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].

• Swelling

  Swelling in the legs and abdomen. The increased pressure in the portal vein can cause fluid to accumulate in the legs, called edema, and in the abdomen, called ascites. [mayoclinic.org]

  Rangroo Thrane explains: – These studies have shown that glial cells that are exposed to ammonia swell quite rapidly. Our research shows that swelling of glial cells is not required for ammonia to be toxic to the brain. [med.uio.no]

  Astrocytes synthesize glutamine excessively in the setting of hyperammonemia, resulting in astrocyte swelling and the generation of reactive oxygen species. [journalofhospitalmedicine.com]

  Glutamine in the mechanism of ammonia-induced astrocyte swelling. [cghjournal.org]

  Mild, diffuse cerebral swelling and sulcal effacement from the diffuse cortical injury without midline shift. [ruralneuropractice.com]

• Poor Feeding

  The clinical manifestations are variable but common features include vomiting, hyperactivity or lethargy, diarrhea, poor feeding, seizures, hypotonia, global development delay, psychiatric symptoms and respiratory distress. [orpha.net]

  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 [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]

  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

  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]

  Assessment Red flag features in Red History: Symptoms of hypoglycaemia Palpitations, tremor, anxiety, sweating, hunger, paraesthesia Severe hypoglycaemia - lethargy, irritability, uncharacteristic behaviour, hypothermia, confusion, coma, seizures Neonate [rch.org.au]

  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]

  Perioperative precautions included minimizing fasting period, hypothermia prevention, relieving anxiety and pain, perioperative infusion of D10W and benzoate sodium, as well as a pediatric endocrinology consultation. [anesthpain.com]

  […] by ASL, ASS1, CPS1, OTC or the cofactor producer encoded by NAGS 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 [invitae.com]

• Fatigue

  We report a case of incidental IPSVS in a patient who presented with complaints of fatigue and failure to thrive. [eventscribe.com]

  When symptoms do occur, they may include: Fatigue. Easily bleeding or bruising. Loss of appetite. Nausea. Swelling in the legs, feet or ankles, called edema. Weight loss. Itchy skin. Yellow discoloration in the skin and eyes, called jaundice. [mayoclinic.org]

  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]

  Ammonia's odor provides adequate early warning of its presence, but ammonia also causes olfactory fatigue or adaptation, reducing awareness of one's prolonged exposure at low concentrations. [health.ny.gov]

  These episodes are accompanied by fatigue, chills, abdominal pain, swelling of affected lymph nodes (lymphadenopathy), a rash, joint inflammation (arthritis) and pain (arthralgia). [rarediseases.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]

  On the night following the surgery, he became confused and combative, with tachycardia, 106° hyperthermia, and generalized tonic-clonic seizures that the local hospital was unable to control, progressing to status epilepticus. [nucdf.org]

• Respiratory Distress

  The physical presentation of respiratory distress is generally referred to as labored breathing, while the sensation of respiratory distress is called shortness of breath or dyspnea. [ncbi.nlm.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]

  Physical examination showed no clinical signs of respiratory distress. The laboratory results showed an elevated C reactive protein of 8.02 mg/dl and increased erythrocyte sedimentation of 100 mm. [casereports.bmj.com]

• Cough

  Pus in the pleural space can’t be coughed out. Instead, it needs to be drained by a needle or surgery. Empyema usually develops after pneumonia, which is an infection of the lung tissue. Empyema can develop after you have pneumonia. [healthline.com]

  All the patients were enquired regarding symptoms such as breathlessness, fever, cough, chest pain, constitutional symptoms such as loss of appetite and loss of weight. [ncbi.nlm.nih.gov]

• Dyspnea

  Presentation acute onset of dyspnea, known case of pulmonary tuberculosis. Patient Data Age: 30 year Gender: Male Vascular markings are absent in the left lung field suggestive of collapsed left lung. [radiopaedia.org]

  The physical presentation of respiratory distress is generally referred to as labored breathing, while the sensation of respiratory distress is called shortness of breath or dyspnea. [ncbi.nlm.nih.gov]

  Type I presents as a life-threatening disorder during the neonatal period with tachypnea, dyspnea, profound acidosis, severe hypotonia and convulsions. [genedx.com]

  Despite treatment with an aerosol bronchodilator, she continued to have bronchospasm and dyspnea with wheezes. The patient was admitted and intravenous steroids were initiated. [nucdf.org]

  He presented on the day of admission with dyspnea from refractory ascites that had acutely worsened during the prior 3 weeks, despite weekly large volume paracentesis. [cghjournal.org]

• Vomiting

  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]

  The clinical manifestations are variable but common features include vomiting, hyperactivity or lethargy, diarrhea, poor feeding, seizures, hypotonia, global development delay, psychiatric symptoms and respiratory distress. [orpha.net]

  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]

  Symptoms include vomiting, refusal to eat, progressive lethargy, and coma. NAGS deficiency is inherited as an autosomal recessive trait. [rarediseases.org]

• Nausea

  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]

  When symptoms do occur, they may first include fatigue; weakness and weight loss; nausea; bruising or bleeding easily; swelling in your legs, feet or ankles; itchy skin; redness on the palms of your hands; and spider-like blood vessels on your skin. [mayoclinic.org]

  One course of mFOLFOX6 therapy (oxaliplatin with 5-FU 2400 mg/m2/week) was administered postoperatively, but due to mild lack of appetite and nausea, the patient had poor oral intake and reduced water consumption; therefore, central vein nutritive therapy [journals.lww.com]

• Diarrhea

  The clinical manifestations are variable but common features include vomiting, hyperactivity or lethargy, diarrhea, poor feeding, seizures, hypotonia, global development delay, psychiatric symptoms 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]

