Original Article
Neurologic Crises in Hereditary Tyrosinemia
N Engl J Med 1990; 322:432-437February 15, 1990
- Abstract
- Abstract
Hereditary tyrosinemia results from an inborn error in the final step of tyrosine metabolism. The disease is known to cause acute and chronic liver failure, renal Fanconi's syndrome, and hepatocellular carcinoma. Neurologic manifestations have been reported but not emphasized as a common problem. In this paper, we describe neurologic crises that occurred among children identified as having tyrosinemia on neonatal screening since 1970.
Of the 48 children with tyrosinemia, 20 (42 percent) had neurologic crises that began at a mean age of one year and led to 104 hospital admissions. These abrupt episodes of peripheral neuropathy were characterized by severe pain with extensor hypertonia (in 75 percent), vomiting or paralytic ileus (69 percent), muscle weakness (29 percent), and self-mutilation (8 percent). Eight children required mechanical ventilation because of paralysis, and 14 of the 20 children have died. Between crises, most survivors regained normal function. We found no reliable biochemical marker for the crises (those we evaluated included blood levels of tyrosine, succinylacetone, and hepatic aminotransferases). Urinary excretion of δ-aminolevulinic acid, a neurotoxic intermediate of porphyrin biosynthesis, was elevated during crises but also during the asymptomatic periods. Electrophysiologic studies in seven patients and neuromuscular biopsies in three patients showed axonal degeneration and secondary demyelination.
We conclude that episodes of acute, severe peripheral neuropathy are common in hereditary tyrosinemia and resemble the crises of the neuropathic porphyrias. (N Engl J Med 1990; 322:432–7.)
Media in This Article
Figure 1
Effect of Hereditary Hepatorenal Tyrosinemia on Porphyrin Metabolism.Figure 2
Cross Section (A) and Longitudinal Section (B) of a Sural-Nerve Specimen from a 15-Month-Old Girl with Tyrosinemia (Epon-Embedded Semithin Section Stained with Paraphenylenediamine, ×10).Article Activity
- Article
IN the province of Quebec, hereditary tyrosinemia (tyrosinemia Type I; McKusick no. 27670) is a common genetic disorder. This autosomal recessive disorder of amino acid metabolism is caused by a deficiency of fumarylacetoacetate hydrolase, the final enzyme in the metabolic pathway of tyrosine breakdown1 (Fig. 1Figure 1
Effect of Hereditary Hepatorenal Tyrosinemia on Porphyrin Metabolism.). The accumulation of tyrosine metabolites proximal to the enzymatic block is believed to be the cause of acute liver failure, hepatic cirrhosis, hepatocellular carcinoma, and renal Fanconi's syndrome,2 any or all of which may occur in a single patient. In our experience, however, the major clinical problem in many patients is neither hepatic nor renal disease but recurrent neurologic crises. Because only isolated reports of these episodes have appeared in the medical literature,3 4 5 6 we describe our findings to date in 48 patients with hereditary tyrosinemia.Methods
We defined a neurologic crisis as the presence of paralysis or painful dysesthesia (in patients more than one year old), with or without hypertonic posturing during hospitalization, as judged from a review of hospital records. To establish the incidence of such episodes, we reviewed all hospital admissions of patients with tyrosinemia born since October 1970 (when neonatal screening for tyrosinemia began in Quebec) and followed at the Hôpital de Chicoutimi or Hôpital Sainte Justine. To identify a biochemical marker of these episodes, we reviewed the laboratory values for these patients; in 13 children with tyrosinemia we obtained values for blood tyrosine, blood inhibitor (succinylacetone), and urinary excretion of δ-aminolevulinic acid.
All patients were found to have hypertyrosinemia on neonatal blood screening7 and evidence of hepatic abnormalities consistent with the diagnosis. All patients in whom the disorder had been diagnosed since 1980 were tested and found to be positive for the blood inhibitor effect, which is specific to hepatorenal tyrosinemia and which measures the inhibition of δ-aminolevulinic acid dehydratase activity by a patient's serum.8 In correlating levels of tyrosine, δ-aminolevulinic acid, and inhibitor with the occurrence of neurologic crises, we classified each patient as being asymptomatic if the patient had no neurologic symptoms at the time of blood sampling and for at least one month previously, or as having a neurologic crisis if the patient was in active neurologic crisis at the time of sampling (periods of recovery from paralysis were excluded from this category). When multiple values were available (such as serial measurements obtained during a crisis or measurements obtained less than one month apart during asymptomatic periods), the earliest value was used.
