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Hyperammonemia Type 3

NAGS Deficiency

Hyperammonemia type 3 refers to a urea cycle disorder inherited as an autosomal recessive trait. Affected individuals suffer from N-acetylglutamate synthase deficiency, which results in a reduced activity of carbamoyl phosphate synthetase I and subsequent accumulation of neurotoxic ammonia.

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Presentation

Clinical features of HAT3 are those of hyperammonemic encephalopathy. Parents of neonates born with NAGS gene defects often claim feeding difficulties; retrospectively, poor feeding can generally be traced back to the first day of the child's life, but affected neonates are usually not presented until several days later. Meanwhile, about one-third of patients becomes somnolent or lethargic, two out of three suffer from vomiting [10]. Fluctuations of body temperature and hyperventilation may also be noted. Seizures are common, but subclinical seizures may not be readily observable. Eventually, the patient's level of consciousness decreases and they may fall into a hyperammonemic coma.

Late-onset HAT3 may manifest at any age. Chronic headaches and nausea are the most common cause of presentation in adolescents and adults developing hyperammonemia due to NAGS deficiency. Ataxia, tremor, visual impairment, confusion and psychiatric symptoms may also be experienced.

Patients who are currently under treatment for HAT3 are still at risk of hyperammonemia crises, independent of age. Such crises are stroke-like episodes, possibly triggered by recent infections and fever, fasting and weight loss as well as protein overload or intense physical exercise. Drugs that may provoke a hyperammonemia crisis are valproate, asparaginase and other chemotherapeutics, glucocorticoids and much more [12].

