`
`Urea Cycle Disorders Overview GeneReviews® NCBI Bookshelf
`
`NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
`
`Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of
`Washington, Seattle; 19932015.
`
`Urea Cycle Disorders Overview
`
`Nicholas Ah Mew, MD, Brendan C Lanpher, MD, Andrea Gropman, MD, Kimberly A Chapman, MD, PhD,
`Kara L Simpson, MS, CGC, Urea Cycle Disorders Consortium, and Marshall L Summar, MD.
`
`Author Information
`
`Initial Posting: April 29, 2003; Last Revision: April 9, 2015.
`
`Summary
`
`The urea cycle disorders (UCD) result from defects in the metabolism of
`Clinical characteristics.
`waste nitrogen from the breakdown of protein and other nitrogencontaining molecules. Severe
`deficiency or total absence of activity of any of the first four enzymes (CPS1, OTC, ASS, ASL) in
`the urea cycle or the cofactor producer (NAGS) results in the accumulation of ammonia and other
`precursor metabolites during the first few days of life. Infants with a severe urea cycle disorder are
`normal at birth but rapidly develop cerebral edema and the related signs of lethargy, anorexia,
`hyper or hypoventilation, hypothermia, seizures, neurologic posturing, and coma. In milder (or
`partial) deficiencies of these enzymes and in arginase (ARG) deficiency, ammonia accumulation
`may be triggered by illness or stress at almost any time of life. In these disorders the elevations of
`plasma ammonia concentration and symptoms are often subtle and the first recognized clinical
`episode may not occur for months or decades.
`
`The diagnosis of a urea cycle disorder is based on clinical suspicion and
`Diagnosis/testing.
`biochemical and molecular genetic testing. A plasma ammonia concentration of 150 μmol/L or
`higher associated with a normal anion gap and a normal plasma glucose concentration is an
`indication for the presence of a UCD. Plasma quantitative amino acid analysis and measurement of
`urinary orotic acid can distinguish between the specific UCDs. A definitive diagnosis of a urea
`cycle defect depends on either molecular genetic testing or measurement of enzyme activity.
`Molecular genetic testing is possible for all urea cycle defects.
`
`Deficiencies of CPS1, ASS1, ASL, NAGS, and ARG are inherited in an
`Genetic counseling.
`autosomal recessive manner. OTC deficiency is inherited in an Xlinked manner. Carrier testing for
`atrisk relatives and prenatal testing for pregnancies at increased risk using molecular genetic
`testing is possible for any of the urea cycle disorders if the pathogenic variant(s) in the family are
`known.
`
`Treatment of manifestations: Acute severe hyperammonemia: Dialysis and
`Management.
`hemofiltration to reduce plasma ammonia concentration; intravenous administration of arginine
`hydrochloride and nitrogen scavenger drugs to allow alternative pathway excretion of excess
`nitrogen; restriction of protein for 12 to 24 hours to reduce the amount of nitrogen in the diet;
`calories given as carbohydrates and fat; and physiologic stabilization with intravenous fluids and
`cardiac pressors while avoiding overhydration.
`
`Prevention of primary manifestations: Longterm management: prevention of catabolism to avoid
`hyperammonemic episodes by dietary restriction of protein, use of specialized formulas, and use of
`oral nitrogenscavenging drugs.
`
`Prevention of secondary complications: Minimize risk of respiratory and gastrointestinal illnesses;
`routine immunizations; multivitamin and fluoride supplementation; appropriate use of antipyretics.
`http://www.ncbi.nlm.nih.gov/books/NBK1217/
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`Surveillance: Routine monitoring by a physician experienced in the treatment of metabolic
`disorders.
`
`®
`Agents/circumstances to avoid: Valproic acid (Depakote ); prolonged fasting or starvation;
`intravenous steroids; large boluses of protein or amino acids.
`
`Evaluation of relatives at risk: Identification of affected atrisk relatives before symptoms occur
`allows dietary therapy and other measures to prevent hyperammonemia.
