Dynactin Subunit 1 (DCTN1)-Related Neurodegeneration

Disease Overview

Summary

DCTN1-related neurodegeneration is a term that refers to a group of disorders that are caused by a change (variant) in DCTN1 gene and characterized by a wide range of symptoms.

The most common condition associated with variants in the DCTN1 gene is Perry syndrome, which is characterized by symptoms resembling Parkinson’s disease (parkinsonism), psychiatric symptoms, weight loss and difficulty breathing. Symptoms begin around the age of 50 and lead to death in about 5 years. The most common cause of death is respiratory failure or suicide. Other conditions that may be caused by a variant in the DCTN1 gene include distal hereditary motor neuronopathy type 7B (dHMN7B), frontotemporal dementia (DCTN1-FTD), motor neuron disease/amyotrophic lateral sclerosis (DCTN1-ALS) and progressive supranuclear palsy (DCTN1-PSP).

There is no cure or disease-modifying treatment for Perry syndrome but there are some ways to manage the symptoms. Ventilatory support can help with breathing, while a high-calorie diet is important to prevent weight loss. If necessary, a feeding tube may be used to prevent choking and ensure adequate nutrition. In addition, dopaminergic and antidepressant medications may help manage some of the symptoms.

Introduction

DCTN1-related neurodegeneration was first described by Dr. Thomas L. Perry in Canada in 1975, when he described a single affected family with symptoms including rapidly progressive parkinsonism, depression, weight loss, sleep disturbances and central hypoventilation.¹ This most common manifestation of DCTN1-related neurodegeneration is thus called Perry syndrome.² In 2009, a variant in the DCTN1 gene was found to cause symptoms of Perry syndrome.³ Since then, several reports have expanded the knowledge of the clinical features of DCTN1-related neurodegeneration, which, in addition to Perry syndrome, include distal hereditary motor neuronopathy type 7B, DCTN1-related frontotemporal dementia (FTD), DCTN1-related motor neuron disease or amyotrophic lateral sclerosis (ALS) and DCTN1-related progressive supranuclear palsy (PSP).²

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Synonyms

• DCTN1-related neurodegeneration
• DCTN1-RD

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Subdivisions

• Perry syndrome
• distal hereditary motor neuronopathy type 7B
• DCTN1-related frontotemporal dementia (FTD)
• DCTN1-related motor neuron disease or amyotrophic lateral sclerosis (ALS)
• DCTN1-related progressive supranuclear palsy (PSP)

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Signs & Symptoms

DCTN1-related neurodegeneration includes Perry syndrome, distal hereditary motor neuronopathy type 7B (dHMN7B), frontotemporal dementia (FTD), motor neuron disease/amyotrophic lateral sclerosis (ALS) and progressive supranuclear palsy. It is possible, however, that an affected person could have a combination of clinical features.  In most people, clinical symptoms are similar in members of the same family.^2,4-11

Perry syndrome is the most common manifestation of DCTN1-related neurodegeneration. Symptoms of Perry syndrome include:^2,4-9

• Parkinsonism: Symptoms are similar to Parkinson’s disease, such as slow movement, tremors, muscle stiffness and balance problems. However, unlike Parkinson’s disease, the symptoms of Parkinsonism are usually symmetrical, and they often do not improve with the usual medication used to treat Parkinson’s disease (dopaminergic treatments). Some people with Perry syndrome may also have motor fluctuations and peak-dose dyskinesia. Peak-dose dyskinesias are involuntary movements caused by the medication used to treat Parkinson’s disease.
• Hypoventilation: This condition refers to a breathing difficulty that is not caused by obstructive or structural respiratory tract abnormalities. The symptoms are caused by brain dysfunction. Symptoms are usually most severe at night or during sleep, with rapid breathing alternating with normal respiratory cycles or temporary cessation of breathing (apnea) leading to frequent awakenings. These symptoms usually appear later in the course of the disease and gradually get worse, eventually leading to breathing difficulties and, in some people, respiratory failure or even death.
• Neuropsychiatric symptoms: Most affected people experience depression and apathy, which can include social withdrawal and a loss of interest in activities. Cognitive symptoms are often similar to frontotemporal dementia, leading to behavior changes such as impulsivity and lack of self-control.
• Weight loss: About half of people with Perry syndrome experience weight loss. Weight loss can be caused by the central impairment of body weight regulation or in later stages of the disease by low-calorie intake. It is often caused by difficulty swallowing, along with psychiatric symptoms.
• Autonomic failure: This is a set of symptoms connected with dysfunction of the autonomic system (part of the nervous system that controls involuntary bodily functions). These symptoms include a drop in blood pressure when standing up (orthostatic hypotension) which can cause dizziness or fainting, inability to control urination or bowel movements (bladder and bowel incontinence), erectile dysfunction and reduced or no sweating which can affect the body’s ability to cool down.