Poor Feeding
  • The clinical manifestations are variable but common features include vomiting, hyperactivity or lethargy, diarrhoea, poor feeding, seizures, hypotonia, delayed psychomotor development and respiratory distress.[orpha.net]
  • If parents note lethargy, poor feeding, vomiting and diarrhea, hyperventilation or seizures in their babies, a physician should be advised immediately.[symptoma.com]
  • feeding, anorexia, hypotonia) ( Table 66-54 ) Hepatomegaly and hepatosplenomegaly ( Table 66-55 ) Liver failure, ascites, edema ( Table 66-56 ) Cardiomyopathy ( Table 66-57 ) Interstitial pulmonary infiltrates ( Table 66-58 ) Tubulopathy (renal Fanconi[ommbid.mhmedical.com]
  • Affected infants may exhibit refusal to eat and poor feeding habits, progressive lethargy, recurrent vomiting, diarrhea, irritability and an abnormally enlarged liver (hepatomegaly).[rarediseases.org]
  • The baby is well day 1,2 lethargy, irritability, poor feeding, vomiting. hyperventilation ,grunting respiration, seizures ammonia level of 100-150 µmol/L, 2-3 times the reference range. 64.[slideshare.net]
Hypothermia
  • Neurologic Poor coordination Dysdiadochokinesia Hypotonia or hypertonia Ataxia Tremor Seizures and hypothermia Lethargy progressing to combativeness to obtundation to coma Decorticate or decerebrate posturing Causes The mode of inheritance is an autosomal[emedicine.medscape.com]
  • Hypothermia 6. Slurring of speech 7. Blurring of vision 8. Seizures 9. Neurologic posturing 10. Coma Treatments for Urea cycle disorders most aimed at decr. ammonia levels 1. Decr. protein in diet 2. Dialysis to reduce plasma [ammonia] 3.[quizlet.com]
  • Clinical Presentation Poor feeding Lethargy Tachypnea Hypothermia Irritability Vomiting Ataxia Seizures Hepatomegaly Coma Apart from arginase deficiency, which usually presents as a subacute or chronic neurologic syndrome with spasticity and cognitive[newenglandconsortium.org]
  • Full-term neonates, with no obstetric risk factors, appear healthy for 24–48 hours and then exhibit progressive lethargy, hypothermia, and apnea, accompanied by high blood ammonium levels.[ajnr.org]
Hyperthermia
  • […] synthetase, carbamyl phosphate synthetase, ornithine transcarbamylase; all begin in late infancy or childhood, except arginase deficiency, which is neonatal Clinical Accumulation of urea precursors–eg, ammonia, glutamine causes progressive lethargy, hyperthermia[medical-dictionary.thefreedictionary.com]
Fatigue
  • Chiari-Frommel syndrome, 'Chief, ' CHILD syndrome, China syndrome, China paralytic syndrome, Chinese restaurant syndrome, Christian syndrome, Christ-Siemens-Touraine syndrome, Chromosome breakage syndrome, Chronic exertional compartment syndrome, Chronic fatigue[acronymattic.com]
Weight Loss
  • Such crises are stroke-like episodes, possibly triggered by recent infections and fever, fasting and weight loss as well as protein overload or intense physical exercise.[symptoma.com]
Respiratory Distress
  • The clinical manifestations are variable but common features include vomiting, hyperactivity or lethargy, diarrhoea, poor feeding, seizures, hypotonia, delayed psychomotor development and respiratory distress.[orpha.net]
  • These infants do not have any neurologic sequelae. 2 The severe form of transient hyperammonemia in the newborn occurs most commonly in premature infants, often in conjunction with respiratory distress.[nature.com]
  • More severe complications can also develop including seizures, confusion, respiratory distress, and the abnormal accumulation of fluid in the brain (cerebral edema).[rarediseases.org]
  • She required intubation because of respiratory distress, and anticonvulsant therapy was started with the onset of clonic arm jerking.[ajnr.org]
  • See A&V syndrome, Aarskog syndrome, Aase-Smith syndrome, Abortion trauma syndrome, Achard-Thiers syndrome, Achoo syndrome, Acute coronary syndrome, Acute HIV syndrome, Acute radiation injury syndrome, Acute urethral syndrome, Adult respiratory distress[acronymattic.com]
Vomiting
  • Signs and symptoms may include sudden vomiting, lack of coordination, confusion, and coma. NAGS is caused by mutations in the NAGS gene and is inherited in an autosomal recessive fashion.[rarediseases.info.nih.gov]
  • The clinical manifestations are variable but common features include vomiting, hyperactivity or lethargy, diarrhoea, poor feeding, seizures, hypotonia, delayed psychomotor development and respiratory distress.[orpha.net]
  • If parents note lethargy, poor feeding, vomiting and diarrhea, hyperventilation or seizures in their babies, a physician should be advised immediately.[symptoma.com]
  • Early symptoms include lethargy, vomiting, and deep coma. See also [ edit ] Hyperammonemia Urea cycle References [ edit ] Hall L, Metzenberg R, Cohen P (1958).[en.wikipedia.org]
  • Signs and symptoms may include sudden vomiting, lack of coordination, confusion, and coma. N-acetylglutamate synthase deficiency is caused by mutations in the NAGS gene and is inherited in an autosomal recessive fashion.[diseaseinfosearch.org]
Nausea
  • Chronic headaches and nausea are the most common cause of presentation in adolescents and adults developing hyperammonemia due to NAGS deficiency. Ataxia, tremor, visual impairment, confusion and psychiatric symptoms may also be experienced.[symptoma.com]
  • Early symptoms include appetite loss, nausea, insomnia, agitation, personality changes and clinical signs of hyperammonemia occur at concentrations 60 μmol/L. [4] Decreased ammonia elimination can be secondary to hepatic failure, inherited defects of[ijpm.info]
