Pathologic alterations in the brain and liver in hyperpipecolic acidemia

Pipecolic acid is a cyclic secondary imino acid produced in the metabolism of lysine. The metabolic role and fate of pipecolic acid in the human central nervous system are largely unknown. The biochemical defect in two brothers, both less than two years of age, with minor dysmorphic features, progressive neurological dysfunction, and hepatomegaly was identified as hyperpipecolatemia. At autopsy, the older brother’s brain weight was increased, with bilateral pallor of the putamen. Distinctive changes included accumulation of 1-1.5 micrometer periodic acid-Schiff (PAS) positive, diastase-resistant, Alcian blue-negative, non-lipid, non-fluorescent granules in astrocytes, satellite cells, and perivascular foot processes. Both light and electron microscopy showed total absence of these granules in neurons. In the older sibling, the liver showed micronodular cirrhosis with distinctive intrahepatocytic accumulation of 0.2-1 micrometer membrane-bound material of low electron density. Pericellular fibrosis and similar cytoplasmic inclusions were present in the liver biopsy from his brother. The distinctive astrocytic storage phenomenon and the liver changes are compared to the findings in Zellweger’s syndrome and lysinuric protein intolerance, which are also associated with altered pipecolate metabolism.