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 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.
Vitamin D-dependent rickets (VDD1) is an autosomal recessive disorder that was recognized in Saguenay-Lac-St-Jean (SLSJ) in 1970. The great majority of the VDD1 cases reported in the French Canadian population of Quebec originated from SLSJ, Charlevoix, and the Haute Côte Nord, all regions located in northeastern Quebec. The prevalence at birth in SLSJ was estimated at 1/2916 live borns, and the carrier rate was estimated at 1/27 inhabitants in the SLSJ region. The mean coefficient of inbreeding was not elevated in the VDD1 group of SLSJ compared with three matched control groups. The mean coefficient of kinship was 2.5 times higher in the VDD1 group than in the control groups. In the SLSJ region, the places of origin of the VDD1 children and their children did not show a clustered non-uniform distribution. Endogamy was not found to be higher in the VDD1 group than in control groups. The genealogical reconstruction showed all the obligate carriers of the VDD1 gene, but one, to be related to a small set of founders who settled in New France in the 17th century. All these results, as well as a strong linkage disequilibrium between RFLPs located on the long arm of chromosome 12 and the VDD1 locus, support the hypothesis of a founder effect for VDD1. They also suggest that a unique mutation accounts for most, if not all, of the cases known in northeastern Quebec.
A new French-Canadian family from the province of Quebec is reported, in which a male child was diagnosed as hyperargininaemic after showing positive tests for cystinuria on neonatal screening. The child has no residual activity of erythrocyte arginase, and a plasma arginine level of 633 mumol/l. Both parents have 32-38% of arginase activity. A newborn sister has normal enzyme levels. The propositus did not show abnormal plasma ammonia elevation even after a protein tolerance test (1.5 g protein/kg body weight) but excretes high levels of urinary orotate (845 mg/g creatinine). At 3 1/2 years of age the hyperargininaemic child had started showing abnormal gait, ataxia and slowing of intellectual development. It is suggested that all newborn children showing cystinuria-lysinuria pattern of amino acid excretion be tested for arginase deficiency.
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