.
4. No deletions or duplications involving FAH as causative of tyrosinemia type I have been reported; mutation detection frequency is unknown and may be very low. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
To confirm the diagnosis in a proband
Measure serum concentration of AFP and PT/PTT and liver function enzymes (AST, ALT, and GGT).
If AFP, PT, and PTT are markedly abnormal, evaluate urine organic acids for tyrosine metabolites and succinylacetone.
Perform molecular genetic testing to confirm the diagnosis in individuals with biochemical findings consistent with tyrosinemia type I.
Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.
Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.
No other phenotypes are known to be associated with mutations in FAH.
Untreated tyrosinemia type I usually presents either in young infants with severe liver involvement or later in the first year with liver dysfunction and significant renal involvement, growth failure, and rickets. Growth failure results from chronic illness with poor nutritional intake, liver involvement, and/or chronic renal disease. Death in the untreated child usually occurs before age ten years, typically from liver failure, neurologic crisis, or hepatocellular carcinoma.
Liver involvement. Untreated children presenting before age six months typically have acute liver failure with initial loss of synthetic function for clotting factors [Croffie et al 1999]. PT and PTT are markedly prolonged and not corrected by vitamin K supplementation; factor II, VII, IX, XI, and XII levels are decreased; factor V and factor VIII levels are preserved. Paradoxically, serum transaminase levels may be only modestly elevated; serum bilirubin concentration may be normal or only slightly elevated, in contrast to most forms of severe liver disease in which marked elevation of transaminases and serum bilirubin concentration occur concomitantly with prolongation of PT and PTT. Resistance of affected liver cells to cell death may explain the observed discrepancy in liver function [Vogel et al 2004].
This early phase can progress to liver failure with ascites, jaundice, and gastrointestinal bleeding. Children may have a characteristic odor of "boiled cabbage" or "rotten mushrooms." Infants occasionally have persistent hypoglycemia; some have hyperinsulinism [Baumann et al 2005]. Others have chronic low-grade acidosis [CR Scott, unpublished data]. Untreated affected infants may die from liver failure within weeks or months of first symptoms.
Renal tubular involvement. In the more chronic form of the untreated disorder, symptoms develop after age six months; renal tubular involvement is the major manifestation. The renal tubular dysfunction involves a Fanconi-like renal syndrome with generalized aminoaciduria, phosphate loss, and, for many, renal tubular acidosis. The continued renal loss of phosphate is believed to account for rickets; serum calcium concentrations are usually normal.
Neurologic crises. Untreated children may have repeated neurologic crises similar to those seen in older individuals with acute intermittent porphyria. These crises include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation. Crises can last one to seven days. Repeated neurologic crises often go unrecognized. Mitchell et al [1990] reported that 42% of untreated French Canadian children with tyrosinemia type I had experienced such episodes. In an international survey, van Spronsen et al [1994] reported that 10% of deaths in untreated children occurred during a neurologic crisis.
Hepatocellular carcinoma. Those children who are not treated with nitisinone and a low-tyrosine diet and who survive the acute onset of liver failure are at high risk of developing and succumbing to hepatocellular carcinoma.
Figure 2. Survival of children with tyrosinemia before 1992 [van Spronsen et al 1994]
).
The natural history of tyrosinemia type I in children who are treated with nitisinone is markedly different from that in untreated children. Furthermore, the natural history of tyrosinemia type I in children who are treated before age two years with the combination of nitisinone and low-tyrosine diet is markedly different from the natural history in those treated with low-tyrosine diet alone. The combined nitisinone and low-tyrosine diet treatment has resulted in a greater than 90% survival rate, normal growth, improved liver function, prevention of cirrhosis, correction of renal tubular acidosis, and improvement in secondary rickets [McKiernan 2006, Masurel-Paulet et al 2008].
Neurologic crises observed in treated children have always been associated with a prolonged interruption in nitisinone treatment [CR Scott, unpublished data].
Children with acute liver failure require support prior to and during the initiation of treatment with nitisinone. Improvement generally occurs within one week of starting nitisinone treatment.