`
`Definition
`The urea cycle:
`
`Is the sole source of endogenous production of arginine, ornithine, and citrulline;
`
`Is the principal mechanism for the clearance of waste nitrogen resulting from protein
`turnover;
`
`Is the principal mechanism for the metabolism of other nitrogenous metabolic compounds
`such as adenosine monophosphate;
`
`Includes enzymes that overlap with the nitric oxide production pathway (ASS and ASL).
`
`The urea cycle comprises the following (Figure 1) [Krebs & Henseleit 1932]:
`
`Figure 1.
`The urea cycle (see Differential Diagnosis)
`
`Five catalytic enzymes:
`
`Carbamoylphosphate synthetase I (CPS1)
`
`Ornithine transcarbamylase (OTC)
`
`Argininosuccinic acid synthetase (ASS1)
`
`Argininosuccinic acid lyase (ASL)
`
`Arginase (ARG)
`
`A cofactorproducing enzyme: Nacetyl glutamate synthetase (NAGS)
`
`Urea cycle disorders (UCD) result from inherited deficiencies in the six enzymes of the urea cycle
`pathway (CPS1, OTC, ASS1, ASL, ARG, and NAGS).
`
`The urea cycle also depends on two transporters (discussed in Differential Diagnosis).
`Abnormalities in these transporters can present with hyperammonemia.
`
`Two transporters:
`
`Ornithine translocase (ORNT1)
`
`Citrin
`
`Specific Urea Cycle Disorders (Catalytic Enzymes)
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`NAGS deficiency. Deficiency of this enzyme has been described in a number of affected
`individuals. Symptoms mimic those of CPS1 deficiency, as CPS1 is rendered inactive in the
`absence of NAGS [Caldovic et al 2003].
`
`Carbamoylphosphate synthetase I deficiency (CPS1 deficiency) is the most severe of the urea
`cycle disorders. Individuals with complete CPS1 deficiency rapidly develop hyperammonemia in
`the newborn period. Children who are successfully rescued from crisis are chronically at risk for
`repeated bouts of hyperammonemia.
`
`Ornithine transcarbamylase deficiency (OTC deficiency). Absence of OTC activity in males is
`as severe as CPS1 deficiency. Approximately 15% of carrier females develop hyperammonemia
`during their lifetime and many require chronic medical management for hyperammonemia. More
`recently it has been recognized that carrier females who have never had symptoms of overt
`hyperammonemia have deficiencies in executive function.
`
`Citrullinemia type I (ASS1 deficiency). The hyperammonemia in this disorder can also be quite
`severe. Affected individuals are able to incorporate some waste nitrogen into urea cycle
`intermediates, which makes treatment slightly easier than in the other UCDs.
`
`Argininosuccinic aciduria (ASL deficiency) can also present with rapidonset hyperammonemia
`in the newborn period. This enzyme defect is past the point in the metabolic pathway at which all
`the waste nitrogen has been incorporated into the cycle. Some affected individuals develop chronic
`hepatic enlargement and elevation of transaminases. Liver biopsy shows enlarged hepatocytes,
`which may over time progress to fibrosis, the etiology of which is unclear. Affected individuals can
`also develop trichorrhexis nodosa, a nodelike appearance of fragile hair that usually responds to
`arginine supplementation. Affected individuals who have never had prolonged coma nevertheless
`have been reported to have significant developmental disabilities [Summar 2001, Summar &
`Tuchman 2001, Nagamani et al 2012].
`
`Arginase deficiency (hyperargininemia, ARG deficiency) is not typically characterized by
`rapidonset hyperammonemia, however, some individuals present earlier with more severe
`symptoms [JainGhai et al 2011]. Affected individuals develop progressive spasticity and can also
`develop tremor, ataxia, and choreoathetosis. Growth is also affected [Cederbaum et al 2004].
