About propionic acidemia (PA) and methylmalonic acidemia (MMA)

PA and MMA are rare, autosomal recessive disorders that present most often during the neonatal period. Incidence worldwide is believed to be between 1/100,00 and 1/150,000 for PA and 1/50,000 for MMA.^1,2,3 Although rare, PA and MMA are the most common organic acidemias – a diverse group of inborn errors of metabolism that are characterized by the excretion of non-amino organic acids in urine.^4,5

Acute hyperammonemia can occur during metabolic decompensation in some PA and MMA patients as a result of a secondary deﬁciency of the urea cycle enzyme N-acetylglutamate synthase (NAGS).^6,7 Note that during an acute metabolic crisis, individuals with PA or MMA can develop life-threatening complications that may or may not be associated with hyperammonemia.^1,3,6,8

PA and MMA pathophysiology

PA and MMA are disorders of propionate catabolism.¹

PA is caused by a deficiency of the enzyme activity of propionyl-CoA carboxylase (PCC) resulting from mutations in either the PCCA or PCCB gene.^1,8

MMA is most commonly caused by a deficiency of the enzyme activity of methylmalonyl-CoA mutase (MUT) resulting from mutations in the MUT gene. MMA may also be caused by defects in the transport or synthesis of adenosylcobalamin, a cofactor of MUT, resulting from mutations in the MMAA, MMAB, or MMADHC genes. These disorders are also known as cobalamin A (cblA) defect, cblB defect, and cblD-MMA defect, respectively.^1,3

The deficiency of PCC enzyme activity in PA, or the deﬁciency of MUT enzyme activity or cofactor availability in MMA, impairs the body’s ability to completely catabolize the amino acids isoleucine, valine, methionine, and threonine; odd-chain fatty acids; cholesterol side chains; and propionic acid from the gut.¹

As a result, toxic metabolites accumulate that can cause various biochemical abnormalities, including secondary hyperammonemia.⁶

In PA and MMA, the urea cycle can become blocked due to:^13,17

Competitive inhibition of the enzyme N-acetylglutamate synthase (NAGS)
Depletion of hepatic acetyl-CoA, so less is available to form N-acetylglutamate (NAG)
Less NAG reduces activation of the enzyme carbamoyl phosphate synthetase 1 (CPS 1). NAG is a cofactor of CPS 1, which catalyzes the first reaction of the urea cycle.

This secondary impairment of the urea cycle can lead to acute hyperammonemia with neurotoxic effects during metabolic decompensation in PA or MMA.⁶
However, not all metabolic crises in PA or MMA will involve hyperammonemia. ^8,9

Signs and symptoms of
acute hyperammonemia in PA and MMA

Signs and symptoms of acute hyperammonemia may be observed in individuals with PA or MMA during acute metabolic crises. Clinical signs and symptoms are non-specific but are mostly neurological in origin.¹

Clinicians should also be aware that during acute metabolic crises, accumulation of toxic metabolites due to PA or MMA can lead to life-threatening complications that may or may not be associated with hyperammonemia.^1,6,8

Testing for plasma ammonia levels

As soon as hyperammonemia is suspected, plasma ammonia levels should be tested.^10,11

Normal levels, according to the Association of Clinical Biochemistry, are:¹²

Premature neonates: < 150 μmol/L
Term neonates: < 100 μmol/L
Infants: < 40 μmol/L
Adults: 11-32 μmol/L

Important Considerations¹¹

Proper procedures for obtaining plasma ammonia levels must be followed in order to prevent measurement errors, including false high ammonia levels.
Low or slightly elevated ammonia levels should lead to retesting, particularly since ammonia concentrations can fluctuate and may not entirely correlate with already impaired brain function.
Management should be guided by the clinical condition of the patient, rather than solely by ammonia concentrations.

Emergency management of acute hyperammonemia in PA and MMA patients during a metabolic crisis

Hyperammonemia is one of the most severe and life-threatening events in PA and MMA:^1,7,13

Longer duration and more severe hyperammonemia correlates with poor neurological outcome.
Hyperammonemia can progress to coma and death if untreated.

The electronic medical records of patients who have been diagnosed with PA or MMA are generally flagged with treatment information provided by the patient’s metabolic team, and each patient has a letter for their local ER with instructions on what to do in a metabolic crisis. If such a patient presents in the ER, emergency management procedures should be followed:^14,15

Contact specialized metabolic center for instructions, and arrange for emergency transport, if needed.
Stop protein intake for no more than 24-48 hours
Initiate IV glucose
Initiate IV lipids
Determine if treatment with CARBAGLU may be right based on the patient's clinical condition. Consider administering CARBAGLU along with other ammonia lowering therapies

The start of ammonia detoxification and measures to reverse catabolism must not be delayed. This also holds true for patients suspected of having acute hyperammonemia due to PA and MMA.¹ Note that the severity of metabolic decompensation in PA and MMA does not depend on hyperammonemia alone. Other abnormalities associated with PA and MMA, including metabolic acidosis, ketosis, and lactic acidemia, must also be identified, monitored, and treated accordingly.^1,6,16

Get instructions for 24/7 STAT delivery of CARBAGLU^® (carglumic acid) for hospital emergencies