Corneal crystals. Nitisinone blocks the tyrosine catabolic pathway such that succinylacetone is not produced but tissue tyrosine levels are raised. Blood tyrosine concentration greater than 600 mol/L confers risk of precipitation of tyrosine as bilateral, linear, branching subepithelial corneal opacities [Ahmad et al 2002], causing photophobia and itchy, sensitive eyes. The crystals resolve once tyrosine levels are reduced.
Hepatocellular carcinoma. Although Holme & Lindstedt [2000] and van Spronsen et al [2005] reported hepatocellular carcinoma in individuals after years of nitisinone therapy, it is estimated that fewer than 5% of children placed on nitisinone therapy before age two years develop hepatocellular carcinoma by age ten years [CR Scott, unpublished data]. In Quebec, where tyrosinemia type I is included in the newborn screening program, hepatocellular carcinoma has not been reported in those individuals placed on nitisinone therapy prior to 30 days of age. The longest period of treatment in this group is seven years [G Mitchell, preliminary data].
No correlation is observed between clinical presentation and genotype. Both acute and chronic forms have been seen in the same families, as well as in unrelated individuals with the same genotype [Poudrier et al 1998].
One mechanism that explains this clinical variation is gene reversion. Hepatic nodules removed from livers of individuals with the chronic form of tyrosinemia type I have been shown to have cells that are immunologically positive for FAH protein and to have enzymatic activity for FAH [Kvittingen et al 1994, Grompe 2001]. These seemingly "normal" cells appear to have arisen by gene reversion, that is, the spontaneous self-correction (i.e., back-mutation) of the germline mutation to the normal gene sequence during somatic cell division. Spontaneous somatic mutation that suppresses the pathologic mutations and allows for normal or near-normal gene expression in these cells has also been reported [Bliksrud et al 2005]. This is a true reversion of the mutant sequence and not the result of maternal cell colonization or maternal cell fusion [Bergeron et al 2004]. The “normal” (i.e., reverted) cells have a selective growth advantage because they are no longer at risk for apoptosis from the accumulation of FAA. These foci of revertant “normal” cell colonies comprise many of the liver nodules in untreated individuals with chronic tyrosinemia type I who have a milder biochemical and clinical phenotype [Kim et al 2000, Demers et al 2003]. However, the continued production of succinylacetone and FAA by the non-revertant mutant cells places the individual at continued risk for hepatocellular carcinoma [Kim et al 2000].
Previously used terms referring to tyrosinemia type I include tyrosinosis.
Tyrosinemia type I affects approximately one in 100,000 to 120,000 births [Mitchell et al 2001]. Because of the inconsistent and confusing nature of its clinical presentation, it is estimated that fewer than 50% of affected individuals are diagnosed while alive.
In the general US population, the carrier frequency is estimated at 1:150 to 1:100.
Two regions of the world have a higher than expected frequency of tyrosinemia type I:
A founder effect from colonization by French settlers is present in the province of Quebec, Canada. The c.1062+5G>A (IVS12+5 G>A) mutation accounts for 87% of gene mutations in this population.
The birth prevalence in the province of Quebec is 1:16,000; in the Saguenay-Lac Saint-Jean region of Quebec, it is one in 1,846 live births.
The overall carrier frequency in Quebec is 1:66 based on newborn screening data. The carrier frequency in the Saguenay-Lac St-Jean region is 1:16-1:20.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
| Presenting Finding | Differential Diagnosis |
|---|---|
| Hypertyrosinemia | −High-protein diet 1, 2 −Tyrosinemia type II −Tyrosinemia type III −Other liver disease |
| Hypermethioninemia | −Homocystinuria −Disorders of methionine metabolism −Other liver disease |
| Liver disease | −Galactosemia −Hereditary fructose intolerance −Fructose 1, 6 diphosphatase deficiency −Niemann-Pick C disease −Wilson disease −Neonatal hemochromatosis −Hemophagocytic lymphohistiocytosis −Mitochondrial cytopathies −Congenital disorders of glycosylation −Transaldolase deficiency −Acetaminophen toxicity −Bacterial infections (sepsis, salmonella, TB) −Viral infections (e.g., CMV, hepatitis A/B, herpes) −Mushroom poisoning 3 −Herbal medicines 3 −Idiosyncratic drug reaction, toxin, vascular/ischemic or infiltrative process 3 |
| Renal syndrome | −Lowe syndrome −Cystinosis −Renal tubular acidosis −Fanconi syndrome |
| Rickets | −Hypophosphatasia −Vitamin D deficiency (nutritional/genetic) −Hypophosphatemic rickets −Vitamin D-dependent rickets −Fanconi syndrome |
| Neurologic crisis | −Cerebral hemorrhage/edema −Bacterial/viral meningitis −Hypernatremic dehydration −Acute intermittent porphyria |
2. Undiluted goat's milk Hendriksz & Walter [2004]
Tyrosinemia type II is caused by a defect in tyrosine aminotransferase (TAT) (EC 2.6.1.5). Establishing the diagnosis of tyrosinemia type II relies on the following:
Plasma tyrosine concentration typically greater than 500 µmol/L that may exceed 1000 µmol/L (The concentration of other amino acids is normal.)
