| Pelizaeus–Merzbacher disease | |
|---|---|
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| Pelizaeus–Merzbacher disease is inherited in an x-linked recessive manner[1] | |
| Specialty | Neurology  |
Pelizaeus–Merzbacher disease is anX-linked neurological disorder that damagesoligodendrocytes in thecentral nervous system. It is caused by mutations inproteolipid protein 1 (PLP1), a majormyelin protein. It is characterized by a decrease in the amount of insulatingmyelin surrounding the nerves (hypomyelination) and belongs to a group of genetic diseases referred to asleukodystrophies.[2]
The hallmark signs and symptoms of Pelizaeus–Merzbacher disease include little or no movement in the arms or legs, respiratory difficulties, and characteristic horizontal movements of the eyes left to right.[citation needed]
The onset of Pelizaeus–Merzbacher disease is usually in early infancy. The most characteristic early signs arenystagmus (rapid, involuntary, rhythmic motion of the eyes) andlow muscle tone. Motor abilities are delayed or never acquired, mostly depending upon the severity of the mutation. Most children with Pelizaeus–Merzbacher disease learn to understand language, and usually have some speech. Other signs may includetremor, lack of coordination, involuntary movements, weakness, unsteadygait, and over time, spasticity in legs and arms.Muscle contractures often occur over time. Mental functions may deteriorate. Some patients may haveconvulsions and skeletal deformation, such asscoliosis, resulting from abnormal muscular stress on bones.[3]
Pelizaeus–Merzbacher disease is caused byX-linked recessive mutations in the major myelinproteinproteolipid protein 1 (PLP1). This causeshypomyelination in thecentral nervous system and severe neurological disease. The majority of mutations result in duplications of the entirePLP1 gene. Deletions ofPLP1 locus (which are rare) cause a milder form of Pelizaeus–Merzbacher disease than is observed with the typical duplication mutations, which demonstrates the critical importance ofgene dosage at this locus for normal CNS function.[4]
The diagnosis of Pelizaeus–Merzbacher disease is often first suggested after identification bymagnetic resonance imaging of abnormal white matter (high T2 signal intensity, i.e. T2 lengthening) throughout the brain, which is typically evident by about 1 year of age, but more subtle abnormalities should be evident during infancy. Unless a family history consistent withsex-linked inheritance exists, the condition is often misdiagnosed as cerebral palsy. Once aPLP1 mutation is identified,prenatal diagnosis or preimplantation genetic diagnostic testing is possible.[citation needed]
The disease is one in a group ofgenetic disorders collectively known asleukodystrophies that affect the growth of themyelin sheath, the fatty covering—which acts as an insulator—onnerve fibers in thecentral nervous system. The several forms of Pelizaeus–Merzbacher disease include classic, congenital, transitional, and adult variants.[5] Pelizaeus–Merzbacher disease is the common name for hypomyelinating leukodystrophies (HLD).[6] There are at least 26 HLD variants cataloged by the National Institutes of Health National Library of Medicine[7] and the Online Mendelian Inheritance in Man (OMIM) compendium of human genes and genetic phenotypes.[8]
Milder mutations of thePLP1 gene that mainly cause leg weakness and spasticity, with little or no cerebral involvement, are classified as spastic paraplegia 2 (SPG2).[citation needed]
No cure for Pelizaeus–Merzbacher disease has been developed.[9] Outcomes are variable: people with the most severe form of the disease do not usually survive to adolescence, although with milder forms, survival into adulthood is possible.[9]
Ionis Pharmaceuticals is currently testing ION356, an antisense oligonucleotide targeted againstPLP1, in a Phase 1b trial in PMD patients.[10]
In December 2008,StemCells, Inc received clearance in the United States to conduct aphase I clinical trials of humanneural stem cell transplantation.[11] The trial did not show meaningful efficacy and the company has since gone bankrupt.[12]
In 2019Paul Tesar, a professor at Case Western Reserve University, usedCRISPR andantisense therapy in a mouse model of Pelizaeus–Merzbacher with success.[13][14][15] In 2022 Case Western Reserve University entered an exclusive licensing agreement with Ionis Pharmaceuticals to develop a human treatment for the disorder.[16]
Their research was published online July 1 in the journal Nature. "The pre-clinical results were profound. PMD mouse models that typically die within a few weeks of birth were able to live a full lifespan after treatment," said Paul Tesar