Plasma tyrosine was measured fluorometrically.7 Inhibitor effect8 was expressed as micromoles of succinylacetone per liter. δ-Aminolevulinic acid was assayed with a kit (Bio-Rad Laboratories [Canada], Mississauga, Ont.).
Results
Forty-eight children had been hospitalized for hereditary tyrosinemia since 1970, and neurologic crises had occurred in 20 (42 percent). All 20 patients except 1, whose early course has been reported previously,9 , 10 were followed in the participating centers from the time of diagnosis. Six of the 20 patients are alive at 2 to 19 years of age; 7 died at less than 1 year of age, 2 died between 1 and 2 years, 4 died between 2 and 3 years, and 1 died at 12 years. Among these 20 patients, 104 of a total of 149 hospital admissions (70 percent) were for treatment of neurologic crises. The mean age at the onset of neurologic crises was 11.7 months (range, 1 to 21) for all the patients except one, in whom the first recorded episode occurred at 60 months of age. Fifty-five of the crises (53 percent) were preceded or accompanied by an infection, most commonly (35 cases) an upper respiratory infection.
The features of the patients are summarized in Table 1Table 1
Clinical Characteristics of Neurologic Crises in 20 Children with Tyrosinemia.. Hypertonia was observed in 79 (76 percent) of the crises, during which the patients were conscious and in pain. The pain was poorly localized in the legs and occasionally in the abdomen. The hypertonia was typically axial and extensor and ranged in severity from slight resistance to neck flexion to opisthotonic posturing. It intensified episodically and sometimes persisted during sleep. Weakness was noted during 30 crises (29 percent), and in 8 instances mechanical ventilation was required for periods of 19 to 106 days. A marked recovery of motor function was observed over weeks to months after the onset of paralysis in all five episodes in which paralysis was not fatal. In eight crises we observed oral self-mutilation in the form of tongue biting with laceration (four crises) or bruxism with avulsion of teeth (four crises). Five patients had at least one crisis each in which sustained arterial hypertension was documented.In eight instances seizures were reported in association with the crises. In three instances they were associated with hyponatremia (112 to 120 mmol per liter). In one case the seizures occurred in association with cerebral edema that followed an episode of anoxia. Serum sodium values were not determined at the time of the other convulsions. Electroencephalograms obtained during five neurologic crises showed no evidence of epileptic activity. Slow-wave activity was present over the posterior regions in three patients. Two electroencephalograms obtained during the acute phase of an episode of paralysis were normal.
The cerebrospinal fluid cell count and protein and glucose levels were determined during eight crises. All values were normal except one: the protein level was 0.94 g per liter in a three-week-old patient during an episode of paralysis.
Peripheral-nerve conduction was studied a total of 11 times in seven patients. In one patient, three studies were performed during a single crisis. The first study, conducted one day after the onset of complete quadriparesis and anesthesia, was normal. After three days of quadriparesis, reduced-amplitude motor action potentials were observed, with normal conduction velocity. At day 15, no motor or sensory potentials were detected despite maximal stimulation. Five other studies, performed in four patients between two weeks and five months after an episode of paralysis or after a series of painful crises with some weakness, were similar, showing fibrillations, undetectable or low-amplitude potentials, and slightly reduced conduction velocity. The results of the remaining three studies of nerve conduction were normal. They were performed four days, one week, and five months after painful crises without reported weakness. In one episode of paralysis, the administration of neostigmine (Prostigmin) had no effect.