Increased excretion of p-hydroxyphenylpyruvate, p-hydroxyphenyllactate, and p-hydroxyphenylacetate and presence of small quantities of N-acetyltyrosine and 4-tyramine on urine organic acid analysis
Affected individuals have painful, non-pruritic, and hyperkeratotic plaques on the soles and palms. The plantar surface of the digits may show marked yellowish thickening associated with the hyperkeratosis. Ophthalmologic involvement is recalcitrant pseudodendritic keratitis [Macsai et al 2001]. Although developmental delay appears to be common, it is unclear if ascertainment bias accounts for this and the reports of neurologic symptoms.
Findings improve on a diet restricted in tyrosine and phenylalanine [Ellaway et al 2001].
Tyrosinemia type III, the rarest of the tyrosine disorders, is caused by a deficiency of p-hydroxyphenylpyruvic acid dioxygenase (EC.1.13.11.27). Plasma concentration of tyrosine ranges from 350 to 650 µmol/L. Excretion of 4-hydroxyphenylpyruvic acid, 4-hydroxyphenyllactate, and 4-hydroxyphenylacetate is increased. The precise quantities vary with protein intake.
Few individuals have been identified with the disorder, and its clinical phenotype remains ill-defined. The first affected individuals came to medical attention because of mental retardation or ataxia; another was detected on routine screening [Mitchell et al 2001]. These individuals, like those with tyrosinemia type II, have no liver involvement but have skin or ocular changes. It remains unclear if tyrosinemia type III is truly associated with cognitive delays or if the association has resulted from ascertainment bias [Ellaway et al 2001].
A diet low in phenylalanine and tyrosine can lower plasma tyrosine concentration.
CBC with platelet count; serum concentration of electrolytes; assessment of liver function (PT, PTT, serum bilirubin concentration, liver enzyme concentrations [AST, ALT, GGT, alkaline phosphatase], serum AFP concentration); assessment of renal function (BUN, creatinine)
Baseline abdominal imagining by CT or MRI with contrast to evaluate for liver adenomas or nodules (see Dubois et al [1996]) and renal size
X-ray of wrist to document presence or absence of rickets
Acute management of liver failure. Children may require respiratory support, appropriate fluid management, and blood products for correction of bleeding diathesis.
).
Nitisinone should be prescribed as soon as the diagnosis of tyrosinemia type I is confirmed.
Nitisinone is generally prescribed at 1.0 mg/kg/day; individual doses may vary. Dosage should be adjusted to maintain blood nitisinone levels between 40 and 60 µmol/L, which theoretically blocks greater than 99% of p-HPPD activity. Rarely, an individual may require higher blood levels of nitisinone (70 um) to suppress succinylacetone excretion. As long as blood concentration of nitisinone is within the therapeutic range, urine succinylacetone does not need to be measured.
Nitisinone is typically given in two divided doses; however, because of the long half-life (50-60 hours), affected individuals who are older and more stable may maintain adequate therapy with once-per-day dosing.
Rare side effects of nitisinone have included transient low platelet count and transient low neutrophil count that resolved without intervention and photophobia that resolved with stricter dietary control and subsequent lowering of blood tyrosine concentrations.
