Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia

Abstract

Methylmalonic Acidemia (MMA) is a heterogenous group of inborn errors of metabolism caused by a defect in the methylmalonyl‐CoA mutase (MMUT) enzyme or the synthesis and transport of its cofactor, 5′‐deoxy‐adenosylcobalamin. It is characterized by life‐threatening episodes of ketoacidosis, chronic kidney disease, and other multiorgan complications. Liver transplantation can improve patient stability and survival and thus provides clinical and biochemical benchmarks for the development of hepatocyte‐targeted genomic therapies. Data are presented from a US natural history protocol that evaluated subjects with different types of MMA including mut‐type (N = 91), cblB‐type (15), and cblA‐type MMA (17), as well as from an Italian cohort of mut‐type (N = 19) and cblB‐type MMA (N = 2) subjects, including data before and after organ transplantation in both cohorts. Canonical metabolic markers, such as serum methylmalonic acid and propionylcarnitine, are variable and affected by dietary intake and renal function. We have therefore explored the use of the 1‐13C‐propionate oxidation breath test (POBT) to measure metabolic capacity and the changes in circulating proteins to assess mitochondrial dysfunction (fibroblast growth factor 21 [FGF21] and growth differentiation factor 15 [GDF15]) and kidney injury (lipocalin‐2 [LCN2]). Biomarker concentrations are higher in patients with the severe mut0‐type and cblB‐type MMA, correlate with a decreased POBT, and show a significant response postliver transplant. Additional circulating and imaging markers to assess disease burden are necessary to monitor disease progression. A combination of biomarkers reflecting disease severity and multisystem involvement will be needed to help stratify patients for clinical trials and assess the efficacy of new therapies for MMA.

Successful adult domino living donor liver transplantation in methylmalonic acidemia: case report

“…FGF21 correlates closely in MMA patients (and perhaps then DLT recipients of MMA livers) with mitochondrial dysfunction and metabolic stress ( 31 ). The reduced renal function in this patient could be caused by the significantly high plasma MMA levels, likely the high FGF21 levels reveal that this liver is most likely severely affected by the mitochondriopathy of MMA ( 32 ).…”

“…The liver produces 95% of the insoluble transthyretin (TTR) which is responsible for the disease progression, meaning a liver transplant for FAP patients is curative ( 29 - 31 ). Initially, it was thought that the transmission of the FAP disease to a DLT recipient would take 20–30 years, however we now know that recurrence may occur earlier and in a more severe form than anticipated ( 30 , 32 ). A 23% rate of recurrence has been reported in recipients who received a DLT using a FAP liver graft, after a median follow-up of 7 years ( 24 , 25 ).…”

“…While short-term outcomes are good, studies that report on the long-term outcome of DLT recipients are needed to determine the long-term viability of DLT using MMA livers ( Table 4 ) ( 32 , 33 ). Our experience shows that both patients have had complex post-transplant courses, wherein the role of the domino MMA liver is not entirely clear ( 34 ).…”

Methylmalonyl Coenzyme A (CoA) Epimerase Deficiency, an Ultra-Rare Cause of Isolated Methylmalonic Aciduria With Predominant Neurological Features

“…Patient 2 had less severe clinical manifestations and higher urinary and serum AMM than his elder brother (patient 1). Spot MMAuria is highly variable, and 24-hour urine collection is not accessible in young children or the neurologically impaired [ 17 ]. Urine MCA and blood/plasma C3 levels were also elevated in all the patients reported (10 patients and 13 patients, respectively), including patients 1 and 2.…”

Methylmalonic acidemia triggers lysosomal-autophagy dysfunctions

“…Over the past years, the understanding of phenotype-genotype correlations in MMA has improved, and different circulating markers have been proposed to assess disease burden, monitor disease progression and therapeutic response [ 7 ], as patients who respond to administration of vitamin B12 have a more favorable prognosis. In fact, MMA patients are classified into two distinct clinical phenotypes depending on the complete or partial loss of MUT apoenzyme as mut0 or mut–, with only the latter having a partial response to vitamin B12.…”