Asunto(s)
Hepatopatías/complicaciones , Tamizaje Neonatal/métodos , Tirosinemias/diagnóstico , Biomarcadores/sangre , Ciclohexanonas/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Femenino , Cromatografía de Gases y Espectrometría de Masas , Heptanoatos/sangre , Humanos , Recién Nacido , Hepatopatías/diagnóstico , Nitrobenzoatos/uso terapéutico , Tirosinemias/tratamiento farmacológico , Tirosinemias/genética , Tirosinemias/orina , UrinálisisAsunto(s)
Raquitismo/etiología , Tirosinemias/diagnóstico , Biomarcadores/sangre , Biomarcadores/orina , Biopsia , Preescolar , Hepatomegalia/etiología , Humanos , Hígado/metabolismo , Hígado/patología , Masculino , Valor Predictivo de las Pruebas , Índice de Severidad de la Enfermedad , Esplenomegalia/etiología , Tirosinemias/sangre , Tirosinemias/complicaciones , Tirosinemias/orinaRESUMEN
OBJECTIVE: To establish the diagnostic method of tyrosinemia type 1 and evaluate its value, the succinylacetone levels in the blood of suspected patients with tyrosinemia were tested by tandem mass spectrometry, and the succinylacetone in the urine was tested by gas chromatography-mass spectrometry. METHOD: A total of 190 patients suspected of having tyrosinemia, were tested by tandem mass spectrometry for measurement of the level of succinylacetone in the blood, and detected by gas chromatography-mass spectrometry for measurement of the level of succinylacetone and organic acid in the urine. The method of measuring the level of succinylacetone in blood by tandem mass spectrometry as follows: After the diameter of 3 mm dry blood spots were punched into wells of 96-well plate, 100 µl 80% acetonitrile were added into each well, which contained hydrazine monohydrate and the internal standard of succinylacetone. The supernatant fluid were transferred to another 96-well plate and dried under heated nitrogen, after the plate was incubated for 30 min at 65°C. The residual hydrazine reagent was removed by addition of 100 µl methanol to each well and evaporated under heated nitrogen. The mobile phase (80% acetonitrile) was added to each well and 20 µl samples were tested by tandem mass spectrometry. The diagnostic terms were the clinical manifestation and the high level of succinylacetone in both blood and urine. RESULT: Eleven patients were diagnosed as tyrosinemia type 1, with 9 males and 2 females. Their ages ranged from 2 months to 6 years. The succinylacetone levels in the blood of the patients were remarkably increased (7.26-31.09 µmol/L), with an average of (14.2 ± 7.8)µmol/L. Seven patients were tested for the level of succinylacetone in the urine by gas chromatography-mass spectrometry, and 4 were positive and 3 negative. Their tyrosine levels in the blood were 190-543 µmol/L(Normal: 20 - 100 µmol/L), with an average of (327.3 ± 125.8) µmol/L. All the patients presented the symptoms of hepatomegaly. Among them, 9 patients died and 2 patients were improved after treatment. CONCLUSION: The higher levels of succinylacetone in the blood or urine is a remarkable evidence for the diagnosis of tyrosinemia type 1. Determination of succinylacetone in the dry blood spots using tandem mass spectrometry was a good method for diagnosis of tyrosinemia type 1. To test succinylacetone in urine by gas chromatography-mass spectrometry may yield a false-negative result for tyrosinemia type 1.
Asunto(s)
Heptanoatos/sangre , Heptanoatos/orina , Tirosinemias/diagnóstico , Adolescente , Niño , Preescolar , Femenino , Cromatografía de Gases y Espectrometría de Masas , Humanos , Lactante , Recién Nacido , Masculino , Espectrometría de Masas en Tándem , Tirosinemias/sangre , Tirosinemias/orinaRESUMEN
Renal Fanconi syndromes are both clinically challenging and physiologically fascinating. The diagnosis requires a certain index of suspicion to correctly identify the clinical symptomatology and pursue the appropriate laboratory evaluations. The renal Fanconi syndrome (FS) is a defect of proximal tubular function attributable to different rare inherited diseases or acquired disorders caused by a multitude of exogenous agents. It can manifest as complete or incomplete FS, characterized by low molecular weight proteinuria, glucosuria, aminoaciduria, and loss of electrolytes, bicarbonate and lactate. Implementation of new methods and recent findings from urinary proteome pattern in patients with renal FS has led to the identification of new markers for proximal tubular dysfunction. Future combined proteomic and metabonomic studies will provide additional potential biomarkers and may help to gain novel insights in the diagnosis and differentiation of the various forms of FS. Moreover, the observation of poor renal uptake of 99 mTc-DMSA in patients with tubular proteinuria, which is not fully understood yet, may also help to elucidate the individual basis of FS in early stages. This review focuses on the new advances in the evaluation of proximal tubular dysfunction in various forms of Fanconi syndrome.