Low-tyrosine diet. Nitisinone increases blood concentration of tyrosine, necessitating a low-tyrosine diet to prevent tyrosine crystals from forming in the cornea. Dietary management should be started immediately upon diagnosis and should provide a nutritionally complete diet with controlled intakes of phenylalanine and tyrosine using a vegetarian diet with low-protein foods and a medical formula such as Tyrex® (Ross) or Tyros-1® (Mead Johnson).
Phenylalanine and tyrosine requirements are interdependent and vary from individual to individual and within the same individual depending on growth rate, adequacy of energy and protein intakes, and state of health. With appropriate dietary management, plasma tyrosine concentration should be 200-500 µmol/L, regardless of age; plasma phenylalanine concentration should be 20-80 µmol/L (0.3-1.3 mg/dL). If the blood concentration of phenylalanine is too low (<20 µmol/L), additional phenylalanine should be added to the diet from milk or foods.
Liver transplantation. Prior to the availability of nitisinone for the treatment of tyrosinemia type I, the only definitive therapy was liver transplantation.
Recent clinical experience indicates that liver transplantation should now be reserved for those children who (1) have severe liver failure at clinical presentation and fail to respond to nitisinone therapy or (2) have documented evidence of malignant changes in hepatic tissue [Mohan et al 1999].
Transplant recipients require long-term immunosuppression. Mortality associated with liver transplantation in young children is 10% or higher.
Transplant recipients may also benefit from low-dose nitisinone therapy to prevent continued renal tubular and glomerular dysfunction resulting from succinylacetone generated in renal tissue [Pierik et al 2005].
Treatment with nitisinone (Orfadin®) should begin as soon as the diagnosis is confirmed.
Because carnitine deficiency secondary to the renal tubular Fanconi syndrome can cause skeletal muscle weakness, serum concentration of carnitine should be measured so that carnitine deficiency, if identified, can be treated [Nissenkorn et al 2001].
Osteoporosis and rickets resulting from renal tubular damage are treated by correction of acidosis, restoring calcium and phosphate balance, and administration of 25-OH-vitamin D.
| Evaluation | Initiation of Therapy (Baseline) | First 6 Months | After Age 6 Months | |||||
|---|---|---|---|---|---|---|---|---|
| Monthly | Every 3 months | Every 3 months | Every 6 months | Yearly | ||||
| Tyrosinemia type 1 markers | ||||||||
| Plasma concentration of methionine, phenylalanine, tyrosine | x | x | x | |||||
| Urine succinylacetone | x | x | + | |||||
| Blood nitisinone concentration | x | x | ||||||
| CBC (complete blood count) | ||||||||
| Hemoglobin, hematocrit, WBC, platelet count | x | x | Every 6 months or yearly | |||||
| Liver evaluation | ||||||||
| Serum AFP concentration | x | x | Every 3 or 6 months | |||||
| Prothrombin time (PT) | x | x | ||||||
| Partial thromboplastin time (PTT) | x | x | + | |||||
| Bilirubin | x | + | ||||||
| ALT/AST | x | x | + | |||||
| GGT | x | x | + | |||||
| Alkaline phosphatase | x | x | + | |||||
| CT or MRI 1 | x | x | ||||||
| Renal studies | ||||||||
| BUN, creatinine | x | x | x | |||||
| Skeletal evaluation | ||||||||
| X-ray of wrist (rickets) | x | + | ||||||
+ = if indicated
1. MRI with contrast to evaluate for liver adenomas or nodules and for kidney size
Although it is unlikely that the healthy older sibs of a newly diagnosed infant with tyrosinemia type I also have tyrosinemia type I, it is prudent to perform organic acid analysis of urine for measurement of succinylacetone.
All subsequent children of the parents of a child with tyrosinemia type I should have urine succinylacetone analyzed as soon as possible after birth to enable the earliest possible diagnosis and initiation of therapy.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Prior to the availability of nitisinone, the only available non-transplant therapy was a diet limiting the availability of phenylalorine and tyrosine. Although modestly helpful, recurrent episodes of neurologic crises and progression of liver disease occurred. The average age of survival was less than ten years.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Tyrosinemia type I is inherited in an autosomal recessive manner.
