Perry syndrome is a progressive brain disease that is characterized by four major features: a pattern of movement abnormalities known as parkinsonism, psychiatric changes, weight loss, and abnormally slow breathing (hypoventilation). These signs and symptoms typically appear in a person's forties or fifties.

Parkinsonism and psychiatric changes are usually the earliest features of Perry syndrome. Signs of parkinsonism include unusually slow movements (bradykinesia), stiffness, and tremors. These movement abnormalities are often accompanied by changes in personality and behavior. The most frequent psychiatric changes that occur in people with Perry syndrome include depression, a general loss of interest and enthusiasm (apathy), withdrawal from friends and family, and suicidal thoughts. Many affected individuals also experience significant, unexplained weight loss early in the disease.

Hypoventilation is a later feature of Perry syndrome. Abnormally slow breathing most often occurs at night, causing affected individuals to wake up frequently. As the disease worsens, hypoventilation can result in a life-threatening lack of oxygen and respiratory failure.

People with Perry syndrome typically survive for about 5 years after signs and symptoms first appear. Most affected individuals ultimately die of respiratory failure or pneumonia. Suicide is another cause of death in this condition.

Perry syndrome results from mutations in the DCTN1 gene. This gene provides instructions for making a protein called dynactin-1, which is involved in the transport of materials within cells. To move materials, dynactin-1 interacts with other proteins and with a track-like system of small tubes called microtubules. These components work together like a conveyer belt to move materials within cells. This transport system appears to be particularly important for the normal function and survival of nerve cells (neurons) in the brain.

Mutations in the DCTN1 gene alter the structure of dynactin-1, making it less able to attach (bind) to microtubules and transport materials within cells. This abnormality causes neurons to malfunction and ultimately die. A gradual loss of neurons in areas of the brain that regulate movement, emotion, and breathing underlies the signs and symptoms of Perry syndrome.

Normal Function

The DCTN1 gene provides instructions for making a protein called dynactin-1. At least two different versions of this protein are produced in cells. The two versions differ in size; the larger version is called p150-glued, and the smaller version is called p135.

Both versions of the dynactin-1 protein interact with several other proteins to form a group (a complex) of proteins called dynactin. The p150-glued version of dynactin-1 is the largest component (subunit) of the dynactin complex. This complex plays a critical role in cell division and the transport of materials within cells. To carry out these roles, the complex's p150-glued subunit attaches (binds) to a protein called dynein, which acts as a motor, and also binds to a track-like system of small tubes called microtubules. The dynactin complex, dynein, and microtubules work together like a conveyer belt to move materials within cells.

Researchers believe that the dynactin complex is particularly important for the proper function of axons, which are specialized extensions of nerve cells (neurons). Axons transmit impulses from nerve to nerve and from nerves to muscles. Axons can be quite long; some are more than 3 feet in length. The dynactin complex is a critical part of a rapid transport system that supplies axons with materials to keep them healthy and functioning efficiently.

Health Conditions Related to Genetic Changes

Amyotrophic lateral sclerosis

MedlinePlus Genetics provides information about Amyotrophic lateral sclerosis

Perry syndrome

At least five mutations in the DCTN1 gene have been found to cause Perry syndrome. This progressive brain disease is characterized by a pattern of movement abnormalities known as parkinsonism, psychiatric changes, weight loss, and abnormally slow breathing (hypoventilation).

Most of the mutations that cause Perry syndrome change single protein building blocks (amino acids) in the dynactin-1 protein. These genetic changes impair the ability of the p150-glued version of dynactin-1 to bind to the dynactin complex and to microtubules. An incomplete dynactin complex has a reduced ability to transport materials within cells. Slow or abnormal transport of materials needed for the normal function of neurons causes these cells to malfunction and ultimately die. A gradual loss of neurons in areas of the brain that regulate movement, emotion, and breathing underlies the signs and symptoms of Perry syndrome.

Charcot-Marie-Tooth disease

MedlinePlus Genetics provides information about Charcot-Marie-Tooth disease

Other disorders

Researchers have identified at least one DCTN1 gene mutation that causes a nervous system disorder called distal hereditary motor neuronopathy type VIIB. Signs and symptoms of this disorder first appear in early adulthood and include breathing difficulties and progressive weakness of muscles in the face and hands. Muscle weakness in the feet and legs develops later. The mutation that causes this disorder changes one of the amino acids used to make dynactin-1. Specifically, it replaces the amino acid glycine with the amino acid serine at protein position 59 (written as Gly59Ser or G59S). It is unclear how this mutation causes distal hereditary motor neuronopathy type VIIB. The altered protein may result in an abnormal dynactin complex and disturb interactions between the complex and microtubules, which would disrupt transport activities and impair the function of axons in neurons.

At least one DCTN1 gene mutation is associated with a brain disorder called frontotemporal dementia (FTD) without the features of amyotrophic lateral sclerosis (ALS). This disorder occurs in mid- to late adulthood and is characterized by changes in personality and behavior that may make it difficult for affected individuals to interact with others in a socially appropriate manner. Changes in speech and language can also occur, such as problems using the correct word and difficulty with language comprehension. The DCTN1 gene mutation associated with this disorder replaces the amino acid arginine with the amino acid lysine at protein position 1101 (written as Arg1101Lys or R1101K). It is unclear how this mutation causes FTD. This mutation likely alters the 3-dimensional shape of dynactin-1, which may impair its binding with the dynactin complex and microtubules. This impaired binding may slow the transport of materials needed for the proper function of axons and the efficient transmission of nerve impulses.

Other Names for This Gene

• 150 kDa dynein-associated polypeptide
• DAP-150
• DP-150
• DYNA_HUMAN
• dynactin 1
• dynactin 1 (p150, glued homolog, Drosophila)

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In most cases, an affected person inherits the mutation from one affected parent. However, some cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

Perry syndrome is very rare; about 50 affected individuals have been reported worldwide.