  In addition to chills and fever, patients may have abdominal pain, vomiting or diarrhea, headache, and arthralgias. [merckmanuals.com]

  Attacks are characterized by high spiking fever,abdominal pain, vomiting, diarrhea, headache, arthralgias, and swollen, tender lymph nodes. Red macules of the skin and aphthous ulcers may also be observed. [genedx.com]

  […] disease's episodes decreases over time.[2] Last updated: 6/26/2017 Hyper IgD syndrome is characterized by periodic high fevers that may be associated with other symptoms including:[3][5][2] Cold chills Swollen lymph nodes (lymphadenopathy) Abdominal pain Diarrhea [rarediseases.info.nih.gov]

• Failure to Thrive

  […] to thrive MedGen UID: 746019 •Concept ID: C2315100 • Disease or Syndrome Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm. [ncbi.nlm.nih.gov]

  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]

  Clinical features include mitochondrial encephalopathy, psychomotor retardation, ataxia, severe failure to thrive, liver dysfunction, renal tubulopathy, muscle weakness and exercise intolerance. [malacards.org]

  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]

• Loss of Appetite

  Case Description/Methods: 82-year-old African American male with hypertension, diabetes mellitus and prostate cancer (treated) presented with complaints of fatigue and loss of appetite for one-month. [eventscribe.com]

  The symptoms of simple empyema include: shortness of breath dry cough fever sweating chest pain when breathing that may be described as stabbing headache confusion loss of appetite Complex empyema Complex empyema occurs in the later stage of the illness [healthline.com]

  All the patients were enquired regarding symptoms such as breathlessness, fever, cough, chest pain, constitutional symptoms such as loss of appetite and loss of weight. [ncbi.nlm.nih.gov]

• 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]

  Clinical features of this disorder are characterized by hepatomegaly and in some cases abnormally kinky hair as well as hyperammonemia. Elevation of ammonium is mostly due to arginine deficiency, and restriction of arginine and protein is effective. [academic.oup.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]

  Patients may have muscle weakness, cardiomyopathy, hepatomegaly, and/or growth retardation. [emedicine.medscape.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]

• Muscle Weakness

  Clinical features include mitochondrial encephalopathy, psychomotor retardation, ataxia, severe failure to thrive, liver dysfunction, renal tubulopathy, muscle weakness and exercise intolerance. [malacards.org]

  Patients may have muscle weakness, cardiomyopathy, hepatomegaly, and/or growth retardation. [emedicine.medscape.com]

  […] spastic paraplegia type 3 is a rare, pure or complex subtype of hereditary spastic paraplegia, with highly variable phenotype, typically characterized by childhood-onset of minimally progressive, bilateral, mainly symmetric lower limb spasticity and weakness [mendelian.co]

  Muscle weakness is a common finding in late-onset presentations of GA-II. [rarediseasesjournal.com]

• Seizure

  Seizure 2008;17:658-664. Epub 2008 Mar 5 [jcrpe.org]

  The section offers management reviews in headache, seizures, epilepsy, neurobehavioral disorders, school readiness, developmental delay and a range of other conditions. [books.google.com]

  A similar effect would be considered to be involved in idiopathic epileptic seizure patients as well. [ncbi.nlm.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, diarrhea, poor feeding, seizures, hypotonia, global development delay, psychiatric symptoms and respiratory distress. [orpha.net]

• Confusion

  He became confused, disoriented and progressively unresponsive. He was admitted to the ICU in coma. [nucdf.org]

  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]

  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]

  Safety Considerations Confusion: Treat the medical condition; correlate confusion with the need to reverse altered electrolytes; evaluate medications; prevent falls and injury through use of postural support, bed alarm, or the appropriate use of restraints [nursing.unboundmedicine.com]

• Lethargy

  Lethargy 3. Anorexia 4. Hyper/hypoventilation 5. 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. [quizlet.com]

  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]

  Manifestations range from neonatal presentation of poor feeding, vomiting, lethargy, tachypnea, convulsions and coma to adult-onset headaches, hazy gastrointestinal symptoms, seizures, behavioral/psychiatric problems, confusion and lethargy. [orpha.net]

  Symptoms include vomiting, refusal to eat, progressive lethargy, and coma. NAGS deficiency is inherited as an autosomal recessive trait. [rarediseases.org]

• Irritability

  Category 1 Serious eye damage/eye irritation - Category 1 The signal word is danger. [ccohs.ca]

  Even low concentrations of ammonia vapor (100 ppm) produce rapid onset of eye irritation. [wwwn.cdc.gov]

  These produce allergens and irritants that can cause asthma attacks among those allergic to mould. They also irritate the eyes, skin, nose, throat, and lungs of both mould-allergic and non-allergic people. Read more about damp and mould here or here. [who.int]

  Inhalation of lower concentrations can cause coughing, and nose and throat irritation. [health.ny.gov]

  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]

• Headache

  Migraine headache Migraine headaches [ more ] 0002076 Papule 0200034 Recurrent aphthous stomatitis Recurrent canker sores 0011107 Urticaria Hives 0001025 Vasculitis Inflammation of blood vessel 0002633 5%-29% of people have these symptoms Acrocyanosis [rarediseases.info.nih.gov]

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].

• Ammonia Increased

  Ammonia is stable for several days at -20°C. Caution: Blood ammonia increases rapidly at room temperature. [labcorp.com]

  Ammonia increases rapidly in the collected specimen, so analysis should be performed within 20 min of collection. [nursing.unboundmedicine.com]

  Ammonia is a metabolite of 5-FU; thus, in theory, the level of the metabolite, ammonia, increases depending up on the dosage of 5-FU. [journals.lww.com]

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.

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.

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.

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.

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.

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.

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.

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.

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