Parents of a proband
The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).
Heterozygotes (carriers) are asymptomatic.
Sibs of a proband
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
Offspring of a proband. The offspring of an individual with tyrosinemia type I are obligate heterozygotes (carriers) for a disease-causing mutation in FAH.
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier testing for at-risk relatives is possible once the disease-causing mutations have been identified in the family.
For unrelated reproductive partners of carriers, molecular genetic testing for the four common mutations that account for approximately 60% of alleles in the general US population is available.
Biochemical testing. Biochemical methods of carrier detection are not available.
See Management, Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.
Family planning
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Molecular genetic testing. Prenatal diagnosis for pregnancies at 25% risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles must be identified before prenatal testing can be performed. Molecular genetic testing is the preferred method for prenatal diagnosis.
Biochemical testing. Prenatal diagnosis for pregnancies at 25% risk is possible by detection of succinylacetone in amniotic fluid or measurement of fumarylacetoacetase in cultured amniotic cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation. Detection of succinylacetone in amniotic fluid is diagnostic; however, because false negatives have been reported this method should only be used by laboratories consistently able to identify succinylacetone at low levels by stable isotope detection.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name | HGMD |
|---|---|---|---|
| FAH | 15q23-q25 | Fumarylacetoacetase | FAH |
| 276700 | TYROSINEMIA, TYPE I |
Normal allelic variants. The gene is approximately 35 kbp in size and consists of 14 exons. A single pseudodeficiency allele (p.Arg341Trp [c.1021C>T]) leads to decreased FAH enzyme activity and very little immunoreactive protein but normal amounts of FAH mRNA.
Ashkenazi Jewish mutation: p.Pro261Leu (P261L)
Finnish mutation: p.Trp262X (W262X)
French Canadian mutation: c.1062+5G>A (IVS 12+5 G>A)
Pakistani mutation: p.Gln64His (Q64H)
Scandinavian mutation: p.Gly337Ser (G337S)
Turkish mutation: p.Asp233Val (D233V)
Northern European mutation: c.1062+5G>A (IVS 12+5 G>A)
Southern European mutation: c.554-1G>T (IVS 6-1 G>T)
[Bergman et al 1998, Bergeron et al 2001, Arranz et al 2002, Elpeleg et al 2002, Heath et al 2002]
| Class of Variant Allele | DNA Nucleotide Change (Alias 1) | Protein Amino Acid Change | Reference Sequence |
|---|---|---|---|
| Pseudodeficiency | c.1021C>T | p.Arg341Trp | NM_000137.1NP_000128.1 |
| Pathologic | c.192G>T | p.Gln64His | |
| c.554-1G>T (IVS6-1G>T) | -- | ||
| c.607-6T>G (IVS7-6T>G) | -- | ||
| c.698A>T | p.Asp233Val | ||
| c.782C>T | p.Pro261Leu | ||
| c.786G>A | p.Trp262X | ||
| c.1009G>A | p.Gly337Ser | ||
| c.1062+5G>A (IVS12+5G>A) | -- |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).
1. Variant designation that does not conform to current naming conventions
Normal gene product. FAH is a cytosolic protein that acts as a homodimer and has a molecular weight of approximately 80 kd. The wild-type FAH has a Km for FAA of about 3.5 μmol/L. FAH catalyzes the conversion of FAA to fumarate and acetoacetate and the conversion of succinylacetoacetate to succinate and acetoacetate.
Abnormal gene product. Missense, nonsense, and splice-site mutations result in a virtual absence of FAH enzyme activity, leading to an intracellular accumulation of FAA, succinylacetoacetate, and succinylacetone causing cellular damage and apoptosis.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
Supported by grants from the Food and Drug Administration (FD-4-001445) and Rare Disease Therapeutics. The authors are appreciative of the collaboration and discussions with Dr. Grant Mitchell of Montreal, Canada, and Dr. Sven Lindstedt and Dr. Elisabeth Holme of Gothenburg, Sweden.
21 October 2008 (cg) Comprehensive update posted live
24 July 2006 (me) Review posted to live Web site
29 June 2005 (crs) Original submission