Histopathological examination of peripheral-nerve specimens was done in three patients two weeks to six months after the onset of severe episodes of paralysis. All three specimens showed evidence of axonal degeneration and secondary demyelination (Fig. 2Figure 2
Cross Section (A) and Longitudinal Section (B) of a Sural-Nerve Specimen from a 15-Month-Old Girl with Tyrosinemia (Epon-Embedded Semithin Section Stained with Paraphenylenediamine, ×10).).Table 1 shows the results of laboratory tests performed during crises. Although the levels of serum aminotransferases and prothrombin times were slightly increased in 38 percent and 55 percent of crises, respectively, acute hepatic failure with ascites was observed in only two patients. The plasma ammonia level was slightly increased on 2 of 10 occasions (1.15 and 1.65 times the upper limit of normal). A single patient (a six-week-old girl evaluated at the time of a crisis involving paralysis) had plasma glucose values that repeatedly were less than 2.2 mmol per liter (40 mg per deciliter). No patients had repeat values for glucose above 16.7 mmol per liter (300 mg per deciliter).
As compared with normal subjects, both neurologically asymptomatic patients and symptomatic patients had lower mean blood tyrosine values (Fig. 3AFigure 3
Levels of Blood Tyrosine (A), Blood Inhibitor (B), and δ-Aminolevulinic Acid Excretion (C) in 13 Patients with Tyrosinemia.), presumably as a result of their tyrosine-restricted diets. Furthermore, the mean of all values recorded in patients during crises was lower than the mean of their values between crises, although this relation was not observed in all patients (e.g., Patient 3, Fig. 3A). The inhibitor effect in normal subjects (in whom it was undetectable) was clearly different from that in the patients with tyrosinemia, but no striking difference was observed between values recorded in patients during crises and those recorded between crises. The excretion of δ-aminolevulinic acid in urine was increased in all patients, although it was nearly normal in one patient with liver failure but no neurologic crises (Patient 12, Fig. 3C). The mean urinary δ-aminolevulinic acid excretion in the patients as a group was higher during neurologic crises than during asymptomatic periods. In individual patients, however, excretion was not reliably correlated with the occurrence of crises (Fig. 3C).Thirteen of the 14 deaths among the 20 patients with tyrosinemia and neurologic crises occurred in the participating institutions. Eleven deaths were caused by complications of respiratory insufficiency or mechanical ventilation; liver dysfunction was not considered to be a major contributing factor. In one patient, who had no symptoms of neurologic crisis in the terminal phase, death was attributed to hepatic failure. Finally, in another patient, who died immediately after hepatic transplantation, there were no symptoms of neurologic crisis. Five of the 20 patients with tyrosinemia and neurologic crises have undergone hepatic transplantation. None of these five have had neurologic crises over a total follow-up period of 54 patient-months.
Discussion
Neurologic crises caused incapacity and sometimes death in nearly half our patients with hereditary tyrosinemia. Although these crises have been reported previously,3 4 5 6 little attention has been focused on their clinical aspects. In contrast, laboratory evaluations of patients during the neurologic crisis of tyrosinemia have led to the finding of increased excretion of the porphyrin precursor δ-aminolevulinic acid4 5 6 and to the subsequent identification of succinylacetone ("inhibitor"),1 a tyrosine metabolite capable of blocking porphyrin synthesis.1 , 11 This finding in turn allowed the deduction of the primary enzyme defect in hepatorenal tyrosinemia, fumarylacetoacetate hydrolase deficiency (Fig. 1).1
The lack of clinical descriptions of neurologic crises in tyrosinemia may reflect the small number of patients described previously. However, we cannot eliminate the possibility that children with tyrosinemia in Quebec may be somehow predisposed to these crises. In Quebec, neonatal screening for this condition leads to placing most patients on dietary therapy before the appearance of symptoms and prevents some cases of fatal liver failure during infancy, the major cause of death in early reports of tyrosinemia.12 , 13 This early intervention may allow extrahepatic manifestations to develop in surviving patients.
In tyrosinemia, the spectrum of neurologic status ranges from normal to the virtual extinction of peripheral-nerve function. In contrast to this clinical variability, genealogic evidence suggests that in Quebec, all patients with tyrosinemia are homozygotes for a single mutant allele.14 Furthermore, we and others3 , 4 have observed different clinical phenotypes in affected siblings. Environmental factors and genes other than that for fumarylacetoacetate hydrolase must therefore be necessary to allow the phenotype of neurologic crisis to appear. Catabolic stresses such as infections are frequent precipitating events, but other factors remain unidentified.
