Evidence for Cholinergic Dysfunction in Autosomal Dominant Kufs Disease

Area of Science:

• Neuroscience
• Genetics
• Neuropathology

Background:

• Neuronal ceroid-lipofuscinoses (NCLs) are inherited neurodegenerative diseases characterized by lysosomal accumulation of lipopigments in neurons.
• Kufs disease, a rare form of NCL, typically presents with seizures, cognitive decline, and myoclonus.
• While most Kufs disease cases are autosomal recessive, autosomal dominant forms linked to DNAJC5 gene mutations have been reported.

Purpose of the Study:

• To describe the clinical, genetic, and neuropathological features of a family with autosomal dominant Kufs disease.
• To investigate the role of DNAJC5 gene mutations in the pathogenesis of Kufs disease.
• To elucidate the specific neurochemical changes associated with this form of NCL.

Main Methods:

• Clinical assessment of a family cohort presenting with Kufs disease symptoms.
• Genetic analysis to identify mutations in the DNAJC5 gene.
• Neuropathological examination of the proband's brain, including immunohistochemistry for specific neuronal markers.

Main Results:

• A family with autosomal dominant Kufs disease was identified, with affected members exhibiting cognitive impairment, seizures, and myoclonus.
• All affected individuals carried a c.346_348delCTC(p.L116del) mutation in the DNAJC5 gene.
• Neuropathology revealed widespread lipofuscin accumulation and a significant depletion of choline acetyltransferase, particularly in the basal ganglia and forebrain, while cholinergic neurons appeared spared.

Conclusions:

• Autosomal dominant Kufs disease can be caused by mutations in the DNAJC5 gene.
• The neuropathological findings suggest that choline acetyltransferase depletion, rather than neuronal loss, is a key feature.
• This study contributes to understanding the genetic and molecular basis of Kufs disease and its specific neurochemical alterations.