Wiedemann-Rautenstrauch syndrome is a type of progeria, which is a group of genetic conditions characterized by the dramatic, rapid appearance of aging earlier in life than expected. Signs and symptoms of Wiedemann-Rautenstrauch syndrome begin before birth. Affected individuals do not grow and gain weight at the expected rate before and after birth. People with this condition have distinctive facial features that give the appearance of old age. They often have a large head, a triangular face with a prominent forehead and pointed chin, a small mouth with a thin upper lip, low-set ears, and abnormal lower eyelids. In most affected individuals, the middle of the face looks as though it has been drawn inward (midface retraction). On the head, hair is sparse and the veins stand out. Also contributing to the appearance of aging is a lack of fatty tissue under the skin (lipodystrophy), particularly in the face, arms, and legs. In addition, the skin is thin and translucent. Some affected individuals develop joint abnormalities called contractures that can limit movement.

In people with Wiedemann-Rautenstrauch syndrome, the spaces (fontanelles) between the skull bones (that are noticeable as "soft spots" on the heads of infants) are larger than normal. The fontanelles normally close in early childhood, but they may remain open throughout life in people with this condition. Many affected infants are born with teeth (natal teeth), which fall out a few weeks after birth; however, some or all of their permanent (adult) teeth may never develop (hypodontia).

In some individuals with Wiedemann-Rautenstrauch syndrome, movement problems, such as difficulty with coordination and balance (ataxia) or involuntary rhythmic shaking (tremor), appear in childhood and worsen over time.

The life expectancy in Wiedemann-Rautenstrauch syndrome is variable. While some affected individuals do not survive past infancy, others live into young adulthood.

Wiedemann-Rautenstrauch syndrome is caused by mutations in a gene called POLR3A. This gene provides instructions for making the largest piece (subunit) of an enzyme called RNA polymerase III. This enzyme is involved in the production (synthesis) of ribonucleic acid (RNA), a chemical cousin of DNA. RNA polymerase III helps synthesize several forms of RNA, including those that assemble protein building blocks (amino acids) into working proteins. This process is essential for the normal functioning and survival of cells in tissues throughout the body.

The POLR3A gene mutations that cause Wiedemann-Rautenstrauch syndrome lead to production of abnormal subunit proteins. The abnormal subunits may prevent assembly of the RNA polymerase III enzyme or result in an RNA polymerase III with impaired ability to synthesize RNA. Reduced function of the RNA polymerase III molecule likely affects development and function of many parts of the body, but how the POLR3A gene mutations result in the specific signs and symptoms of Wiedemann-Rautenstrauch syndrome is unknown.

Normal Function

The POLR3A gene provides instructions for making the largest piece (subunit) of an enzyme called RNA polymerase III. This enzyme is involved in the production (synthesis) of ribonucleic acid (RNA), a chemical cousin of DNA. The RNA polymerase III enzyme attaches (binds) to DNA and synthesizes RNA molecules in accordance with the instructions carried by the DNA, a process called transcription. RNA polymerase III helps synthesize several forms of RNA, including ribosomal RNA (rRNA) and transfer RNA (tRNA). Molecules of rRNA and tRNA assemble protein building blocks (amino acids) into working proteins; this process is essential for the normal functioning and survival of cells.

Health Conditions Related to Genetic Changes

Pol III-related leukodystrophy

At least 70 POLR3A gene mutations have been associated with Pol III-related leukodystrophy. Leukodystrophies are conditions that involve abnormalities of the nervous system's white matter. White matter consists of nerve fibers covered by a fatty substance called myelin, which insulates nerve fibers and promotes the rapid transmission of nerve impulses. A reduced ability to form myelin (hypomyelination) leads to the signs and symptoms of Pol III-related leukodystrophy, which include intellectual disability and difficulty with coordinating movements (ataxia). Development of the teeth (dentition) is also abnormal in this disorder.

