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

Pyruvate carboxylase (PC) is a key enzyme in the gluconeogenesis and anaple rotic metabolic pathways. PC deficiency is a rare autosomal recessive disor der 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 brai n lesions at birth and died in the first week of life with intractable lact ic 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. Thi s is the first reported case of ischemia-like brain lesions documented pren atally in PC deficiency. The lesions were detected at a time of maximal per iventricular metabolic demand. We postulate that energy deprivation induced by PC deficiency impairs astrocytic buffering capacity against excitotoxic insult and compromises normal microvascular morphogenesis and autoregulati on, both mechanisms leading to cystic degeneration of the periventricular w hite matter. Discovery of cystic PVL on cerebral ultrasound at birth in a n ewborn infant presenting with primary lactic acidemia is highly suggestive of PC deficiency. Moreover, PC deficiency should also be considered when is chemia-like brain lesions are documented by fetal ultrasonography, Am. J, M ed, Genet, 84:94-101, 1999, (C) 1999 Wiley-Liss, Inc.