  • Glycine toxicity causes hyperammonemia, which manifests as CNS symptoms and nausea.[en.wikipedia.org]
  • Side effects of IV Ammonul may occur in children, including nausea and vomiting. This may be controlled with antiemetic medications such as ondansetron, either prior to or during the infusion.[newenglandconsortium.org]
Failure to Thrive
  • Evaluation of Failure to Thrive: Diagnostic Yield of Testing for Renal Tubular Acidosis. Pediatrics. 2003;112: e463–e466. Belldina EB, Huang MY, Schneider JA, Brundage RC, Tracy TS.[pedclerk.bsd.uchicago.edu]
  • Common symptoms include hypoglycemia, hyperlactacidemia, severe generalized hypotonia, myopathy, cardiomyopathy, failure to thrive, cardiac failure, circulatory collapse, sudden infant death syndrome, and congenital malformations, the last suggesting[ommbid.mhmedical.com]
  • Symptoms may include failure to grow and gain weight at the expected rate (failure to thrive), poor growth, avoidance of protein from the diet, inability to coordinate voluntary movements (ataxia), lethargy, vomiting, and/or diminished muscle tone (hypotonia[rarediseases.org]
  • In addition, affected infants may fail to grow and gain weight at the expected rate for age and gender (failure to thrive).[rarediseases.org]
  • Failure to thrive: ( poor feeding and frequent vomiting ) 66. Gait abnormality: In arginase deficiency, spastic diplegia, ( toe walking) Behavior disturbances: sleep disturbances, irritability, hyperactivity, manic episodes, psychosis.[slideshare.net]
Diarrhea
  • If parents note lethargy, poor feeding, vomiting and diarrhea, hyperventilation or seizures in their babies, a physician should be advised immediately.[symptoma.com]
  • Table 66-50 ) Pancytopenia, neutropenia, thrombocytopenia ( Table 66-51 ) Increased neutrophil granulocytes Bleeding tendency ( Table 66-52 ) Acanthocytosis ( Table 66-53 ) Visceral Symptoms or Syndromes (intestine, liver, heart, lung, kidney) Chronic diarrhea[ommbid.mhmedical.com]
  • Affected infants may exhibit refusal to eat and poor feeding habits, progressive lethargy, recurrent vomiting, diarrhea, irritability and an abnormally enlarged liver (hepatomegaly).[rarediseases.org]
  • When a patient has failure to thrive and a normal anion gap metabolic acidosis, the following pathologies beyond RTA are in the differential: Congenital hypothyroidism Obstructive uropathy Uremic acidosis (kidney failure) Bicarbonate loss secondary to: Diarrhea[pedclerk.bsd.uchicago.edu]
Vomiting in Infancy
  • Common symptoms of the disorders of urea cycle are vomiting in infancy, avoidance of high protein diet, intermittent ataxia, irritability, lethargy and mental retardation. 1.[biologydiscussion.com]
Hepatomegaly
  • A congenital form occurs in two types: Type 1, due to deficiency of the enzyme ornithine carbamoyltransferase, is marked by vomiting, lethargy, coma, and hepatomegaly; symptoms are aggravated by protein ingestion.[medical-dictionary.thefreedictionary.com]
  • […] neutrophil granulocytes Bleeding tendency ( Table 66-52 ) Acanthocytosis ( Table 66-53 ) Visceral Symptoms or Syndromes (intestine, liver, heart, lung, kidney) Chronic diarrhea (with failure to thrive, poor feeding, anorexia, hypotonia) ( Table 66-54 ) Hepatomegaly[ommbid.mhmedical.com]
  • Abdominal: Hepatomegaly may be present and is usually mild.[emedicine.medscape.com]
  • […] and decreased absorption from the gut Hartnup disease leads to pellagra (d/t tryptophan being a minor source of niacin) Hartnup disease severe hypoketotic hypoglycemia (no serum ketones), C8-C10 acyl carnitines in blood, AR; lethargy, seizures, coma, hepatomegaly[memorize.com]
  • Infants with argininosuccinic lyase : hepatomegaly 70.[slideshare.net]
Long Arm
  • This gene is located on the long arm of chromosome 17. More than twenty mutations of this gene have been described to date and an excellent review on this topic has been published a few years ago.[symptoma.com]
  • Investigators have determined that the PYCR1 gene is located on the long arm of chromosome 17 (17q25.3) and that the ALDH18A1 gene is located on the long arm of chromosome 10 (10q24.1).[rarediseases.org]
Visual Impairment
  • Ataxia, tremor, visual impairment, confusion and psychiatric symptoms may also be experienced. Patients who are currently under treatment for HAT3 are still at risk of hyperammonemia crises, independent of age.[symptoma.com]
Visual Impairment
  • Ataxia, tremor, visual impairment, confusion and psychiatric symptoms may also be experienced. Patients who are currently under treatment for HAT3 are still at risk of hyperammonemia crises, independent of age.[symptoma.com]
Psychiatric Symptoms
  • Ataxia, tremor, visual impairment, confusion and psychiatric symptoms may also be experienced. Patients who are currently under treatment for HAT3 are still at risk of hyperammonemia crises, independent of age.[symptoma.com]
  • symptoms ( Tables 66-4, 66-5, 66-6 ) Metabolic acidosis ( Table 66-7 ) Ketosis ( Table 66-9 ) Hyperlactacidemias ( Table 66-10 ) Hypoglycemia: general approach ( Table 66-11 ) Hypoketotic hypoglycemias due to inborn errors of ketogenesis ( Fig. 66-1[ommbid.mhmedical.com]
  • In the intensive care unit, patients with acute neurological and psychiatric symptoms or coma should have plasma ammonia levels measured to disclose a possible late-onset UCDs if there is any suspicion.[jintensivecare.biomedcentral.com]
Severe Mental Retardation
  • If symptoms are detected early enough and the patient is injected with this compound, levels of severe mental retardation can be slightly lessened, but brain damage is irreversible.[en.wikipedia.org]
