Ornithine aminotransferase deficiency

Presentation

Quite often, the presenting symptom of ornithine aminotransferase (OAT) deficiency is myopia which progresses to night blindness. The onset of myopia is often in early childhood. Ophthalmological findings in affected individuals include constricted visual fields, posterior subcapsular cataracts (can begin in late teens), elevated dark adaptation thresholds and decreased or absent electroretinographic responses. Symptoms of OAT deficiency are progressive, and between the ages of 45 and 65, most affected individuals are almost completely blind.

In some cases, affected individuals will present in the neonatal period with disease that closely mimics a classic urea cycle defect, such as ornithine transcarbamylase deficiency, as the block in ornithine metabolism leads to secondary dysfunction of the urea cycle. These individuals present with hyperammonemia, poor feeding, failure to thrive and increased excretion of orotic acid.

Genetics

OAT deficiency is inherited in an autosomal recessive manner, meaning an affected individual must inherit a mutated allele from both parents. The enzyme, ornithine aminotransferase is coded for by the gene OAT, located at 10q26. OAT deficiency has an increased incidence in Finland, and this population has a common mutation accounting for more than 85% of mutant alleles in this population. It has not been described in any other populations.

Pathophysiology

Due to elevated levels of ornithine in RPE cells, it might interfere with proline uptake. Proline is used for metabolic processes in RPE, such as reductive carboxylation. Again, elevated ornithine levels stimulate polyamine synthesis, and because of this, there are elevated levels of hydrogen peroxide and acrolein in RPE.

Because of the ornithine-induced chronic toxicity in RPE, the outer blood-retina barrier breaks down, which might make the retina more permeable to toxic substances.

Diagnosis

Upon clinical suspicion, diagnostic testing will often consist of measurement of amino acid concentrations in plasma, in search of a significantly elevated ornithine concentration. Measurement of urine amino acid concentrations is sometimes necessary, particularly in neonatal onset cases to identify the presence or absence of homocitrulline for ruling out ornithine translocase deficiency (hyperornithinemia, hyperammonemia, homocitrullinuria syndrome, HHH syndrome). Ornithine concentrations can be an unreliable indicator in the newborn period, thus newborn screening may not detect this condition, even if ornithine is included in the screening panel. Enzyme assays to measure the activity of ornithine aminotransferase can be performed from fibroblasts or lymphoblasts for confirmation or during the neonatal period when the results of biochemical testing is unclear. Molecular genetic testing is also an option.

Treatment

To reduce the levels of ornithine in the blood, a diet restricted in arginine has been used. Some research has shown that when diet or other treatment is initiated early in life, the outcome can be improved.

References

References

1. "Gyrate atrophy of the choroid and retina". National Institutes of Health.
2. "#288870 - Gyrate atrophy of the choroid and retina". Johns Hopkins University.
3. (2023-09-04). "Clinical, biochemical and molecular analysis in a cohort of individuals with gyrate atrophy". Orphanet Journal of Rare Diseases.
4. (2012). "Inborn Metabolic Diseases: Diagnosis and Treatment". Springer.
5. (2024-01-01). "Vision on gyrate atrophy: why treat the eye?". EMBO Molecular Medicine.
6. (2025). "Molecular and cellular mechanisms underlying gyrate atrophy: Why is the retina primarily affected?". Acta Ophthalmologica.