Presence of novel DCTN1 mutation may be indicator of prodromal Perry syndrome

Key takeaways:

• Researchers examined 27 individuals with a family history of atypical Parkinsonism.
• A novel DCTN1 Gly67Val variant was found in 10 individuals, three of whom were asymptomatic.

CHICAGO — Researchers have reported a link between a novel DCTN1 variant and Perry syndrome, which was identified both in asymptomatic individuals and those with mild neurological abnormalities, suggesting a prodromal stage of disease.

“Perry syndrome is a neurodegenerative genetic disorder with most patients developing parkinsonism, depression/apathy, respiratory symptoms and weight loss,” Jaroslaw Dulski, MD, PhD, senior researcher in the department of neurology at Mayo Clinic Florida and assistant professor at the Medical University of Gdansk, said in his presentation at the International Association of Parkinsonism and Related Disorders World Congress. “It has distinct molecular pathophysiology (DCTN1 mutations) and neuropathology (TDP-43 proteinopathy).”

As the current body of knowledge on Perry syndrome comes from retrospective studies on symptomatic cases, Dulski and colleagues sought to examine asymptomatic DCTN1 mutation carriers and their conversion to disease.

Researchers attended a family reunion of a patient with Perry syndrome in Louisiana and investigated 27 individuals (median age, 45 years) from the family (n = 104), which has a history of atypical Parkinsonism. They analyzed clinical (neurological status, motor and nonmotor measures), genetic (next-generation and Sanger sequencing) and laboratory (plasma glial fibrillary acidic protein [pGFAP] and neurofilament light[pNFL]) factors relating to disease course and progression and performed neuropathological examinations on two individuals.

According to results, 20 individuals had health complaints, including sleep disorders (n = 15), autonomic disturbances (n = 10), weight loss (n = 8) and neuropsychiatric symptoms (n = 8). Based on neurological evaluations, abnormal findings were reported in 18 individuals, including parkinsonism (n = 7) and tremor (n = 2), among other observations.

Researchers also discovered a novel DCTN1 Gly67Val variant via genetic testing in 10 individuals, which was in the “hotspot” for mutations related to Perry syndrome, present in all four individuals with Perry syndrome phenotype and was pathogenic, according to computational models.

Of the mutation carriers, three were asymptomatic and three displayed isolated findings on neurological examination. Researchers reported no differences in pGFAP and pNFL levels among the group. The individuals on whom neuropathological examinations were performed had typical features of Perry syndrome.

“Some DCTN1 mutation carriers displayed mild neurological abnormalities decades before the age of onset in that family,” Dulski said. “We plan to study these individuals along with asymptomatic DCTN1 carriers to learn more about the natural progression of the disease and conversion to the symptomatic stage. In the long run, that may help to pave the way towards curative therapy.”