Our clinical, electrophysiologic, and neuropathological evidence indicates that peripheral axons of long nerves are the primary targets in the crises of tyrosinemia, with secondary demyelination. Children with tyrosinemia have normal development and perform normally at school, suggesting that the central nervous system is relatively spared in this disease. At present, it is uncertain whether the striking hyperextended posturing, convulsions, nonspecific electroencephalographic changes, vomiting, diarrhea, and arterial hypertension during crises are direct effects of tyrosinemia on the central or autonomic nervous system.
There is no reliable biochemical marker for the crises, and the basis for diagnosis remains clinical. In tyrosinemia, in contrast to several other aminoacidopathies, the crises are not strongly associated with acidosis, irregularities in blood glucose metabolism, hyperammonemia, liver failure, or increased blood levels of tyrosine, the precursor amino acid. Blood inhibitor values measured during crises are not clearly different from those measured during asymptomatic periods, nor do they differ between children with tyrosinemia who have had neurologic crises and those who have never had them. The δ-aminolevulinic acid concentration was markedly elevated during all the crises we studied, but it remained elevated during neurologically asymptomatic periods in most but not all patients. We observed severe hyponatremia in some crises. In this regard, it may be of interest that succinylacetone inhibits renal sodium transport in vitro.15
Our patients were restricted in their dietary intake of phenylalanine and tyrosine, for a mean combined intake of about 80 mg per kilogram of body weight per day. As expected, their blood tyrosine concentrations were lower than those of controls. This intake supports normal growth in patients with two other errors of aromatic—amino acid metabolism, phenylketonuria and tyrosine aminotransferase deficiency.16 , 17 Mean plasma tyrosine values were lower during crises than during asymptomatic periods, which may be a result of anorexia and vomiting during crises. The means shown in Figure 3 were derived from unpaired values in several patients and are presented for descriptive purposes only. Given the scatter observed between patients and among values of individual patients, we draw no therapeutic conclusions from this observation. Obtaining multiple paired values before and during crises will be necessary for such analysis.
Therapy for the crises includes the provision of adequate caloric intake, respiratory support during paralysis, and the control of pain, arterial hypertension, hyponatremia, and self-mutilation. By analogy with the treatment of other inborn errors of amino acid and porphyrin metabolism, we employ high-carbohydrate, high-calorie gavage without phenylalanine or tyrosine for the initial treatment of crises. Glucose decreases endogenous protein breakdown and inhibits the porphyrin-synthesizing enzyme δ-aminolevulinic acid synthase.18 If vomiting or paralysis develops, we begin parenteral nutrition. Phenylalanine and tyrosine are reintroduced within 24 to 48 hours. We administer narcotics for the excruciating pain of some crises. Since respiratory failure can develop rapidly, we monitor the patient's respiratory status carefully. Therapy with vitamins B1 and B6 or adenosine triphosphate,19 N-acetylcysteine,20 or hematin21 has not been evaluated rigorously. We avoid giving barbiturates and other agents contraindicated in porphyria.
Considerable evidence supports the hypothesis1 , 4 5 6 , 20 that abnormal porphyrin metabolism underlies the neurologic crises of tyrosinemia. Elevated δ-aminolevulinic acid excretion is seen in acute intermittent porphyria,11 symptomatic lead poisoning,22 and familial δ-aminolevulinic acid dehydratase deficiency,23 all of which are associated with peripheral neuropathy. The axonal degeneration and secondary demyelination in our patients resemble those seen in acute intermittent porphyria.24 25 26 As in tyrosinemia, the δ-aminolevulinic acid level is only loosely correlated with clinical status in acute intermittent porphyria,18 and the absence of symptoms in patients with biochemical features of the disorder is common in those with porphyria18 and lead intoxication.22 δ-Aminolevulinic acid, the only metabolite whose levels are elevated in all the neuropathic porphyrias, lead poisoning, hereditary δ-aminolevulinic acid dehydratase deficiency, and tyrosinemia, enters the brain27 and is neurotoxic.28 29 30 31 As compared with the known primary and secondary porphyrias, tyrosinemia has the earliest onset of symptoms and particularly severe manifestations. Therefore, it may be the most severe known porphyria-like condition.