`
`Clinical Manifestations of Urea Cycle Disorders
`Severity of the urea cycle defect is influenced by the position of the defective enzyme in the
`pathway and the severity of the enzyme defect.
`
`Severe deficiency or total absence of activity of any of the first four enzymes in the pathway
`(CPS1, OTC, ASS1, and ASL) or the cofactor producer (NAGS) results in the accumulation of
`ammonia and other precursor metabolites during the first few days of life.
`
`Because no effective secondary clearance system for ammonia exists, complete disruption of this
`pathway results in the rapid accumulation of ammonia and development of related symptoms.
`Individuals with complete defects normally present in the newborn period, when the immaturity of
`the neonatal liver accentuates defects in the urea cycle enzymes [Pearson et al 2001, Summar 2001,
`Summar & Tuchman 2001]. Infants with a urea cycle disorder appear normal at birth but rapidly
`develop cerebral edema and the related signs of lethargy, anorexia, hyper or hypoventilation,
`hypothermia, seizures, neurologic posturing, and coma.
`
`Because newborns are usually discharged from the hospital within one to two days after birth, the
`symptoms of a urea cycle disorder often develop when the child is at home and may not be
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`recognized in a timely manner by the family and primary care physician. The typical initial
`symptoms of a child with hyperammonemia are nonspecific: failure to feed, loss of
`thermoregulation with a low core temperature, and somnolence [Summar 2001].
`
`Symptoms progress from somnolence to lethargy and coma. Abnormal posturing and
`encephalopathy are often related to the degree of central nervous system swelling and pressure on
`the brain stem [Summar 2001]. About 50% of neonates with severe hyperammonemia may have
`seizures, some without overt clinical manifestations. Individuals with closed cranial sutures are at
`higher risk for rapid neurologic deterioration from the cerebral edema that results from ammonia
`elevation. Hyperventilation secondary to the effect of hyperammonemia on the brain stem, a
`common early finding in hyperammonemic attacks, results in respiratory alkalosis. Hypoventilation
`and respiratory arrest follow as pressure increases on the brain stem.
`
`With rapid identification and current treatment strategies, survival of neonates with
`hyperammonemia has improved dramatically in the last few decades [Summar 2001, Summar &
`Tuchman 2001, Enns et al 2007 (full text), Summar et al 2008, Tuchman et al 2008, Krivitzky et al
`2009]. However, hyperammonemia is not the only influence on intellectual outcome. Specifically,
`individuals with ASL deficiency appear to have intellectual disability that is out of proportion to
`their hyperammonemia [Ah Mew et al 2013].
`
`In milder (or partial) urea cycle enzyme deficiencies, ammonia accumulation may be triggered
`by illness or stress at almost any time of life, including surgery, prolonged fasting, holidays, and the
`peripartum period, resulting in multiple mild elevations of plasma ammonia concentration.
`Hyperammonemia in the milder defects is typically less severe and the symptoms more subtle than
`the neonatal presentation of a UCD. In individuals with partial enzyme deficiencies, the first
`recognized clinical episode may be delayed for months or years. Although the clinical
`abnormalities vary somewhat with the specific urea cycle disorder, in most the hyperammonemic
`episode is marked by loss of appetite, vomiting, lethargy, and behavioral abnormalities
`[Gardeitchik et al 2012]. Sleep disorders, delusions, hallucinations, and psychosis may occur. An
`encephalopathic (slowwave) EEG pattern may be observed during hyperammonemia and
`nonspecific brain atrophy may be seen subsequently on MRI.
`
`Defects in the final enzyme in the pathway (ARG) cause hyperargininemia, a more subtle
`disorder involving neurologic symptoms; however, neonatal hyperammonemia has been reported
`(see Arginase Deficiency.)
`
`Neurologic aspects of UCDs. Ammonia can cause brain damage through a variety of proposed
`mechanisms, a major component of which is cerebral edema. The specific roles of ammonia,
`glutamate, and glutamine in cerebral edema are still under investigation; they are thought to affect
`the aquaporin system and water and potassium homeostasis in brain [LichterKonecki 2008,
`LichterKonecki et al 2008, Albrecht et al 2010].
