Hereditary primary lateral sclerosis and progressive nonfluent aphasia

Area of Science:

• Neuroscience
• Genetics
• Neuropathology

Background:

• Hereditary primary lateral sclerosis (PLS) is a rare neurodegenerative disorder.
• Progressive nonfluent aphasia (PNFA) is a form of frontotemporal dementia.
• The association between hereditary PLS and PNFA is not well-established.

Purpose of the Study:

• To report a kindred with a dominantly inherited association between PLS and PNFA.
• To investigate the underlying neuropathological and genetic mechanisms.

Main Methods:

• Studied six affected members from a three-generation kindred.
• Performed neuropathological examination on two deceased individuals.
• Conducted extensive genetic testing, including exome sequencing and whole-genome sequencing.

Main Results:

• Clinical presentation included spasticity, effortful speech, nonfluent language, and dementia, with onset in the sixth decade or later.
• Neuropathology revealed degeneration of lateral corticospinal tracts without loss of motor neurons, suggesting a central distal axonopathy.
• Genetic testing did not identify causative mutations for PLS, ataxia, or frontotemporal dementia.

Conclusions:

• A central distal axonopathy affecting the corticospinal tract plays a role in this dominantly inherited PLS-PNFA association.
• Further molecular studies are required to identify the specific causative mutation.