Hepatic allograft transplantation is an exciting new therapy for children with tyrosinemia and hepatocellular insufficiency and presumably eliminates their risk of hepatocellular carcinoma.32 The central role of the liver in hepatic porphyrias22 suggests that transplantation may eliminate the porphyria-related crises. In the limited number of patients with tyrosinemia who have undergone liver transplantation, no neurologic complications have subsequently developed, to our knowledge. In at least two patients,33 , 34 δ-aminolevulinic acid excretion became normal after transplantation. However, some extrahepatic signs of tyrosinemia, such as renal dysfunction33 and succinylacetone excretion,34 , 35 may persist. We hope that the initial optimism about transplantation will be borne out by careful longitudinal follow-up of patients with grafts. At present, neurologic crises are the most challenging problem in the short-term management of tyrosinemia and a major cause of mortality in our patients with hereditary tyrosinemia who have not undergone transplantation.
During the study. Dr. Mitchell was a bursar of the Réseau de Médecine Génétique du Québec, and later of the Fonds de la Recherche en Santé du Québec.
Presented in part in abstract form (Pediatr Res 1986; 20:Suppl:269A; Can J Neurol Sci 1987; 14:97).
We are indebted to Drs. S. Sassa, D. Valle, S. Brusilow, G. Sherwood, K. Morgan, R. Laframboise, P. Goodyer, R. Gagné, C. Laberge, D. Cole, and L. Brody for stimulating discussions; to Dr. G. Brisson for the determination of porphyrin metabolites; to Dr. A. Bonin for obtaining control blood samples; to B. Grignon, G. Lafontaine, and Gilles Doucet for laboratory assistance; to L. Bouthillier for expert dietary evaluations; to Drs. J.-M. Laberge and H. Blanchard and the Sainte Justine–Montreal Children's Hospital liver-transplantation team for their collaboration; and to M. Stevens, C. Blais, and C. Trottier for help in preparing the manuscript.
Source Information
From the Departments of Genetics (G.M., M.L., H.O., Y.L., S.M., L.D.), Pathology (J.M.), Intensive Care (M.G., J. Lacroix), Neurology (M.V., A.L.), and Gastroenterology (K.P., A.W.), Hôpital Sainte Justine, Montreal; the Department of Pediatrics (J. Larochelle), Hôpital de Chicoutimi, Chicoutimi, Que.; and the Réseau de Médecine Génétique du Québec (A.G.), Centre Hospitalier de l'Université Laval, Quebec. Address reprint requests to Dr. Mitchell at the Service de Génétique, Hôpital Sainte Justine, 3175 Chemin de la Côte Ste. Catherine, Montreal. PQ H3T 1C5, Canada.
- References
References
1
Lindblad
CrossRef | Web of Science | Medline2
Goldsmith LA, Laberge C. Tyrosinemia and related disorders. In: Scriver C, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease. 6th ed. Vol. 1. New York: McGraw-Hill, 1989:547–62.
3
Gentz
Web of Science | Medline4
Gentz
CrossRef | Web of Science | Medline5
Kang
CrossRef | Web of Science | Medline6
Strife
CrossRef | Web of Science | Medline7
Grenier
CrossRef | Web of Science | Medline8
Grenier
CrossRef | Web of Science | Medline9
Goulden
CrossRef | Web of Science | Medline10
Cole
CrossRef | Web of Science | Medline11
Sassa
CrossRef | Web of Science | Medline12
Larochelle
Web of Science | Medline13
Conference on Hereditary Tyrosinemia held at the Hospital for Sick Children, Toronto, Ontario, March 8, 1966 . Can Med Assoc J 1967; 97:1045–101.
Web of Science14
Laberge
Web of Science | Medline15
Spencer
CrossRef | Web of Science | Medline16
Koch
CrossRef | Web of Science | Medline17
Nyhan WL. Abnormalities in amino acid metabolism in clinical medicine. Norwalk, Conn.: Appleton-Century-Crofts, 1984.
18
Kappas A, Sassa S, Galbraith RA, Nordmann Y. The porphyrias. In: Scriver C, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease. 6th ed. Vol. 1. New York: McGraw-Hill. 1989:1305–65.
