SNP Shot: Genomic Insights

Progressive external ophthalmoplegia (PEO) is a condition characterized by weakness in the muscles that control eye movement. It typically begins in adulthood, between the ages of 18 and 40, and gradually worsens. The first noticeable symptom is often drooping eyelids (ptosis), affecting either one or both eyes. As ptosis progresses, individuals may unconsciously raise their eyebrows to try to lift the eyelids or tilt their chin upward to improve their vision. Another key feature of PEO is ophthalmoplegia, which is weakness or paralysis of the eye muscles. This forces individuals to turn their head to see in different directions, especially as the ophthalmoplegia becomes more severe. Some individuals with PEO also experience general muscle weakness (myopathy), particularly in the neck, arms, or legs. This weakness can be more pronounced during exercise (exercise intolerance). Difficulty swallowing (dysphagia) can also result from muscle weakness.

Microscopic examination of stained muscle cells from affected individuals usually reveals abnormalities. Specifically, these cells contain an excessive number of mitochondria, cellular structures, leading to their classification as ragged-red fibers.

While muscle weakness is the primary symptom of PEO, the condition can sometimes present with additional signs and symptoms. In these cases, it's referred to as progressive external ophthalmoplegia plus (PEO+). These additional symptoms may include hearing loss due to nerve damage in the inner ear (sensorineural hearing loss), weakness and numbness in the limbs due to nerve damage (neuropathy), impaired coordination (ataxia), movement problems resembling Parkinson's disease (parkinsonism), and depression.

PEO is part of a group of related disorders that share overlapping symptoms. Similar conditions include ataxia neuropathy spectrum and Kearns-Sayre syndrome. Like PEO, these disorders can also involve eye muscle weakness. However, they are distinguished by the presence of additional features that are not typically observed in individuals with PEO.

Inheritance:

The inheritance pattern of PEO varies depending on the specific gene involved. When mutations occur in nuclear genes such as POLG, TWNK, RRM2B, or SLC25A4, PEO is typically inherited in an autosomal dominant manner. This means that only one copy of the mutated gene is needed in each cell to cause the disorder. Certain mutations in the POLG or RRM2B genes can also result in an autosomal recessive inheritance pattern, where both copies of the gene in each cell must be mutated for the condition to develop. In autosomal recessive inheritance, each parent carries one copy of the mutated gene, but they usually don't exhibit symptoms of the disorder. When PEO is caused by mutations in the MT-TL1 gene or other mitochondrial transfer RNA genes, it follows a mitochondrial (maternal) inheritance pattern. This pattern affects genes located in mitochondrial DNA (mtDNA). Because only egg cells contribute mitochondria to the developing embryo, children can only inherit mtDNA mutations from their mother. These disorders can appear in every generation of a family and affect both males and females, but fathers cannot pass on mtDNA mutations to their children. Large, single deletions of mtDNA are generally not inherited; instead, they occur spontaneously during the formation of a mother's egg cells or in the early stages of embryo development. Individuals with these mutations usually have no family history of the disorder.