Seizure
  • NAGS and other similar disorders are a type of metabolic condition known as a urea cycle disorder. [1] [2] Signs and symptoms in newborns with NAGS may include a lack of energy, unwillingness to eat, seizures, unusual body movements, and poorly controlled[rarediseases.info.nih.gov]
  • Seizures are common, but subclinical seizures may not be readily observable. Eventually, the patient's level of consciousness decreases and they may fall into a hyperammonemic coma. Late-onset HAT3 may manifest at any age.[symptoma.com]
  • The clinical manifestations are variable but common features include vomiting, hyperactivity or lethargy, diarrhoea, poor feeding, seizures, hypotonia, delayed psychomotor development and respiratory distress.[orpha.net]
  • The section offers management reviews in headache, seizures, epilepsy, neurobehavioral disorders, school readiness, developmental delay and a range of other conditions.[books.google.com]
  • Signs and symptoms in newborns may include a lack of energy, unwillingness to eat, seizures, unusual body movements, and poorly controlled breathing or body temperature. Complications may include coma, developmental delay, and learning disability.[diseaseinfosearch.org]
Lethargy
  • The clinical manifestations are variable but common features include vomiting, hyperactivity or lethargy, diarrhoea, poor feeding, seizures, hypotonia, delayed psychomotor development and respiratory distress.[orpha.net]
  • Early symptoms include lethargy, vomiting, and deep coma. See also [ edit ] Hyperammonemia Urea cycle References [ edit ] Hall L, Metzenberg R, Cohen P (1958).[en.wikipedia.org]
  • If parents note lethargy, poor feeding, vomiting and diarrhea, hyperventilation or seizures in their babies, a physician should be advised immediately.[symptoma.com]
  • Symptoms include vomiting, refusal to eat, progressive lethargy, and coma. NAGS deficiency is inherited as an autosomal recessive trait.[rarediseases.org]
  • Type 2, due to deficiency of the enzyme carbamoyl phosphate synthetase (ammonia), is marked by vomiting, lethargy, and flaccidity and by elevated plasma and urinary levels of glycine.[medical-dictionary.thefreedictionary.com]
Confusion
  • Signs and symptoms may include sudden vomiting, lack of coordination, confusion, and coma. NAGS is caused by mutations in the NAGS gene and is inherited in an autosomal recessive fashion.[rarediseases.info.nih.gov]
  • Signs and symptoms may include sudden vomiting, lack of coordination, confusion, and coma. N-acetylglutamate synthase deficiency is caused by mutations in the NAGS gene and is inherited in an autosomal recessive fashion.[diseaseinfosearch.org]
  • They may experience sudden episodes of ammonia toxicity, resulting in vomiting, lack of coordination, confusion or coma, in response to illness or other stress. N-acetylglutamate synthase deficiency is a very rare disorder.[ghr.nlm.nih.gov]
  • Ataxia, tremor, visual impairment, confusion and psychiatric symptoms may also be experienced. Patients who are currently under treatment for HAT3 are still at risk of hyperammonemia crises, independent of age.[symptoma.com]
  • Her carbamazepine levels were not done as she did not have any signs of carbamazepine toxicity except for asterixis and confusion. Subsequently patient was started on a combination of lithium and risperidone with adequate response.[ijpm.info]
Irritability
  • Ravicti is a form of phenylbutyrate that is less irritating to the gastrointestinal track.[rarediseases.org]
  • For these reasons, the family of urea cycle defects is considered individually in this article; however, the common denominator, hyperammonemia, can be manifested clinically by some or all of the following: Anorexia Irritability Heavy or rapid breathing[emedicine.medscape.com]
  • The pathophysiology of hyperammonemia is that of a CNS toxin that causes irritability, somnolence, vomiting, cerebral edema, and coma that leads to death.[emedicine.medscape.com]
  • Common symptoms of the disorders of urea cycle are vomiting in infancy, avoidance of high protein diet, intermittent ataxia, irritability, lethargy and mental retardation. 1.[biologydiscussion.com]
  • Suspected inborn error of metabolism associated with hyperammonemia in children (ammonia levels and associated signs): 50 to 100 µmol/L: usually asymptomatic 100 to 200 µmol/L: anorexia, vomiting, ataxia, irritability, hyperactivity Above 200 µmol/L:[ebmconsult.com]
Somnolence
  • Meanwhile, about one-third of patients becomes somnolent or lethargic, two out of three suffer from vomiting. Fluctuations of body temperature and hyperventilation may also be noted.[symptoma.com]
  • […] cycle defects is considered individually in this article; however, the common denominator, hyperammonemia, can be manifested clinically by some or all of the following: Anorexia Irritability Heavy or rapid breathing Lethargy Vomiting Disorientation Somnolence[emedicine.medscape.com]
  • The other patient had IgA gκ type myeloma and somnolence and died of malignant pleurisy despite intensive chemotherapy. Autopsy showed widespread multiple myeloma and an almost normal liver.[karger.com]
  • The pathophysiology of hyperammonemia is that of a CNS toxin that causes irritability, somnolence, vomiting, cerebral edema, and coma that leads to death.[emedicine.medscape.com]
  • Our patient developed emesis, headache, hallucinations and somnolence progressing to coma 6 hours after administration of the last L-Asp dose.[omicsonline.org]

