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Pediatric Summary Report Secondary Findings in Pediatric Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening Permalink P Current Version Rule-Out Dashboard Release History Status (Pediatric): Passed (Consensus scoring is Complete) Curation Status (Pediatric): Released 1.0.0 Status (Adult): Passed (Consensus scoring is Complete) A

GENE/GENE PANEL: NAGS

Condition: N-Acetyl Glutamate Synthase Deficiency (NAGSD)

Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

Gene Condition Pairs(s)

Final Assertion

NAGS⇔0009377 (hyperammonemia due to n-acetylglutamate synthase deficiency)

Strong Actionability

Actionability Rationale

Most experts agreed with the assertion computed according to the rubric. The paucity of evidence related to prevalence of late-onset or milder extent of disease led some experts to conclude moderate actionability.

Final Consensus Scoresa

Outcome / Intervention Pair

Severity

Likelihood

Effectiveness

Nature of the
Intervention

Total
Score

Gene Condition Pairs: NAGS ⇔ 0009377 (OMIM:237310)

Morbidity and mortality due to hyperammonemia / Referral to a specialist to guide management, including N-carbamylglutamate, diet, and emergency planning

10NC

a. To see the scoring key, please go to : https://www.clinicalgenome.org/site/assets/files/2180/actionability_sq_metric.png

Topic

Narrative Description of Evidence

Ref

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The estimated incidence of N-acetyl glutamate synthetase deficiency (NAGSD) is estimated to be <1:2,000,000 births and is considered to be the rarest of the urea cycle disorders (UCDs). To date, approximately 100 cases have been reported worldwide.

1 2 3

Clinical Features
(Signs / symptoms)

NAGSD is due to a deficiency of the urea cycle cofactor-producing enzyme N-acetyl glutamate synthetase (NAGS), which is an essential activator of carbamoyl phosphate synthetase 1 (CPS1). Symptoms are indistinguishable from those CPS1 deficiency, as CPS1 is rendered inactive in the absence of NAGS. These two conditions have identical clinical and laboratory manifestations. NAGSD is characterized by hyperammonemia of variable severity, which can lead to encephalopathy and development of related symptoms. 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. Other manifestations include headaches, hazy gastrointestinal symptoms, behavioral problems, and confusion. Clinical features are heterogenous depending on the age of the patient and on severity of the deficiency.

The early signs of decompensation in NAGSD may be subtle - lethargy, loss of appetite, or exacerbation of pre-exiting neurological problems (irritability, fits, etc.). Neonatal cases often present with poor feeding or feeding intolerance, vomiting, lethargy, hypertonia and/or hypotonia, seizures, and tachypnea. Common symptoms in later onset cases include vomiting, confusion or disorientation, ataxia, lethargy, decreased level of consciousness, seizures, and hypotonia. The major complication of these disorders is cerebral edema, which can be severe and of sudden onset.

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Natural History
(Important subgroups & survival / recovery)

In general, individuals with complete UCD defects normally present in the newborn period. In individuals with partial (milder) deficiencies, ammonia accumulation and the first recognized clinical episode may be delayed for months or years. Onset of NAGSD may occur at any age, ranging from the neonatal period to the fifth decade of life. Decompensation is often triggered by metabolic stress such as febrile illness (particularly diarrhea or vomiting), fasting and any protein loading, pregnancy, and delivery. However, an obvious precipitant is not always apparent. Hyperammonemia might be severe and may lead to coma and even death if not urgently treated.

Although the severity of NAGSD is variable, the prognosis without treatment may be poor with neurological deficit and a potentially fatal outcome. In general, hyperammonemic encephalopathy is associated with high mortality rates. The total duration of hyperammonemic coma and the extent of hyperammonemia are negatively correlated with the patient’s outcome. Historically the outcome of newborns with UCDs with hyperammonemia was considered poor. With rapid identification and current treatment strategies, survival of neonates with hyperammonemia has improved dramatically in the last few decades, including less severe intellectual outcomes. In most individuals with NAGSD, early treatment (i.e., before the onset of permanent neurological sequelae) with carbamylglutamate (an oral NAGS analog) allows normal global development and an excellent quality of life without dietary restrictions.

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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making during transition to adult health care: https://www.acmg.net/PDFLibrary/Nags-Deficiency-Transition.pdf.

