Anatomic Pathology: Neuropathology

• A large number of neurodegenerative diseases can be caused by genetic mutations or abnormalities. Genetic abnormalities can include single gene mutations and microsatellite repeat instability leading to expansion of tandem triplet repeats.

• Mutations in the gene for α-synuclein, SNCA, cause some familial cases of Parkinson’s disease. α-synuclein is a protein that forms the pathologic inclusions (Lewy body) in Parkinson’s disease, diffuse Lewy bodies, and multiple system atrophy.

• In Huntington disease, an increase in the number of repeats of the CAG sequence is seen in the HTT gene localized in the short arm of chromosome 4 and coding for the protein huntingtin.

• Mutations in the APP gene have been associated with autosomal dominant forms of Alzheimer disease. The APP gene is located on chromosome 21 (thus, the association of Alzheimer disease and Down syndrome) and codes for the amyloid-β precursor protein (APP).

• The tau gene, MAPT, is located on chromosome 17 and codes for the microtubule-associated protein, tau. Mutations in this gene are associated with chromosome 17-linked frontotemporal lobar dementia.

• In X-linked bulbospinal neuronopathy (like Kennedy disease), a CAG repeat region in the first exon of the androgen receptor gene on the X chromosome causes slowly progressive lower motor neuron weakness of facial, bulbar, and proximal limb muscles.