Yuan-Harel-Lupski (YUHAL) syndrome is a rare neurological condition that has a combination of features of two other disorders, Potocki-Lupski syndrome and type 1A Charcot-Marie-Tooth disease.

The first signs and symptoms of YUHAL syndrome begin in infancy. Infants with YUHAL syndrome usually have weak muscle tone (hypotonia), which may lead to feeding problems. They typically do not grow and gain weight at the expected rate. Babies and children with YUHAL syndrome have delayed development, including delayed speech and language skills and motor skills such as walking. YUHAL syndrome is also associated with behavioral difficulties. Many affected individuals have sleep problems, including pauses in breathing during sleep (sleep apnea) or trouble falling asleep and staying asleep. Some people with YUHAL syndrome have subtle differences in facial features, including outside corners of the eyes that point downward (down-slanting palpebral fissures), a triangular face, and eyes that do not look in the same direction (strabismus). These signs and symptoms are similar to those of Potocki-Lupski syndrome.

Other signs and symptoms of YUHAL syndrome begin in childhood and result from damage to peripheral nerves, which connect the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, and heat. Damage to peripheral nerves can lead to loss of sensation and wasting (atrophy) of muscles in the legs. Children with YUHAL syndrome often develop muscle weakness, particularly in the lower legs, which may lead to an unusual walking style (gait). Some affected individuals have foot abnormalities such as flat feet (pes planus), high arches (pes cavus), or an inward- and upward-turning foot (clubfoot). They may also experience reduced reflexes and a decreased sensitivity to touch, heat, and cold in the feet and lower legs. Similar features are seen in individuals with type 1A Charcot-Marie-Tooth disease, although they may appear earlier in people with YUHAL syndrome, often before age 5.

Abnormal development of other tissues and organs, such as the heart or kidneys, can occur in YUHAL syndrome.

YUHAL syndrome results from an extra copy (duplication) of a small piece of chromosome 17 in each cell. The duplication occurs on the short (p) arm of the chromosome in a region designated 17p12-17p11.2. The duplicated segment ranges in size from approximately 3.2 million DNA building blocks (also written as 3.2 megabases or 3.2 Mb) to 19.7 Mb.

The duplicated region always contains at least two genes, RAI1 and PMP22. Researchers believe that having an extra copy of both of these genes underlies the characteristic features of YUHAL syndrome.

The RAI1 gene provides instructions for making a protein that helps regulate the activity (expression) of other genes. Although most of the genes regulated by the RAI1 protein have not been identified, the protein appears to play a role in many body processes, including the sleep-wake cycle and development of the brain and bones in the head and face (craniofacial bones). Research suggests that duplications involving this gene lead to higher-than-normal amounts of the RAI1 protein, which disrupts the expression of genes that influence brain and craniofacial development and the sleep-wake cycle. Excess RAI1 protein likely causes feeding and sleep problems, delayed development, behavioral difficulties, and facial differences in people with YUHAL syndrome. Duplications that involve the RAI1 gene but not the PMP22 gene cause Potocki-Lupski syndrome, which shares these features.

The PMP22 gene provides instructions for making a protein that is a component of myelin, a protective substance that covers nerves and promotes the efficient transmission of nerve impulses. It is thought that an extra copy of the PMP22 gene leads to overproduction of PMP22 protein. Too much PMP22 protein may overwhelm the cells' ability to process it correctly, leading to a buildup of unprocessed, nonfunctional protein. This buildup may impair the formation of myelin. A shortage of functional PMP22 protein leads to instability and loss of myelin (demyelination). Demyelination reduces the ability of the peripheral nerves to activate muscles used for movement or to relay information from sensory cells back to the brain. As a result, individuals with a duplication of the PMP22 gene develop muscle weakness and impaired sensitivity to touch, heat, and cold. Duplications that involve the PMP22 gene but not the RAI1 gene cause type 1A Charcot-Marie-Tooth disease, which is characterized by similar problems with muscle weakness and sensation.

Researchers suspect that having an extra copy of additional genes in the duplicated region contribute to other features of the disorder, such as kidney abnormalities.

Normal Function

The RAI1 gene provides instructions for making a protein that is active in cells throughout the body, particularly nerve cells (neurons) in the brain. Located in the nucleus of the cell, the RAI1 protein helps control the activity (expression) of certain genes. Most of the genes regulated by RAI1 have not been identified. However, studies suggest that this protein controls the expression of several genes involved in daily (circadian) rhythms, such as the sleep-wake cycle. The RAI1 protein also appears to play a role in development of the brain and of bones in the head and face (craniofacial bones).

