Biochemical phenotype and its relationship to treatment in 16 individuals with PCCB c.1606A > G (p.Asn536Asp) variant propionic acidemia

Abstract Background Propionic acidemia (PA), an inborn error of metabolism, is caused by a deficiency in propionyl-CoA carboxylase. Patients have to follow a diet restricted in the propiogenic amino acids isoleucine (Ile), valine (Val), methionine (Met) and threonine (Thr); proper adherence can prevent and treat acute decompensation and increase life expectancy. However, chronic complications occur in several organs even though metabolic control may be largely maintained. Bone marrow aplasia and anemia are among the more common. Materials and methods In this retrospective study, data for patients with PA being monitored at the Hospital Ramón y Cajal (Madrid, Spain) (n = 10) in the past 10 years were examined to statistically detect relationships between persistent severe anemia outside of metabolic decompensation episodes and dietary practices such as natural protein intake and medical food consumption (special mixture of precursor-free amino acids) along with plasma levels of branched-chain amino acids (BCAA). High ferritin levels were deemed to indicate that a patient had received repeated transfusions for persistent anemia since data on hemoglobin levels at the moment of transfusion were not always passed on by the attending centers. Results Three patients had severe, persistent anemia that required repeated blood transfusions. Higher medical food consumption and plasma Leu levels were associated with iron overload. Notably, natural protein intake and plasma Val were negatively correlated with ferritin levels. We also observed an inverse relationship between plasma Val/Leu and Ile/Leu ratios and ferritin. Conclusion The present results suggest that severe anemia in patients with PA might be associated with low natural protein intake and BCAA imbalance.

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3-Hydroxypropionate: Significance of -Oxidation of Propionate in Patients with Propionic Acidemia and Methylmalonic Acidemia

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.69.10.2807 ◽

1972 ◽

Vol 69 (10) ◽

pp. 2807-2811 ◽

Cited By ~ 51

Author(s):

T. Ando ◽

K. Rasmussen ◽

W. L. Nyhan ◽

D. Hull

Keyword(s):

Propionic Acidemia ◽

Methylmalonic Acidemia

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Current Perspectives on Neonatal Screening for Propionic Acidemia in Japan: An Unexpectedly High Incidence of Patients with Mild Disease Caused by a Common PCCB Variant

International Journal of Neonatal Screening ◽

10.3390/ijns7030035 ◽

2021 ◽

Vol 7 (3) ◽

pp. 35

Author(s):

Go Tajima ◽

Reiko Kagawa ◽

Fumiaki Sakura ◽

Akari Nakamura-Utsunomiya ◽

Keiichi Hara ◽

...

Keyword(s):

Neonatal Screening ◽

Acid Metabolism ◽

Neonatal Period ◽

Propionic Acidemia ◽

Cardiac Complications ◽

Mild Disease ◽

Follow Up Study ◽

Organic Acid Metabolism ◽

High Incidence

Propionic acidemia (PA) is a disorder of organic acid metabolism which typically presents with acute encephalopathy-like symptoms associated with metabolic acidosis and hyperammonemia during the neonatal period. The estimated incidence of symptomatic PA in Japan is 1/400,000. The introduction of neonatal screening using tandem mass spectrometry has revealed a far higher disease frequency of approximately 1/45,000 live births due to a prevalent variant of c.1304T>C (p.Y435C) in PCCB, which codes β-subunit of propionyl-CoA carboxylase. Our questionnaire-based follow-up study reveals that most of these patients remain asymptomatic. However, reports on symptomatic patients exhibiting cardiac complications such as cardiomyopathy and QT prolongation have been increasing. Moreover, there were even cases in which these cardiac complications were the only symptoms related to PA. A currently ongoing study is investigating the risk of cardiac complications in patients with neonatal screening-detected PA caused by this common variant.

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Cardiomyocytes Derived from Induced Pluripotent Stem Cells as a Disease Model for Propionic Acidemia

International Journal of Molecular Sciences ◽

10.3390/ijms22031161 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1161

Author(s):

Esmeralda Alonso-Barroso ◽

Belén Pérez ◽

Lourdes Ruiz Desviat ◽

Eva Richard

Keyword(s):

Stem Cells ◽

Induced Pluripotent Stem Cells ◽

Pluripotent Stem Cells ◽

Ex Vivo ◽

Disease Model ◽

Propionic Acidemia ◽

Heart Tissue ◽

Altered Expression ◽

Cellular Models ◽

Induced Pluripotent

Propionic acidemia (PA), one of the most frequent life-threatening organic acidemias, is caused by mutations in either the PCCA or PCCB genes encoding both subunits of the mitochondrial propionyl-CoA carboxylase (PCC) enzyme. Cardiac alterations (hypertrophy, dilated cardiomyopathy, long QT) are one of the major causes of mortality in patients surviving the neonatal period. To overcome limitations of current cellular models of PA, we generated induced pluripotent stem cells (iPSCs) from a PA patient with defects in the PCCA gene, and successfully differentiated them into cardiomyocytes. PCCA iPSC-derived cardiomyocytes exhibited reduced oxygen consumption, an accumulation of residual bodies and lipid droplets, and increased ribosomal biogenesis. Furthermore, we found increased protein levels of HERP, GRP78, GRP75, SIG-1R and MFN2, suggesting endoplasmic reticulum stress and calcium perturbations in these cells. We also analyzed a series of heart-enriched miRNAs previously found deregulated in the heart tissue of a PA murine model and confirmed their altered expression. Our novel results show that PA iPSC-cardiomyocytes represent a promising model for investigating the pathological mechanisms underlying PA cardiomyopathies, also serving as an ex vivo platform for therapeutic evaluation.

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