Asunto(s)
Síndrome de Fanconi/etiología , Síndrome de Fanconi/orina , Proteinuria , Animales , Biomarcadores/sangre , Biomarcadores/orina , Cistinosis/complicaciones , Cistinosis/orina , Síndrome de Fanconi/diagnóstico , Intolerancia a la Fructosa/sangre , Intolerancia a la Fructosa/orina , Galactosemias/sangre , Galactosemias/diagnóstico , Galactosemias/orina , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/orina , Degeneración Hepatolenticular/sangre , Degeneración Hepatolenticular/orina , Humanos , Nefrolitiasis/genética , Nefrolitiasis/orina , Síndrome Oculocerebrorrenal/genética , Síndrome Oculocerebrorrenal/orina , Proteómica , Ácido Dimercaptosuccínico de Tecnecio Tc 99m/farmacocinética , Tirosinemias/sangre , Tirosinemias/genética , Tirosinemias/orinaRESUMEN
The objective of our work was to identify known and unknown metabolites of the drug NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione) in urine from patients during the treatment of hereditary tyrosinemia type 1 (HT-1) disease, a severe inborn error of tyrosine metabolism. Two different mass spectrometric techniques, a triple stage quadrupole and an LTQ-Orbitrap (Fourier transform mass spectrometry (FTMS)), were used for the identification and the structural elucidation of the detected metabolites. Initially, the mass spectrometric (MS) approach consisted of the precursor ion scan detection of the selected product ions, followed by the corresponding collision-induced dissociation (CID) fragmentation analysis (MS(2)) for the targeted selected reaction monitoring (SRM) mode. Subsequently, accurate and high-resolution full scan and MS/MS measurements were performed on the possible metabolites using the LTQ-Orbitrap. Final confirmation of the identified metabolites was achieved by measuring commercially supplied or laboratory-synthesized standards. Altogether six metabolites, including NTBC itself, were extracted, detected and identified. In addition, two new NTBC metabolites were unambiguously identified as amino acid conjugates, namely glycine-NTBC and beta-alanine-NTBC. These identifications were based on their characteristics of chromatographic retention times, protonated molecular ions, elemental compositions, product ions (using CID and higher-energy C-trap dissociation (HCD) techniques) and synthesized references. The applied MS strategy, based on two different MS platforms (LC/MS/MS and FTMS), allowed the rapid identification analysis of the drug metabolites from human extracts and could be used for pharmaceutical research and drug development.
Asunto(s)
Ciclohexanonas/orina , Espectrometría de Masas/métodos , Nitrobenzoatos/orina , Tirosinemias/orina , Ciclohexanonas/química , Ciclohexanonas/metabolismo , Ciclohexanonas/uso terapéutico , Humanos , Modelos Moleculares , Peso Molecular , Nitrobenzoatos/química , Nitrobenzoatos/metabolismo , Nitrobenzoatos/uso terapéutico , Tolueno/análogos & derivados , Tolueno/química , Tolueno/metabolismo , Tolueno/orina , Tirosinemias/tratamiento farmacológicoRESUMEN
Organic extracts of six urine samples from children treated with nitisinone, a medicine against tyrosinemia type I, were investigated by (1)H and (19)F NMR spectroscopy. The presence of unchanged 2-[2-nitro-4-(trifluoromethyl)benzoyl]cyclohexane-1,3-dione (NTBC), 6-hydroxy-2-[2-nitro-4-(trifluoromethyl)benzoyl]cyclohexane-1,3-dione (NTBC-OH) and 2-nitro-4-trifluoromethylbenzoic acid (NTFA) as well as a few other unidentified compounds containing CF(3) group was documented.