19
Larochelle
Medline20
Stoner
CrossRef | Web of Science | Medline21
Dhar
Web of Science | Medline22
Chisholm
CrossRef | Web of Science | Medline23
Doss
CrossRef | Web of Science | Medline24
Gibson
CrossRef | Web of Science | Medline25
Thorner
Web of Science | Medline26
Stein
Web of Science | Medline27
Moore MR, Meredith PA. The association of delta-aminolaevulinic acid with the neurological and behavioural effects of lead exposure. In: Delbert DH, ed. Conference on Trace Substances in Environmental Health, X: proceedings of University of Missouri's 10th annual Conference on Trace Substances in Environmental Health. Columbia, Mo.: University of Missouri Press, 1976:363–71.
28
Müller
CrossRef | Web of Science | Medline29
Brennan
CrossRef | Web of Science | Medline30
Silbergeld
Web of Science31
Sima
Web of Science | Medline32
Starzl
CrossRef | Web of Science | Medline33
Van Thiel
CrossRef | Web of Science | Medline34
Kvittingen
CrossRef | Web of Science | Medline35
Tuchman
CrossRef | Web of Science | Medline
- Citing Articles (43)
Citing Articles
1
Richard J. Thompson, Bernard C. Portmann, Eve A. Roberts. 2012. Genetic and metabolic liver disease. , 157-259.
CrossRef2
Jonathan B Cooper, Peter T Erskine. 2011. 5-Aminolaevulinic Acid Dehydratase. .
CrossRef3
A. Daly, H. Gokmen-Ozel, A. MacDonald, M. A. Preece, P. Davies, A. Chakrapani, P. McKiernan. (2011) Diurnal variation of phenylalanine concentrations in tyrosinaemia type 1: should we be concerned?. Journal of Human Nutrition and Dieteticsno-no
CrossRef4
Hanaa El-Karaksy, Mona Fahmy, Mona El-Raziky, Nehal El-Koofy, Rokaya El-Sayed, Mohamed S. Rashed, Hasan El-Kiki, Ahmad El-Hennawy, Nabil Mohsen. (2011) Hereditary tyrosinemia type 1 from a single center in Egypt: clinical study of 22 cases. World Journal of Pediatrics 7:3, 224-231
CrossRef5
Faiqa Imtiaz, Mohamed S. Rashed, Bashayer Al-Mubarak, Rabab Allam, Hanaa El-Karaksy, Zuhair Al-Hassnan, Mohammed Al-Owain, Hamad Al-Zaidan, Zuhair Rahbeeni, Alya Qari, Brian F. Meyer, Moeen Al-Sayed. (2011) Identification of mutations causing hereditary tyrosinemia type I in patients of Middle Eastern origin. Molecular Genetics and Metabolism
CrossRef6
H. Hesham A-Kader, Fayez K. Ghishan. 2011. Abnormalities of Hepatic Protein Metabolism. , 786-794.
CrossRef7
A. García-Cazorla, N. I. Wolf, M. Serrano, B. Pérez-Dueñas, M. Pineda, J. Campistol, E. Fernández-Alvarez, J. Colomer, S. DiMauro, G. F. Hoffmann. (2009) Inborn errors of metabolism and motor disturbances in children. Journal of Inherited Metabolic Disease 32:5, 618-629
CrossRef8
Carmen del Castillo, Lidia Morales, Luis F. Alguacil, Elisabet Salas, Elisa Garrido, Elba Alonso, Carmen Pérez-García. (2009) Proteomic analysis of the nucleus accumbens of rats with different vulnerability to cocaine addiction. Neuropharmacology 57:1, 41-48
CrossRef9
J.-U. Schlump, C. Perot, K. Ketteler, M. Schiff, E. Mayatepek, U. Wendel, U. Spiekerkoetter. (2008) Severe neurological crisis in a patient with hereditary tyrosinaemia type I after interruption of NTBC treatment. Journal of Inherited Metabolic Disease 31:S2, 223-225
CrossRef10
Keli Hansen, Simon Horslen. (2008) Metabolic liver disease in children. Liver Transplantation 14:4, 391-411
CrossRef11
A. Masurel-Paulet, J. Poggi-Bach, M.-O. Rolland, O. Bernard, N. Guffon, D. Dobbelaere, J. Sarles, H. Ogier Baulny, G. Touati. (2008) NTBC treatment in tyrosinaemia type I: Long-term outcome in French patients. Journal of Inherited Metabolic Disease 31:1, 81-87
CrossRef12
F. Sedel, C. Barnerias, O. Dubourg, I. Desguerres, O. Lyon-Caen, Jean-Marie Saudubray. (2007) Peripheral neuropathy and inborn errors of metabolism in adults. Journal of Inherited Metabolic Disease 30:5, 642-653
CrossRef13
Frédéric Sedel, Olivier Lyon-Caen, Jean-Marie Saudubray. (2007) Therapy Insight: inborn errors of metabolism in adult neurology—a clinical approach focused on treatable diseases. Nature Clinical Practice Neurology 3:5, 279-290
CrossRef14
Monte S. Willis, Alice A. Basinger, Zheng Fan, Surekha Pendyal, Joseph Muenzer, Catherine Hammett-Stabler. (2006) Hepatosplenomegaly in an 8-Month-Old Child. Laboratory Medicine 37:11, 665-695
CrossRef15
C. Ronald Scott. (2006) The genetic tyrosinemias. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 142C:2, 121-126
CrossRef16
Jonathan B Cooper, Peter T Erskine. 2006. 5-Aminolaevulinic Acid Dehydratase. .
