Expansion of the Phenotypic Spectrum of Propionic Acidemia with Isolated Elevated Propionylcarnitine

Abstract

We report three patients with elevations of propionylcarnitine (C3), one without elevations of 2-methylcitrate and 3-hydroxypropionate in urine organic acid analysis, and the other two showing only mild elevations, all of whom were subsequently confirmed to have propionic acidemia by molecular analysis of PCCA and PCCB genes. To date, they have had a mild clinical course. These cases illustrate the importance of considering high C3 as the only biochemical abnormality in a diagnosis of propionic acidemia. Since mild C3 elevations may be overlooked and considered non-diagnostic in isolation, we advise considering a diagnosis of propionic acidemia even in the absence of significant elevations 2-methylcitrate or 3-hydroxypropionate in urine organic acid analysis.Abbreviations 2-MCA 2-Methylcitrate 3-OHP 3-Hydroxypropionate C3 Propionylcarnitine

A metabolomic map of Zellweger spectrum disorders reveals novel disease biomarkers

“…9,10 Global metabolomic profiling is a novel method for utilizing untargeted metabolomics on clinical samples. [11][12][13][14][15][16] This metabolic screening methodology can detect abnormalities in amino acid, fatty acid, lipid, nucleotide, bile acid, and other small molecule metabolism in a single test. 13 The power of the broad detection platform has been utilized in individual samples for diagnostic purposes, 14,15 resulting in the successful diagnosis of a number of inborn errors of metabolism, including adenylosuccinate lyase deficiency 15 and aromatic amino acid decarboxylase deficiency, 17 among others.…”

“…13 The power of the broad detection platform has been utilized in individual samples for diagnostic purposes, 14,15 resulting in the successful diagnosis of a number of inborn errors of metabolism, including adenylosuccinate lyase deficiency 15 and aromatic amino acid decarboxylase deficiency, 17 among others. 12,13,16 Utilizing this methodology as a screening approach to identify individuals on the mild end of the phenotypic spectrum, who might not have otherwise been diagnosed or would have had significant delay in diagnosis, illustrates the power of this technique for earlier diagnosis and the potential contribution to expand our understanding of the range of severity across metabolic disorders.…”

Novel mutation causing propionic acidemia associated with unexplained autoimmune thyrotoxicosis

“…Isolated elevated propionylcarnitine (C3) has been studied in a case series of three patients, however unlike the reported case, they had extremely mild disease without recurrent decompensation [ 9 ]. In fact, one of the three patients only manifested in the newborn period with a mildly elevated ammonia and required treatment with ammonia scavengers, levocarnitine and IV fluids [ 9 ]. Their urine organic acid profile was significant for only moderate elevations in methylcitric acid and 3-hydroxypropionate [ 9 ].…”

Severity modeling of propionic acidemia using clinical and laboratory biomarkers

“…Affected patients display a range of clinical severity. 1 – 4 The existence of a mild PA phenotype was suggested more than 40 years ago with the description of a “Mennonite Amish” variant of PA, eventually linked to a homozygous c.1606A>G (p.Asn536Asp) variant in PCCB . 5 , 6 However, what constitutes mild versus more severe types of PA, their defining features, such as other genotypes and biomarkers associated with them, has not been established.…”

“…Propionylcarnitine (C3) and 2-methylcitrate (2-MC) are widely used diagnostic biomarkers to screen presymptomatic newborns for disorders of propionate metabolism, 7 , 8 yet their usefulness to predict the natural history of PA is incompletely understood. 4 Liver transplantation in PA aiming to restore hepatic oxidation of propionate created an opportunity to evaluate the performance of C3 and 2-MC pharmacodynamic (response) and, potentially, as surrogate biomarkers. Surprisingly, several studies of the long-term outcomes of liver transplantation in PA revealed that C3 levels before and after the transplant were not significantly different, 9 – 11 prompting questions whether these biomarkers can serve as pharmacodynamic (response) or surrogate biomarkers for PA in a treatment trial.…”