Neurologic Crises in Hereditary Tyrosinemia

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 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.

Mechanistic Inferences from the Crystal Structure of Fumarylacetoacetate Hydrolase with a Bound Phosphorus-based Inhibitor

“…FAH activity was assayed spectrophotometrically using acetopyruvate (AP) (Sigma Chemical Co.) and fumarylacetoacetate (FAA) prepared enzymatically from homogentisic acid (Sigma) as described previously (17,18,30). Assays were initiated by adding recombinant His-tagged FAH to reaction mixtures that covaried AP (0.625, 0.833, 1.25, 2.5, and 5.0 mM) with HMPOBA (0.0, 250, 500, and 750 M) or covaried FAA (3,8, and 15 M) with HMPOBA (0, 125, 250, 500, or 750 M). The disappearance of AP and FAA was followed at 292 and 330 nm for 2-3 min at 37°C, respectively.…”

“…HT1 is an autosomal recessive disease with an acute form that causes death in infancy due to liver failure and a chronic form that causes an early age death due to hepatocellular carcinoma, liver cirrhosis, and neurologic crises (2,3). The lethal nature of HT1 is most likely due to the accumulation of the toxic intermediate fumarylacetoacetate in the absence of FAH activity (4 -6).…”

Clinical Features of 29 Patients with Hereditary Tyrosinemia I in Western Turkey

“…Önenli Mungan et al (24) and Schlump et al (25) reported that interruption of nitisinone treatmentcan cause severe neurological crisis inpatients with HTI. These crises occur in up to 50% of untreated children and these are one of the major causes of mortality (5,26). In follow up, regular abdominal USG was performed every 6-12 months and AFP levels, plasma amino acids and urine succinylacetone were checked every 3 months.…”

Alkaptonuria: Leading to the Treasure in Exceptions

“…Fanconi syndrome with renal tubular acidosis may develop; and with the accumulation of the secondary metabolite, succinylacetone (4,6: dioxoheptanoate, a potent inhibitor of 5-aminolaevulinate dehydratase), neurovisceral episodes mimicking acute porphyria occur (Mitchell et al 1990(Mitchell et al , 2001Sassa and Kappas 1983).…”