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Prenatal onset of the neuroradiologic phenotype of pyruvate carboxylase deficiency due to homozygous PC c.1828G > A mutations.

ABSTRACT: Pyruvate carboxylase (PC) deficiency (MIM# 266150) is an autosomal recessive disorder with three subtypes. Patients homozygous for the c.1828G > A mutation in the PC gene belong to type A, which typically has infantile onset, severe to profound developmental delay, hypotonia, and lactic acidemia. We report the neuroimaging abnormalities in a 33-week gestation infant homozygous for the c.1828G > A mutation. Brain magnetic resonance imaging on day 10 of life revealed increased T2 signal within the subcortical and periventricular white matter, an immature gyral pattern, large periventricular cysts with mass effect on the lateral ventricles, and dilatation of the occipital and temporal horns. Magnetic resonance spectroscopy showed reduced creatine and NAA peaks, a relatively high choline peak and no lactate peak. These findings were observed prior to the neonate experiencing any episodes of decompensation with lactic acidosis. The presence of these brain anomalies at this gestational age, prior to any metabolic decompensation, supports the essential role of PC in normal brain morphogenesis and the resulting in-utero brain anomalies secondary to its deficiency. Our experience with this affected premature infant and many others we have managed with the same founder mutation suggests that the clinical phenotypes of the type A and the more severe type B PC deficient patients are on a spectrum rather than distinct subtypes.

SUBMITTER: Mhanni AA

PROVIDER: S-EPMC8411104 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Fatty acids (FA) provide an energy source to the liver during negative energy balance; however, when FA influx is excessive, FA can be stored as liver lipids or incompletely oxidized to β-hydroxybutyrate (BHB). The objectives of this study were to quantify plasma and liver FA profiles and hepatic gene expression in cows diagnosed with hyperketonemia (HYK; BHB ≥ 1.2 mM) or not (nonHYK; BHB < 1.2 mM) to determine a relationship between FA profile and expression of hepatic genes related to oxidation and gluconeogenesis. Production parameters, blood samples (-28, -3, 1, 3, 5, 7, 9, 11, and 14 d relative to parturition; n = 28 cows), and liver biopsies (1, 14, and 28 d postpartum; n = 22 cows) were collected from Holstein cows. Cows were retrospectively grouped as HYK or nonHYK based on BHB concentrations in postpartum blood samples. Average first positive test (BHB ≥ 1.2 mM) was 9 ± 5 d (± SD). Cows diagnosed with HYK had greater C18:1 and lower C18:2 plasma proportions. Liver FA proportions of C16:0 and C18:1 were related to proportions in plasma, but C18:0 and C18:2 were not. Some interactions between plasma FA and HYK on liver FA proportion suggests that there may be preferential use depending upon metabolic state. Cows diagnosed with HYK had decreased pyruvate carboxylase (PC) expression, but no difference at 1 d postpartum in either cytosolic or mitochondrial isoforms of phosphoenolpyruvate carboxykinase (PCK). The increased PC to PCK ratios in nonHYK cows suggests the potential for greater hepatic oxidative capacity, coinciding with decreased circulating BHB. Interestingly, FA, known regulators of PC expression, were not correlated with PC expression at 1 d postpartum. Taken together, these data demonstrate that HYK cows experience a decrease in the ratio of hepatic PC to PCK at 1 day postpartum prior to HYK diagnosis which, on average, manifested a week later. The differential regulation of PC involved in HYK diagnosis may not be completely due to shifts in FA profiles and warrants further investigation.

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Prenatal onset of the neuroradiologic phenotype of pyruvate carboxylase deficiency due to homozygous PC c.1828G > A mutations.

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