DiagnosisClinical DiagnosisTyrosinemia 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.TestingDeficiency of fumarylacetoacetate hydrolase (FAH) (EC 3.7.1.2) results in tyrosinemia type I [Lindblad et al 1977]. FAH is the terminal enzyme in the tyrosine catabolic pathway (Figure 1). In FAH deficiency, the immediate precursor, fumarylacetoacetate (FAA):FigureFigure 1. The tyrosine catabolic pathway 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 concentrationPBG 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-ALATyrosinemia type I is characterized by the following biochemical findings:Increased succinylacetone concentration in the blood and excretion in the urineNote: (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 phenylalanineNote: (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 testingIncreased 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 1-3 months and <12 ng/mL for children age 3 months to 18 years)Prolonged prothrombin and partial thromboplastin timesNote: (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.Note: Homozygosity for the pseudodeficiency allele (p.Arg341Trp) or compound heterozygosity for the pseudodeficiency allele and a pathologic allele results in low FAH enzyme activity but no clinical symptoms and normal serum concentration of tyrosine, thus potentially complicating the interpretation of FAH enzyme activity particularly in prenatal testing. This potential difficulty is now avoided because assay of FAH enzyme activity is no longer in routine use.Newborn screeningBlood tyrosine or methionine concentration. Elevated concentration of tyrosine or methionine in the blood suggests liver disease; the diagnosis of tyrosinemia type I 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, Al-Dirbashi et al 2008]
Note: Succinylacetone is now a routine biomarker for tyrosinemia-1 in newborn screening laboratories.Delta-ALA-dehydratase (PBG synthase) enzyme activity is 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].Molecular Genetic TestingGene. FAH is the only gene in which mutation is known to cause tyrosinemia type I.Clinical testingTargeted mutation analysis (see Table 4)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. Deletion/duplication analysis. Park et al [2009] reported the identification of a large deletion involving FAH as causative of tyrosinemia type I. Table 1. Summary of Molecular Genetic Testing Used in Tyrosinemia Type 1View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Gene and Test Method ^{1Test AvailabilityFAHTargeted mutation analysisMutations 2c.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)60% in general US population 3, 4ClinicalSequence analysisSequence variants 5>95%Deletion / duplication analysis 6Partial or whole-gene deletions Unknown 71. The ability of the test method used to detect a mutation that is present in the indicated gene2. Mutations assayed may vary by laboratory.3. p.Pro261Leu (P261L) accounts for >99% of the mutations in the Ashkenazi Jewish population [Elpeleg et al 2002].4. c.1062+5G>A (IVS12+5 G>A) accounts for 87.9% of mutations in the French Canadian population [Poudrier et al 1996].5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. 7. Park et al [2009]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband1.Measure serum concentration of AFP and PT/PTT and liver function enzymes (AST, ALT, and GGT).2.If AFP, PT, and PTT are markedly abnormal, evaluate urine organic acids for tyrosine metabolites and succinylacetone.3.Perform molecular genetic testing to confirm the diagnosis in individuals with biochemical findings consistent with tyrosinemia type I beginning with targeted mutation analysis. 4.If neither or only one disease-causing allele is detected by targeted mutation analysis, sequence analysis may be performed on FAH to identify rare mutations. 5.If neither or only one disease-causing allele is detected, deletion/duplication analysis may be considered. 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. Genetically Related (Allelic) DisordersA rare and atypical form of tyrosinemia type 1 has been reported in a four-month-old Belgian infant with severe liver disease. Liver function studies were abnormal with markedly elevated alpha-fetoprotein, prolonged PT and PTT, and undetectable succinylacetone in urine. Fumarylacetoacetase (FAH) protein and activity was decreased, but not absent. A unique homozygous mutation, c.103G>A (p.Ala35Thr), was identified [Cassiman et al 2009].}

Natural HistoryUntreated 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.Survival in untreated children. Untreated infants diagnosed before age two months had a two-year survival rate of 29% [van Spronsen et al 1994]. Those diagnosed between ages two and six months had a 74% two-year survival rate; those diagnosed after age six months had a 96% two-year survival rate. After more than five years the survival rate of the group diagnosed between ages two and six months dropped to approximately 30% and that of the group diagnosed after age six months dropped to approximately 60% (Figure 2).FigureFigure 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 different from that in untreated children. Affected children younger than age two years who are treated with a combination of nitisinone and low-tyrosine diet are markedly improved compared to those children 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 individuals who were placed on nitisinone therapy prior to age 30 days. The longest period of treatment in this group is 12 years [G Mitchell, preliminary data].