Other manifestations of DCNT1-related neurodegeneration include:²

DCTN1-Distal hereditary motor neuronopathy type 7B, a progressive disease that causes weakness in the hands, legs and facial muscles, along with difficulty breathing due to weakness in both vocal cords.^6-10

DCTN1-related frontotemporal dementia (FTD) which mainly causes symptoms similar to the behavioral type of FTD. These include apathy, impulsive behavior, loss of empathy, obsessive actions, changes in food preferences, problems with decision-making and planning, and a lack of awareness about the condition.²

DCTN1-related motor neuron disease or amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder that damages nerve cells in the brain and spinal cord. Over time, this causes a loss of muscle control, making it harder for a person to move, speak, eat and breathe. The average life expectancy is about three years, with most people passing away due to breathing problems.²

DCTN1-related progressive supranuclear palsy (PSP), which can cause symptoms similar to progressive supranuclear palsy (PSP). PSP is a disorder that affects eye movement (especially looking up and down), causes balance problems, early falls, and issues with thinking and behavior. Most people with DCTN1-related PSP have symptoms that are mainly like Parkinson’s disease and frontotemporal dementia (FTD).^4,5,11

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Causes

DCTN1-related neurodegeneration is caused by a change (variant) in the DCTN1 gene.   The DCTN1 gene provides instructions to make (codify) a protein called dynactin-1. This protein is involved in cell division and transport of materials within cells by interacting with the motor protein dynein and microtubules. The dynactin complex is particularly important for the proper function of axons, which are extensions of nerve cells that transmit impulses. Variants in the DCTN1 gene can lead to several diseases because they impair the ability of dynactin-1 to bind to the dynactin complex and microtubules. This disruption affects the transport of materials within cells, leading to cellular dysfunction and death.^6,12,13

Inheritance

DCTN1-related neurodegeneration follows autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

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Affected populations

As of 2025, more than 30 families with DCTN1-related neurodegeneration and 200 affected individuals have been identified worldwide. The average age of onset is 49 years, ranging from 35 to 70 years. Survival is typically 5 years, ranging from 2 to 14 years.^2,14 The most common cause of death is hypoventilation or suicide. Most affected people have symptoms of Perry syndrome.²

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Disorders with Similar Symptoms

Parkinson’s disease is characterized by symptoms such as slow movement, stiffness, tremors and posture problems, along with non-motor symptoms like autonomic dysfunction. These symptoms also appear in Perry syndrome, but in Perry syndrome, they tend to be more symmetrical and usually do not respond as well to dopamine-based treatments in standard doses, however symptoms tend to respond to high levodopa doses.

Frontotemporal dementia (FTD) is a group of neurodegenerative disorders that result in behavioral changes and language problems. Motor symptoms are, however, rare in FTD.

Progressive supranuclear palsy (PSP) is a rare neurodegenerative disorder that affects movement, balance, speech and eye movements. While both conditions share some similarities, the presence of central hypoventilation and significant weight loss are important distinguishing features of Perry syndrome.

Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder that affects motor neurons in the brain and spinal cord. These neurons are responsible for controlling voluntary muscle movements, such as walking, speaking and breathing.

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Diagnosis

Diagnosis of DCTN1-related neurodegeneration is made by a neurologist after thorough examination that involves a combination of clinical evaluation, genetic testing and imaging studies.

Suspicion of DCTN1-related neurodegeneration should arise when a patient shows symptoms like parkinsonism, mood and behavioral changes, breathing difficulties and weight loss, especially if these symptoms are present in someone with a family history of similar issues.

Diagnostic criteria for Perry syndrome were established in 2018 and the disease was defined the presence of four cardinal signs (parkinsonism, depression/apathy, respiratory symptoms and weight loss) accompanied by a variant in DCTN1; or a family history of the disease, parkinsonism and a variant in DCTN1; or the presence of four cardinal signs and pathological findings that include nigral neuronal loss and TDP-43 pathology.⁷

Examinations that can help with diagnosis include:^2,5,6

• Imaging tests such as brain computer tomography or magnetic resonance might reveal atrophy of the frontal and temporal lobes or the midbrain.
• Functional imaging with different tracers including 123I-Ioflupa, f-dopa, DTBZ, RAC, DASB and MIBG can be helpful in diagnosis but many of these tracers are limited to research use only.
• Transcranial sonography may show increased brightness in the substantia nigra, similar to what is seen in Parkinson’s disease.
  • Transcranial sonography is a painless test that uses sound waves to detect conditions that affect blood flow to and within the brain.
• Nerve conduction study may reveal nerve damage, particularly in motor function.
  • A nerve conduction study uses electrical impulses to assess nerve damage.
• Electromyography may show signs of nerve degeneration.
  • An electromyography is a diagnostic test that measures the electrical activity of muscles and nerves.

Final diagnosis is made by genetic testing when a variant in the DCNT1 gene is identified.