Asunto(s)
Ciclohexanonas/química , Espectroscopía de Resonancia Magnética/métodos , Nitrobenzoatos/química , Tirosinemias/orina , Niño , Preescolar , Femenino , Flúor , Humanos , Masculino , ProtonesRESUMEN
La tirosinemia tipo I es una enfermedad hereditaria infrecuente causada por un fallo enzimático en la vía metabólica de la tirosina. La detección de succinilacetato en orina como metabolito tóxico es un hallazgo patognomónico. También son habituales unas cifras elevadas de alfafetoproteína. Existe un tratamiento eficaz, la 2-(2 nitro-4-trifluorometilbenzoil)-1,3-ciclohexanodiona (NTBC), cuyo mecanismo de acción consiste en la inhibición de la enzima 4-hidroxifenilpiruvato dioxigenasa. Hemos revisado un total de seis casos de tirosinemia tipo Icontrolados en el Hospital Infantil «La Fe». Uno de ellos se detectó mediante test de cribado neonatal, cinco pacientes debutaron en forma de fallo hepático agudo y tres de ellos presentaron disfunción tubular proximal, concordando la clínica de nuestra serie con la descrita en la bibliografía. Se constata una excelente respuesta a la NTBC, mejorando en unos pocos días la función hepática sin prácticamente efectos tóxicos (AU)
Tyrosinemia type I is a rare hereditary disease caused by an enzymatic defect in the metabolic pathway of the tyrosine. The detection of succinylacetone in the urine as toxic metabolite is a pathognomonic sign. High levels of alpha-fetoprotein are also frequent. There is an efficient treatment, the 2-(2 nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione (NTBC), whose action mechanism consists on the inhibition of the enzyme 4-hydroxyphenylpyruvate dioxygenase. We have revised a total of six cases of tyrosinemia type Icontrolled in the Childrens Hospital La Fe. One of our cases was detected through a neonatal screening test, five presented as acute hepatic failure and three of them showed proximal tubular dysfunction, with the clinical manifestations of our series coinciding with those described in literature. An excellent response to the NTBC is seen, improving the hepatic function in just a few days with hardly any toxic effects (AU)
Asunto(s)
Humanos , Masculino , Femenino , Lactante , Tirosinemias/genética , Tirosinemias/fisiopatología , Tirosinemias/terapia , Tirosinemias/orina , Enzimas/biosíntesis , Enzimas/deficiencia , Hepatocitos/citología , Hepatocitos , Hepatocitos/patología , Hígado/anomalías , Hígado/metabolismo , Hígado/patologíaRESUMEN
High-resolution (1)H NMR spectroscopy of body fluids has proved to be very useful in diagnostics of inherited metabolic diseases, whereas (13)C NMR remains almost unexploited. In this paper the application of (13)C NMR spectroscopy of fivefold concentrated urine samples for diagnosis of selected metabolic diseases is reported. Various marker metabolites were identified in test urine samples from 33 patients suffering from 10 different diseases, providing information which could be crucial for their diagnoses. Spectra were accumulated for 2 h or overnight when using spectrometers operating at 9.4 or 4.7 T magnetic fields, respectively. Interpretation of the measurement results was based on a comparison of the peak positions in the measured spectrum with reference data. The paper contains a table with (13)C NMR chemical shifts of 73 standard compounds. The method can be applied individually or as an auxiliary technique to (1)H NMR or any other analytical method.
Asunto(s)
Espectroscopía de Resonancia Magnética/métodos , Enfermedades Metabólicas/diagnóstico , Urinálisis/métodos , Biomarcadores/orina , Enfermedad de Canavan/orina , Glutaratos/orina , Hemiterpenos , Humanos , Ácido Láctico/orina , Enfermedades Metabólicas/orina , Modelos Químicos , Ácido Orótico/orina , Ácidos Pentanoicos/orina , Fenilcetonurias/orina , Ácido Pirrolidona Carboxílico/orina , Tirosinemias/orinaRESUMEN
Mutations in the gene for 4-hydroxyphenylpyruvic acid dioxygenase (HPD) cause either autosomal recessive tyrosinemia type III or autosomal dominant hawkinsinuria. We report a 6-month-old Indian infant who is compound heterozygous for both alleles and who has hawkinsinuria but not tyrosinemia type III based on biochemical investigations. The HPD gene was directly sequenced in the proband and both parents. The mechanistic model of the enzymatic function was built using the known structure of rat HPD. We identified a novel hawkinsinuria mutation, Asn241Ser, and a known tyrosinemia type III mutation, Ile335Met, in trans configuration. The structural analysis of the active site revealed that the IIe335Met mutation is situated in the close vicinity of one of the two highly conserved Phe rings which stack with the phenol ring of the substrate. The Asn241Ser mutation is situated further away from the 4-hydroxyphenylpyruvate binding pocket. Assuming that Asn241Ser causes hawkinsinuria, we propose positioning the dioxygen molecule in the HPD-catalyzed reaction as a novel role for the Asn residue. The IIe335Met allele is equivalent to a null mutation while the Asn241Ser allele results in a partially active enzyme with an uncoupled turnover causing hawkinsinuria.