`
`Damage resulting from acute hyperammonemia in infancy resembles that seen in hypoxicischemic
`events or stroke. Lacunar infarcts and white matter disruption are common findings.
`
`Chronic hyperammonemia may disrupt iongradients and neurotransmitters, transport of
`metabolites, mitochondrial function, and the alphaketoglutarate/glutamate/glutamine ratio.
`
`Seizures are common in acute hyperammonemia and may result from cerebral damage. Recent
`findings suggest that subclinical seizures are common in acute hyperammonemic episodes and their
`effects on cerebral metabolism in an otherwise compromised state should be addressed (see
`Management, Treatment of Acute Manifestations). (Note: Valproic acid should be avoided because
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`of its effects on CPS1 function. See Management, Agents/Circumstances to Avoid.)
`
`Newer neuroimaging techniques that provide information about the timing, extent, reversibility,
`and possible mechanism of neural injury in a noninvasive manner can be used as an adjunct to
`predict clinical and neurocognitive outcome [Gropman 2010, Bireley et al 2012, Gunz et al 2013].
`
`The limitations of routine neuroimaging:
`
`Damage can only be detected at a macroscopic level, typically at a time when symptoms are
`already present.
`
`MRI findings may lag behind clinical changes.
`
`Advanced imaging sequences such as magnetic resonance spectroscopy (MRS), diffusion tensor
`imaging (DTI), and functional magnetic resonance imaging (fMRI) provide additional details about
`the pattern and type of injury and have shed light on various neurologic problems seen in urea
`cycle disorders.
`
`MRS. In OTC deficiency, biochemical markers of brain injury resulting from
`hyperammonemia that can be measured quantitatively on 1H MRS include increased
`glutamine levels and depletion of myoinositol.
`
`DTI
`
`In UCDs, DTI commonly shows a pattern of white matter injury affecting the
`cingulum, a major fiber bundle that underlies pathways involving working memory
`and attention.
`
`In arginase deficiency, DTI demonstrates additionally decreased fiber density
`reflecting the predilection of corticospinal tracts to brain injury corresponding to the
`spastic diplegia observed in this disorder.
`
`fMRI. Persons with lateonset OTC deficiency, who have traditionally been considered
`intellectually normal, often show altered neural circuitry by fMRI when performing tasks
`requiring working memory and attention.
`
`Historically the outcome of newborns with hyperammonemia was considered poor [Brusilow
`1995]. More recent data from the NIHsponsored longitudinal study on patients treated with the
`more recent protocols show IQ measures within a less severe range.
`
`Table 1.
`Cognitive and Adaptive Outcome in Children with UCD Age 316 Years
`
`Age Group
`
`Age at Onset
`
`Age 35 Years
`1
`2
`Neonatal
`Late
`(n=5)
`(n=7)
`4
`3
`WASI/WPPSIIII composite scores (SD)
`
`Age 616 Years
`1
`2
`Neonatal
`Late
`(n=8)
`(n=39)
`
`Verbal IQ
`
`81.3 (16.6) 101.7 (24.4) 72.9 (14.3) 94.3 (21.7)
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`Assessment
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`Urea Cycle Disorders Overview GeneReviews® NCBI Bookshelf
`Performance IQ 77.7 (15.0) 95.6 (17.4) 74.4 (11.7) 89.5 (20.4)
`
`Full scale IQ
`
`77.7 (16.3) 99.6 (22.6) 71.4 (12.8) 94.1 (22.0)
`
`5
`4
`ABASII general adaptive composite (SD)
`73.2 (31.2) 91.4 (23.6) 66.0 (17.9) 84.4 (21.6)
`
`Adapted from Krivitzky et al [2009]
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Clinical presentation in 1st month
`
`Clinical onset after 1st month or diagnosis based on family history
`
`Wechsler Abbreviated Scales of Intelligence / Wechsler Preschool and Primary Scale of Intelligence, 3rd
`Edition
`
`Clinically significant difference between groups for cognitive and adaptive outcome
`
`Adaptive Behavior Assessment System, 2nd Edition
`
`While hyperammonemia is thought to be the main contributor to brain damage in UCDs, other
`factors, such as adverse effects on the nitric oxide production system [Nagamani et al 2012], may
`also contribute. For instance, neonates with CPS1 deficiency or OTC deficiency have more severe
`hyperammonemia than those with ASS deficiency or ASL deficiency; however, their intellectual
`outcomes appear similar [Ah Mew et al 2013].