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Standard Therapies

There is no FDA-approved disease modifying treatment for DCTN1-related neurodegeneration. There are several potential treatments that might help with managing symptoms of this disease.

Dopaminergic treatments which are typically used to help manage motor symptoms in Parkinson’s disease, often don’t work well in Perry syndrome. When they do work, the response can be inconsistent or work for only a short period of time. However, some studies suggest that taking large doses of levodopa may help reduce Parkinson’s-like symptoms in people with Perry syndrome.

Ventilator support can help extend the life of people with Perry syndrome, especially since some people with breathing problems during the day or difficulty breathing at night have died suddenly, likely due to not getting enough air while sleeping. A bilateral diaphragmatic pacemaker may also help improve breathing for people with respiratory issues. For people with vocal cord paralysis, a surgery to remove the arytenoid cartilage (arytenoidectomy) should be considered to provide a larger airway for breathing.

Weight should be monitored carefully to ensure proper calory intake.

Depression can be treated with antidepressive medication.

Some patients might need nasogastric or percutaneous endoscopic gastrostomy (PEG) feeding to reduce risk of choking. Nasogastric” refers to a feeding tube inserted through the nose, while “gastrostomy” refers to a tube inserted directly into the stomach through the abdominal wall, often used for longer-term feeding needs. PEG is a minimally invasive surgical procedure that involves placing a feeding tube directly into the stomach through a small incision in the abdominal wall.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
http://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

1. Perry TL, Bratty PJ, Hansen S, Kennedy J, Urquhart N, Dolman CL. Hereditary mental depression and Parkinsonism with taurine deficiency. Arch Neurol. 1975;32(2):108-113. doi:10.1001/archneur.1975.00490440058009
2. Dulski J, Konno T, Wszolek Z. DCTN1-Related Neurodegeneration. 2010 Sep 30 [Updated 2021 Aug 5]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK47027/ Accessed April 2, 2025.
3. Farrer MJ, Hulihan MM, Kachergus JM, et al. DCTN1 mutations in Perry syndrome. Nat Genet. 2009;41(2):163-165. doi:10.1038/ng.293
4. Caroppo P, Le Ber I, Clot F, et al. DCTN1 mutation analysis in families with progressive supranuclear palsy-like phenotypes. JAMA Neurol. 2014;71(2):208-215. doi:10.1001/jamaneurol.2013.5100
5. Konno T, Ross OA, Teive HAG, Sławek J, Dickson DW, Wszolek ZK. DCTN1-related neurodegeneration: Perry syndrome and beyond. Parkinsonism Relat Disord. 2017;41:14-24. doi:10.1016/j.parkreldis.2017.06.004
6. Zhang J, Wang H, Liu W, et al. A novel Q93H missense mutation in DCTN1 caused distal hereditary motor neuropathy type 7B and Perry syndrome from a Chinese family. Neurol Sci. 2021;42(9):3695-3705. doi:10.1007/s10072-020-04962-w
7. Mishima T, Fujioka S, Tomiyama H, et al. Establishing diagnostic criteria for Perry syndrome. J Neurol Neurosurg Psychiatry. 2018;89(5):482-487. doi:10.1136/jnnp-2017-316864
8. Tsuboi Y, Mishima T, Fujioka S. Perry Disease: Concept of a New Disease and Clinical Diagnostic Criteria. J Mov Disord. 2021;14(1):1-9. doi:10.14802/jmd.20060
9. Milanowski Ł, Sitek EJ, Dulski J, et al. Cognitive and behavioral profile of Perry syndrome in two families. Parkinsonism Relat Disord. 2020;77:114-120. doi:10.1016/j.parkreldis.2020.05.019
10. Hwang SH, Kim EJ, Hong YB, et al. Distal hereditary motor neuropathy type 7B with Dynactin 1 mutation. Mol Med Rep. 2016;14(4):3362-3368. doi:10.3892/mmr.2016.5664
11. Barreto RD, Rodrigues R, Roriz JM, Alonso I, Magalhães M. Perry syndrome with progressive supranuclear palsy-like phenotype in a Portuguese family – Long-term clinical follow-up. Parkinsonism Relat Disord. 2021;84:74-76. doi:10.1016/j.parkreldis.2021.02.004
12. Deshimaru M, Kinoshita-Kawada M, Kubota K, et al. DCTN1 binds to TDP-43 and regulates TDP-43 aggregation. Int J Mol Sci. 2021;22(8):3985. Published 2021 Apr 13. doi:10.3390/ijms22083985
13. Moughamian AJ, Holzbaur EL. Dynactin is required for transport initiation from the distal axon. Neuron. 2012;74(2):331-343. doi:10.1016/j.neuron.2012.02.025
14. Puls I, Jonnakuty C, LaMonte BH, et al. Mutant dynactin in motor neuron disease. Nat Genet. 2003;33(4):455-456. doi:10.1038/ng1123

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