Health Conditions Related to Genetic Changes

Potocki-Lupski syndrome

Having an extra copy of the RAI1 gene in each cell is thought to underlie many of the major features of Potocki-Lupski syndrome. This condition is characterized by delayed development, mild to moderate intellectual disability, autism spectrum disorder (which affects social interaction and communication), sleep disturbances, and other health problems. The condition results from abnormal copying (duplication) of a small piece of the short (p) arm of chromosome 17 at position p11.2. In about two-thirds of affected individuals, the duplicated segment includes approximately 3.7 million DNA building blocks (base pairs), also written as 3.7 megabases (Mb). (A deletion of this segment causes Smith-Magenis syndrome, described below.) In the remaining one-third of cases, the duplication is larger or smaller, ranging from less than 1 Mb to almost 20 Mb. All of these duplications affect one of the two copies of chromosome 17 in each cell.

All of the duplications known to cause Potocki-Lupski syndrome contain the RAI1 gene. Studies suggest that the duplication increases the amount of RAI1 protein, which disrupts the expression of genes that influence circadian rhythms. These changes may account for the sleep disturbances that occur with Potocki-Lupski syndrome. Too much RAI1 protein may also disrupt brain development, which could account for delayed development, intellectual disability, behavioral problems, and other neurological features of this condition. Development of the bones in the head and face may also be affected, leading to subtle facial differences in people with Potocki-Lupski syndrome.

Smith-Magenis syndrome

Researchers believe that a partial or total loss of function of the RAI1 gene accounts for most of the signs and symptoms of Smith-Magenis syndrome. The major features of this condition include mild to moderate intellectual disability, delayed speech and language skills, distinctive facial features, sleep disturbances, behavioral problems, and other abnormalities affecting many parts of the body.

In most people with Smith-Magenis syndrome, the condition results from a deletion of a small piece of chromosome 17 in each cell. Most often, this chromosome segment, located at 17p11.2, is the same one that is duplicated in Potocki-Lupski syndrome (described above). Occasionally the deletion is larger or smaller. All of the deletions affect one of the two copies of chromosome 17 in each cell.

All of the deletions known to cause Smith-Magenis syndrome contain the RAI1 gene. Studies suggest that the deletion leads to a reduced amount of RAI1 protein in cells, which disrupts the expression of genes involved in circadian rhythms. These changes may account for the sleep disturbances that occur with Smith-Magenis syndrome. It is unclear how a loss of one copy of the RAI1 gene leads to the other physical, mental, and behavioral problems associated with this condition.

A small percentage of people with Smith-Magenis syndrome have a mutation in the RAI1 gene instead of a chromosomal deletion. Although these individuals have many of the major features of the condition, they are less likely than people with a deletion to have certain other features, including short stature, hearing loss, and heart or kidney abnormalities. It is likely that, in people with a deletion, the loss of other genes in the deleted region accounts for these additional signs and symptoms; the role of these genes is under study.

Yuan-Harel-Lupski syndrome

Having an extra copy of the RAI1 gene in each cell is thought to underlie many of the major features of Yuan-Harel-Lupski (YUHAL) syndrome, which is characterized by multiple neurological problems. This condition results from duplication of a small piece of chromosome 17 in a region designated p12-p11.2. In YUHAL syndrome, the duplicated segments can range in size from 3.2 Mb to 19.7 Mb. These duplications affect one of the two copies of chromosome 17 in each cell.

The duplications that cause YUHAL syndrome all contain the RAI1 gene and a nearby gene called PMP22; the segments may also contain additional genes. Some features of YUHAL syndrome, such as delayed development, behavioral and sleep problems, and unusual facial features, are similar to those of Potocki-Lupski syndrome (described above) and are likely caused by an extra copy of the RAI1 gene. Other features of YUHAL syndrome, such as muscle weakness and decreased sensitivity to touch, heat, and cold in the lower legs and feet, likely result from an extra copy of the PMP22 gene.

Other Names for This Gene

• KIAA1820
• RAI1_HUMAN
• SMCR
• SMS

Genomic Location

Normal Function

The PMP22 gene provides instructions for making a protein called peripheral myelin protein 22 (PMP22). This protein is found in the peripheral nervous system, which connects the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound.

The PMP22 protein is a component of myelin, a protective substance that covers nerves and promotes the efficient transmission of nerve impulses. The protein is produced primarily by specialized cells called Schwann cells that wrap around and insulate nerves. Within Schwann cells, PMP22 plays a crucial role in the development and maintenance of myelin. Studies suggest that the PMP22 protein is particularly important in protecting nerves from physical pressure, helping them restore their structure after being pinched or squeezed (compressed). Compression can interrupt nerve signaling, leading to the sensation commonly referred to as a limb "falling asleep." The ability of nerves to recover from normal, day-to-day compression, for example when sitting for long periods, keeps the limbs from constantly losing sensation. The PMP22 gene also plays a role in the growth of Schwann cells and the process by which cells mature to carry out specific functions (differentiation).

Before they become part of myelin, newly produced PMP22 proteins are processed and packaged in specialized cell structures called the endoplasmic reticulum and the Golgi apparatus. Completion of these processing and packaging steps is critical for proper myelin function.

