In a collaborative effort, scientists from the University of Zurich and the German Mouse Clinic investigated the potential of a new mouse model for the autosomal recessive rare disease methylmalonic aciduria (MMAuria). The results were recently published in BBA – Molecular Basis of Disease.
MMAuria is a rare autosomal recessive inborn error of metabolism caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT). MUT deficiency results in the accumulation of methylmalonic acid (MMA), propionyl-carnitine (C3) and other metabolites. Patients often exhibit lethargy, failure to thrive and metabolic decompensation leading to coma or even death.
The Mut-ko/ki mouse model analyzed in this joint study combines a knock-in (ki) missense allele and a ko-allel of Mut. To induce symptoms, the scientists developed a dietary challenge by feeding the mice 51% protein diet early on, which lead to the accumulation of metabolites at young age, as observed in the patients. Mice with this metabolic profile underwent a phenotypic screen covering all clinically relevant organ systems. The mutant mice showed many of the common clinical manifestations of the disease.
The most prominent one, growth delay accompanied by decreased feeding and drinking, is akin to failure to thrive in patients. Failure to thrive is one of the key clinical findings in the first months to years of life and may be the revealing sign in patients that have not been diagnosed through a neonatal metabolic crisis or by newborn screening programs. The kidney impairment of the mice, reflected by changes in the electrolytes, match to the renal complication, which are common in 47% of the patients at young age.
Some phenotypes found in the mouse model were rarely observed in patients before, like cardiovascular and hematological abnormalities or even not yet described, like decline in anxiety-related behaviour and bone mineral density, and ovarian atrophy. Either this could be mouse specific or new clinical manifestations of the disorder, that could be add on the clinical assessment of the disease. Once confirmed and studied in patients, the new readouts could lead to improved diagnosis and even new therapeutic options.
In-depth phenotyping reveals common and novel disease symptoms in a hemizygous knock-in mouse model (Mut-ko/ki) of mut-type methylmalonic aciduria
Lucienne M, Aguilar-Pimentel JA, Amarie OV, Becker L, Calzada-Wack J, da Silva-Buttkus P, Garrett L, Hölter SM, Mayer-Kuckuk P, Rathkolb B, Rozman J, Spielmann N, Treise I, Busch DH, Klopstock T, Schmidt-Weber C, Wolf E, Wurst W, Forny M, Mathis D, Fingerhut R, Froese DS, Gailus-Durner V, Fuchs H, de Angelis MH, Baumgartner MR. Biochim Biophys Acta Mol Basis Dis. 2019 Nov 23:165622. doi: 10.1016/j.bbadis.2019.165622