Asunto(s)
4-Hidroxifenilpiruvato Dioxigenasa/genética , Aminoácidos Sulfúricos/orina , Ciclohexenos/orina , Tirosinemias/genética , Tirosinemias/orina , 4-Hidroxifenilpiruvato Dioxigenasa/deficiencia , ADN/sangre , ADN/genética , ADN/aislamiento & purificación , Tamización de Portadores Genéticos , Humanos , Lactante , Modelos Moleculares , Reacción en Cadena de la Polimerasa , Conformación ProteicaRESUMEN
Flow injection electrospray ionization tandem mass spectrometric methods for succinylacetone (SA) in 250 microL urine, using d5-SA as internal standard, and in 3 mm dried bloodspots, using 13C4-SA as internal standard, are described. Selectivity and sensitivity of analysis is achieved by the use of a mono-Girard T derivative. Measured SA infant urine normal range (n=20) is 0.013-0.27 micromol/mmol creatinine. Measured SA newborn bloodspot normal range (n=152) is 0-0.30 micromol/L. Bloodspots from children with hepatorenal tyrosinemia type 1, and kept at room temperature for up to 7 years, afforded SA concentrations of 0.9-5.7 micromol/L.
Asunto(s)
Betaína/análogos & derivados , Heptanoatos/sangre , Heptanoatos/orina , Betaína/química , Niño , Eritrocitos/química , Análisis de Inyección de Flujo , Humanos , Indicadores y Reactivos , Lactante , Recién Nacido , Cetosteroides/análisis , Espectrometría de Masa por Ionización de Electrospray , Tirosinemias/sangre , Tirosinemias/diagnóstico , Tirosinemias/orinaRESUMEN
BACKGROUND: Hepatorenal tyrosinemia (HT1) is considered a treatable inherited metabolic disease, particularly when detected early in life. Succinylacetone (SA), a unique metabolic marker for HT1, is normally circulating or excreted at very low physiological concentrations and is significantly increased in HT1 patients. METHODS: We developed and validated a new method for the determination of SA in urine using high-pressure liquid chromatography with fluorescence detection. SA and its homologue 5,7-dioxooctanoic acid used as internal standard (IS) were extracted from urine, derivatized with pyrenebutyric hydrazide and separated on a C18 column within 11 min. Calibration curves were linear between 0.025 to 100 micromol/l. Within- and between-day variations were <5% and results obtained by the current method compared favorably with a reference liquid chromatography tandem mass spectrometric method. The method was applied retrospectively to the analysis of urine samples from HT1 patients. CONCLUSIONS: The method requires a minimal sample volume (0.1 ml) with simple instrumentation. The method enabled us to differentiate HT1 cases (n=14) from controls (n=104), regardless of the years of urine storage.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Heptanoatos/orina , Enfermedades Renales/orina , Hepatopatías/orina , Espectrometría de Fluorescencia/métodos , Tirosinemias/orina , Calibración , HumanosRESUMEN
The chemical diagnosis of tyrosinemia type I generally involves the detection of succinylacetone (SA) in patient urine. However, 5-aminolevulinate (5ALA), which accumulates due to succinylacetone's inhibition of porphyrin synthesis, can also be used as diagnostic metabolites. Here we examined the stabilities of these markers on dried urine filter paper. After two weeks at room temperature, the succinylacetone was 10% of its original level, but over 80% of 5-aminolevulinate remained. Thus, although insufficient succinylacetone was recovered from dried urine filter paper to diagnose tyrosinemia type I, 5-aminolevulinate was readily detected, permitting the diagnosis.