Health Conditions Related to Genetic Changes

Charcot-Marie-Tooth disease

Mutations in the PMP22 gene cause several forms of a neurological disorder called Charcot-Marie-Tooth disease. This disorder damages the peripheral nerves, which can result in loss of sensation and wasting (atrophy) of muscles in the feet, legs, and hands.

An extra copy of the PMP22 gene in each cell caused by a duplication of genetic material on chromosome 17 is the most common genetic change that causes Charcot-Marie-Tooth disease type 1A (CMT1A). The extra gene leads to an overproduction of PMP22 protein. The connection between excess PMP22 protein and the signs and symptoms of CMT1A is unclear. Research suggests that excess PMP22 protein may overwhelm the cells' ability to process it correctly, leading to a buildup of unprocessed, nonfunctional protein. This buildup may impair the formation of myelin and disrupt other Schwann cell activities, leading to instability and loss of myelin (demyelination). Demyelination reduces the ability of the peripheral nerves to activate muscles used for movement or relay information from sensory cells back to the brain. Typically beginning in adolescence, affected individuals experience atrophy of the muscles of the lower legs and hands and decreased sensitivity to touch, heat, and cold.

CMT1A is also caused by mutations that add, delete, or change the building blocks (amino acids) used to make PMP22 protein. The altered protein is probably processed at a slower rate, and some of the protein is processed abnormally. These disruptions of PMP22 processing impair the normal functions of the Schwann cell, leading to demyelination and producing the signs and symptoms of CMT1A.

In addition to muscle and sensory problems, hearing loss is experienced by some people with a form of Charcot-Marie-Tooth disease called type 1E (CMT1E). CMT1E is associated with particular amino acid substitutions and deletions in the PMP22 gene. The most frequently reported mutation causing hearing loss replaces the amino acid alanine with the amino acid proline at protein position 67 (also written as Ala67Pro).

Some mutations in the PMP22 gene cause a severe form of Charcot-Marie-Tooth disease sometimes referred to as Dejerine-Sottas disease or type 3 Charcot-Marie-Tooth disease. This form of the disorder usually begins in infancy, causing muscle weakness and atrophy and delayed development of motor skills such as walking. The mutations that cause this form of Charcot-Marie-Tooth disease are thought to reduce the amount of functional PMP22 protein in cells. It is unclear why they cause more severe features than the mutations that cause CMT1A. Studies suggest that cell function is sensitive to the amount of PMP22 protein, and that having either too much or too little of this protein can cause disease.

Hereditary neuropathy with liability to pressure palsies

Loss (deletion) of one copy of the PMP22 gene from each cell is the most common genetic cause of hereditary neuropathy with liability to pressure palsies. This disorder is characterized by recurrent episodes of numbness, tingling, or loss of muscle function, usually triggered by pressure on a nerve in an arm or leg. Deletion of one copy of the PMP22 gene reduces the amount of PMP22 protein produced by about half. This disorder can also be caused by PMP22 gene mutations that change single amino acids in the PMP22 protein or that lead to production of an abnormally small protein that is rapidly broken down. The consequences of a shortage of PMP22 protein are not clearly understood. Shortage of PMP22 protein may affect the structure of the myelin covering, impairing the transmission of nerve impulses. In addition, nerves are less able to recover from compression, which also interrupts nerve signaling, causing the signs and symptoms of hereditary neuropathy with liability to pressure palsies.

Yuan-Harel-Lupski syndrome

Having an extra copy of the PMP22 gene in each cell is thought to underlie many of the major features of Yuan-Harel-Lupski (YUHAL) syndrome, which is characterized by multiple neurological problems. Some features of this condition, particularly muscle weakness and decreased sensitivity to touch, heat, and cold in the lower legs and feet, are similar to those of CMT1A (described above). Other features of YUHAL syndrome include delayed development and behavioral problems.

YUHAL syndrome results from abnormal copying (duplication) of a small piece of the short (p) arm of chromosome 17 in a region designated p12-p11.2. In YUHAL syndrome, the duplicated segments can range in size from 3.2 million DNA building blocks (also written as 3.2 megabases or 3.2Mb) to 19.7Mb. These segments contain the PMP22 gene, a nearby gene called RAI1, and sometimes additional genes.

As in Charcot-Marie-Tooth disease (described above), an extra copy of the PMP22 gene leads to nerve problems that cause lower leg and foot abnormalities. Duplication of the RAI1 gene accounts for delayed development, behavioral problems, and some of the other abnormalities characteristic of YUHAL syndrome.

Other Names for This Gene

• GAS-3
• GAS3
• growth arrest-specific 3
• HNPP
• MGC20769
• PMP22_HUMAN
• Sp110

Genomic Location

YUHAL syndrome follows an autosomal dominant pattern of inheritance, which means one copy of the chromosome duplication in each cell is sufficient to cause the disorder. Most cases of this condition result from new (de novo) duplications that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. These cases occur in people with no history of the disorder in their family.

The prevalence of YUHAL syndrome is unknown. More than 20 people with the condition have been described in the medical literature.