MITOCHONDRIAL ABNORMALITIES IN CLN2 AND CLN3 FORMS OF BATTEN-DISEASE

The storage of subunit c of mitochondrial ATP synthase, other hydropho bic peptides, and autofluorescent pigment in both late infantile (CLN2 ) and juvenile (CLN3) neuronal ceroid lipofuscinosis, but not in infan tile (CLN1), has raised the question of abnormal mitochondrial functio n. We now report a partial deficiency in three types of fatty acid oxi dation in intact skin fibroblasts from CLN2 and CLN3 patients, but not CLN1. We observed a statistically significant 33% reduction in palmit ate (beta-oxidation; mainly mitochondrial) and lignocerate (beta-oxida tion; mainly peroxisomal), and a 50% reduction in phytanic acid (alpha -oxidation; mainly peroxisomal) in the absence of exogenous carnitine. In contrast, when we measured fatty acid beta-oxidation (lignoceric a cid and palmitic acid), in the same human skin fibroblasts, following lysis in the presence of carnitine, we found no difference in enzyme a ctivity among normal, CLN1, CLN2, and CLN3. However, we did observe a 40% reduction in peroxisomal particulate (bound) catalase activity in CLN1 and CLN2 fibroblasts, which typically results from organellar lip id accumulation or a membrane abnormality. However, total catalase lev els were normal, and Western blot analysis of this and three other maj or oxidant protective enzymes (Mn-dependent superoxide dismutase [MnSO D], CuZn-dependent superoxide dismutase [CuZnSOD], and glutathione per oxidase) were normal in CLN1, CLN2 and CLN3, as well as in liver from an animal (English Setter dog) model for CLN, which shows similar path ology and subunit c storage. Our data showing differences between CLN1 and forms CLN2 and CLN3 suggest some type of mitochondrial membrane a bnormality as the source of the pathology in CLN2 and CLN3.