Asunto(s)
Ácido Aminolevulínico/análisis , Biomarcadores/análisis , Cromatografía de Gases y Espectrometría de Masas/métodos , Tirosinemias/orina , Filtración/instrumentación , Humanos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Tirosinemias/diagnósticoRESUMEN
The presence of succinylacetone in urine or blood or amniotic fluid is pathognomonic of an inherited metabolic disorder, named tyrosinemia type I. We developed a capillary electrophoretic method for the fast analysis of succinylacetone in urine samples. The separation was performed at reversed polarity mode using either a cationic surfactant as the buffer additive, or a capillary coated with a positively charged polyelectrolyte. Under these conditions, urine samples were directly injected to the capillary without any pretreatment step. The utility of the method was demonstrated by the identification of succinyacetone in urine from patients with hereditary tyrosinemia type I. For all patients, diagnostic peaks at the expected migration times were detected. The developed method is rapid, simple, inexpensive, and suitable for the determination of succinylacetone in clinical urine samples.
Asunto(s)
Electroforesis Capilar/métodos , Heptanoatos/orina , Tirosinemias/diagnóstico , Humanos , Reproducibilidad de los Resultados , Tirosinemias/orinaRESUMEN
We describe an isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of succinylacetone (SA) in urine for the diagnosis of hepatorenal tyrosinemia (HT1). The method used 15N-labeled 5(3)-methyl-3(5)-isoxazole propionic acid as internal standard. Urine samples were oximated with hydroxylamine hydrochloride at 80 degrees C, extracted by solvent-solvent extraction, and followed by derivatization of the butyl ester. The butylated isoxazole derivatives of SA and its internal standard were detected and quantified using positive ion electrospray LC-MS/MS with selected reaction monitoring. The turnaround time between injections was 10 min. Calibration curves were linear over the range of 0.0633-63.3 micromol/L. The intra- and interday assay variations were less than 7%. Mean recoveries of SA at three different concentrations ranged from 96 to 109%. During the course of this study, we identified 12 new patients with HT1 and applied this method to follow up the treatment of 4 of these patients as well as previously diagnosed HT1 patients.
Asunto(s)
Heptanoatos/orina , Tirosinemias/orina , Adolescente , Adulto , Niño , Preescolar , Ciclohexanonas/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Humanos , Lactante , Recién Nacido , Espectrometría de Masas , Persona de Mediana Edad , Tamizaje Neonatal/métodos , Nitrobenzoatos/uso terapéutico , Reproducibilidad de los Resultados , Tirosinemias/tratamiento farmacológicoRESUMEN
A simple and versatile low-capacity cation-exchange chromatography system for the simultaneous determination of creatinine and UV-absorbing amino acids was developed. The separation column was packed with a newly developed low-capacity sulfoacylated macro-porous polystyrene-divinylbenzene resin selective for amino-acid cations. Urinary creatinine, creatine, tyrosine, histidine, phenylalanine, and tryptophan were simultaneously separated and determined by an isocratic elution with phosphate/acetonitrile eluent in 25 min. Relative standard deviations (R.S.D.) of the retention times for the analytes were between 0.28 and 1.06%. R.S.D. of peak area responses for the analytes were between 0.75 and 3.51%. The r(2) values for the calibration lines were between 0.9994 and 0.9999. The method could provide the creatinine ratios for the analytes, and was applicable to the screening and/or chemical diagnosis of several inherited disorders of amino-acid metabolism such as phenylketonuria (PKU).
Asunto(s)
Aminoácidos/orina , Cromatografía por Intercambio Iónico/métodos , Creatinina/orina , Errores Innatos del Metabolismo/diagnóstico , Cromatografía por Intercambio Iónico/instrumentación , Humanos , Recién Nacido , Tamizaje Masivo , Síndrome Oculocerebrorrenal/orina , Fenilcetonurias/orina , Tirosinemias/orinaAsunto(s)
Tirosina/análogos & derivados , Tirosina/administración & dosificación , Tirosina/orina , Tirosinemias/inducido químicamente , Tirosinemias/genética , Adolescente , Biomarcadores/sangre , Biomarcadores/orina , Nutrición Enteral/efectos adversos , Femenino , Cromatografía de Gases y Espectrometría de Masas/métodos , Humanos , Lactante , Masculino , Persona de Mediana Edad , Nutrición Parenteral/efectos adversos , Tirosina/efectos adversos , Tirosina/sangre , Tirosina/metabolismo , Tirosinemias/orinaRESUMEN
In this report, we describe a method for the specific quantification of urinary 5-aminolevulinic acid. It is based on gas chromatographic mass spectrometric measurement of the trimethylsilyl ester of the ethylacetoacetate pyrrole derivative of 5-aminolevulinic acid. Selected ion monitoring (SIM) was used for quantification using 3-hydroxymyristic acid as an internal standard. The detection limit of this method was 0.1 nmol/ml. This method was applied to the determination of urinary 5-aminolevulinic acid from a tyrosinemia type I patient and normal subjects, and 21.4 mmol/mol creatinine and 0.54+/- 0.49 mmol/mol creatinine (n = 7), respectively, were detected. Less than 0.2 ml urine was sufficient for the determination of 5-aminolevulinic acid in healthy subjects.