In Pol III-related leukodystrophy, POLR3A gene mutations may impair the ability of the subunits of the RNA polymerase III enzyme to assemble properly or result in an RNA polymerase III with impaired ability to bind to DNA. Reduced function of the RNA polymerase III molecule likely affects development and function of many parts of the body, but the relationship between POLR3A gene mutations and the specific signs and symptoms of this disorder is unknown.

People with Pol III-related leukodystrophy may have different combinations of its signs and symptoms. These varied combinations of clinical features were originally described as separate disorders. Affected individuals may be diagnosed with ataxia, delayed dentition, and hypomyelination (ADDH); hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); tremor-ataxia with central hypomyelination (TACH); leukodystrophy with oligodontia (LO); or hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). Because these disorders were later found to have the same genetic cause, researchers now group them as variations of the single condition Pol III-related leukodystrophy.

Wiedemann-Rautenstrauch syndrome

Mutations in the POLR3A gene cause Wiedemann-Rautenstrauch syndrome, which is a condition characterized by the dramatic, rapid appearance of aging beginning early in life. Affected individuals grow slowly before and after birth. They have a characteristic facial appearance, a lack of fatty tissue under the skin (lipodystrophy), sparse hair on their head, and abnormal tooth development. Some of the mutations that cause this condition alter the blueprint for making proteins. Other mutations lead to an abnormally short blueprint. Both types of mutations result in production of abnormal subunit proteins that are thought to impair the function of RNA polymerase III. The resulting shortage of RNA synthesis likely impairs protein production in cells, affecting development and function of many parts of the body. However, it is not known exactly how changes in the POLR3A gene lead to the features of Wiedemann-Rautenstrauch syndrome.

Researchers suspect that mutations that cause Wiedemann-Rautenstrauch syndrome reduce RNA polymerase III function more drastically than mutations that cause Pol III-related leukodystrophy (described above), which may explain why development is affected even before birth in individuals with Wiedemann-Rautenstrauch syndrome. Because of its distinct signs and symptoms, Wiedemann-Rautenstrauch syndrome is not thought to be part of the Pol III-related leukodystrophy spectrum.

Shingles

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Other disorders

Mutations in the POLR3A gene have been found in individuals with ataxia and dental abnormalities. Unlike in Pol III-related leukodystrophy (described above), these individuals do not have reduced myelination in the nervous system. When associated with POLR3A gene mutations, ataxia typically begins in adolescence. Affected individuals may also develop rhythmic shaking (tremor) in the arms or legs and have a reduced ability to sense vibrations, particularly in the feet. It is unclear why mutations in the same gene lead to several disorders of varying severity. Researchers are unsure if this condition is part of the spectrum of Pol III-related leukodystrophies.

Other Names for This Gene

• ADDH
• DNA-directed RNA polymerase III largest subunit
• DNA-directed RNA polymerase III subunit A
• DNA-directed RNA polymerase III subunit RPC1
• HLD7
• HRPC155
• polymerase (RNA) III (DNA directed) polypeptide A, 155kDa
• polymerase (RNA) III subunit A
• RNA polymerase III 155 kDa subunit
• RNA polymerase III subunit C1
• RNA polymerase III subunit C160
• RNA polymerase III subunit RPC155-D
• RPC1
• RPC155
• RPC1_HUMAN

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

• Subcutaneous lipoatrophy (deficiency or absence of the fat layer beneath the skin) which gives infants an aged appearance at birth
• Intrauterine growth restriction
• Failure to thrive
• Feeding difficulties
• Distinctive craniofacial features such as a triangular face; large skull with wide anterior (front) fontanelle; small, underdeveloped facial bones; natal teeth; low-set, posteriorly (towards the back) rotated ears, ectropion; and/or unusually sparse scalp hair, eyebrows, and eyelashes
• Thin arms and legs with disproportionately large hands and feet
• Small fingers and toes with underdeveloped nails
• Osteopenia (low bone density)
• Horizontal nystagmus
• Developmental delay
• Mild to severe intellectual disability

Wiedemann-Rautenstrauch syndrome is a rare disorder. Its prevalence is unknown.