Differential DiagnosisChildren with any of the following presenting findings should be evaluated for tyrosinemia type I (Table 2):Table 2. Differential Diagnosis of Tyrosinemia Type I in Infants by Presenting FindingView in own windowPresenting FindingDifferential DiagnosisHypertyrosinemia−High-protein diet ^{1, 2−Tyrosinemia type II
−Tyrosinemia type III
−Other liver diseaseHypermethioninemia−Homocystinuria
−Disorders of methionine metabolism
−Other liver diseaseLiver 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 3Renal syndrome−Lowe syndrome
−Cystinosis
−Renal tubular acidosis
−Fanconi syndromeRickets−Hypophosphatasia
−Vitamin D deficiency (nutritional/genetic)
−Hypophosphatemic rickets
−Vitamin D-dependent rickets
−Fanconi syndromeNeurologic crisis−Cerebral hemorrhage/edema
−Bacterial/viral meningitis
−Hypernatremic dehydration
−Acute intermittent porphyria1. Techakittiroj et al [2005]2. Undiluted goat's milk [Hendriksz & Walter 2004]3. Bansal & Dhawan [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 analysisAffected 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 with the disorder have been identified, and the clinical phenotype remains ill defined. The first affected individuals came to medical attention because of intellectual disability 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.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).}

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with tyrosinemia type 1 on the basis of clinical presentation, the following evaluations are recommended (see Table 3):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 sizeX-ray of wrist to document presence or absence of ricketsTreatment of ManifestationsAcute management of liver failure. Children may require respiratory support, appropriate fluid management, and blood products for correction of bleeding diathesis.Nitisinone (Orfadin®). 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC) was approved by the Food and Drug Administration in April 2002 for treatment of tyrosinemia type I [Schwetz 2002]. Nitisinone blocks parahydroxyphenylpyruvic acid dioxygenase (p-HPPD), the second step in the tyrosine degradation pathway, and prevents the accumulation of FAA and its conversion to succinylacetone (Figure 1).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 requirements 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 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 protein 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].Prevention of Primary ManifestationsTreatment with nitisinone (Orfadin^®) should begin as soon as the diagnosis is confirmed.Prevention of Secondary ComplicationsBecause 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-hydroxy-vitamin D.SurveillanceFrequent evaluation of the following parameters is typical in the management of individuals with tyrosinemia type I (Table 3) [CR Scott, personal recommendations]. Table 3. Guidelines for Monitoring in Tyrosinemia Type IView in own windowEvaluationInitiation of
Therapy (Baseline)First 6 MonthsAfter 6 Months of RxMonthlyEvery 3 monthsEvery 3 monthsEvery 6 monthsYearlyTyrosinemia type 1 markers Plasma concentration of methionine, phenylalanine, tyrosinexxxUrine succinylacetonexx+Blood nitisinone concentrationxxCBC (complete blood count)Hemoglobin, hematocrit, WBC, platelet countxxxLiver evaluationSerum AFP concentrationxxxProthrombin time (PT)xx (until normal)Partial thromboplastin time (PTT)xx (until normal)Bilirubinx+ALT/ASTxx+GGTxx+Alkaline phosphatasexx+CT or MRI ^{1xxRenal studiesBUN, creatininexxSkeletal evaluationX-ray of wrist (rickets)x+ = if indicated clinically1. MRI with contrast to evaluate for liver adenomas or nodules and for kidney sizeEvaluation of Relatives at RiskAlthough 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 blood or 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.Pregnancy ManagementNo data exist on the use of nitisinone during pregnancy. Speculation would assume that the pregnant woman remains safe from untoward events; however, the developing fetus may be at risk because of alterations in tyrosine metabolism.Therapies Under InvestigationSearch 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.OtherPrior 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.}

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Tyrosinemia Type I: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFAH15q25​.1FumarylacetoacetaseFAH homepage - Mendelian genesFAHData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Tyrosinemia Type I (View All in OMIM) View in own window 276700TYROSINEMIA, TYPE INormal allelic variants. The gene is approximately 35 kbp in size and comprises 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.Pathologic allelic variants. See Table 4. Missense, nonsense, and splice-site mutations, along with small deletions and indels of FAH, have been reported. No multiexonic or whole-gene deletions or duplications that cannot be detected by standard sequence analysis of FAH have been reported. The following population-specific mutations result from founder effect or genetic drift [Bergman et al 1998, Bergeron et al 2001, Arranz et al 2002, Elpeleg et al 2002, Heath et al 2002]: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)Table 4. Selected FAH Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide Change
(Alias ¹)Protein Amino Acid ChangeReference SequencesPseudodeficiencyc.1021C>Tp.Arg341TrpNM_000137​.1
NP_000128​.1Pathologicc.192G>Tp.Gln64Hisc.554-1G>T
(IVS6-1G>T)--c.607-6T>G
(IVS7-6T>G)--c.698A>Tp.Asp233Valc.782C>Tp.Pro261Leuc.786G>Ap.Trp262Xc.1009G>Ap.Gly337Serc.1062+5G>A
(IVS12+5 G>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 conventionsNormal 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 resulting in cellular damage and apoptosis.