Workup

In neonates, hyperammonemia encephalopathy is frequently misdiagnosed as sepsis. Thus, blood levels of ammonia should be assessed in all neonates presenting with clinical symptoms consistent with sepsis. This also applies to elder patients presenting with otherwise not explainable neurological deficits, reduced consciousness, or suspected intoxication. If hyperammonemia is detected, hepatic failure and urea cycle disorders move up the list of differential diagnoses. Immediately following, plasma acylcarnitines, amino acids, liver enzymes, urine organic acids and orotic acid should be determined. Findings may be interpreted as follows:

  • Accumulation of specific acylcarnitines may imply branched-chain organic acidemias, e.g., enhanced propionyl carnitine concentrations may indicate methylmalonic acidemia or propionic acidemia
  • Glutamine and alanine levels are increased in case of HAT3, CPSI deficiency, and ornithine transcarbamylase deficiency, with the latter urea cycle disorders being much more common than NAGS deficiency
  • Contrary to HAT3, CPSI deficiency is usually associated with reduced concentrations of citrulline
  • Highly increased urine orotic acid is characteristic of ornithine transcarbamylase deficiency, but not of HAT3 or CPSI deficiency

Furthermore, routine blood biochemistry and blood gas analyses should be carried out to assess the overall condition of the patient.

In order to confirm HAT3, the enzymatic activity of NAGS in a liver biopsy specimen may be evaluated. Furthermore, molecular biological techniques may be employed to determine the precise gene defect underlying HAT3. Molecular diagnostic tests are most sensitive [4].

