Pyruvate carboxylase deficiency: Prenatal onset of ischemia-like brain lesions in two sibs with the acute neonatal form

Abstract

Pyruvate carboxylase (PC) is a key enzyme in the gluconeogenesis and anaplerotic metabolic pathways. PC deficiency is a rare autosomal recessive disorder with three clinical presentations: an infantile form, a severe neonatal form, and a benign form. We report brother and sister sibs with the severe form of PC deficiency. Both had macrocephaly and severe ischemia-like brain lesions at birth and died in the first week of life with intractable lactic acidemia. In the girl, increased head circumference and periventricular leukomalacia (PVL) were detected on fetal ultrasonography at 29.4 weeks of gestation. PC activity in cultured skin fibroblasts was <2% of control. This is the first reported case of ischemia-like brain lesions documented prenatally in PC deficiency. The lesions were detected at a time of maximal periventricular metabolic demand. We postulate that energy deprivation induced by PC deficiency impairs astrocytic buffering capacity against excitotoxic insult and compromises normal microvascular morphogenesis and autoregulation, both mechanisms leading to cystic degeneration of the periventricular white matter. Discovery of cystic PVL on cerebral ultrasound at birth in a newborn infant presenting with primary lactic acidemia is highly suggestive of PC deficiency. Moreover, PC deficiency should also be considered when ischemia-like brain lesions are documented by fetal ultrasonography.

Cranial Ultrasound in Metabolic Disorders Presenting in the Neonatal Period: Characteristic Features and Comparison with MR Imaging

“…[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] cUS has the advantage that it is readily available on neonatal units when infants are admitted. We have shown in a large cohort of neonates with diagnosed metabolic disorders that cUS detects many abnormalities that support a clinical diagnosis, detects structural abnormalities that lead to further investigations, or depicts ongoing injurious or metabolic processes.…”

“…[5][6][7] Metabolic disorders can be difficult to diagnose, and recognition of characteristic neuroimaging features is very helpful in the diagnostic process. 8,9 Structural brain abnormalities and more acute changes detected on cUS scan in metabolic disorders have been described in individual case reports, [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] but there is no large study systematically reviewing these imaging findings and their accuracy or comparing them with MR imaging. The aim of this study, therefore, was primarily to investigate the role and range of abnormalities seen on cUS examination in a wide range of metabolic disorders that present during the neonatal period; a secondary aim, when possible, was to address the question of whether brain MR imaging is more informative by comparing cUS to MR imaging findings.…”

Long-term Outcome and Clinical Spectrum of 73 Pediatric Patients With Mitochondrial Diseases

“…Interestingly, prenatal evaluation of these patients showed hydrocephalus in a girl with PDH deficiency, and intraventricular hemorrhage, asymmetric ventricular dilatation, and periventricular leucomalacia in a male patient with pyruvate carboxylase deficiency. 23 Of note, we found a high rate of pregnancy complications for the whole cohort including gestational diabetes (8 [11%] of 73); hypertension/preeclampsia (5 [7%] of 73); intrauterine growth retardation (4 [5%] of 73; hemolytic anemia, elevated liver enzymes, and low platelets (HELLP) syndrome (1 of 73); and steatohepatitis (1 of 73). Birth weight was below the third percentile in 13 of 66 patients (20%; P Ͻ .0001).…”

Anaplerotic roles of pyruvate carboxylase in mammalian tissues

“…Increased levels of substrates for pyruvate carboxylation also enhanced production of glutamate in astrocytes [89]. The importance of PC in the nervous system can be clearly seen in mental retardation in PC-deficient patients who carry one or more forms of mutations of the PC gene and by the brain abnormalities that severely compromise their psychomotor development [95,96].…”