Management aims to maintain stable metabolic control, to reduce or eliminate chronic complications, and to achieve as close to normal development and growth as possible. The mainstay of long-term management of NAGSD is treatment with carbamylglutamate (also called carglumic acid or N-carbamyl-L-glutamate), an oral NAGS analogue. Although carbamylglutamate is typically used as a monotherapy, the sensitivity and specificity of the initial response to carbamylglutamate is not 100%; therefore, adjunct treatment with nitrogen scavengers (also known as ammonia scavengers such as sodium benzoate, sodium phenylacetate, sodium phenylbutyrate, and glycerol phenylbutyrate), and a restricted protein diet can be considered. Although long-term outcome data on the effectiveness of carbamylglutamate are scarce, 20 NAGSD patients known to be utilizing this treatment are doing well. There are no reports on long-term safety or on adverse effects of this drug other than high dose-triggered MSG syndrome. (Tier 2)

In a review of 34 individuals with NAGSD (mainly neonatal-onset) from 28 families, carbamylglutamate appeared to correct the metabolic defect in individuals with NAGSD, who no longer required ammonia-scavenging agents (n=10 individuals from 5 case reports and 1 prospective series). Dietary protein restriction was eased in two individuals. It is possible that a higher daily carbamylglutamate dose would allow for greater protein tolerance in these individuals, since there is one carbamylglutamate-treated individual whose protein intake has been entirely liberalized, with no adverse effects. However, 2 NAGS-deficient individuals on carbamylglutamate were reported to have experienced breakthrough hyperammonemia during episodes of acute illness. (Tier 3)

A recent review identified 27 individuals with NAGSD that had been treated with carbamylglutamate. Sixteen of these cases were diagnosed and treated in the neonatal period, 11 of which (69%) reported improved growth and/or cognitive abilities. Of the 7 pediatric cases treated with carbamylglutamate, 2 reported improved outcomes. Of the 4 cases diagnosed and treated as adults (age range 20-59 years), 2 reported discontinuation of symptoms. All 19 of the case reports published in the last 20 years were treated with carbamylglutamate as monotherapy. (Tier 5)

Given the risk of acute metabolic decompensation during surgery and general anesthesia, elective surgery should only be carried out in centers able and prepared to deal with hyperammonemic decompensations. The patient should be well, with normal preoperative ammonia and amino acid concentrations and without even minor intercurrent illness. Postsurgical close monitoring of the clinical status and ammonia is required. (Tier 2)

Prompt diagnosis of hyperammonemia is vital for a good outcome. The family should be taught to recognize the symptoms and signs to initiate treatment at earliest possible stage. An emergency regimen for treatment of intercurrent illness is recommended. A management plan should be provided to parents, caregivers, nursery, and school. The treatment of hyperammonemia is based on clinical status, with particular attention to any degree of encephalopathy, and should be started without delay. If the patient is not well or at risk of illness, emergency treatment could be initiated at home followed by hospital admission, if needed. Acute treatment of hyperammonemia in individuals with NAGSD is aimed at reducing the production of ammonia by oral treatment with carbamylglutamate. Acute treatment also includes high glucose perfusion (with withdrawal of proteins and lipids) and administration of intravenous nitrogen scavengers to promote waste nitrogen excretion, L-arginine (or L-citrulline), essential nutrients, and essential amino acids. Any infection or constipation (which increases ammonia absorption from the gut), should be treated. Regular monitoring should include blood pH and gases, ammonia, urea and electrolytes, and glucose. If there is any hint of encephalopathy, neurological observations should be done at least hourly. The individual should be transferred to a specialist center without delay. (Tier 2)

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Successful pregnancies in UCD patients require addressing the special nutritional needs of pregnancy and lactation, avoiding undernutrition of protein. Continuation of treatment with nitrogen scavengers is generally necessary in pregnant individuals with UCDs. Based on biochemical mechanisms, the use of nitrogen scavengers is suggested. There is insufficient evidence to comment on fetal outcomes after nitrogen scavenger therapy in pregnancy. Close monitoring during and early after delivery is essential to recognize hyperammonemia within the first 5 days after delivery. (Tier 2)

Surveillance

Individuals with UCDs require lifelong monitoring by a multidisciplinary team. Clinical and biochemical monitoring depends on age and metabolic status. Young and severely affected individuals should be seen at least every 3 months while older or less severely affected individuals may only need annual appointments.

