DeCure for Perry syndrome

Perry syndrome is a rare autosomal dominant neurodegenerative disorder caused by mutations in the DCTN1 gene, which encodes dynactin p150glued. The 2017 study examined three cases of Perry syndrome and one of a related motor neuropathy, HMN7B, alongside cases of other TDP-43 proteinopathies. Perry syndrome cases showed TDP-43 inclusions in neuronal cytoplasmic inclusions, dystrophic neurites, and frequent perivascular astrocytic inclusions and axonal spheroids. Dynactin p50 inclusions were found in both Perry syndrome and HMN7B but not in ALS, FTLD-MND, or hippocampal sclerosis. No TDP-43 pathology was detected in HMN7B. The authors concluded Perry syndrome may be a distinctive type of TDP-43 proteinopathy.

A 2021 review of new patients from New Zealand, Poland, and Colombia, plus all published cases since 1975, reported that parkinsonism in Perry disease is symmetrical, progresses rapidly, and is poorly responsive to L-Dopa, though a trial of high doses is warranted. Depression is severe and associated with suicidal ideation, and may benefit from antidepressants and L-Dopa. Respiratory symptoms are the leading cause of death; artificial ventilation or a diaphragm pacemaker can prolong survival. Weight loss occurs in most patients and is multifactorial. Autonomic dysfunction is frequent but underdiagnosed. An autopsy showed distinctive pallidonigral degeneration with TDP-43 pathology. Genetic testing found evidence of a common founder for two families. The authors noted striking phenotypic variability in DCTN1-related disorders and hypothesised oligogenic or polygenic inheritance.

A 2019 review described respiratory insufficiency, including central hypoventilation, as the most devastating symptom. A diaphragmatic pacemaker may be an option. The authors stated that development of disease-modifying therapies requires basic science studies and clinical trials, along with the study of other neurodegenerative diseases.

A 2023 study of 27 members of a Louisiana kindred and an isolated case from Virginia identified seven suspected cases in the Louisiana family. Mean age of first symptoms was 54 years, with non-motor symptoms (weight loss, neuropsychiatric symptoms) most common initially. 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. Smell testing was unremarkable. A novel DCTN1 p.Gly67Val mutation was found in the proband and another case. Autopsy of the proband confirmed TDP-43 proteinopathy with predominant pallido-nigro-luysial involvement. The Virginia patient developed apathy at 58, then depression, parkinsonism with upgaze limitation and pyramidal signs, weight loss, and breathing pauses. She died at 69; autopsy revealed TDP-43 pathology with pallidonigral involvement. Genetic testing found a novel DCTN1 Gly42Ser mutation, presumed de novo as parents were unaffected. The authors noted increasing recognition of clinical and genetic heterogeneity.