DCTN1-related neurodegeneration: Perry syndrome and beyond

Abstract

Perry syndrome (PS) is a rare hereditary neurodegenerative disease characterized by autosomal dominant parkinsonism, psychiatric symptoms, weight loss, central hypoventilation, and distinct TDP-43 pathology. The mutated causative gene for PS is DCTN1, which encodes the dynactin subunit p150Glued. Dynactin is a motor protein involved in axonal transport; the p150Glued subunit has a critical role in the overall function. Since the discovery of DCTN1 in PS, it has been increasingly recognized that DCTN1 mutations can exhibit more diverse phenotypes than previously thought. Progressive supranuclear palsy- and/or frontotemporal dementia-like phenotypes have been associated with the PS phenotypes. In addition, DCTN1 mutations were identified in a family with motor-neuron disease before the discovery in PS. In this review, we analyze the clinical and genetic aspects of DCTN1-related neurodegeneration and discuss its pathogenesis. We also describe three families with PS, Canadian, Polish, and Brazilian. DCTN1 mutation was newly identified in two of them, the Canadian and Polish families. The Canadian family was first described in late 1970’s but was never genetically tested. We recently had the opportunity to evaluate this family and to test the gene status of an affected family member. The Polish family is newly identified and is the first PS family in Poland. Although still rare, DCTN1-related neurodegeneration needs to be considered in a differential diagnosis of parkinsonian disorders, frontotemporal dementia, and motor-neuron diseases, especially if there is family history.

Corticobasal degeneration with TDP-43 pathology presenting with progressive supranuclear palsy syndrome: a distinct clinicopathologic subtype

“…This distribution pattern is distinct from other neurodegenerative diseases, such as amyotrophic lateral sclerosis, FTLD-TDP, and AD, which supports the idea that vulnerability to TDP-43 is associated with vulnerability unique to each neurodegeneration disorder [54]. An analogous situation has been reported for TDP-43 pathology in Perry syndrome due to mutations DCTN1 [31,44]. …”

New phenotype of DCTN1‐related spectrum: early‐onset dHMN plus congenital foot deformity

“…However, Patient 1 with distal motor neuropathy had an extremely early age of onset as well as congenital foot deformity, in comparison with all other DCTN1‐related cases reported before. Interestingly, DCNT1 mutation can also lead to Perry syndrome, which is characterized by rapidly progressive parkinsonism accompanied by depression/apathy, unintentional weight loss and respiratory failure . Patients usually show levodopa‐resistant/responsive resting tremor, rigidity, bradykinesia, postural instability and autonomic dysfunction, and reminiscent of Parkinson’s disease.…”

“…Dynactin 1 (DCTN1), the largest subunit of the dynactin complex, interacts with microtubule and tubulin dimer, plays a protective role in stabilizing neuron cytoskeleton, and initiates dynein‐mediated axonal retrograde transport . DCTN1 ‐related axonal deficiency leading to inherited motor neuron degeneration, ranges widely from distal hereditary motor neuronopathy (dHMN), Perry syndrome to amyotrophic lateral sclerosis (ALS) . Different phenotypes are mainly characterized as involvement of inferior motor neurons or superior motor neurons or both, with different ages of onset and various progress speed.…”

“…Different phenotypes are mainly characterized as involvement of inferior motor neurons or superior motor neurons or both, with different ages of onset and various progress speed. DCTN1 ‐related dHMN, also known as dHNM type 7B, presents with distal limb dystrophy and weakness appearing at early adulthood, whereas Perry syndrome is characterized by middle‐age‐onset parkinsonism, depression, weight loss, and central hypoventilation . Recently, frontotemporal dementia (FTD) has also been considered as one of the phenotypes, indicating the DCTN1 ‐related spectrum is still expanding.…”

“…Recently, frontotemporal dementia (FTD) has also been considered as one of the phenotypes, indicating the DCTN1 ‐related spectrum is still expanding. Since the year of 2003, DCTN1 mutation was first associated with human disease, more than 20 variations have been reported in sporadic or familial cases . However, rare of the DCTN1 mutations have been functionally examined and the pathogenesis remains elusive.…”