We studied 27 members of the large new kindred from Louisiana and a new isolated case from Virginia. We performed two postmortem examinations.   

We identified 7 cases suspected of PS in the Lousiana family. The mean age of first symptoms was 54 years, with non-motor symptoms (weight loss, neuropsychiatric symptoms) being the most common initial manifestation. Parkinsonism was present in 7/7, neuropsychiatric features in 4/7, weight loss in 5/7, respiratory symptoms in 3/7, dysautonomia in 4/7, and sleep disorders in 7/7 patients. Smell testing was unremarkable. Proband and another case tested positive for a novel DCTN1 p.Gly67Val mutation within the CAP-Gly domain; the results of other cases were underway. The autopsy of the proband confirmed TDP-43 proteinopathy with predominant pallido-nigro-luysial involvement.

The patient from Virginia developed apathy at 58 years, followed by depression, parkinsonism with upgaze limitation and pyramidal signs, weight loss, and pauses in breathing. She died at 69, and the pathological evaluation at autopsy revealed TDP-43 pathology with pallidonigral involvement, consistent with PS with known mutations in the DCTN1 gene. Her genetic testing found a novel DCTN1 Gly42Ser mutation, located on exon 2 but beyond the CAP-Gly domain. As her parents were not affected, we presume it was a de novo mutation. 

The heterogeneity of clinical and genetic characteristics of PS is increasingly recognized. Better understanding of the disease could translate into enhanced management strategy, improved quality of life, and extended life expectancy.