•Record growth and head circumference; inspect for thin, sparce hair or hair loss, skin rashes, or other signs of protein/vitamin deficiency

•Brain MRI, even in the absence of neurological and/or cognitive impairment, with timing based on the individual

•Neurological and neurocognitive assessments should be performed at regular intervals even in individuals with milder presentation

•Liver size and structure should be assessed by ultrasound scan

•Regular dietary assessment is essential, including review of supplementations

•Monitor plasma ammonia and amino acid profile as well as vitamin, mineral, trace elements, carnitine, ferritin, cholesterol, triglyceride, alpha-fetoprotein, and essential fatty acid levels

•Psychological monitoring and counseling to address health-related quality of life, anxiety, stress, and psychosocial factors. (Tier 2)

Circumstances to Avoid

Steroids should be avoided as they increase the amount of protein turnover and hence increase the nitrogen load. (Tier 2)

Valproic acid should be avoided in any patient who has known risk for hyperammonemia. It is known to decrease urea cycle function by inhibition of NAGS. (Tier 2)

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Recessive

NAGSD is inherited in an autosomal recessive manner.

1 2 3 6 12

Prevalence of Genetic Variants

Information on the prevalence of pathogenic variants associated with NAGS was not available.

1 2

In a longitudinal study of 614 patients with UCDs, three were reported with NAGSD (0.5%), all with a late-onset form. (Tier 3)

A recent review by Kenneson and Singh (2020; k=48) found DNA testing results reported for 76 cases in the literature, with the identification of 47 different pathogenic mutations, although a second mutation was not identified in three of the cases. (Tier 5)

Penetrance
(Include any high risk racial or ethnic subgroups)

Kenneson and Singh reported the following features in individuals with NAGSD based on age at presentation:

In 38 cases with neonatal presentation:

•n=16 (42%) experienced poor feeding/anorexia/intolerance

•13 (34%) experienced vomiting

•12 (32%) coma and/or lethargy

•7 (18%) hypotonia

•6 (16%) experienced hypertonia, seizures, and/or tachypnea

In n=28 cases with post-neonatal presentation:

•n=12 (43%) experienced vomiting

•7 (25%) confusion and/or ataxia

•6 (21%) avoidance of high-protein foods, coma, and/or decreased level of consciousness. (Tier 5)

About 50% of neonates with a UCD with severe hyperammonemia may have seizures, some without overt clinical manifestations. (Tier 4)

Relative Risk
(Include any high risk racial or ethnic subgroups)

Information on relative risk was not available.

Expressivity

In UCDs, severe deficiency manifests during the first few days of life and leads to the development of related symptoms. Hyperammonemia in the milder (partial) defects is typically less severe and the symptoms more subtle than the neonatal presentation of a UCD. (Tier 4)

Presentation of NAGS varies by age and symptoms (Tier 5)

4. What is the Nature of the Intervention?

Nature of Intervention

Long-term treatment of UCDs can be challenging for patients and families because of the poor palatability of the diet, the volume and frequency of diet and drug administrations; all these are serious barriers to adherence. Hyperammonemia treatment includes cessation of protein intake and interventions (medications, dialysis) for ammonia removal. Carbamylglutamate must be taken as an oral preparation and during acute treatment may be administered through a nasogastric tube if necessary. Reported adverse reactions include abdominal pain, diarrhea, vomiting, anemia, otitis media, tonsillitis, nasopharyngitis, fever, and headache. Nitrogen scavengers may be administered orally as a powder, capsule, tablet, or liquid. During a hyperammonemic crisis, nitrogen scavengers may be oral or intravenous depending on severity of the clinical status. Generally, all treatments used during hyperammonemic crises are well tolerated and adverse reactions are only relevant if dosages are very high. Adverse reactions associated with ammonia scavengers include hypotension, injection site reaction, hyperglycemia, hypokalemia, hypernatremia, vomiting, diarrhea, altered mental status, seizure, cerebral edema, and fever. Sodium phenylbutyrate causes amenorrhea or menstrual dysfunction in 25% of females, decreased appetite, taste disturbances, body odor, and can deplete branch chain amino acids which increases the risk of endogenous protein catabolism. Sodium benzoate and sodium phenylbutyrate can cause mucositis or gastritis in the granule, tablet, or undiluted liquid preparations. Metabolic acidosis has been observed with high doses of nitrogen scavengers.

