Clinical, pathological and genetic characteristics of Perry disease-new cases and literature review

Abstract

Background and purpose: Perry disease (or Perry syndrome) is an autosomal dominant neurodegenerative disorder characterized by parkinsonism, neuropsychiatric symptoms, central hypoventilation, weight loss and distinct TDP-43 pathology. It is caused by mutations of the DCTN1 gene encoding an essential component of axonal transport. The objectives were to provide the current state of knowledge on clinical, pathological and genetic aspects of Perry disease, as well as practical suggestions for the management of the disease.

Methods: Data on new patients from New Zealand, Poland and Colombia were collected, including autopsy report. Also all of the published papers since the original work by Perry in 1975 were gathered and analyzed.

Results: Parkinsonism was symmetrical, progressed rapidly and was poorly responsive to L-Dopa; nonetheless, a trial with high doses of L-Dopa is warranted. Depression was severe, associated with suicidal ideations, and benefited from antidepressants and L-Dopa. Respiratory symptoms were the leading cause of death, and artificial ventilation or a diaphragm pacemaker prolonged survival. Weight loss occurred in most patients and was of multifactorial etiology. Autonomic dysfunction was frequent but underdiagnosed. There was a clinical overlap with other neurodegenerative disorders. An autopsy showed distinctive pallidonigral degeneration with TDP-43 pathology. Genetic testing provided evidence of a common founder for two families. There was striking phenotypic variability in DCTN1-related disorders. It is hypothesized that oligogenic or polygenic inheritance is at play.

Conclusions: Perry disease and other DCTN1-related diseases are increasingly diagnosed worldwide. Relatively effective symptomatic treatments are available. Further studies are needed to pave the way toward curative/gene therapy.

Keywords: DCTN1 gene; TDP-43; dynactin; neurodegenerative disorder; parkinsonism.

Fig. 1.

New Zealand and Polish Perry syndrome families. A, The combined pedigree of the New Zealand family. B, The pedigree of the new Polish family (Poland-2).

Fig 2.

Neuropathologic findings of the patient from the Colombian family. a. A coronal section of brain at the level of the fornix shows atrophy and rusty discoloration of the globus pallidus (asterisk). b. Two levels of the midbrain, both showing severe loss of neuromelanin pigment in the substantia nigra (asterisks). c. Histologic section of substantia nigra with hematoxylin and eosin stain shows only rare neuromelanin-containing neurons, with gliosis and granular axonal spheroids (arrow). d. Low power image of substantia nigra immunostained for phospho-TDP-43 shows scattered immunoreactive structures illustrated at higher magnification in e, f, g, h. e. ring-like neuronal inclusion; f. star-shaped neuronal inclusion, g. torpedo-shaped dystrophic neurite, h. bilobed perivascular oligodendroglial inclusion. (bar in c = 100 microns (also for d); bar in h = 20 microns (also for e, f, and g).