Ornithine aminotransferase deficiency

Ornithine aminotransferase deficiency
Ornithine aminotransferase deficiency
Other names	Gyrate atrophy (of the choroid and retina)
	Ornithine
Specialty	Ophthalmology, medical genetics

Last updated October 28, 2023

Ornithine aminotransferase deficiency (also known as gyrate atrophy of the choroid and retina) is an inborn error of ornithine metabolism, caused by decreased activity of the enzyme ornithine aminotransferase. Biochemically, it can be detected by elevated levels of ornithine in the blood.^[1] Clinically, it presents initially with poor night vision, which slowly progresses to total blindness.^[2] It is believed to be inherited in an autosomal recessive manner. Approximately 200 known cases have been reported in the literature. The incidence is highest in Finland, estimated at 1:50,000.^[2]

Treatment may include vitamin B6, lysine or dramatic dietary change to minimise arginine from patients diet. Research has indicated that these treatments may be somewhat effective in lowering ornithine blood concentration levels in some patients, either in combination or individually. Vitamin B6 has been found to be very effective in a small proportion of patients.

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.^[3] Symptoms of OAT deficiency are progressive, and between the ages of 45 and 65, most affected individuals are almost completely blind.^[3]

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.^[3]

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,^[2] 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.^[3]

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).^[3] 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.^[3] Molecular genetic testing is also an option.^[3]

Treatment

To reduce the levels of ornithine in the blood, a diet restricted in arginine has been used.^[2] Some research has shown that when diet or other treatment is initiated early in life, the outcome can be improved.^[2]

Related Research Articles

The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that produces urea (NH₂)₂CO from ammonia (NH₃). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic.

Ornithine transcarbamylase (OTC) is an enzyme that catalyzes the reaction between carbamoyl phosphate (CP) and ornithine (Orn) to form citrulline (Cit) and phosphate (P_i). There are two classes of OTC: anabolic and catabolic. This article focuses on anabolic OTC. Anabolic OTC facilitates the sixth step in the biosynthesis of the amino acid arginine in prokaryotes. In contrast, mammalian OTC plays an essential role in the urea cycle, the purpose of which is to capture toxic ammonia and transform it into urea, a less toxic nitrogen source, for excretion.

Hyperammonemia is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to brain injury and death. It may be primary or secondary.

Arginase (EC 3.5.3.1, arginine amidinase, canavanase, L-arginase, arginine transamidinase) is a manganese-containing enzyme. The reaction catalyzed by this enzyme is:

Ornithine transcarbamylase deficiency also known as OTC deficiency is the most common urea cycle disorder in humans. Ornithine transcarbamylase, the defective enzyme in this disorder, is the final enzyme in the proximal portion of the urea cycle, responsible for converting carbamoyl phosphate and ornithine into citrulline. OTC deficiency is inherited in an X-linked recessive manner, meaning males are more commonly affected than females.

<span class="mw-page-title-main">Citrullinemia</span> Medical condition

Citrullinemia is an autosomal recessive urea cycle disorder that causes ammonia and other toxic substances to accumulate in the blood.

<span class="mw-page-title-main">Lysinuric protein intolerance</span> Medical condition

Lysinuric protein intolerance (LPI) is an autosomal recessive metabolic disorder affecting amino acid transport.

Argininosuccinic aciduria is an inherited disorder that causes the accumulation of argininosuccinic acid in the blood and urine. Some patients may also have an elevation of ammonia, a toxic chemical, which can affect the nervous system. Argininosuccinic aciduria may become evident in the first few days of life because of high blood ammonia, or later in life presenting with "sparse" or "brittle" hair, developmental delay, and tremors.

<i>N</i>-Acetylglutamate synthase Class of enzymes

N-Acetylglutamate synthase (NAGS) is an enzyme that catalyses the production of N-acetylglutamate (NAG) from glutamate and acetyl-CoA.

<span class="mw-page-title-main">N-Acetylglutamate synthase deficiency</span> Medical condition

N-Acetylglutamate synthase deficiency is an autosomal recessive urea cycle disorder.

Ornithine translocase deficiency, also called hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, is a rare autosomal recessive urea cycle disorder affecting the enzyme ornithine translocase, which causes ammonia to accumulate in the blood, a condition called hyperammonemia.

L-Arginine:glycine amidinotransferase is the enzyme that catalyses the transfer of an amidino group from L-arginine to glycine. The products are L-ornithine and glycocyamine, also known as guanidinoacetate, the immediate precursor of creatine. Creatine and its phosphorylated form play a central role in the energy metabolism of muscle and nerve tissues. Creatine is in highest concentrations in the skeletal muscle, heart, spermatozoa and photoreceptor cells. Creatine helps buffer the rapid changes in ADP/ATP ratio in muscle and nerve cells during active periods. Creatine is also synthesized in other tissues, such as pancreas, kidneys, and liver, where amidinotransferase is located in the cytoplasm, including the intermembrane space of the mitochondria, of the cells that make up those tissues.

