Pelizaeus– Merzbacher disease is an

X-linked Sex linked describes the sex-specific patterns of inheritance and presentation when a gene mutation (allele) is present on a sex chromosome (allosome) rather than a non-sex chromosome (autosome). In humans, these are termed X-linked recessive, ...

neurological disorder that damages

oligodendrocytes Oligodendrocytes (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in the ...

in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

. It is caused by mutations in proteolipid protein 1 (''PLP1''), a major

myelin Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...

protein. It is characterized by a decrease in the amount of insulating

surrounding the nerves (hypomyelination) and belongs to a group of genetic diseases referred to as

leukodystrophies Leukodystrophies are a group of usually inherited disorders characterized by degeneration of the white matter in the brain. The word ''leukodystrophy'' comes from the Greek roots ''leuko'', "white", ''dys'', "abnormal" and ''troph'', "growth". Th ...

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. The onset of Pelizaeus–Merzbacher disease is usually in early infancy. The most characteristic early signs are

nystagmus Nystagmus is a condition of involuntary (or voluntary, in some cases) eye movement. Infants can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in reduced or limited vision. Due to the invol ...

(rapid, involuntary, rhythmic motion of the eyes) and low 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 include tremor, lack of coordination, involuntary movements, weakness, unsteady gait, and over time, spasticity in legs and arms. Muscle contractures often occur over time. Mental functions may deteriorate. Some patients may have

convulsions A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is sometimes used as a s ...

and skeletal deformation, such as scoliosis, resulting from abnormal muscular stress on bones.

Cause

Pelizaeus–Merzbacher disease is caused by

X-linked recessive X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily homozygous for the gene mutation because they have one X and one Y ...

mutations in the major myelin

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

proteolipid protein 1 (''PLP1''). This causes hypomyelination in the

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 Gene dosage is the number of copies of a particular gene present in a genome. Gene dosage is related to the amount of gene product (proteins or functional RNAs) the cell is able to express. Since, a gene acts as a template, the number of templates ...

at this locus for normal CNS function.

Diagnosis

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

sex-linked Sex linked describes the sex-specific patterns of inheritance and presentation when a gene mutation (allele) is present on a sex chromosome (allosome) rather than a non-sex chromosome ( autosome). In humans, these are termed X-linked recessive, ...

inheritance exists, the condition is often misdiagnosed as cerebral palsy. Once a ''PLP1'' mutation is identified,

prenatal diagnosis Prenatal testing consists of prenatal screening and prenatal diagnosis, which are aspects of prenatal care that focus on detecting problems with the pregnancy as early as possible. These may be anatomic and physiologic problems with the health of ...

or preimplantation genetic diagnostic testing is possible.

Classification

The disease is one in a group of

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

s collectively known as

that affect the growth of the

sheath, the fatty covering—which acts as an insulator—on nerve fibers in the

. The several forms of Pelizaeus–Merzbacher disease include classic, congenital, transitional, and adult variants. 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).

Treatment

No cure for Pelizaeus–Merzbacher disease has been developed. 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.

Research

In December 2008, StemCells, Inc received clearance in the United States to conduct a phase I clinical trials of human

neural stem cell Neural stem cells (NSCs) are self-renewing, multipotent cells that firstly generate the radial glial progenitor cells that generate the neurons and glia of the nervous system of all animals during embryonic development. Some neural progenitor ste ...

transplantation. The trial did not show meaningful efficacy and the company has since gone bankrupt. In 2019 Paul Tesar, a professor at Case Western Reserve University, used CRISPR and

antisense therapy Antisense therapy is a form of treatment that uses antisense oligonucleotides (ASOs) to target messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre- ...

in a mouse model of Pelizaeus–Merzbacher with success. In 2022 Case Western Reserve University entered a exclusive licensing agreement with Ionis Pharmaceuticals to develop a human treatment for the disorder.

References

External links

Pelizaeus-Merzbacher Disease
- PMD Foundation

NINDS/National Health Institutes. * {{DEFAULTSORT:Pelizaeus-Merzbacher Disease Lipid storage disorders Leukodystrophies X-linked recessive disorders Rare diseases Demyelinating diseases of CNS