CrossRef17
Keith Nemergut, Edward C. Littlewood. 2006. Liver Diseases. , 151-201.
CrossRef18
Toshihiro Shinka, Morimasa Ohse, Yoshito Inoue, Tomiko Kuhara. (2005) Stability of 5-aminolevulinic acid on dried urine filter paper for a diagnostic marker of tyrosinemia type I. Journal of Chromatography B 823:1, 44-46
CrossRef19
Suzanne V. Mcdiarmid. 2005. Liver Transplantation for Metabolic Disease. , 337-366.
CrossRef20
B. Rodeck, U. Baumann. (2004) Tyrosin
mie Typ I. Monatsschrift Kinderheilkunde 152:10, 1095-1101
CrossRef21
Deepali Karnik, Niranjan Thomas, C. E. Eapen, A. K. Jana, A. Oommen. (2004) Tyrosinemia type I: A clinico-laboratory case report. The Indian Journal of Pediatrics 71:10, 929-932
CrossRef22
Toshihiro Shinka, Tomiko Kuhara. (2004) Quantification of urinary 5-aminolevulinic acid by gas chromatography–mass spectrometry. Journal of Chromatography B 806:1, 19-23
CrossRef23
Sylvie I Demers, Pierre Russo, Francine Lettre, Robert M Tanguay. (2003) Frequent mutation reversion inversely correlates with clinical severity in a genetic liver disease, hereditary tyrosinemia. Human Pathology 34:12, 1313-1320
CrossRef24
T. M. Burns, M. M. Ryan, B. Darras, H. R. Jones. (2003) Current Therapeutic Strategies for Patients With Polyneuropathies Secondary to Inherited Metabolic Disorders. Mayo Clinic Proceedings 78:7, 858-868
CrossRef25
Raj Barathur, Jack Bookout, Srinand Sreevatsan, John Gordon, Martina Werner, Gautam Thor, Mark Worthington. (2002) New disc-based technologies for diagnostic and research applications. Psychiatric Genetics 12:4, 193-206
CrossRef26
Gayatri Bhasin, Hina Kausar, Mohammad Athar. (2002) Protoporphyrin-IX accumulation and cutaneous tumor regression in mice using a ferrochelatase inhibitor. Cancer Letters 187:1-2, 9-16
CrossRef27
Sari T Pitkänen, Matti K Salo, Markku Heikinheimo. (2000) Hereditary tyrosinaemia type I: from basics to progress in treatment. Annals of Medicine 32:8, 530-538
CrossRef28
Qian Peng, Trond Warloe, Kristian Berg, Johan Moan, Magne Kongshaug, Karl-Erik Giercksky, Jahn M. Nesland. (1997) 5-Aminolevulinic acid-based photodynamic therapy. Cancer 79:12, 2282-2308
CrossRef29
Josée Dubois, Laurent Garel, Heidi Patriquin, Khazal Paradis, Sylviane Forget, Denis Filiatrault, Andrée Grignon, Pierre Russo, Dickens St-Vil. (1996) Imaging features of type 1 hereditary tyrosinemia: a review of 30 patients. Pediatric Radiology 26:12, 845-851
CrossRef30
JACQUES POUDRIER, MARYSE ST-LOUIS, FRANCINE LETTRE, KARINE GIBSON, CLAUDE PRÉVOST, JEAN LAROCHELLE, ROBERT M. TANGUAY. (1996) FREQUENCY OF THE IVS12+5G→A SPLICE MUTATION OF THE FUMARYLACETOACETATE HYDROLASE GENE IN CARRIERS OF HEREDITARY TYROSINAEMIA IN THE FRENCH CANADIAN POPULATION OF SAGUENAY-LAC-ST-JEAN. Prenatal Diagnosis 16:1, 59-64