Orotic aciduria is a disease caused by an enzyme deficiency, resulting in a decreased ability to synthesize pyrimidines. It was the first described enzyme deficiency of the de novo pyrimidine synthesis pathway.

<span class="mw-page-title-main">Ornithine aminotransferase</span> Class of enzymes

Ornithine aminotransferase (OAT) is an enzyme which is encoded in human by the OAT gene located on chromosome 10.

Guanidinoacetate methyltransferase deficiency is an autosomal recessive cerebral creatine deficiency that primarily affects the nervous system and muscles. It is the first described disorder of creatine metabolism, and results from deficient activity of guanidinoacetate methyltransferase, an enzyme involved in the synthesis of creatine. Clinically, affected individuals often present with hypotonia, seizures and developmental delay. Diagnosis can be suspected on clinical findings, and confirmed by specific biochemical tests, brain magnetic resonance spectroscopy, or genetic testing. Biallelic pathogenic variants in GAMT are the underlying cause of the disorder. After GAMT deficiency is diagnosed, it can be treated by dietary adjustments, including supplementation with creatine. Treatment is highly effective if started early in life. If treatment is started late, it cannot reverse brain damage which has already taken place.

Cerebral creatine deficiencies are a small group of inherited disorders that result from defects in creatine biosynthesis and utilization. Commonly affected tissues include the brain and muscles. There are three distinct CCDs. The most common is creatine transporter defect (CTD), an X-linked disorder caused by pathogenic variants in SLC6A8. The main symptoms of CTD are intellectual disability and developmental delay, and these are caused by a lack of creatine in the brain, due to the defective transporter. There are also two enzymatic defects of creatine biosynthesis, arginine:glycine amidinotransferase deficiency, caused by variants in GATM and guanidinoacetate methyltransferase deficiency, caused by variants in GAMT. The single enzyme defects are both inherited in an autosomal recessive manner.

<span class="mw-page-title-main">Iminoglycinuria</span> Medical condition

Iminoglycinuria is an autosomal recessive disorder of renal tubular transport affecting reabsorption of the amino acid glycine, and the imino acids proline and hydroxyproline. This results in excess urinary excretion of all three acids.

Argininemia is an autosomal recessive urea cycle disorder where a deficiency of the enzyme arginase causes a buildup of arginine and ammonia in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if levels become too high; the nervous system is especially sensitive to the effects of excess ammonia.

Transient hyperammonemia of the newborn (THAN) is an idiopathic disorder occasionally present in preterm newborns but not always symptomatic. Continuous dialysis or hemofiltration have proven to be the most effective treatment. Nutritional support and sodium benzoate have also been used to treat THAN.

Citrullinemia type I (CTLN1), also known as arginosuccinate synthetase deficiency, is a rare disease caused by a deficiency in argininosuccinate synthetase, an enzyme involved in excreting excess nitrogen from the body. There are mild and severe forms of the disease, which is one of the urea cycle disorders.

References

↑ "Gyrate atrophy of the choroid and retina". National Institutes of Health. Retrieved 2012-08-23.
1 2 3 4 5 "#288870 - Gyrate atrophy of the choroid and retina". Johns Hopkins University. Retrieved 2012-08-23.
1 2 3 4 5 6 7 Baumgartner, Matthias R.; Valle, David (2012). "Disorders of Ornithine Metabolism". In Saudubray, Jean-Marie; van den Berghe, Georges; Walter, John H. (eds.). Inborn Metabolic Diseases: Diagnosis and Treatment (5th ed.). New York: Springer. pp. 323–332. ISBN 978-3-642-15719-6.

External links

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[ordr-1] "Gyrate atrophy of the choroid and retina". National Institutes of Health. Retrieved 2012-08-23.

[omim-2] 1 2 3 4 5 "#288870 - Gyrate atrophy of the choroid and retina". Johns Hopkins University. Retrieved 2012-08-23.

[saudubray-3] 1 2 3 4 5 6 7 Baumgartner, Matthias R.; Valle, David (2012). "Disorders of Ornithine Metabolism". In Saudubray, Jean-Marie; van den Berghe, Georges; Walter, John H. (eds.). Inborn Metabolic Diseases: Diagnosis and Treatment (5th ed.). New York: Springer. pp. 323–332. ISBN 978-3-642-15719-6.

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