Canine hereditary ceroid‐lipofuscinosis: Evidence for a defect in the carnitine biosynthetic pathway

Abstract

The ceroid-lipofuscinoses are a group of autosomal-recessive hereditary lysosomal storage diseases that have been characterized in humans and other mammalian species. In a canine model for the juvenile form of the human disease, a major constituent of the storage bodies is the subunit c protein of mitochondrial ATP synthase that contains an epsilon-N-trimethyllysine (TML) residue. TML is a precursor in carnitine biosynthesis. To determine whether accumulation of the TML-containing protein could result from a defect in the carnitine biosynthetic pathway, plasma carnitine and trimethyllysine levels were measured in homozygous affected, heterozygous carriers, and in normal dogs. When compared top normal animals, mean carnitine levels were reduced by 67% in affected and 50% in carrier dogs. Mean plasma TML levels were elevated almost 50% above control levels in the carriers, but were decreased by approximately 25% in the affected animals. The changes in plasma carnitine and TML levels in the carriers are consistent with the possibility that the disease involves a defect in the carnitine biosynthetic pathway. Secondary effects of the disease process may account for the apparently contradictory decrease in plasma TML levels in affected animals.

In the Rat Brain Acetyl-l-carnitine Treatment Modulates the Expression of Genes Involved in Neuronal Ceroid Lipofuscinosis

“…The changes in plasma carnitine and TML levels in the carriers are consistent with the possibility that the disease involves a defect in the carnitine biosynthetic pathway. Both TML and carnitine levels were significantly depressed in the affected individuals [7,32]. In addition, dietary supplementation with carnitine delayed the progression of cognitive decline in NCL dogs [33].…”

Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions

“…We therefore hypothesized that the apparent lack of adequate degradation of the subunit c protein in NCL would result in decreased tissue carnitine levels. Indeed, blood plasma carnitine and TML levels were found to be low in both human subjects with CLN3 NCL and in English Setters with CLN8 NCL (Katz, 1996; Katz and Siakotos, 1995). This led to the hypothesis that NCL-related pathology in at least some forms of the disease can result in part from inadequate tissue levels of carnitine.…”

Assessment of plasma carnitine concentrations in relation to ceroid lipofuscinosis in Tibetan Terriers

“…On the basis of the findings that carnitine concentrations are low in humans with CL and in the similar disorder of English Setters, 15,16,18 our study was undertaken to determine whether CL in Tibetan Terriers was also associated with low plasma carnitine concentrations. The existence of such an association might enable plasma carnitine determinations to be used to identify potentially affected dogs.…”

“…In English Setters with an early onset form of CL, as well as in humans with some forms of CL, subunit c accumulation is accompanied by a decrease in plasma carnitine concentrations. 15,16 This suggests that subunit c may be a major source of trimethyl-lysine for carnitine biosynthesis.…”