Treatment

Therapy of HAT3 comprises the immediate treatment of hyperammonemia and long-term prevention of renewed increases in blood ammonia levels by daily administration of carbamoyl glutamate. The latter is a structural analogue of N-acetylglutamate, may activate CSPI and thus compensates for NAGS deficiency. Although the affinity of N-acetylglutamate to CPSI is higher, this compound has poor pharmacokinetic properties [1]. Recommended dosages vary and range from 15 mg/kg/d to 200 mg/kg/d [13]. Initially, higher doses are preferred; an adjustment of the total daily dose is then performed according to the patient's response to therapy and normalization of ammonia levels [14]. Furthermore, a restriction of dietary protein intake to less than 3 g/kg/day may be necessary, especially during metabolic crises.

Emergency treatment of hyperammonemia is not specific for HAT3 and may comprise the following measures [12]:

  • Prevent any further intake of proteins for up to 36 hours
  • Fluid therapy, intravenous application of dextrose (possibly plus insulin) and Intra lipids
  • Provide L-arginine, L-citrulline and nitrogen scavenger medication
  • In case of an unsatisfactory response to therapy or severe hyperammonemia (>250 μmol/l), prepare patient for hemodialysis or hemofiltration
  • In any case, monitor blood ammonia levels every three hours

If at all possible, patients known to suffer from HAT3 should not be treated with drugs that possibly induce a hyperammonemia crisis.

Prognosis

If left untreated, HAT3 has a poor outcome. Hyperammonemia may provoke hyperammonemia coma, irreversible brain damage, and death. In fact, acute mortality of patients suffering from severe neonatal hyperammonemia encephalopathy open link due to complete enzymatic deficiencies interfering with the urea cycle may amount to almost 50% [11]. Survivors frequently suffer from developmental delays and their median survival time is less than four years. Thus, an early diagnosis and initiation of treatment are of utmost importance. Affected individuals who receive carbamyl glutamate before brain damage occurs are generally able to lead a normal life. Neither motor nor cognitive development is affected in these cases.

Etiology

In older literature, HAT3 is defined as a severely reduced activity of NAGS as assessed in hepatic tissue [3]. Detoxification of ammonia takes place in the liver, and NAGS deficiency is indeed the trigger of HAT3. Later, NAGS deficiency could be related to sequence anomalies affecting the gene encoding for NAGS. This gene is located on the long arm of chromosome 17. More than twenty mutations of this gene have been described to date and an excellent review on this topic has been published a few years ago [4]. Still, HAT3-related gene defects unknown by then have been reported afterwards [5] [6]. In sum, both nonsense and frame-shift mutations, as well as missense mutations, have been described. While the former are generally associated with a complete absence of NAGS activity, missense mutations may be related to the residual enzymatic activity. The latter has been proposed to account for late-onset HAT3 [4]. All mutations known to date show recessive behavior; thus, heterozygous individuals don't develop HAT3. In contrast, NAGS activity is severely diminished or undetectable in homozygous patients.

Of note, secondary NAGS deficiency is a clinically indistinguishable entity of different etiology. Here, NAGS activity is diminished by toxic metabolites or provoked by lack of substrates [7]. This may be the case in isovaleric acidemia, methylmalonic acidemia, propionic acidemia and other branched-chain organic acidemias as well as valproate-induced hyperammonemia.

Epidemiology

The overall incidence of urea cycle disorders has been estimated to be about 1 per 35,000 inhabitants. HAT3 is the least common urea cycle disorder, accounting for less than 1% of those cases. Accordingly, less than 1 per 3,500,000 people is expected to suffer from HAT3. Analyses based on newborn screens yield similar values, with an estimation of a maximum incidence of 1 in 2,000,000 [8]. Neither racial nor gender predilection have been reported to date. HAT3 has initially been described as a congenital disease with symptom onset within days after birth, but case reports of adult-onset HAT3 have been published later [5] [9]. While symptom onset may occur at any age, neonatal HAT3 is still considered the most common form of the disease.

