To describe a person with Perry Syndrome (PS) that carries a novel Tyr78His DCTN1 variant and propose expansion of pathogenic PS genetic variants. 

PS is a rare hereditary neurodegenerative disease characterized by autosomal dominant Parkinsonism, psychiatric symptoms, central hypoventilation and weight change. Nine missense mutations in exon 2 of DCTN1 and one intronic splice mutation MAPT genes have been found to be pathogenic.

Sequence analysis via FTD/ALS/PD panel on 38 genes and C9orf72 deletion/duplication testing performed by Invitae (San Francisco, CA).

Fifty-seven year-old adopted male with history of erectile dysfunction, apathy, knee replacement complicated by septic arthritis presented with three years of progressive imbalance, bradykinesia, shuffling gait, depression, fatigue, concentration difficulties, perseveration and falls. Exam revealed masked facies, impaired vertical pursuits, delayed movements/speech, decreased arm swing, minimal episodic tremor, relatively spared memory and preserved sense of smell. Symptoms did not respond to carbidopa/levodopa. Within months he developed refractory recurrent hypercarbic respiratory failure due to nocturnal central hypoventilation, which eventually required tracheostomy and scheduled nocturnal positive pressure ventilation. Patient’s weight loss was reversed after tracheostomy.

Serum evaluation confirmed nocturnal hypercarbia. EMG, MRI, EEG, and CSF analysis (including paraneoplastic panel, VGCC and IgLON5 antibodies) failed to explain central nocturnal hypopnea. Genetic testing revealed Tyr78His DCTN1 variant of unknown significance, which had never been described in healthy or affected individuals. In silico analyses suggested pathogenicity. Tyr78His disrupts hydrophobic cluster near Tyr78 similarly to Tyr78Cys, a recognized pathogenic variant. Segregation analysis could not be performed given patient’s adopted status.

We argue Tyr78HIS DCTN1 variant is the tenth pathogenic missense mutation causing PS; based on our patient’s phenotype, the mutation’s similarity to known pathogenic variant at the same codon and concordant in silico results. This case broadens the understanding of genetic variants of PS and thereby contributes to diagnosis of this seldom recognized genetic disorder.