CELLULAR BIOENERGETICS AND CEREBRAL DYSMORPHOGENESIS: LESSONS FROM AMISH MICROCEPHALY

Objectives: To examine the intersection of biochemical disorders and morphogenetic pathways in determining the ultimate size and shape of the brain and craniofacial structures with particular reference to energy metabolism.

Methods: Case study of Amish microcephaly, with serial neuroimaging, biochemical and molecular studies to explore this relationship. The male proband is the first child born to consanguineous Mennonite/Amish parents. Ultrasound at 21 weeks gestation revealed microcephaly (biparietal diameter and head circumference at -3SD). At birth, cranial size was in the severely microcephalic range. Marked ridging was noted over the confluence of the sagittal and lambdoid sutures. The infant became critically ill with metabolic and lactic acidosis at age 5 months. After stabilization of acidosis and treatment with dichloroacetate, he was placed on the ketogenic diet, with stabilization and survival (presently 21/2yrs). He has profound developmental delay.

Results: Urine organic acids were initially normal, but revealed elevation of á-ketoglutaric acid during a later period of metabolic stability. Serial magnetic resonance imaging studies disclosed marked ventriculomegaly, agenesis of the corpus callosum, a thinned cortical mantle with lissencephalic appearance, pontocerebellar hypoplasia, absence of the cerebellar vermis and mega cisterna magna. Molecular diagnostic testing confirmed homozygosity for the G177A mutation in the SLC25A19 gene which encodes a nuclear mitochondrial deoxynucleotide carrier (DNC).

Conclusion: The biochemical perturbations suggest a defect in cellular bioenergetics. The imaging studies beginning at 21 weeks until present show a profound impact on cerebral and cranial morphogenesis. The relationship between the genetic mutation, cellular energy metabolism and brain development will be discussed.