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5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Newborn screening panels in the United States screen for several of the UCDs, but currently NAGSD is not included in most panels. Because newborns are usually discharged from the hospital within one or two days after birth, the symptoms of a UCD often develop when the child is at home and may not be recognized in a timely manner by the family and primary care physician. (Tier 3)

Kenneson and Singh identified 98 cases of NAGS deficiency from 79 families and reported that approximately 5% of individuals were asymptomatic at diagnosis and another 5% or more were not diagnosed until adulthood. The oldest age at presentation was 59 years. (Tier 5)

Description of sources of evidence:

Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.

Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.

Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.

Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.

Tier 5: Evidence from a non-systematically identified source.

Date of Search: 01.03.2023

Gene Condition Associations

Gene

Condition Associations

OMIM Identifier

Primary MONDO Identifier

Additional MONDO Identifiers

NAGS

237310

0009377

Reference List

1. N Ah Mew, BC Lanpher, A Gropman, KA Chapman, KL Simpson, , ML Summar. Urea Cycle Disorders Overview. 2003 Apr 29 [Updated 2015 Apr 09]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1217

2. Hyperammonemia due to N-acetylglutamate synthase deficiency. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=927

3. Kenneson A, Singh RH. Presentation and management of N-acetylglutamate synthase deficiency: a review of the literature. Orphanet J Rare Dis. (2020) 15(1750-1172):279.

4. Alfadhel M, Mutairi FA, Makhseed N, Jasmi FA, Al-Thihli K, Al-Jishi E, AlSayed M, Al-Hassnan ZN, Al-Murshedi F, Häberle J, Ben-Omran T. Guidelines for acute management of hyperammonemia in the Middle East region. Ther Clin Risk Manag. (2016) 12(1176-6336):479-87.

5. Häberle J, Burlina A, Chakrapani A, Dixon M, Karall D, Lindner M, Mandel H, Martinelli D, Pintos-Morell G, Santer R, Skouma A, Servais A, Tal G, Rubio V, Huemer M, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis. (2019) 42(1573-2665):1192-1230.

6. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. N-ACETYLGLUTAMATE SYNTHASE DEFICIENCY; NAGSD. MIM: 237310: 2019 Jun 28. World Wide Web URL: http://omim.org.

7. Hyperammonemia in Urea Cycle Disorders - NAGS. British Inherited Metabolic Disease Group (BIMDG). (2017) Website: https://www.bimdg.org.uk/store/guidelines/ADULT_UCD-rev_2015_422170_09012016.pdf

8. General dietary information for emergency regimens. British Inherited Metabolic Disease Group (BIMDG). (2017) Website: https://www.bimdg.org.uk/store/guidelines/General_dietary_information_for_ER_2016_441245_09092016.pdf

9. Adult Emergency Management: Oral Emergency Regimen. British Inherited Metabolic Disease Group (BIMDG). (2016) Website: https://www.bimdg.org.uk/tempdoc/13032023_213847_BIMDG_ADULT-OralERGSD_2017HOLDING_414672_05042017.pdf

10. Adult Emergency Management: Urea Cycle Defects. British Inherited Metabolic Disease Group (BIMDG). (2018) Website: https://bimdg.org.uk/store/guidelines/ADULT_UCD-rev_2015_422170_09012016.pdf

11. Raina R, Bedoyan JK, Lichter-Konecki U, Jouvet P, Picca S, Mew NA, Machado MC, Chakraborty R, Vemuganti M, Grewal MK, Bunchman T, Sethi SK, Krishnappa V, McCulloch M, Alhasan K, Bagga A, Basu RK, Schaefer F, Filler G, Warady BA. Consensus guidelines for management of hyperammonaemia in paediatric patients receiving continuous kidney replacement therapy. Nat Rev Nephrol. (2020) 16(1759-507X):471-482.

12. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. N-ACETYLGLUTAMATE SYNTHASE; NAGS. MIM: 608300: 2019 Jun 28. World Wide Web URL: http://omim.org.