`
`Establishing the Diagnosis of a Urea Cycle Disorder
`The diagnosis of a urea cycle disorder in a symptomatic individual is based on clinical,
`biochemical, and molecular genetic data.
`
`Family history. A threegeneration family history with attention to other relatives (particularly
`children) with neurologic signs and symptoms suggestive of UCD should be obtained.
`Documentation of relevant findings in relatives can be accomplished either through direct
`examination of those individuals or review of their medical records including the results of
`biochemical testing, molecular genetic testing, and autopsy examination. A family history
`consistent with Xlinked inheritance suggests OTC deficiency.
`
`Physical examination. No findings on physical examination distinguish among the six types of
`urea cycle defect; however, trichorrhexis nodosa can be suggestive of ASL deficiency and
`progressive spasticity of the lower extremities of arginase deficiency.
`
`Testing
`The algorithm in Figure 2 may assist with the evaluation of a newborn with hyperammonemia. 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 UCD [Summar & Tuchman 2001].
`
`Figure 2.
`Steps in the evaluation of a newborn with hyperammonemia
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`Figure 3 highlights the use of the following recommended diagnostic tests to identify the specific
`urea cycle disorder.
`
`Figure 3.
`Testing used in the diagnosis of urea cycle disorders
`
`Serum ammonia concentration elevation is usually the first identified laboratory abnormality in
`most of the urea cycle disorders.
`
`Quantitative plasma amino acid analysis can be used to arrive at a tentative diagnosis. (As the
`liver is not fully mature at birth, affected newborns often have plasma amino acid concentrations
`that are quite different from those in older children and adults.)
`
`Plasma concentration of citrulline helps discriminate between the proximal and distal urea
`cycle defects, as citrulline is the product of the proximal enzymes (OTC and CPS1) and a
`substrate for the distal enzymes (ASS1, ASL, ARG).
`
`Plasma citrulline is either absent or present only in trace amounts in neonatalonset
`CPS1 deficiency and OTC deficiency and present in low to lownormal
`concentrations in lateonset disease.
`
`A tenfold elevation in plasma citrulline concentration is seen in ASS deficiency.
`
`A more moderate (~2 to 5fold) increase in plasma citrulline concentration is seen in
`ASL deficiency, which is also associated with high levels of argininosuccinic acid
`(ASA) in plasma and urine. ASA is normally absent [Summar 2001, Summar &
`Tuchman 2001].
`
`Plasma concentration of arginine may be reduced in all urea cycle disorders except ARG
`deficiency, in which it is elevated five to sevenfold; however, in partial enzyme defects, it
`may be normal.
`
`Note: Plasma concentrations of glutamine, alanine, and asparagine, which serve as storage
`forms of waste nitrogen, are frequently elevated.
`
`Urinary orotic acid is measured to distinguish CPS1 deficiency from OTC deficiency. It is
`normal or low in CPS1 deficiency and significantly elevated in OTC deficiency. Note: Urinary
`orotic acid excretion can also be increased in argininemia (ARG deficiency) and citrullinemia type
`I (ASS1 deficiency).
`
`Molecular genetic testing is used for diagnosis, carrier detection, and prenatal diagnosis for all six
`UCDs (see Table 2). It has supplanted measurement of enzyme activity as the definitive diagnostic
`test.
