What is Pelizaeus-Merzbacher disease?

Risk Factors

PMD occurs in 1 out of every 200,000 to 500,000 male newborns in the United
States. It is an X-linked disorder, predominantly affecting males who inherit it
from their mothers, who are carriers. The condition rarely affects females. For
females who carry the PLP1 gene, there is a 50 percent risk of
passing it on with every pregnancy—sons have a 50 percent chance of inheriting the
gene and having PMD, while daughters are at a 50 percent risk of being carriers.
Genetic
counseling and in utero testing are advised for those with a
family history.

Etiology and Genetics

PMD is one of the leukodystrophies, a group of inherited
and progressive metabolic diseases affecting myelination of the nervous system and
the development of white matter in the brain. Each disorder has a separate gene
abnormality that affects a different enzyme (protein). In PMD, the defect is in
the PLP1 gene, caused by a point mutation (substitution of a
single AT or GC base), which results in misfolding of the proteolipid protein 1
and DM20 protein, or a duplication of the entire gene, causing overexpression of
the protein. These mutant proteins are toxic to the oligodendrocyte cells that
make myelin.

Myelin constitutes the myelin sheath, which is a fatty covering surrounding
axons in the central and peripheral nervous systems and acts as an electrical
insulator, allowing impulses to be transmitted quickly along the nerve cells.
Without myelin, impulses leak out and nerves cannot function normally. Normal
myelination is a step-by-step, ordered process that begins at about five months
gestation and continues until a child is two to three years old. In PMD, myelin
simply never develops, resulting in permanent hypomyelination and axonal
degeneration, primarily in the subcortical region of the cerebrum, cerebellum,
and/or brain stem. This prevents impulses from being transmitted from neuron to
neuron and causes a range of neurological and motor dysfunctions. It is now known
that duplication of the PLP1 gene accounts for 50 to 75 percent
of PMD cases.

The gene encoding the PLP protein is located on the long arm of the X chromosome at band Xq22 and is about 17 kilobases in size, consisting of seven exons and six introns. Two transcript variants encoding distinct isoforms (Isoform 1 and Isoform DM-20) have been identified. The normal PLP protein is a four-transmembrane domain structure that correlates well with one exon of the gene, except at the C terminal end, and binds strongly to other copies of itself.

Many mutations in the PLP1 gene have been reported. Molecular
analysis of the gene revealed a variety of mutations, deletions, and duplications,
including two mutations in the 5 untranslated region, missense mutations in exon
2, and an A-to-T transition in exon 4 leading to an Asp-to-Val substitution at
residue 202. Exonic mutations tend to be more severe than simple point mutations.
Forms of the disorder include the classical X-linked PMD, a severe acute infantile
(connatal) PMD, and an autosomal dominant late-onset PMD.

Symptoms

Symptoms of PMD are typically progressive and can appear in the first year of
life. In the case of connatal PMD, symptoms can begin in infancy. The first
symptom in infants is usually involuntary oscillatory movements of the eyes
(nystagmus) and may be concomitant with labored and noisy
breathing (stridor) and lack of muscle tone/floppiness (hypotonia). Involuntary
muscle spasms (spasticity) and associated muscle and joint stiffness develop. With
time, other symptoms become evident, such as impaired ability to coordinate
movement (ataxia), developmental delays, loss of motor function and
head/trunk control, and deterioration of intellectual abilities.

Screening and Diagnosis

DNA-based testing can be used to diagnose PMD in symptomatic patients, as well
as in utero, and to determine carrier status in family members. Identification of
pathologic mutations and copies of the PLP1 gene is the
definitive test, using sequence analysis and quantitative polymerase chain
reaction (PCR) or fluorescence in situ hybridization
(FISH) methods, respectively. Pathological signs of dysmyelination can be examined
using magnetic
resonance imaging (MRI), once a child is one to two years old
when white matter pathways in the brain are maturing and hypomyelination can be
detected.

Treatment and Therapy

PMD cannot be cured and there is no effective treatment. Currently, treatment
is symptomatic and supportive, but medications are available to alleviate
stiffness or spasticity and to control seizures. Cell-based therapies are
being investigated, including transplantation of a functioning neuregulin gene
into unmyelinated nerve cells, which may reprogram cells to produce myelin and the
use of human adult-derived glial progenitor cells as vectors.

Prevention and Outcomes

There are no means of preventing PMD, but genetic counseling and testing is
available for couples who have the PLP1 gene mutation. The
prognosis for patients with PMD varies by the severity of mutation and form of
PMD, with survival as short as early childhood and as long as into the
sixties.

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