Sex distribution
Age distribution

Pathophysiology

The urea cycle comprises complex biochemical reactions that allow for the breakdown of proteins, amino acids and other nitrogen compounds while at the same time preventing the accumulation of neurotoxic ammonia: The main source of ammonia in the human body is the conversion of glutamate to α-ketoglutarate, catalyzed by glutamate dehydrogenase and yielding ammonia as a by-product. Considerable shares of ammonia are used for the production of carbamoyl phosphate, and this reaction is catalyzed by CPSI. The latter is dependent on N-acetylglutamate that, in turn, is synthesized from glutamate and acetyl-CoA. Because this reaction is mediated by NAGS, NAGS deficiency triggers a chain of pathophysiological events including reduced levels of N-acetylglutamate, diminished activity of CPSI and impaired detoxification of ammonia. In fact, carbamoyl phosphate synthase deficiency entails similar clinical consequences as HAT3 and is an important differential diagnosis of NAGS deficiency.

HAT3 patients are constantly at risk of sustaining hyperammonemia crises, which is usually defined as clinical symptoms due to ammonia levels >100 μmol/l [10]. They may be triggered by infectious diseases, lack of nutrients and protein overload, drug intake and a variety of other factors. As has been indicated above, the central nervous system is most sensitive to increased concentrations of ammonia. Patients who survive a hyperammonemia crisis are thus at risk of irreversible brain damage, persistent neurological deficits and developmental delays.

Prevention

Most neonates suffering from HAT3 and other urea cycle disorders develop hyperammonemia shortly after birth, more than half of them within four days, two out of three within a week [15]. Consequently, analyses of blood samples within their first week of life may yield increased concentrations of ammonia and may prompt a corresponding workup. Moreover, prenatal diagnosis of HAT3 is feasible but requires a target-oriented, more arduous approach [16]. Despite such tests being readily available in many countries, neither pre- nor postnatal screens for urea cycle disorders are routinely conducted at present. In any case, parents-to-be with a familial history of HAT3 should be offered the corresponding analyses. Affected families that wish to have children may benefit from genetic counseling.

Summary

Hyperammonemia type 3 (HAT3) is a genetic disease associated with disturbances of urea metabolism caused by the deficiency of the enzyme N-acetyl glutamate synthase (NAGS) [1]. This enzyme catalyzes the conversion of glutamate and acetyl-CoA to N-acetyl glutamate, and the latter serves as an allosteric activator of carbamoyl phosphate synthetase I (CPSI). This enzyme catalyzes the production of carbamoyl phosphate from ammonia and bicarbonate. Consequently, NAGS deficiency results in a reduced activity of CPSI and an accumulation of ammonia in the body of the affected individual.

Due to the genetic etiology of the disease, HAT3 is a congenital disorder. However, symptoms don't necessarily manifest shortly after birth. Despite neonatal HAT3 being the most common form of the disease, symptom onset may be delayed until well into adulthood. Symptoms are provoked by a deficient detoxification of ammonia, which is a neurotoxic substance. Patients frequently develop seizures and may suffer from lethargy, vomiting, diarrhea and breathing difficulties. Severe hyperammonemia is often associated with a reduced level of consciousness, and patients may fall into a hyperammonemic coma.

Molecular testing is indicated to confirm a tentative diagnosis of HAT3. Treatment mainly consists in compensating for NAGS deficiency by administration of carbamoyl glutamate. This compound assumes the function of N-acetyl-glutamate and activates CPSI. Therapy largely improves the outcome of this potentially life-threatening disease: Hyperammonemic crises are associated with mortality rates of up to 10% [2]. Adequate treatment, however, generally allows for a good quality of life.

Patient Information

Hyperammonemia type 3 (HAT3) is a metabolic disorder associated with disturbances of urea metabolism. It is caused by a deficiency of the enzyme N-acetyl-glutamate synthase (NAGS), which, in turn, is provoked by mutations of the gene encoding for NAGS. For a better understanding of the clinical consequences of NAGS deficiency, biochemical reactions that play a crucial role in the urea cycle shall be illustrated briefly:

  • The breakdown of proteins, amino acids, and other nitrogen compounds may yield ammonia as a by-product.
  • The enzyme carbamoyl phosphate synthetase I (CPSI) catalyzes the conversion of ammonia and bicarbonate to carbamoyl phosphate.
  • The activity of CPSI depends on the presence of an allosteric activator, namely N-acetyl glutamate.
  • N-acetyl-glutamate is synthesized from glutamate and acetyl-CoA, and this reaction is mediated by NAGS.

