André Grenier

Neurologic Crises in Hereditary Tyrosinemia

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 Fanconis 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 delta-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.

Effect of nitisinone (NTBC) treatment on the clinical course of hepatorenal tyrosinemia in Québec.

BACKGROUND Hepatorenal tyrosinemia (HT1, fumarylacetoacetate hydrolase deficiency, MIM 276700) can cause severe hepatic, renal and peripheral nerve damage. In Québec, HT1 is frequent and neonatal HT1 screening is practiced. Nitisinone (NTBC, Orfadin ®) inhibits tyrosine degradation prior to the formation of toxic metabolites like succinylacetone and has been offered to HT1 patients in Québec since 1994. METHODS We recorded the clinical course of 78 Québec HT1 patients born between 1984 and 2004. There were three groups: those who never received nitisinone (28 patients), those who were first treated after 1 month of age (26 patients) and those treated before 1 month (24 patients). Retrospective chart review was performed for events before 1994, when nitisinone treatment began, and prospective data collection thereafter. FINDINGS No hospitalizations for acute complications of HT1 occurred during 5731 months of nitisinone treatment, versus 184 during 1312 months without treatment (p<0.001). Liver transplantation was performed in 20 non-nitisinone-treated patients (71%) at a median age of 26 months, versus 7 late-treated patients (26%, p<0.001), and no early-treated patient (p<0.001). No early-treated patient has developed detectable liver disease after more than 5 years. Ten deaths occurred in non-nitisinone treated patients versus two in treated patients (p<0.01). Both of the latter deaths were from complications of transplantation unrelated to HT1. One probable nitisinone-related event occurred, transient corneal crystals with photophobia. INTERPRETATION Nitisinone treatment abolishes the acute complications of HT1. Some patients with established liver disease before nitisinone treatment eventually require hepatic transplantation. Patients who receive nitisinone treatment before 1 month had no detectable liver disease after more than 5 years.

Detection of succinylacetone and the use of its measurement in mass screening for hereditary tyrosinemia

A technique designed to measure quantitatively succinylacetone (4,6-dioxoheptanoic acid) is presented. It essentially involves the inhibition of delta-aminolevulinate dehydratase (EC 4.2.1.24) by succinylacetone. Prior to their use in the assay, the samples are heated at 100 degrees C for 30 min in order to transform all succinylacetoacetate (3,5-dioxooctanedioic acid) to succinylacetone. By this transformation of the first abnormal metabolite specific to hereditary tyrosinemia to the second and last one, which is a powerful inhibitor of delta-aminolevulinate dehydratase, we determine in one sensitive assay the total amount of both. Succinylacetone was measured in sera and urines from 19 patients with hereditary tyrosinemia. All sera and urines contained succinylacetone at concentrations ranging, respectively, from 2 to 100 mumol/l and from 190 to 6000 mumol/g creatinine. The technique was also adapted to dried blood spots on paper and was used as a test complementary to blood tyrosine determination in mass screening for hereditary tyrosinemia. A total of 2412 samples having concentrations of 60 mg/l or more of tyrosine were assayed, and ten showed the presence of succinylacetone. These were all from newborns with hereditary tyrosinemia. The test has proven to virtually eliminate false positives, and, thereby, much clerical work and parental anxiety.

Prospective ascertainment of complete and partial serum biotinidase deficiency in the newborn

SummaryWe screened 163 000 newborn filter-paper blood samples for serum biotinidase deficiency (McKusick 25326) and found 15 probands: three had complete deficiency (incidence 18.4 cases per million live births, 95% confidence interval 4–54 cases per million); the others had partial deficiency. The positive predictive value of the test for either form of biotinidase deficiency was 9.86%. We found seasonal variation in biotinidase activity in filter-paper blood samples. The cost per test was Can.

Hereditary tyrosinemia in the province of Quebec: Prevalence at birth and geographic distribution

0.27 (1987 dollar value) and per case of complete deficiency ascertained,

A modified automated fluorometric method for tyrosine determination in blood spotted on paper: a mass screening procedure for tyrosinemia.

15 500. Family studies indicated that complete serum biotinidase deficiency is a homozygous phenotype and partial deficiency is the heterozygous form. Homozygous cases were treated with biotin and have shown no clinical manifestations (55 patient-months of observation). None of the heterozygotes (n=42, age 3 months – 62 years) has clinical manifestations. The number of heterozygotes found by screening was much less than predicted probably because the screening test detects mainly the samples with very low (outlier) biotinidase activity. The variant allele(s) for biotinidase deficiency was more common in French Canadians than in other ethnic groups in Quebec; there was no evidence of regional clustering or founder effect.

A case of tyrosinaemia type I with normal level of succinylacetone in the amniotic fluid.

Hereditary tyrosinemia is a severe metabolic disorder of the newborn for which a very low prevalence at birth has been reported throughout the world. During a 2‐year period, the Quebec Network of Genetic Medicine has tested blood tyrosine in 81.6 % of newborns. Twelve babies with hereditary tyrosinemia were detected by biochemical screening and two more cases were identified by pediatricians. Prevalence at birth way 0.8 case per 10,000 live births in the province of Quebec as a whole; the Chicoutimi‐Lac St. Jean region was found to have an exceptional concentration of 14.6 caqes per 10,000 live births and a frequency of carriers of 1 in 14 persons. such an experimental screening program helps define health problems in a population.

Newborn screening for hepatorenal tyrosinemia by tandem mass spectrometry: analysis of succinylacetone extracted from dried blood spots

Abstract A modified version of the Hochella [2] automated fluorometric technique for tyrosine determination is presented as a mass screening procedure for tyrosinemia. With this technique, 85 000 tests a year can be done with one Auto-Analyzer. In the province of Quebec, 17 cases of hereditary tyrosinemia have been detected with this method over the past three years (208 000 tests). Although the number of false positives is high, blood tyrosine determination remains, to our knowledge, the only mass screening procedure available to detect hereditary tyrosinemia.

Prenatal diagnosis of hereditary tyrosinaemia: Measurement of succinylacetone in amniotic fluid

Prenatal diagnosis of tyrosinaemia type I can be achieved in cultured amniotic cells and in chorionic villus material by testing the activity of fumarylacetoacetate hydrolase and by DNA analysis, and in amniotic fluid by succinylacetone measurement. This specific metabolite can be measured either by gas chromatography–mass spectrometry or by |gd‐aminolevulinate dehydratase inhibition assay. In a series of 65 at‐risk cases tested with the enzyme inhibition assay, one case out of the 18 with the disease had a normal level of succinylacetone. This case is presented.