Proud syndrome is a rare neurological condition that is primarily characterized by severe intellectual disability, agenesis of the corpus callosum, seizures, and spasticity. It usually occurs in males; when it occurs in females, the signs and symptoms are often less severe. Proud syndrome is caused by changes (mutations) in the ARX gene and is inherited in an X-linked recessive manner. Treatment is based on the signs and symptoms present in each person.

ARX gene, which encodes a protein that regulates the activity of other genes. This protein is especially important during early embryonic development since it is thought to be involved in the formation of many different body structures such as the pancreas, testes, brain, and muscles used for movement (skeletal muscles). For example, the protein helps regulate the process by which cells mature to carry out specific functions (differentiation) within the pancreas, testes, and muscles. In the developing brain, it plays many different roles such as assisting with the movement of neurons to their final locations. Specific changes in the ARX gene impair the function of the protein, which may disrupt the normal development of many different parts of the body. This can lead to the many signs and symptoms associated with Proud syndrome.

Normal Function

The ARX gene provides instructions for producing a protein that regulates the activity of other genes. On the basis of this action, the ARX protein is called a transcription factor. The ARX gene is part of a larger family of homeobox genes, which act during early embryonic development to control the formation of many body structures. Specifically, the ARX protein is believed to be involved in the development of the brain, pancreas, testes, and muscles used for movement (skeletal muscles).

In the pancreas, testes, and skeletal muscles, the ARX protein helps to regulate the process by which cells mature to carry out specific functions (differentiation). Within the developing brain, the ARX protein is involved with movement (migration) and communication of nerve cells (neurons). In particular, this protein regulates genes that play a role in the migration of specialized neurons (interneurons) to their proper location. Interneurons relay signals between other neurons.

Health Conditions Related to Genetic Changes

Developmental and epileptic encephalopathy 1

Mutations in the ARX gene can cause developmental and epileptic encephalopathy 1 (DEE1), a disorder characterized by recurrent seizures called infantile spasms that begin in the first year of life. Children with this condition also have intellectual disability.

The normal ARX protein contains four regions where a protein building block (amino acid) called alanine is repeated multiple times. These stretches of alanines are known as polyalanine tracts. The most common ARX gene mutations that cause DEE1 add extra alanines to the first or second polyalanine tract in the ARX protein. This type of mutation is called a polyalanine repeat expansion. Research suggests that these polyalanine repeat expansions reduce the amount of ARX protein in cells, although the mechanism is unclear. Other ARX gene mutations that cause this condition are believed to reduce the function of the ARX protein. A shortage of ARX function is thought to impair the normal development and migration of certain interneurons, which likely underlies infantile spasms and other neurological problems characteristic of DEE1.

Partington syndrome

A few mutations in the ARX gene have been identified in people with Partington syndrome, a neurological disorder that causes intellectual disability and a group of movement problems called focal dystonia that primarily affects the hands. The most common mutation that causes Partington syndrome, a duplication of genetic material written as c.428_451dup, adds extra alanines to the second polyalanine tract in the ARX protein. The polyalanine repeat expansion likely reduces the amount of ARX protein or impairs its function and may disrupt normal interneuron migration in the developing brain, leading to the intellectual disability and dystonia characteristic of Partington syndrome.

X-linked lissencephaly with abnormal genitalia

At least 30 mutations in the ARX gene can cause X-linked lissencephaly with abnormal genitalia (XLAG). This condition is characterized by abnormal brain development that results in the brain having a smooth appearance (lissencephaly) instead of its normal folds and grooves. Males with XLAG also have abnormal genitalia. The ARX gene mutations that cause XLAG lead to the production of a nonfunctional ARX protein or to a complete absence of ARX protein. As a result, the ARX protein cannot perform its role regulating the activity of genes important for interneuron migration. In addition to impairing normal brain development, a lack of functional ARX protein disrupts cell differentiation in the testes, leading to the development of abnormal genitalia. It is thought that the disruption of ARX protein function in the pancreas plays a role in digestive issues, including chronic diarrhea, experienced by individuals with XLAG.

Females with an ARX gene mutation typically have less severe signs and symptoms than males. Affected females may have an absence of the tissue connecting the left and right halves of the brain (agenesis of the corpus callosum), some degree of intellectual disability, and recurrent seizures (epilepsy). Some females with an ARX gene mutation experience no symptoms.

Other disorders

Mutations in the ARX gene can cause a variety of conditions that impair brain function. Some ARX gene mutations result in intellectual disability without other neurological problems. Because the ARX gene is on the X chromosome, this condition is known as X-linked intellectual disability (XLID) or sometimes nonsyndromic XLID. XLID can occur in combination with other neurological problems as part of distinct conditions called XLID syndromes. ARX gene mutations account for 9.5 percent of all cases of XLID.

ARX gene mutations cause several XLID syndromes, including X-linked lissencephaly with abnormal genitalia, early infantile epileptic encephalopathy 1, and Partington syndrome (described above). Another is X-linked myoclonic epilepsy with intellectual disability and spasticity, which causes intellectual disability and epilepsy. ARX gene mutations also cause several syndromes that include structural brain malformations. These include Proud syndrome, which is characterized by agenesis of the corpus callosum as well as abnormal male genitalia, and hydranencephaly with abnormal genitalia, which results in a fluid-filled sac replacing most of the brain tissue (hydranencephaly) and abnormal male genitalia.

For unknown reasons, the same mutation can result in the development of different conditions in different people, even among individuals within the same family. It is not clear why mutations in the ARX gene cause this array of conditions; researchers suggest that other genetic and environmental factors that have not been identified are likely involved.

Other Names for This Gene

• aristaless-related homeobox, X-linked
• ARX_HUMAN
• ISSX
• MRX29
• MRX32
• MRX33
• MRX36
• MRX38
• MRX43
• MRX54
• MRXS1
• PRTS

Genomic Location

The ARX gene is found on the X chromosome.

In X-linked recessive conditions, men develop the condition if they inherit one gene mutation (they have only one X chromosome). Females are generally only affected if they have two gene mutations (they have two X chromosomes), although some females may rarely have a mild form of the condition if they only inherit one mutation. A woman with an X-linked recessive condition will pass the mutation on to all of her sons and daughters. This means that all of her sons will have the condition and all of her daughters will be carriers. A man with an X-linked recessive condition will pass the mutation to all of his daughters (carriers) and none of his sons.

• Agenesis of the corpus callosum
• Severe intellectual disability
• Seizures
• Stiff and/or rigid muscles (spasticity)

Other features may include microcephaly (unusually small head), limb contractures, scoliosis, characteristic facial features, kidney malformations, and genital abnormalities (i.e. cryptorchidism, hypospadias).

Proud syndrome usually occurs in males; when it occurs in females, the signs and symptoms are often less severe.

For personalized information about the treatment and management of Partington syndrome, please speak to a healthcare provider.