Perry syndrome is a rare autosomal dominant neurodegenerative disorder characterized by parkinsonism, depression, weight loss, and central hypoventilation. Early diagnosis is challenging because presentations are heterogeneous. A 51-year-old man presented with hyperthermia, impaired consciousness, tachycardia, and gastrointestinal hypomotility suggestive of anticholinergic toxicity. Despite therapeutic fesoterodine levels, he developed hypercapnia requiring mechanical ventilation and later exhibited rigidity with marked creatine kinase elevation, consistent with malignant parkinsonism. Dopamine transporter imaging demonstrated presynaptic dopaminergic loss, and follow-up magnetic resonance imaging revealed bilateral globus pallidus and substantia nigra hyperintensities. Family history was informative, and genetic testing confirmed a DCTN1 mutation. The presentation was multifactorial, reflecting an interaction between therapeutic anticholinergic exposure, reduced cholinergic reserve related to Perry syndrome, endogenous dopaminergic deficiency, and systemic stress. Early recognition is crucial because central hypoventilation may lead to life-threatening respiratory failure.

Perry syndrome (PS) is a rare, inherited neurodegenerative disorder caused by mutations in the DCTN1 gene. It is characterized by parkinsonism, neuropsychiatric symptoms, central hypoventilation, and progressive weight loss, typically leading to a rapid disease course and early death. As genetic testing becomes more widespread, PS is increasingly diagnosed, and its clinical spectrum is expanding. The authors conducted a comprehensive search of public databases through September 2025 to identify original research, conference proceedings, and book chapters related to Perry syndrome. This review summarizes the current understanding of the disease, including its clinical, pathologic, and genetic aspects. The authors also provide practical recommendations for managing symptoms, particularly through optimization of dopaminergic therapy, antidepressive treatment, and noninvasive or invasive ventilation support, which can greatly improve quality of life and extend survival. Although there are currently no approved disease-modifying therapies for PS, recent research into the underlying pathology, such as TDP-43 and axonal transport dysfunction, offers promising targets for future treatments. A new staging system for PS is recommended for PS, which will help to standardize the clinical assessment of PS and guide therapeutic decision-making.

This study investigated two cases. Case 1 involves a 53-year-old man who suffered from sleep apnea syndrome at age 48. Moreover, he was involved in a rear-end collision while driving and was admitted to the hospital at age. He exhibited impaired consciousness, postural tremors, and bradykinesia in the upper extremities. Subsequently, he was managed on a ventilator due to unexplained alveolar hypoventilation. Case 2 is his younger sister, a 46-year-old woman, who was being treated for depression and began to show signs of parkinsonism around age 43. The metaiodobenzylguanidine (MIBG) myocardial scintigraphy results were normal in both cases. Given that their father was also managed on a ventilator due to unexplained alveolar hypoventilation, exome analyses were performed. Both were found to have a previously reported heterozygous mutation (p.Y78C) in the DCTN1 gene and were diagnosed with Perry disease. Although MIBG myocardial scintigraphy is a useful test for diagnosing Perry disease, it is important to note that there are cases where it may yield normal results.

Mutations in the gene encoding the p150 subunit of the dynactin complex (DCTN1) are linked to amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, and Perry syndrome. These neurodegenerative diseases can cause muscle weakness and atrophy, parkinsonian-like symptoms, and paralysis. To examine the evolution of neuropathology caused by a mutation in DCTN1 and cellular mechanisms of disease for therapeutic discovery, we characterized mice expressing either human wildtype or mutant (G59S) DCTN1. Neuron-specific expression of mutant, but not wildtype, DCTN1 caused fatal age-related paralytic disease and motor neuron (MN) degeneration in the spinal cord with axonopathy and chromatolysis without apoptotic morphology. MNs became positive for cleaved caspase-3, cleaved caspase-8, and nitrated Hsp90. Mitochondria accumulated and appeared fragmented and dysmorphic and then were lost. This pathology was accompanied by invasion of CD95- and CD8-positive mononuclear T cells into the ventral horn and accumulation of TNFα and IL9. Administration of the mitochondrial division inhibitor-1 (Mdivi-1) protected MNs and extended the lifespan of G59S-DCTN1 mice. A mitochondrial permeability transition pore inhibitor also extended lifespan. Thus, mutant DCTN1 causes degeneration of MNs associated with axonopathy, mitochondriopathy, nitrative stress, and caspase activation. It appears as retrograde neurodegeneration and inflammatory T-cell-like cytolysis. Mitochondria are possible therapeutic targets in DCTN1-linked neurodegenerative disorders.

Impairment of axonal transport has been emphasized as a common feature in a series of neurodegenerative diseases (NDs). Variations in DCTN1 have been reported in NDs such as Parkinson's disease (PD), Perry syndrome (PS) and Amyotrophic lateral sclerosis (ALS). The overall objective of this study was to investigate the contribution of DCTN1 variants in different NDs and to explore the correlation between DCTN1 variants and disease phenotypes. We identified a previously published mutation p.G71E in three unrelated PS families. In the PD cohort, 30 putative deleterious variants (PDVs) were identified in DCTN1. Gene-based burden analysis showed a nominal association between DCTN1 rare PDVs and PD (uncorrected p = 0.042); however, this association did not remain statistically significant after multiple testing correction (FDR-corrected p = 0.084). In the ALS cohort, 10 PDVs were all rare damaging missense variants, and the PDVs were not enriched in ALS patients. Our findings first provide the independent evidence that PDVs in DCTN1 may be a risk factor for PD, but do not support the genetic involvement of DCTN1 in ALS of Asian ancestry.