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Autosomal dominant adult-onset neuronal ceroid lipofuscinosis (AD-ANCL) is a multisystem disease caused by mutations in the  DNAJC5  gene.  DNAJC5  encodes Cysteine String Protein-alpha ( CSPα ), a putative synaptic protein. AD-ANCL has been traditionally considered a lysosomal storage disease based on the intracellular accumulation of ceroid material. Here, we report for the first time the pathological findings of a patient in a clinically early stage of disease, which exhibits the typical neuronal intracellular ceroid accumulation and incipient neuroinflammation but no signs of brain atrophy, neurodegeneration or massive synaptic loss. Interestingly, we found minimal or no apparent reductions in  CSPα  or synaptophysin in the neuropil. In contrast, brain homogenates from terminal AD-ANCL patients exhibit significant reductions in SNARE-complex forming presynaptic protein levels, including a significant reduction in  CSPα  and  SNAP-25 . Frozen samples for the biochemical analyses of synaptic proteins were not available for the early stage AD-ANLC patient. These results suggest that the degeneration seen in the patients with AD-ANCL reported here might be a consequence of both the early effects of  CSPα  mutations at the cellular soma, most likely lysosome function, and subsequent neuronal loss and synaptic dysfunction.

Clinically early-stage CSPα mutation carrier exhibits remarkable terminal stage neuronal pathology with minimal evidence of synaptic loss