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Pol III-related leukodystrophy is a condition that affects the brain, spinal cord, and other parts of the body. It belongs to a group of disorders called leukodystrophies, which involve problems with the brain's white matter. White matter is made up of nerve cells (neurons) that are surrounded by myelin, a fatty substance that insulates nerve fibers and allows them to transmit signals quickly.
Pol III-related leukodystrophy is a type of hypomyelinating disease. This means that the body doesn't produce enough myelin. This lack of myelin is the primary cause of the neurological issues seen in this condition. Some individuals also experience a loss of nerve cells in the cerebellum (cerebellar atrophy), which is responsible for coordinating movement, and incomplete development (hypoplasia) of the corpus callosum, the tissue connecting the two halves of the brain. These brain abnormalities likely contribute to the neurological problems.
Individuals with Pol III-related leukodystrophy usually have intellectual disability that ranges in severity from mild to severe and often worsens over time. While some may have normal intelligence early in life, they may develop mild intellectual disability as the condition progresses.
A hallmark of Pol III-related leukodystrophy is difficulty with coordination and balance (ataxia), which starts in childhood and gradually worsens. Children with this condition often experience delays in motor skills like walking. They may have an unsteady gait, walking with their feet wide apart to maintain balance. Over time, some individuals may need to use a walker or wheelchair. Involuntary shaking (tremor) of the arms and hands may also occur. The tremor can be present only during movement (intention tremor) or may occur both during movement and at rest.
Dental development is often abnormal in Pol III-related leukodystrophy. This can result in the absence of some teeth (hypodontia or oligodontia). Some infants may be born with a few teeth (natal teeth) that fall out within the first few weeks of life. The first set of teeth (deciduous teeth) may appear later than expected, typically around age 2. The usual order of tooth eruption may be disrupted, with molars appearing before incisors, or incisors being delayed or absent altogether. Permanent teeth may also be delayed, sometimes not appearing until adolescence. Additionally, the teeth may have an unusual shape.
Some individuals with Pol III-related leukodystrophy experience excessive drooling and difficulty chewing or swallowing (dysphagia), which can lead to choking. Speech may also be impaired (dysarthria). Abnormalities in eye movement are common, including progressive vertical gaze palsy, a condition in which the ability to move the eyes up and down is restricted and worsens over time. Nearsightedness is frequently observed, and clouding of the lens of the eye (cataracts) has been reported. Deterioration (atrophy) of the optic nerves, which transmit visual information to the brain, and seizures can also occur.
Hypogonadotropic hypogonadism, a condition caused by reduced production of hormones that regulate sexual development, can also occur in Pol III-related leukodystrophy. Individuals with this condition may experience delayed puberty and the development of associated physical characteristics, such as body hair.
The signs and symptoms of Pol III-related leukodystrophy can vary widely among affected individuals. These variations were originally described as distinct disorders, such as 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). However, because these conditions share the same genetic cause, they are now understood to be variations of the same disorder, Pol III-related leukodystrophy.
Pol III-related leukodystrophy is inherited in an autosomal recessive manner. This means that a person must inherit two copies of the mutated gene, one from each parent, to develop the condition. The parents, who each carry one copy of the mutated gene, typically do not exhibit any signs or symptoms of the disorder.
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