Introduction and background - PA/MMA

Methylmalonic and propionic acidemia (MMA and PA) are inborn errors of metabolism affecting the propionate catabolic pathway involving four essential amino acids; isoleucine, valine, methionine and threonine.¹ Clinical severity may range from asymptomatic findings in some to life-threatening episodes and multiorgan involvement in others.

Several of these defects reflect a complex pathogenesis related to mitochondrial dysfunction, particularly the 3-methylglutaconic acidurias.²

Severe forms of these disorders usually present as acute, overwhelming illness in the neonatal period if not detected through newborn screening. Moreover, some patients are asymptomatic and identified only through family studies or newborn screening.

The mainstay management consists of limiting intake of the affected amino acid(s) while ensuring optimal growth and preventing catabolism.^1,2

With severe forms of the disorders, a low protein diet ensuring essential requirements by the use of L-amino acid supplements (devoid of the propionic acid presursors (isoleucine, valine, methionine and threonine) to allow for adequate caloric, protein, and other nutrient intake.
Milder forms may only require a moderately reduced natural protein intake.
The amount of natural whole protein tolerated is determined by monitoring parameters such as growth, control of acidosis, excretion of abnormal metabolites, blood amino acid levels, and testing for body protein stores. The least restrictive dietary approach should be taken in order to avoid over-treatment and nutritional deficiencies.
Emergency feeding includes promotion of anabolism using a special high-calorie diet, transient stop of natural protein intake or of the precursor amino acids.
Prescription of amino acid mixtures is not common clinical practise

The outcome of these disorders can vary widely. Newborn screening for MMA/PA has been implemented in some countries. It is associated with a lower mortality rate, but not with regard to the clinical course of these disorders, such as the number of metabolic crises, physical and neurocognitive development and long term complications⁶

Late complications of these diseases must be anticipated, such as liver and renal failure.
In asymptomatic individuals, instructions regarding risks for metabolic stress and fasting avoidance, along with clinical monitoring, represent appropriate prophylactic interventions at this time.

The incidence of MMA is estimated to be approximately 1:50.000 to 1:60.000 and PA of 1:50.000 to 1:500.000, although the true incidence is unknown³. In some regions of the world, the incidence is much higher, such as Saudi Arabia, the incidence for PA is estimated as high as 1:2000 to 1:5000 live births.⁴

References

E-IMD. Methylmalonic and propionic acidurias: quick reference guide. http://www.e-imd.org.
Kerr I, Vockley J, Gibson KM. Disorders of leucine, Isoleucine and Valine Metabolism. In; Blau N (ed) Physician’s guide to the diagnosis, treatment and follow-up of inherited metabolic diseases, 2^nd Springer Heidelberg, 2014:103-142
Deodato F, Boenzi S et al. Methylmalonic and propionic aciduria. Am J Med Genet C Semin Med Genet 2006;142C:104-112
Ozand P, Rashed MS et al. Unusual presentations of propionic academia. Brain Dev 1994;16:46-57
Baumgartner et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic academia. Orphanet Journal of Rare Diseased, 2014;9:130.
Grunert SC. Mullerleile S et al. Propionic acidemia: neonatal versus selective metabolic screening. J Inherit Metab Dis 2012;35:41-49.

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