`
`Table 2.
`Urea Cycle Disorders: Molecular Genetics
`
`Disease Name
`
`Gene
`
`Protein Name
`
`Select OMIM
`Links
`
`Carbamoylphosphate synthetase I
`http://www.ncbi.nlm.nih.gov/books/NBK1217/
`
`Carbamoylphosphate
`
`1
`
`608307
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`Carbamoylphosphate synthetase I
`deficiency
`
`Urea Cycle Disorders Overview GeneReviews® NCBI Bookshelf
`608307
`Carbamoylphosphate
`1
`CPS1
`synthase
`
`237300
`
`Ornithine transcarbamylase deficiency OTC
`
`Ornithine
`carbamoyltransferase
`
`ASS deficiency (Citrullinemia type I)
`
`ASS1 Argininosuccinate synthase
`
`ASL deficiency (argininosuccinic
`aciduria)
`
`ASL
`
`Argininosuccinate lyase
`
`Arginase deficiency
`
`ARG1 Arginase1
`
`NAGS deficiency
`
`NAGS Nacetylglutamate synthase
`
`300461
`
`311250
`
`603470
`
`215700
`
`608310
`
`207900
`
`608313
`
`207800
`
`608300
`
`237310
`
`Enzyme activity. If molecular testing is uninformative, the following disorders can be diagnosed
`by assay of enzyme activity:
`
`CPS1 deficiency, OTC deficiency, or NAGS deficiency: liver biopsy
`
`ARG deficiency: red blood cells
`
`ASS1 deficiency and ASL deficiency: fibroblasts
`
`Newborn Screening
`Current extended newborn screening panels using tandem mass spectrometry detect abnormal
`concentrations of analytes associated with ASS1 deficiency, ASL deficiency, and arginase
`deficiency; however, the sensitivity and specificity of such screening for these disorders is
`unknown. Some newborn screening programs are investigating methods to detect OTC deficiency
`and the proximal urea cycle defects.
`
`Some caveats regarding newborn screening for urea cycle defects:
`
`CPS1 deficiency, OTC deficiency, and NAGS deficiency currently cannot be reliably
`detected.
`
`Although hyperargininemia (i.e., arginase deficiency) has been detected by these methods,
`newborn screening cannot be expected to reliably detect all cases.
`
`Even in UCDs detectable by newborn screening, neonates are often symptomatic prior to
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`availability of the screening results; thus a high level of clinical suspicion on the part of
`healthcare providers is necessary.
`
`Differential Diagnosis of Urea Cycle Disorders
`A number of other disorders that perturb the liver can result in hyperammonemia and mimic the
`effects of a urea cycle disorder. The most common/significant ones are viral infection of the liver
`and vascular bypass of the liver.
`
`Diseases of the liver and biliary tract
`
`Herpes simplex virus infection
`
`Vascular bypass of the liver
`
`Biliary atresia
`
`Acute liver failure
`
`Medications
`
`Valproic acid
`
`Cyclophosphamide
`
`5pentanoic acid
`
`Inborn errors of metabolism
`
`Organic acidemias (e.g., propionic acidemia and methylmalonic acidemia) (see Organic
`Acidemias, Methylmalonic Acidemia)
`
`Tyrosinemia type 1
`
`Galactosemia
`
`Mitochondrial disorders (see Mitochondrial Disorders Overview)
`
`Fatty acid oxidation disorders (see MCAD Deficiency)
`
`Citrin deficiency (see Note). The three phenotypes of citrin deficiency are citrullinemia type
`II (CTLN2), failure to thrive and dyslipidemia (FTTDCD), and neonatal intrahepatic
`cholestasis caused by citrin deficiency (NICCD).
