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These Early Symptoms Reveal the Secrets of Pelizaeus-Merzbacher Disease: Can You Recognize It?
Pelizaeus-Merzbacher disease is an X-linked neurological disorder that causes damage to oligodendrocytes in the central nervous system. The disease is caused by mutations in the major myelin protein, lipopolysaccharide protein 1 (PLP1). One of the hallmarks of Pelizaeus-Merzbacher disease is a decrease in the amount of insulating myelin sheath surrounding nerves, a phenomenon called hypomyelination. The disease belongs to a group of genetic disorders called leukodystrophies.
Symptoms and signs
The hallmark symptoms of Pelizaeus-Merzbacher disease usually develop in early infancy and include minimal movement of the limbs, labored breathing, and noticeable side-to-side eye movements. Typical early signs include nystagmus and low muscle tone. As symptoms progress, motor skills are often delayed or lost, depending on the severity of the gene mutation.
Most children with Pelizaeus-Merzbacher disease are able to understand speech and usually have some speech.
Other possible symptoms include tremors, incoordination, involuntary movements, weakness, unsteady gait, and over time, spasticity in the limbs and legs. As the disease progresses, muscle contractures may occur. Intellectual function may decline, and some patients may even develop epilepsy and spinal deformities, such as scoliosis, due to the effects of abnormal muscle pressure on the bones.
Causes
Pelizaeus-Merzbacher disease is caused by an X-linked recessive mutation affecting the major myelin protein, lipinase protein 1 (PLP1), which is essential for the normal function of the central nervous system. Most mutations result in duplication of the entire PLP1 gene, while deletion of the PLP1 locus (although rare) causes milder forms of Pelizaeus-Merzbacher disease, demonstrating the importance of gene dosage for normal central nervous system function compared to typical duplication mutations. The importance of.
Diagnosis
The diagnosis of Pelizaeus-Merzbacher disease is usually made tentatively by finding abnormal white matter (high T2 signal intensity, i.e., T2 prolongation) on magnetic resonance imaging (MRI) around the age of one year, but more subtle abnormalities should already be apparent during infancy and childhood. come out. Unless there is a family history consistent with sex-linked inheritance, the disorder is often misdiagnosed as cerebral palsy. Once a PLP1 mutation has been identified, prenatal diagnosis or embryo implantation genetic diagnosis testing can be done.
Categories
The disease is part of a group of inherited disorders called leukodystrophies, which affect the growth of myelin, the fatty covering on nerve fibers in the central nervous system that insulates them. There are several forms of Pelizaeus-Merzbacher disease including classic, congenital, transitional, and adult-onset variants. Pelizaeus-Merzbacher disease is a common name for hypomyelinating white matter dysplasia (HLD). According to the National Institutes of Health, at least 26 HLD variants have been catalogued.
TreatmentMilder PLP1 mutations cause primarily leg weakness and spasticity with little involvement of brain function; this form is classified as spastic paraplegia 2 (SPG2).
There are currently no treatment options developed for Pelizaeus-Merzbacher disease. Treatment effectiveness varies from person to person: the most severe cases usually do not survive into adolescence, while milder cases may survive into adulthood. A Phase I clinical trial of an antiviral oligonucleotide (ION356) targeting PLP1 is expected to initiate in early 2024.
Research Progress
In December 2008, StemCells, Inc. obtained approval for a Phase I clinical trial of human neural stem cell transplantation in the United States. However, the trial did not show significant therapeutic effects, and the company subsequently declared bankruptcy. In 2019, Paul Tesar, a professor at Case Western Reserve University, successfully used CRISPR technology and antiviral therapy in Pelizaeus-Merzbacher's mouse model. In 2022, Case Western Reserve University signed an exclusive licensing agreement with Ionis Pharmaceuticals with the goal of developing human treatments for the disease.
As research progresses, our understanding of Pelizaeus-Merzbacher disease has deepened, and identifying early signs is crucial for early diagnosis and treatment of the disease. When you are faced with these symptoms, can you quickly associate them with Pelizaeus-Merzbacher disease?
