Understanding acute metabolic decompensation in propionic and methylmalonic acidemias: a deep metabolic phenotyping approach

Table 3 biochemical parameters that correlate with plasma ammonia for PA and MMA

Analyte	Matrix	N	R²	P-value	Known
Targeted metabolic assays
Ketones	Plasma	5	1.00	< 0.0001	No
2-Methylcitric acid^a	Plasma	42	0.77	< 0.0001	Yes
Arachidonic acid	Plasma	44	0.72	< 0.0001	No
3-Hydroxyisovaleric acid	Plasma	39	0.70	0.0058	No
2-Methylcitric acid^a	Plasma	79	0.67	< 0.0001	Yes
3-Hydroxyisovaleric acid	Urine	163	0.67	< 0.0001	No
3-Hydroxypropionic acid	Plasma	46	0.66	< 0.0001	Yes
Glutaric acid	Urine	149	0.64	< 0.0001	No
Pipecolinic acid	Plasma	68	0.52	0.0432	No
Alanine/lysine ratio	Plasma	94	−0.68	< 0.0001	No
C4-DC carnitine	Plasma	225	−0.55	< 0.0001	No
C14:1 carnitine/C2 carnitine ratio	Plasma	88	−0.53	0.0011	No
Alanine/(phenylalanine+tyrosine) ratio	Plasma	94	−0.51	0.0013	No
Untargeted DI-HRMS
2-Methylcitric acid (3 isomers)	Plasma	157	0.68	< 0.0001	Yes
Alanyl-Isoleucine (3 isomers)	Plasma	157	0.65	< 0.0001	No
3-Hydroxyisovaleric acid (10 isomers)	Plasma	157	0.64	< 0.0001	No
3-Methyl-2-oxovaleric acid (7 isomers)	DBS	122	0.56	< 0.0001	No
Isobutyrylglycine (6 isomers)	Plasma	157	0.55	< 0.0001	No
Indole-5,6-quinone	DBS	122	0.53	< 0.0001	No
Propionylglycine (9 isomers)	DBS	122	0.52	< 0.0001	Yes
3-Hydroxyphenylacetic acid (3 isomers)	Plasma	157	0.51	< 0.0001	No
Indole-5,6-quinone	Plasma	157	0.51	< 0.0001	No
Pyrocatechol sulfate	DBS	122	−0.65	< 0.0001	No
Threonic acid	DBS	122	−0.60	< 0.0001	No
Trimethylamine N-oxide	DBS	122	−0.59	< 0.0001	No
Stearoylcarnitine	DBS	122	−0.58	< 0.0001	No
Methylmalonic acid (3 isomers)	DBS	122	−0.57	< 0.0001	No
Ergothioneine	DBS	122	−0.55	< 0.0001	No

All p-values were adjusted according to the Bonferroni method. A p-value < 0.05 was considered statistically significant. An R² value of > 0.50 or < − 0.50 was considered biologically relevant. ^aDue to methodological developments over time, two different diagnostic assays for 2-methylcitric acid were included in the analysis, both demonstrating a solid positive correlation with plasma ammonia. Abbreviations DI-HRMS direct-infusion high-resolution mass spectrometry, N number of samples

ISSN: 1750-1172