Late‐onset ornithine transcarbamylase deficiency in two families with different mutations in the same codon

Abstract

We report on late-onset ornithine transcarbamylase (OTC) deficiency in two families with mutations in the same codon, but different base substitutions. Onset of symptoms showed great variation, and five hemizygotes finally died. Clinical diagnosis was late and difficult. In family A, 1 patient also developed the signs of Gilbert's disease. In family B, the index case came to attention as OTC deficiency, after the transplantation of his liver when the recipient died of cerebral edema and hyperammonemia. In family A, the hemizygote males died at the ages of 12 and 18 years; in family B, they died at the ages of 20, 26, and 30 years, respectively. Diagnosis was confirmed by reduced OTC activity in liver specimens. The residual activity in autopsy liver of the index patient in family A was less than the activity in the biopsy of the transplanted liver of the index patient in family B. The molecular investigations showed mutations in exon 2 at codon 40 in the OTC gene in both families. However, different bases were substituted. In family A, the single-base mutation was a cytosine-to-thymine transition (Arg 40 Cys); in family B, it was a guanine-to-adenine transition (Arg 40 His). Published data on in vitro expression studies of the recurrent OTC mutation Arg 40 His have shown little effect on the protein structure of the enzyme. These studies would fit well with our observation of higher OTC activity and later age of onset of symptoms in family B.

Partial expression of ornithine transcarbamylase deficiency in an Egyptian female carrier

“…Ornithine transcarbamylase (OTC) is a mitochondrial enzyme that catalyzes the synthesis of citrulline from carbamoyl phosphate and ornithine; it is encoded by the OTC nuclear gene, which comprises 10 exons and is located on Xp21.1 [1].…”

“…Ornithine transcarbamylase deficiency (OTCD; OMIM 311250) is the most prevalent urea cycle defect; its phenotype is extremely heterogeneous, ranging from acute neonatal hyperammonemic encephalopathy in male newborns to silent female carriers [1]. Hyperammonemic symptoms in affected male newborns include lethargy, poor feeding, vomiting, hyperventilation, seizures, deepening coma, and death within the first few days unless urgently treated.…”

“…Males who survive the neonatal period may have a poor neurologic outcome (mental retardation, cerebral palsy, seizures). Diagnosis is usually confirmed by elevated glutamine, very low/absent citrulline, and elevated urinary orotic acid [1]. Carrier mothers are usually ostensibly healthy unless exposed to stressful events; they may have unexplained neuropsychiatric symptoms—especially with high protein intake, which may lead to cerebral edema [2].…”

“…As an X‐linked recessive disease, OTCD is transmitted from a heterozygous mother to her male offspring [1]. According to the Lyon hypothesis, female carriers may be asymptomatic or display overt symptoms, especially on exposure to catabolic triggers [2].…”

Ornithine transcarbamylase deficiency combined with type 1 diabetes mellitus - a challenge in clinical and dietary management

“…Survival is better among those who have late onset of symptoms like some female carriers or males with only slightly reduced OTC activity [6-8]. While neonatal onset cases are usually diagnosed reliably using biochemical parameters (like excretion of large amounts of orotic acid and uracil and a typical amino acid pattern with elevated glutamine and very low or not detectable citrulline levels) diagnosis may be more complicated in late onset cases [9].…”