`
`Hyperornithinemiahyperammonemiahomocitrullinuria (HHH) syndrome (see Note)
`
`Carbonic anhydrase VA deficiency
`
`Note: Some experts, including the Urea Cycle Disorders Consortium (a Rare Diseases Clinical
`Research Network consortium) count citrin deficiency and HHH syndrome as transporter defects
`among the urea cycle disorders, making the total number of urea cycle disorders eight (6 enzyme
`deficiencies and 2 transporter defects).
`
`Prevalence of Urea Cycle Disorders
`The incidence of UCDs is estimated to be at least 1:35,000 births; partial defects may make the
`number much higher.
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`Table 3.
`Estimated Incidence of Individual Urea Cycle Disorders
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`Urea Cycle Disorders Overview GeneReviews® NCBI Bookshelf
`
`Urea Cycle Disorder Estimated Incidence
`NAGS deficiency
`<1 :2,000,000
`CPS1 deficiency
`1:1,300,000
`OTC deficiency
`1:56,500
`ASS1 deficiency
`1:250,000
`ASL deficiency
`1:218,750
`ARG deficiency
`1:950,000
`
`Summar et al [2013]
`
`Genetic Counseling
`Genetic counseling is the process of providing individuals and families with information on the
`nature, inheritance, and implications of genetic disorders to help them make informed medical and
`personal decisions. The following section deals with genetic risk assessment and the use of family
`history and genetic testing to clarify genetic status for family members. This section is not meant to
`address all personal, cultural, or ethical issues that individuals may face or to substitute for
`consultation with a genetics professional. —ED.
`
`Mode of Inheritance
`Deficiencies of CPS1, ASS1, ASL, NAGS, and ARG are inherited in an autosomal recessive
`manner.
`
`OTC deficiency is inherited in an Xlinked manner.
`
`Risk to Family Members — Autosomal Recessive Inheritance
`Parents of a proband
`
`The parents of an affected child are obligate heterozygotes and therefore carry one mutant
`allele.
`
`Heterozygotes (carriers) are asymptomatic.
`
`Sibs of a proband
`
`At conception, each sib of an affected individual has a 25% chance of being affected, a 50%
`chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a
`carrier.
`
`Once an atrisk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
`
`Heterozygotes (carriers) are asymptomatic.
`
`Offspring of a proband. The offspring of an affected individual are obligate heterozygotes
`(carriers) for one mutant allele.
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`Risk to Family Members — XLinked Inheritance
`Parents of a male proband
`
`The father of a male proband is neither affected nor a carrier.
`
`In a family with more than one affected individual, the mother of an affected individual is an
`obligate carrier.
`
`If a woman has more than one affected child and no other affected relatives and if the OTC
`pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism.
`Germline mosaicism has been reported in OTC deficiency [Bowling et al 1999]; however,
`because the frequency is not known the general 3%4% background risk of germline
`mosaicism should be used.
`
`If only one male in the family is affected, the mother may be a carrier or the affected
`individual may have a de novo mutation, in which case the mother is not a carrier. Haldane’s
`rule (i.e., 2/3 of cases are inherited and 1/3 are the result of de novo mutation) is generally
`used for Xlinked lethal diseases. This rule assumes that the mutation rate is equal for male
`and female germ cells. However, a study by Tuchman et al [1995] concluded that the OTC
`mutation rate was significantly higher in female germ cells (80%) than in male germ cells
`(7%) and suggest that in families with a single affected individual, the proportion of inherited
`cases is 9/10 (or higher) if the affected individual is male and approximately 2/10 if the
`affected individual is female. Note: These data have not been replicated with a larger sample
`size.
`
`Parents of a female proband
`
`A female with OTC deficiency may have a de novo mutation or she may have inherited the
`OTC pathogenic variant from either her mother or her father.
`
`If pedigree analysis reveals that the female proband is the only affected family member, it is
`reasonable to offer molecular genetic testing to both of her parents.
`
`Sibs of an affected individual
`
`The risk to sibs depends on the genetic status of the parents.