Consequently, NAGS deficiency results in a reduced activity of CPSI and an accumulation of ammonia. Ammonia is neurotoxic and patients suffering from HAT3 develop hyperammonemia. This condition may cause brain damage, coma, and death. Because HAT3 is a genetic disorder, most patients develop symptoms shortly after birth. In the case of residual NAGS activity, late-onset HAT3 may occur.

Daily administration of carbamoyl glutamate is the mainstay of HAT3 therapy. This compound may activate CPSI and thus compensates for NAGS deficiency. In order to avoid permanent brain damage, treatment should be initiated as early as possible. If parents note lethargy, poor feeding, vomiting and diarrhea, hyperventilation or seizures in their babies, a physician should be advised immediately. Patients who receive carbamoyl glutamate from the start may not sustain brain damage, develop normally and lead a normal life.

References

Article

  1. Ah Mew N, Caldovic L. N-acetylglutamate synthase deficiency: an insight into the genetics, epidemiology, pathophysiology, and treatment. Appl Clin Genet. 2011; 4:127-135.
  2. Batshaw ML, Msall M, Beaudet AL, Trojak J. Risk of serious illness in heterozygotes for ornithine transcarbamylase deficiency. J Pediatr. 1986; 108(2):236-241.
  3. Bachmann C. Long-term outcome of patients with urea cycle disorders and the question of neonatal screening. Eur J Pediatr. 2003; 162 Suppl 1:S29-33.
  4. Caldovic L, Morizono H, Tuchman M. Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene. Hum Mutat. 2007; 28(8):754-759.
  5. van de Logt AE, Kluijtmans LA, Huigen MC, Janssen MC. Hyperammonemia due to Adult-Onset N-Acetylglutamate Synthase Deficiency. JIMD Rep. 2016.
  6. Al Kaabi EH, El-Hattab AW. N-acetylglutamate synthase deficiency: Novel mutation associated with neonatal presentation and literature review of molecular and phenotypic spectra. Mol Genet Metab Rep. 2016; 8:94-98.
  7. Häberle J. Role of carglumic acid in the treatment of acute hyperammonemia due to N-acetylglutamate synthase deficiency. Ther Clin Risk Manag. 2011; 7:327-332.
  8. Summar ML, Koelker S, Freedenberg D, et al. The incidence of urea cycle disorders. Mol Genet Metab. 2013; 110(1-2):179-180.
  9. Cartagena A, Prasad AN, Rupar CA, et al. Recurrent encephalopathy: NAGS (N-acetylglutamate synthase) deficiency in adults. Can J Neurol Sci. 2013; 40(1):3-9.
  10. Lee B, Diaz GA, Rhead W, et al. Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder. Genet Med. 2015; 17(7):561-568.
  11. Maestri NE, Clissold D, Brusilow SW. Neonatal onset ornithine transcarbamylase deficiency: A retrospective analysis. J Pediatr. 1999; 134(3):268-272.
  12. Häberle J, Boddaert N, Burlina A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012; 7:32.
  13. Gessler P, Buchal P, Schwenk HU, Wermuth B. Favourable long-term outcome after immediate treatment of neonatal hyperammonemia due to N-acetylglutamate synthase deficiency. Eur J Pediatr. 2010; 169(2):197-199.
  14. Guffon N, Schiff M, Cheillan D, Wermuth B, Haberle J, Vianey-Saban C. Neonatal hyperammonemia: the N-carbamoyl-L-glutamic acid test. J Pediatr. 2005; 147(2):260-262.
  15. Bachmann C. Long-term outcome of patients with urea cycle disorders and the question of neonatal screening. Eur J Pediatr. 2003; 162(Suppl 1):S29-33.
  16. Häberle J, Koch HG. Genetic approach to prenatal diagnosis in urea cycle defects. Prenat Diagn. 2004; 24(5):378-383.

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Last updated: 2019-07-11 20:54