Disorder of tyrosine metabolism
-Rare genetic disease
Comment:
A heterozygous missense mutation predicting an Ala to Thr change at codon 33 (A33T) was found in the HPD gene in the two patients with hawkinsinuria (PMID:11073718).
The N241S mutation of HPD gene was presumed to be causative for Hawkinsinuria (PMID:20677779).
Hawkinsinuria is an autosomal dominant inborn error of metabolism (Danks et al., 1975; Tomoeda et al., 2000). Metabolic acidosis and tyrosinemia are transient, and symptoms improve within the first year of life. Patients continue to excrete the hawkinsin ... Hawkinsinuria is an autosomal dominant inborn error of metabolism (Danks et al., 1975; Tomoeda et al., 2000). Metabolic acidosis and tyrosinemia are transient, and symptoms improve within the first year of life. Patients continue to excrete the hawkinsin metabolite in their urine throughout life.
Niederwieser et al. (1977) identified a new sulfur amino acid in the urine of a girl with prolonged tyrosinuria and her mother (reported previously by Danks et al., 1975). The new amino acid, called hawkinsin, was identified as ... Niederwieser et al. (1977) identified a new sulfur amino acid in the urine of a girl with prolonged tyrosinuria and her mother (reported previously by Danks et al., 1975). The new amino acid, called hawkinsin, was identified as (2-L-cystein-S-yl-1,4-dihydroxycyclohex-5-en-1-yl)-acetic acid. They postulated that hawkinsin originated from an intermediate in the 4-hydroxyphenylpyruvate hydroxylase reaction (EC 1.13.11.27) and that mother and child were heterozygous for a defect in this hydroxylase system. The child presented at 20 weeks of age with failure to thrive and persistent acidosis. Her urine contained large amounts of 4-hydroxyphenylpyruvic acid, 4-hydroxyphenylactic acid, and 4-hydroxyphenylacetic acid. A diet specifically restricted in phenylalanine and tyrosine resulted in metabolic correction and rapid catch-up growth. After the age of 12 months tolerance for phenylalanine and tyrosine increased and was normal by 18 months. At age 6 years the girl was normal in all respects. Wilcken et al. (1981) described 5 affected persons in 3 generations. The family was Australian but apparently unrelated to the previously reported cases. They confirmed dominant inheritance. The propositus became ill at 2 weeks of age when breastfeeding was discontinued. Regurgitation of feedings, irritability, tachypnea, and failure to thrive were problems. An unusual body odor 'like the smell of a swimming pool' was noted. At 6 months he was noted to be acidotic with enlarged liver. The hair was fair and stubby. Hemoglobin was 8.9 gm% and the blood smear showed anisocytosis, spherocytosis, and polychromasia. Hawkinsin and 4-hydroxycyclohexylacetic acid (4-HCAA) were found in the urine of the sister, mother, maternal aunt and maternal grandfather. All had been breast-fed as babies to ages 8 to 12 months, and none had had untoward symptoms. Wilcken et al. (1981) concluded that hawkinsinuria appears to be an inborn error of metabolism in which the accumulation of a toxic metabolite occurs when the normal conjugation capacities are exceeded. Their findings also supported a role of glutathione in detoxification of a highly reactive intermediate metabolite formed during the 4-hydroxyphenylpyruvate dioxygenase reaction. Borden et al. (1992) described 2 affected families in the United States. In one family, expression of the gene was traced through 3 generations. Metabolic acidosis and failure to thrive appeared to be confined to infancy. Tyrosyl metabolites and 5-oxoproline were also found in the urine in infancy only. One child presented with failure to thrive and fine, sparse hair with persistent metabolic acidosis. Upon confirmation of the diagnosis of hawkinsinuria at 8 months, she was given a protein-restricted diet, following which she improved greatly. Lehnert et al. (1999) described a 10.5-year-old male patient, the third child of a nonconsanguineous Austrian couple, who was followed from birth. The diagnosis of hawkinsinuria was established at the age of 3 years and 8 months, after a first misdiagnosis of fructose intolerance. Symptoms started after weaning from breast milk at the age of 3 months with recurrent vomiting, inappetence, and failure to thrive. Investigations during several hospital admissions revealed renal tubular acidosis of unknown cause, unclear hepatopathy, prolonged tyrosyluria, and 5-oxoprolinuria during acute illness. Despite initial severe failure to thrive and microcephaly, symptoms resolved gradually without specific treatment and the patient was described as physically and mentally normal at the time of report. Investigation of the parents and the 2 sisters did not detect any metabolic abnormalities, consistent with the possibility of a new mutation.
In the original patient with hawkinsinuria described by Danks et al. (1975) and Niederwieser et al. (1977) and in an American patient described by Borden et al. (1992), Tomoeda et al. (2000) found a heterozygous ala33-to-thr mutation in ... In the original patient with hawkinsinuria described by Danks et al. (1975) and Niederwieser et al. (1977) and in an American patient described by Borden et al. (1992), Tomoeda et al. (2000) found a heterozygous ala33-to-thr mutation in 4-hydroxyphenylpyruvate dioxygenase (609695.0005).