`
`If the mother of the proband has an OTC pathogenic variant, the chance of transmitting it in
`each pregnancy is 50%.
`
`Males who inherit the pathogenic variant will be affected; females who inherit the
`pathogenic variant may or may not develop clinical findings related to the disorder
`(see Offspring of a female proband).
`
`If the father of a female proband has the OTC pathogenic variant, all of the proband's female
`sibs and none of the male sibs will inherit the pathogenic variant.
`
`If the proband represents a simplex case (i.e., a single occurrence in a family) and if the OTC
`pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is
`low, but greater than that of the general population because of the possibility of maternal
`germline mosaicism.
`
`Offspring of a male proband
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`Males with OTC deficiency used to die before reproductive age or be too debilitated to
`reproduce. However, prospective treatment at birth and improved rescue therapy followed
`by liver transplant now allows such males to reach reproductive age and reproduce.
`
`Some males with lateonset and/or mild disease survive and are fertile. They will pass the
`OTC pathogenic variant to all of their daughters and none of their sons. The females will
`have a range of possible phenotypic expression.
`
`Offspring of a female proband
`
`Female probands have a 50% chance of transmitting the OTC pathogenic variant with each
`pregnancy.
`
`Males who inherit the OTC pathogenic variant will be affected; females who inherit the
`pathogenic variant may or may not develop clinical findings related to the disorder (see
`Other family members).
`
`Other family members. The proband's maternal aunts may be at risk of having the OTC
`pathogenic variant and the aunts’ offspring, depending on their gender, may be at risk of having
`the pathogenic variant and of being affected.
`
`Carrier Detection
`Molecular genetic testing. Carrier detection for OTC deficiency is possible by molecular genetic
`testing if the OTC pathogenic variant has been identified in the family.
`
`Alternatively, if the OTC pathogenic variant in a family is not known, linkage analysis may be
`helpful in determining the carrier status of atrisk female relatives in informative families.
`
`Note: Molecular genetic testing may be able to identify the family member in whom a de novo
`OTC pathogenic variant arose, information that could help determine genetic risk status of the
`extended family.
`
`Allopurinol challenge. When the OTC pathogenic variant in the family cannot be identified, an
`allopurinol challenge (see OTC Deficiency, Confirming the Diagnosis) may be helpful in
`determining if a female relative is heterozygous (i.e., a carrier).
`
`Related Genetic Counseling Issues
`See Management, Evaluation of Relatives at Risk for information on evaluating atrisk relatives for
`the purpose of early diagnosis and treatment.
`
`OTC deficiency
`
`A significant number of carrier females have hyperammonemia and neurologic compromise
`presumed to be secondary to skewed Xchromosome inactivation in her liver [Yorifuji et al
`1998]. The risk for hyperammonemia is particularly high in pregnancy and the postpartum
`period. Drugs such as valproic acid and corticosteroids may also trigger a hyperammonemia
`crisis in a carrier.
`
`If a male is affected with lateonset disease, the risk for symptoms in a carrier female is much
`lower than in families in which a male is affected with earlyonset severe disease
`[McCullough et al 2000].
`
`Carrier females may have abnormal results on cognitive testing even in the absence of
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`hyperammonemia [Gyato et al 2004].
`
`Family planning
`
`The optimal time for determination of genetic risk, clarification of carrier status, and
`discussion of the availability of prenatal testing is before pregnancy.
`
`It is appropriate to offer genetic counseling (including discussion of potential risks to
`offspring and reproductive options) to young adults who are affected, are carriers, or are at
`risk of being affected or carriers.
`
`DNA banking is the storage of DNA (typically extracted from white blood cells) for possible
`future use. Because it is likely that testing methodology and our understanding of genes, allelic
`variants, and diseases will improve in the future, consideration should be given to banking DNA of
`affected individuals.
`
`Prenatal Testing
`Molecular genetic testing. If the pathogenic variant(s) have been identified in an affected family
`member, prenatal testing for pregnancies at