Spinocerebellar ataxia 34 (SCA34) is a late-onset progressive
ataxia caused by a mutation in ELOVL4, a gene involved in the biosynthesis of very long-chain
fatty acids (VLCFAs). We performed post-mortem neuropathological examinations on four SCA34 patients with the ELOVL4 L168F mutation and compared the findings to age-matched controls. Specific gross findings of SCA34 were limited to pontocerebellar
atrophy. On light microscopy, pontine base showed neuronal loss and storage of an autofluorescent
lipopigment positive on
oil red O, PAS and Hale's colloidal
iron and negative on
Alcian blue and
Luxol fast blue (LFB). Among the swollen neurons were abundant CD68+ /CD163+ /IBA1- macrophages laden with a material with similar histochemical profile as in neurons except for the lack of autofluorescence and
oil red O positivity and the presence of needle-like birefringent inclusions. Normal resting IBA1 + microglia were generally absent from pontine base nuclei but present in normal numbers elsewhere in the pons. In dentate nucleus neurons,
atrophy was milder than in the pontine base and the coarser storage material was LFB-positive, closely resembling
lipofuscin. On electron microscopy, dentate nucleus neurons showed neuronal storage of tridimensionally organized trilaminar spicules within otherwise normal
lipofuscin, while in the more affected pontine base neurons,
lipofuscin was almost completely replaced by the storage material. Storage macrophages were tightly packed with stacks of unorganized trilaminar spicules, reminiscent of the storage material seen in
peroxisomal disorders and thought to represent VLCFAs incorporated in complex polar
lipids. In summary, we provide histochemical and ultrastructural evidence that SCA34 is a
lipid storage disease, the first among the currently known SCAs, and that the storage
lipid is accumulating within neuronal
lipofuscin. Our findings suggest that the storage
lipid is similar to the one accumulating in non-neuronal cells in
peroxisomal disorders and provide the first ultrastructural description of this type of material within neurons.