Asunto(s)
Ácido Aminolevulínico/orina , Cromatografía de Gases y Espectrometría de Masas/métodos , Humanos , Estándares de Referencia , Tirosinemias/orinaRESUMEN
BACKGROUND: It is well known that urine becomes the major route for bile acid excretion in liver diseases and thus we examined bile acid profile in urine obtained from normal children and children having chronic liver diseases using electrospray tandem mass spectrometry (ES/MS/MS). MATERIAL/METHODS: Bile acid were extracted from 5 ml of urine obtained from five healthy children or from twenty patients with various liver diseases including patients with unknown chronic liver diseases, Zellweger syndrome, peroxisomal bifunctional protein deficiency disease, tyrosinema type 1, biliary atresia, and patients with progressive familial intrahepatic cholestasis (PFIC) of undetermined type. Identification and quantification of bile acids were achieved in 5 minutes using electrospray tandem mass spectrometry (ES/MS/MS). RESULTS: Urinary bile acid excretion increased in liver diseases an average of 100 times as compared to control values. There was a specific profile for different liver disease which confirms the pathology of the disease and could be used for its diagnosis. The results also show that the ions used for the diagnosis of oxo-steroid reductase deficiency disease were present in other chronic liver diseases suggesting that these atypical bile acids may not be a result of an inborn error of bile acid metabolism. CONCLUSIONS: The urinary bile acid profile obtained in this study by ES/MS/MS can be of use for the diagnosis of certain chronic liver diseases.
Asunto(s)
Ácidos y Sales Biliares/orina , Colestasis/orina , Errores Innatos del Metabolismo/orina , Espectrometría de Masa por Ionización de Electrospray/métodos , Atresia Biliar/orina , Estudios de Casos y Controles , Niño , Preescolar , Colestasis Intrahepática/genética , Colestasis Intrahepática/orina , Enfermedad Crónica , Humanos , Hepatopatías/diagnóstico , Hepatopatías/orina , Trastorno Peroxisomal/orina , Valores de Referencia , Síndrome , Tirosinemias/orinaRESUMEN
Hereditary tyrosinemia type 1 (HT1) is a severe autosomal recessive metabolic disease associated with point mutations in the human fumarylacetoacetate hydrolase (FAH) gene that disrupt tyrosine catabolism. An acute form of HT1 results in death during the first months of life because of hepatic failure, whereas a chronic form leads to gradual development of liver disease often accompanied by renal dysfunction, childhood rickets, neurological crisis, and hepatocellular carcinoma. Mice homozygous for certain chromosome 7 deletions of the albino Tyr; c locus that also include Fah die perinatally as a result of liver dysfunction and exhibit a complex syndrome characterized by structural abnormalities and alterations in gene expression in the liver and kidney. Here we report that two independent, postnatally lethal mutations induced by N-ethyl-N-nitrosourea and mapped near Tyr are alleles of Fah. The Fah(6287SB) allele is a missense mutation in exon 6, and Fah(5961SB) is a splice mutation causing loss of exon 7, a subsequent frameshift in the resulting mRNA, and a severe reduction of Fah mRNA levels. Increased levels of the diagnostic metabolite succinylacetone in the urine of the Fah(6287SB) and Fah(5961SB) mutants indicate that these mutations cause a decrease in Fah enzymatic activity. Thus, the neonatal phenotype present in both mutants is due to a deficiency in Fah caused by a point mutation, and we propose Fah(5961SB) and Fah(6287SB) as mouse models for acute and chronic forms of human HT1, respectively.