Neurologic Crises in Hereditary Tyrosinemia

• Published in: The New England journal of medicine Vol. 322; no. 7; pp. 432 - 437
• Main Authors: Mitchell, Grant, Larochelle, Jean, Lambert, Marie, Michaud, Jean, Grenier, André, Ogier, Hélène, Gauthier, Marie, Lacroix, Jacques, Vanasse, Michel, Larbrisseau, Albert, Paradis, Khazal, Weber, Andrée, Lefevre, Yolande, Melançon, Serge, Dallaire, Louis
• Format: Journal Article
• Language: English
• Published: Boston, MA Massachusetts Medical Society 15-02-1990
• Subjects: Acute Disease; Adolescent; Adult; Age; Amino Acid Metabolism, Inborn Errors - complications; Amino Acid Metabolism, Inborn Errors - pathology; Amino Acid Metabolism, Inborn Errors - therapy; Aminolevulinic acid; Aminolevulinic Acid - blood; Biochemical markers; Biological and medical sciences; Biosynthesis; Blood levels; Child; Child, Preschool; Children; Demyelination; Electroencephalography; Excretion; Hepatocellular carcinoma; Hospitalization; Humans; Hypesthesia - etiology; Intestinal Pseudo-Obstruction - etiology; Kidneys; Laboratories; Liver diseases; Mechanical ventilation; Medical research; Medical sciences; Metabolic diseases; Metabolism; Metabolites; Muscle Hypertonia - etiology; Neonates; Neurodegeneration; Neurotoxicity; Pain; Pain - etiology; Paralysis; Patient admissions; Peripheral Nerves - pathology; Peripheral Nervous System Diseases - etiology; Peripheral neuropathy; Renal failure; Self Mutilation - etiology; Tyrosine; Tyrosine - blood; Vomiting; Vomiting - etiology; Canada; Quebec Canada; Human; Metabolic diseases; Complication; Tyrosinemia
• ISSN: 0028-4793; 1533-4406
• DOI: 10.1056/NEJM199002153220704

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.)
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 breakdown
1
(Fig. 1). 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 . . .