CrossRef31
Markus Grompe, Sven Lindstedt, Muhsen Al-Dhalimy, Nancy G. Kennaway, John Papaconstantinou, Carlos A. Torres-Ramos, Ching-Nau Ou, Milton Finegold. (1995) Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I. Nature Genetics 10:4, 453-460
CrossRef32
Jeffrey Teckman, David H. Perlmutter. (1995) Conceptual advances in the pathogenesis and treatment of childhood metabolic liver disease. Gastroenterology 108:4, 1263-1279
CrossRef33
F. J. Spronsen, G. P. A. Smit, F. A. Wijburg, Y. Thomasse, G. Visser, H. S. A. Heymans. (1995) Tyrosinaemia type I: considerations of treatment strategy and experiences with risk assessment, diet and transplantation. Journal of Inherited Metabolic Disease 18:2, 111-114
CrossRef34
Si Houn Hahn, Donna Krasnewich, Mark Brantly, Eli Anne Kvittingen, William A. Gahl. (1995) Heterozygosity for an exon 12 splicing mutation and a W234G missense mutation in an American child with chronic tyrosinemia type 1. Human Mutation 6:1, 66-73
CrossRef35
Francjan J. Van Spronsen, Yolande Thomasse, G. Peter A. Smit, James V. Leonard, Peter T. Clayton, Vaclav Fidler, Ruud Berger, Hugo S. A. Heymans. (1994) Hereditary tyrosinemia type I: A new clinical classification with difference in prognosis on dietary treatment. Hepatology 20:5, 1187-1191
CrossRef36
Grompe, MarkusSt.-Louis, MaryseDemers, Sylvie I.Al-Dhalimy, MuhsenLeclerc, BarbaraTanguay, Robert M.. (1994) A Single Mutation of the Fumarylacetoacetate Hydrolase Gene in French Canadians with Hereditary Tyrosinemia Type I. New England Journal of Medicine 331:6, 353-357
Full Text37
R.M. Quinlivan, S.A. Robb, S.M. Hall, M. Honavar, R.A.C. Hughes, V. Dubowitz. (1994) Infantile axonal neuropathy in two siblings. Neuromuscular Disorders 4:3, 227-232
CrossRef38
Roderick R. McInnes, Peter H. Byers. (1993) Biochemical genetics: examples of life after cloning. Current Opinion in Genetics & Development 3:3, 475-483
CrossRef39
Markus Grompe, Muhsen Al-Dhalimy. (1993) Mutations of the fumarylacetoacetate hydrolase gene in four patients with tyrosinemia, type I. Human Mutation 2:2, 85-93
CrossRef40
P. MUSTAJOKI, K. TIMONEN, A. GORCHEIN, A. M. SEPPÄLÄINEN, E. MATIKAINEN, R. TENHUNEN. (1992) Sustained high plasma 5-aminolaevulinic acid concentration in a volunteer: no porphyric symptoms. European Journal of Clinical Investigation 22:6, 407-411
CrossRef41
T. Coşkun, İ. Özalp, N. Koçak, A. Yüce, M. Çaglar, R. Berger. (1991) Type I hereditary tyrosinaemia: Presentation of 11 cases. Journal of Inherited Metabolic Disease 14:5, 765-770
CrossRef42
E. A. Kvittingen. (1991) Tyrosinaemia type I — an update. Journal of Inherited Metabolic Disease 14:4, 554-562
CrossRef43
(1990) HEREDITARY TYROSINAEMIA. The Lancet 335:8704, 1500-1501
CrossRef
