Pelizaeus–Merzbacher disease

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Pelizaeus–Merzbacher disease
Pelizaeus–Merzbacher disease is inherited in an x-linked recessive manner[1]
SpecialtyNeurology Edit this on Wikidata

leukodystrophies.[2]

Signs and symptoms

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 are

convulsions and skeletal deformation, such as scoliosis, resulting from abnormal muscular stress on bones.[3]

Cause

Pelizaeus–Merzbacher disease is caused by

hypomyelination in the central nervous system and severe neurological disease. The majority of mutations result in duplications of the entire PLP1 gene. Deletions of PLP1 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 of gene dosage at this locus for normal CNS function.[4]

Diagnosis

The diagnosis of Pelizaeus–Merzbacher disease is often first suggested after identification by

prenatal diagnosis or preimplantation genetic diagnostic testing is possible.[citation needed
]

Classification

The disease is one in a group of

nerve fibers in the central 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 the PLP1 gene that mainly cause leg weakness and spasticity, with little or no cerebral involvement, are classified as spastic paraplegia 2 (SPG2).[citation needed]

Treatment

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]

A phase I clinical trial using an antisense oligonucleotide (known as ION356) targeted against PLP1 is expected to begin in early 2024.[10]

Research

In December 2008,

phase I clinical trials of human neural stem cell transplantation.[11] The trial did not show meaningful efficacy and the company has since gone bankrupt.[12]

In 2019 Paul Tesar, a professor at Case Western Reserve University, used CRISPR and antisense 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]

See also

References

  1. ^ "OMIM Entry - # 312080 - Pelizaeus-Merzbacher Disease; PMD". omim.org. Retrieved 5 August 2017.
  2. S2CID 25529422
    .
  3. ^ "Pelizaeus-Merzbacher disease: MedlinePlus Genetics". medlineplus.gov. Retrieved 2022-06-25.
  4. ^ Sima, A.A.F.; Pierson, C.R.; Woltjer, R.L.; et, al (2009). "Neuronal loss in Pelizaeus–Merzbacher disease differs in various mutations of the proteolipid protein 1". Acta Neuropathol. 118 (4): 531–539.
    PMID 19562355
    . Retrieved January 14, 2024.
  5. ^ "Pelizaeus-Merzbacher disease (Concept Id: C0205711) - MedGen - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-03-03.
  6. S2CID 229182946
    .
  7. ^ "National Library of Medicine". National Institutes of Health. Retrieved 7 March 2024.
  8. ^ "Online Mendelian Inheritance in Man". Johns Hopkins University.
  9. ^ a b "Pelizaeus-Merzbacher Disease Information Page". National Institute of Neurological Disorders and Stroke.
  10. ^ "Ionis Innovation Day". Retrieved October 4, 2023.
  11. ^ "Stem Cells, Inc".
  12. ^ "End of line for StemCells Inc., pioneering & controversial stem cell biotech". 2016-05-31.
  13. doi:10.1101/508192
    .
  14. PMID 32610343
    .
  15. ^ "Research finds new approach to treating certain neurological diseases". MedicalXpress. 1 July 2020. Retrieved 1 July 2020. 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
  16. ^ "Case Western Reserve University grants exclusive license to Ionis Pharmaceuticals to advance antisense therapy for Pelizaeus-Merzbacher disease". The Daily. 2022-01-27. Retrieved 2022-03-06.

Further reading

External links
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