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Did you know how Pelizaeus-Merzbacher disease changes a child's life and athletic ability?
Pelizaeus–Merzbacher disease is an X-chromosome inherited neurological disorder that affects oligodendrocytes in the central nervous system, causing damage to the myelin sheath surrounding nerve fibers. The underlying cause of the disease lies in mutations in the proteolipid protein 1 (PLP1) gene, a major myelin protein. Under the influence of these mutations, the insulating myelin sheath of the nerves decreases, resulting in what is called hypomyelination, a genetic disorder classified as white matter atrophy.
Signs and symptoms
The main signs and symptoms of Pelizaeus–Merzbacher disease include little or no movement of the limbs, difficulty breathing, and a characteristic eye movement—rapid side-to-side movement of the eyes. The onset of this disease usually occurs in early infancy. The earliest signs include nystagmus (rapid, involuntary eye movements) and low muscle tone.
Although many children with Pelizaeus–Merzbacher disease are delayed in motor skills or unable to learn, they usually understand language and have some verbal expression.
Other possible symptoms include tremors, lack of coordination, involuntary movements, weakness, and unsteady gait. As time goes by, limb spasms may occur, and muscle contractions often worsen. Cognitive function may decrease as the disease progresses. Some patients also develop problems such as epilepsy and spinal deformity, which are caused by abnormal muscle tone.
Cause
The cause of Pelizaeus–Merzbacher disease is primarily due to a recessive mutation on the X chromosome, which affects the major myelin protein, proteolipid protein 1 (PLP1). These mutations lead to hypomyelination in the central nervous system and cause severe neurological disease. Most mutations are duplications of the entire PLP1 gene, while deletions of the PLP1 gene (rarely) cause milder forms of Pelizaeus–Merzbacher disease, suggesting that gene dosage at this locus is critical for normal central nervous system function.
Diagnosis
The diagnosis of Pelizaeus–Merzbacher disease is usually first made after an abnormality (high T2 signal intensity) in the brain's white matter is discovered during magnetic resonance imaging. This abnormality is usually noticeable at about one year of age, but may not occur until More subtle abnormalities may be present in infancy. The disease is often misdiagnosed as cerebral palsy unless there is a family history consistent with gender-linked inheritance. Once a PLP1 mutation is identified, prenatal diagnosis or embryo implantation genetic diagnosis can be performed.
Category
The disease belongs to a group of genetic disorders known as leukoastrophies, which affect the growth of myelin. Several forms of Pelizaeus–Merzbacher disease include classic, congenital, transitional, and adult variants. The disease is colloquially known as hypomyelinating white matter atrophy (HLD). Currently, the National Institutes of Health and Human Genes and Genetic Phenotypes Online Mendelian Genetic Information have listed at least 26 HLD variants. Milder PLP1 gene mutations mainly cause weakness and spasticity in the lower limbs and have little effect on brain function. These conditions are classified as spastic paralysis 2 (SPG2).
Treatment
There is currently no treatment for Pelizaeus–Merzbacher disease. Treatment outcomes vary widely: patients with the most severe forms usually do not survive into adolescence, while with milder cases, survival into adulthood is possible. Phase 1 clinical trials of an anti-sense oligonucleotide targeting PLP1, called ION356, are expected to start in early 2024.
Research status
In December 2008, StemCells, Inc was approved in the United States to conduct the first phase of clinical trials of human neural stem cell transplantation. However, the trial did not show significant results and the company has also closed down. In 2019, Professor Paul Tesar of Case Western Reserve University successfully used CRISPR and anti-sense therapy in a mouse model of Pelizaeus–Merzbacher. In 2022, Case Western Reserve University entered into an exclusive license agreement with Ionis Pharmaceuticals to develop human treatments for the disease.
Pelizaeus–Merzbacher disease not only affects children’s athletic ability, but also profoundly affects their quality of life and family satisfaction. What kind of treatment breakthroughs will there be for this disease in the future?