REFERENCES

Baumgartner MR, Horster F, Dionisi-Vici C, Haliloglu G, Karall D, Chapman KA, Huemer M, Hochuli M, Assoun M, Ballhausen D, Burlina A, Fowler B, Grünert SC, Grünewald S, Honzik T, Merinero B, Pérez-Cerdá C, Scholl-Bürgi S, Skovby F, Wijburg F, MacDonald A, Martinelli D, Sass JO, Valayannopoulos V, Chakrapani A. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis. 2014;9:130.
Grünert SC, Müllerleile S, De Silva L, Barth M, Walter M, Walter K, Meissner T, Lindner M, Ensenauer R, Santer R, Bodamer OA, Baumgartner MR, Brunner-Krainz M, Karall D, Haase C, Knerr I, Marquardt T, Hennermann JB, Steinfeld R, Beblo S, Koch H-G, Konstantopoulou V, Scholl-Bürgi S, van Teeffelen-Heithoff A, Suormala T, Sperl W, Kraus JP, Superti-Furga A, Schwab KO, Sass JO. Propionic acidemia: clinical course and outcome in 55 pediatric and adolescent patients. Orphanet J Rare Dis.. 2013;8:6.
Manoli I, Sloan JL, Venditti CP. Isolated Methylmalonic Acidemia. 2005 Aug 16 [Updated 2016 Dec 1]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1231/.
Vaidyanathan K, Narayanan MP, Vasudevan DM. Organic acidurias: an updated review. Ind J Clin Biochem. 2011;26(4):319-325.
Seashore MR. The Organic Acidemias. 2001 June 27 [Updated 2009 Dec 22]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
Haberle J, Chakrapani A, Ah Mew N, Longo N. Hyperammonaemia in classic organic acidaemias: a review of the literature and two case histories. Orphanet J Rare Dis.. 2018;13:219.
Filippi L, Gozzini E, Fiorini P, Malvagia S, Ia M,G, Donati MA: N-carbamylglutamate in emergency management of hyperammonemia in neonatal acute onset propionic and methylmalonic aciduria. Neonatology. 2010;97(3):286–290.
Shchelochkov OA, Carrillo N, Venditti C. Propionic Acidemia. 2012 May 17 [Updated 2016 Oct 6]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK92946.
Haberle J. Clinical and biochemical aspects of primary and secondary hyperammonemic disorders. Arch Biochem Biophys. 2013;536(2):101–108
Cartagena A, Prasad AN, Rupar CA, Strong M, Tuchman M, Ah Mew N, Prasad C. Recurrent encephalopathy: NAGS (N-acetylglutamate synthase) deficiency in adults. Can J Neurol Sci. 2013;40:3-9.
Haberle J. Clinical practice: the management of hyperammonemia. Eur J Pediatr. 2011;170:21-34.
Hawke L. Ammonia (plasma, blood). The Association for Clinical Biochemistry and Laboratory Medicine. http://www.acb.org.uk/whatwedo/science/amalc.aspx. Published 2012. Accessed December 4, 2017.
Valayannopoulos V, Baruteau J, Bueno Delgado M, Cano A, Couce ML, Del Toro M, Donati MA, Garcia-Cazorla A, Gil-Ortega D, Gomez-de Quero P, Guffon N, Hofstede FC, Kalkan-Ucar S, Coker M, Lama-More R, Martinez-Pardo Casanova M, Molina A, Pichard S, Papadia F, Rosello P, Plisson C, Le Mouhaer J, Chakrapani A. Carglumic acid enhances rapid ammonia detoxification in classical organic acidurias with a favourable risk-benefit profile: a retrospective observational study. Orphanet J Rare Dis.. 2016;11:32.
Chapman KA, Gropman A, MacLeod E, Stagni K, Summar ML, Ueda K, Ah Mew N, Franks J, Island E, Matern D, Pena L, Smith B, Sutton VR, Urv T, Venditti C, Chakrapani A. Acute management of propionic acidemia. Mol Genet Metab. 2012;105(1):16-25.
Orphan Europe, data on file, 2018.
Fraser JL, Venditti CP. Methylmalonic and propionic acidemias: clinical management update. Curr Opin Pediatr. 2016;28(6):682-693.
Chakrapani A, Valayannopoulos V, Garcia Segarra N, Del Toro M, Donati MA, Garcia-Cazorla A, Gonzalez MJ, Plisson C, Giordano V. Effect of carglumic acid with or without ammonia scavengers on hyperammonaemia in acute decompensation episodes of organic acidurias. Orphanet J Rare Dis.. 2018;13:97.

INDICATIONS AND USAGE

Carbaglu^® (carglumic acid) tablets for oral suspension 200mg is a carbamoyl phosphate synthetase 1 (CPS 1) activator indicated in pediatric and adult patients as:

Adjunctive therapy to standard of care for the treatment of acute hyperammonemia due to N-acetylglutamate synthase (NAGS) deficiency.
Maintenance therapy for the treatment of chronic hyperammonemia due to N-acetylglutamate synthase (NAGS) deficiency.
Adjunctive therapy to standard of care for the treatment of acute hyperammonemia due to propionic acidemia (PA) or methylmalonic acidemia (MMA).

IMPORTANT SAFETY INFORMATION

Contraindications: None.
NAGS deficiency: Most common adverse reactions (≥13%) are: vomiting, abdominal pain, pyrexia, tonsillitis, anemia, diarrhea, ear infection, infections, nasopharyngitis, hemoglobin decreased, and headache.
PA and MMA: Most common adverse reactions (≥5%) are neutropenia, anemia, vomiting, electrolyte imbalance, decreased appetite, hypoglycemia, lethargy/stupor, encephalopathy and pancreatitis/lipase increased.

To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1‑800-FDA-1088 or www.fda.gov/medwatch.
If CARBAGLU is administered during pregnancy to women with NAGS deficiency, health care providers should report CARBAGLU exposure to the pregnancy pharmacovigilance program by calling 1-888-575-8344.

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