The Invitae Urea Cycle Disorders Panel analyzes ten genes that encode the enzymes and transporter proteins that participate in the biochemical reactions of the urea cycle, which is responsible for the detoxification of ammonia, the waste product of protein metabolism. Partial or complete deficiency in the function of the affected enzyme or transporter results in hyperammonemia, which, if untreated, can cause severe brain damage and death. The genes in this panel were selected based on the available evidence to date to provide Invitae’s broadest test for urea-cycle disorders.
Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives.
ALDH18A1 ARG1 ASL ASS1 CPS1 HMGCL OAT OTC SLC25A13 SLC25A15
ALDH18A1 ARG1 ASL ASS1 CPS1 HMGCL OAT OTC SLC25A13 SLC25A15
The Invitae Organic Acidemias Panel and the Invitae Fatty Acid Oxidation Defects Panel have been designed to provide a broad genetic analysis of this class of disorders. Depending on the individual’s clinical and family history, one of these broader panels may be appropriate. They can be ordered at no additional cost.
The urea-cycle disorders are a group of inherited metabolic diseases in the liver. Typically, they are caused by a deficiency of one of the enzymes or transporter proteins that participate in urea-cycle reactions. These reactions are required for the detoxification of ammonia—the waste product of protein metabolism. In patients with urea-cycle disorders, the waste-removal function of the liver is impaired, causing the accumulation of ammonia in the blood, which, at a high level, can cause brain damage, coma, and death. Symptoms of urea-cycle disorders are relatively nonspecific; the severity depends on the gene that has been disrupted as well as on the extent of the functional deficiency of the resulting enzyme or transporter. Infants with severe deficiency or total absence of the enzymes encoded by ASL, ASS1, CPS1, or OTC are typically normal at birth but develop severe symptoms in the first few days of life, including cerebral edema, lethargy, irritability, anorexia, vomiting, hyper- or hypoventilation, hypothermia, seizures, and neurologic posturing. If left untreated, the symptoms will become progressively worse and cause hypotonia, coma, and death. In partial deficiencies of enzymes encoded by ARG1, ALS, ASS1, CPS1, or OTC, or in the mitochondrial aspartate-glutamate transporter defect (citrin encoded by SLC25A13), patients may do well until ammonia accumulation is triggered by stress or another illness, causing the body to enter a state of increased protein catabolism. In the case of a partial deficiency, the symptoms and elevated concentrations of ammonia in the plasma are often subtle, with the first recognized clinical episode not occurring for months or even decades.
The ALDH18A1 gene encodes the enzyme delta1-pyrroline-5-carboxylate synthase (P5C synthase), which catalyzes the reduction of glutamate to P5C—a critical step in the de novo biosynthesis of proline, ornithine, and arginine. Biochemically, P5C synthase deficiency leads to a very typical pattern of paradoxical hyperammonemia, as well as to hypoprolinemia and deficiencies of urea-cycle intermediates ornithine, citrulline, and arginine. Enzymatic deficiency caused by disruption of the ADH18A1 gene leads to hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia, and hypoprolinemia and may be associated with neurodegeneration, cataracts, and connective tissue diseases, including ALDH18A1-related cutis laxa and ALDH18A1-related spastic paraplegia.
The HMGCL gene encodes the enzyme HMG-CoA lyase. Patients with HMG-CoA lyase deficiency cannot process the amino acid leucine and are unable to produce ketones for energy during fasting. Even though this is not a urea cycle disorder, patients can present with hyperammonemia. Symptoms of HMG-CoA lyase deficiency usually appear within the first year of life and include episodes of vomiting, diarrhea, dehydration, extreme lethargy, and hypotonia. These episodes are often triggered by stress such as an infection, fasting, or strenuous exercise. During an episode, dangerous hypoglycemia and metabolic acidosis may occur. If untreated, HMG-CoA lyase deficiency can lead to breathing problems, convulsions, coma, and death.
The OAT gene encodes the enzyme ornithine aminotransferase. Deficiency of this enzyme impedes the conversion of ornithine into P5C and causes Gyrate atrophy of the choroid and retina. This disease is characterized by progressive vision loss. Patients suffer from ongoing atrophy of the retina and nearby choroid tissue. Beginning from childhood, patients experience myopia, night blindness, and loss of peripheral vision. These progressive vision changes lead to blindness by age 50. Many people with gyrate atrophy also develop cataracts. Most people with gyrate atrophy have no symptoms other than vision loss. Occasionally, newborns with gyrate atrophy develop hyperammonemia, which may lead to feeding problems, vomiting, seizures, or coma. Neonatal hyperammonemia associated with gyrate atrophy generally responds quickly to treatment and does not recur after the newborn period.
The SLC25A15 gene encodes the mitochondrial ornithine transporter 1 (ORNT1), which is involved in the urea cycle and the ornithine degradation pathway. The metabolic triad of persistent hyperornithinemia, episodic or postprandial hyperammonemia, and urinary excretion of homocitrulline establishes the diagnosis of hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. The neonatal form is seen in approximately 12% of diagnosed patients. Infants have no symptoms for the first 24–48 hours, followed by an onset of hyperammonemia-related symptoms. The majority of patients (>80%) have later onset, with presentations during infancy, childhood, or even adulthood. Affected individuals may present chronic neurocognitive deficits and liver dysfunction, as well as acute encephalopathy that is secondary to hyperammonemic crisis and may have been precipitated by a variety of factors.
Neurologic findings and cognitive abilities that are related to urea-cycle disorders can continue to deteriorate despite early metabolic control preventing hyperammonemia. Further, disorders that perturb the liver, such as viral infection and vascular bypass of the liver, can result in hyperammonemia and resemble the effects of a urea-cycle disorder.
In urea-cycle disorders, hyperammonemia is the primary metabolic abnormality caused by a urea-cycle enzyme or transport deficiency. Secondary hyperammonemia can be caused by other metabolic defects, such as organic-acid disorders and fatty-acid oxidation disorders, drugs, other metabolites that may interfere with urea-cycle function, and severe liver disease. The Invitae Urea Cycle Disorders Panel can help differentiate the underlying primary defect and cause of hyperammonemia and guide appropriate treatment.
The most common urea-cycle defect is OTC deficiency followed by ASL deficiency and ASS deficiency. The following table provides estimated gene attribution for urea-cycle disorders.
The majority of urea-cycle disorders are inherited in an autosomal recessive fashion. Exceptions include ALDH18A1-related cutis laxa and ADH18A1-related spastic paraplegia, which can be inherited in autosomal dominant or recessive modes, and X-linked ornithine transcarbamylase deficiency.
Incidence ranges from 1 in 8,500 to 1 in 35,000 live births. The exact incidence of these disorders is unknown; it is likely underestimated because the clinical symptoms of urea-cycle disorders are nonspecific, and many affected individuals remain undiagnosed. Further, infants may be born with a urea-cycle disorder but die without a definitive diagnosis.
A plasma ammonia concentration of 150 μmol/L or higher associated with a normal anion gap and a normal plasma glucose concentration is a strong indication of a urea-cycle disorder.
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Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|