A LRSAM1 mutation links Charcot-Marie-Tooth type 2 to Parkinson's disease

Abstract

LRSAM1 mutations have been found in recessive and dominant forms of Charcot-Marie-Tooth disease. Within one generation of the original Dutch family in which the dominant LRSAM1 mutation was identified, three of the five affected family members have developed Parkinson's disease between ages 50 and 65 years, many years after neuropathy onset. We speculate that this late-onset parkinsonism is part of the LRSAM1 phenotype, thus associating a hitherto peripheral nerve disease with a central nervous system phenotype. How the mutated Lrsam1 protein, which normally has E3 ubiquitin ligase activity and is expressed in the nervous system, impacts on substantia nigra neurons is unclear.

Figure 1

The top shows the family pedigree. Squares: males, circles: females. Black filled symbols indicate those affected by Charcot–Marie–Tooth (CMT). Symbols that are half black and half lined indicate those affected by both CMT and Parkinson's disease. The bottom shows the abnormal DaT SPECT scans of the three males with both CMT and Parkinson's disease. Note the asymmetrically reduced uptake and pattern of more putamen than caudate involvement.