Pelizaeus–Merzbacher disease is an

X-linked Sex linkage describes the sex-specific patterns of inheritance and expression when a gene is present on a sex chromosome (allosome) rather than a non-sex chromosome ( autosome). Genes situated on the X-chromosome are thus termed X-linked, and ...

neurological disorder that damages oligodendrocytes in the

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

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

myelin Myelin Sheath ( ) is a lipid-rich material that in most vertebrates surrounds the axons of neurons to insulate them and increase the rate at which electrical impulses (called action potentials) pass along the axon. The myelinated axon can be lik ...

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.

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 (sensory), eye movement. People can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in visual impairment, re ...

(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 A tremor is an involuntary, somewhat rhythmic muscle contraction and relaxation involving neural oscillations, oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the h ...

, lack of coordination, involuntary movements, weakness, unsteady

gait Gait is the pattern of Motion (physics), movement of the limb (anatomy), limbs of animals, including Gait (human), humans, during Animal locomotion, locomotion over a solid substrate. Most animals use a variety of gaits, selecting gait based on s ...

, and over time, spasticity in legs and arms.

Muscle contracture Muscle contractures can occur for many reasons, such as paralysis, muscular atrophy, and forms of muscular dystrophy. Fundamentally, the muscle and its tendons shorten, resulting in reduced flexibility. Various interventions can slow, stop, o ...

s 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 often used as a synony ...

and skeletal deformation, such as

scoliosis Scoliosis (: scolioses) is a condition in which a person's Vertebral column, spine has an irregular curve in the coronal plane. The curve is usually S- or C-shaped over three dimensions. In some, the degree of curve is stable, while in others ...

, resulting from abnormal muscular stress on bones.

Cause

Pelizaeus–Merzbacher disease is caused by

X-linked recessive ''Main Article'': Sex linkage X-linked recessive inheritance is a mode of Mendelian inheritance, inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily hemizygous for ...

mutations in the major myelin

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

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 at this locus for normal CNS function.

Diagnosis

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

magnetic resonance imaging Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and ...

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

prenatal diagnosis Prenatal testing is a tool that can be used to detect some birth defects at various stages prior to birth. Prenatal testing consists of prenatal screening and prenatal diagnosis, which are aspects of prenatal care that focus on detecting problem ...

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 chromosome abnormality. Although polygenic disorders ...

s collectively known as leukodystrophies that affect the growth of the

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

nerve fiber An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see spelling differences) is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action pot ...

s in the

. The several forms of Pelizaeus–Merzbacher disease include classic, congenital, transitional, and adult variants. Pelizaeus–Merzbacher disease is the common name for hypomyelinating leukodystrophies (HLD). There are at least 26 HLD variants cataloged by the National Institutes of Health National Library of Medicine and the Online Mendelian Inheritance in Man (OMIM) compendium of human genes and genetic phenotypes. 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. A phase I clinical trial using an antisense oligonucleotide (known as ION356) targeted against ''PLP1'' is expected to begin in early 2024.

Research

In December 2008, StemCells, Inc received clearance in the United States to conduct a phase I clinical trials of human neural stem cell 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 CRISPR (; acronym of clustered regularly interspaced short palindromic repeats) is a family of DNA sequences found in the genomes of prokaryotic organisms such as bacteria and archaea. Each sequence within an individual prokaryotic CRISPR is d ...

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-m ...

in a mouse model of Pelizaeus–Merzbacher with success. In 2022 Case Western Reserve University entered an 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 Diseases named after discoverers