From Wikipedia, the free encyclopedia
Pelizaeus-Merzbacher disease (PMD) is a rare central nervous system disorder
in which coordination, motor abilities, and intellectual function
are delayed to variable extents.
The disease is one in a
group of genetic disorders collectively known
as leukodystrophies that affect growth of the
myelin sheath, the fatty
covering--which acts as an insulator--on nerve fibers in the CNS. PMD is generally caused by a recessive mutation of the gene on the long arm of the X-chromosome (Xq21-22)
that codes for a myelin protein called proteolipid protein 1 or PLP1.
The majority of disease-causing mutations result in duplications of
the entire PLP1 gene. There are several forms of
including, classic, connatal, transitional, and adult variants.
Interestingly, deletions at the PLP1 locus (which are more rare)
cause a milder form of PMD than is observed with the typical
duplication mutations, which demonstrates the critical importance
of gene dosage at this locus for normal CNS function. Some of the
remaining cases of PMD are accounted for by mutations in the gap
junction A12 (GJA12) gene, and are now called
Pelizaeus-Merzbacher-like disease (PMLD). Other cases of apparent
PMD do not have mutations in either the PLP1 or
GJA12 genes, and are presumed to be caused either by
mutations in other genes, or by mutations not detected by
sequencing the PLP1 gene exons and neighboring intronic regions of the gene. Among these is a
new genetic disorder (discovered in 2003,
which is caused by mutation in the transporter of thyroid hormone,
MCT8, also known as SLC16A2, is believed to be account for a
significant fraction of the undiagnosed neurological disorders
(usually resulting in hypotonic/floppy infants with delayed
milestones). This genetic defect was known as Allan-Herndon-Dudley
syndrome (since 1944) without knowing its actual cause. Some of
the symptoms for this disorder as are follows: normal to slightly
elevated TSH, elevated T3
and reduced T4 (ratio of T3/T4 is
about double its normal value). Normal looking at birth and for the
first few years, hypotonic (floppy), in particular difficulty to
hold the head, possibly difficulty to thrive, possibly with delayed
myelination (if so, some cases are reported with an MRI pattern
similar to Pelizaeus-Merzbacher
disease, known as PMD),
possibly with decreased mitochondrial enzyme activities, possibly
with fluctuating lactate level. Patients have an alert face,
a limited IQ, patients may never talk/walk, 50% need feeding tube,
patients have a normal life span. MCT8 can be ruled out with a
simple TSH/T4/T3 thyroid test.
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). The onset of
Pelizaeus-Merzbacher disease is usually in early infancy. The most
characteristic early signs are nystagmus (rapid, involuntary,
rhythmic motion of the eyes) and hypotonia (low muscle tone). Motor
abilities are delayed or never acquired, mostly depending upon the
severity of the mutation. Most children with PMD 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.
contractures (shrinkage or shortening of a muscle) often occur
over time. Mental functions may deteriorate. Some patients may have
convulsions and skeletal deformation, such
as scoliosis, resulting
from abnormal muscular stress on bones.
The diagnosis of PMD is often first suggested after
identification by magnetic resonance imaging
(MRI) 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 there is a family history consistent
with sex-linked inheritance, the condition is
often misdiagnosed as cerebral palsy. Once a PLP1 or
GJA12 mutation is identified, prenatal
diagnosis or preimplantation genetic diagnostic testing is
There is no cure for PMD, nor is there a standard course of
treatment. Treatment, which is symptomatic and supportive, may
include medication for seizures and spasticity. Regular evaluations
by physical medicine and rehabilitation, orthopedic, developmental
and neurologic specialists should be made to ensure optimal therapy
and educational resources. The prognosis for those with
Pelizaeus-Merzbacher disease is highly variable, with children with
the most severe form (so-called connatal) usually not surviving to
adolescence, but survival into the sixth or even seventh decades is
possible, especially with attentive care. Genetic counseling should
be provided to the family of a child with PMD.
In December 2008, StemCells Inc., a biotech company in Palo
Alto, received clearance from the U.S. Food and
Drug Administration (FDA) to conduct Phase I clinical trials in PMD to assess the safety
of transplanting human neural stem cells
as a potential treatment for PMD. The trial was initiated in
November 2009 at the University of California, San Francisco (UCSF) Children's
- ^ Dumitrescu Edith C. H. Friesema, Sumita
Ganguly, Amal Abdalla, Jocelyn E. Manning Fox, Andrew P. Halestrap,
and Theo J. Visser (October 2003-received January 2003).
"Identification of Monocarboxylate Transporter 8 as a Specific
Thyroid Hormone Transporter". THE JOURNAL OF BIOLOGICAL
CHEMISTRY 278: 40128–40135.
- ^ Dumitrescu AM, Liao XH, Best TB, Brockmann
K, Refetoff S (January 2004). "A novel syndrome combining
thyroid and neurological abnormalities is associated with mutations
in a monocarboxylate transporter gene". Am. J. Hum.
Genet. 74 (1): 168–75. doi:10.1086/380999. PMID 14661163.
- ^ Vaurs-Barrière C, Deville M, Sarret C,
Giraud G, Des Portes V, Prats-Viñas JM, De Michele G, Dan B, Brady
AF, Boespflug-Tanguy O, Touraine R (January 2009).
"Pelizaeus-Merzbacher-Like disease presentation of MCT8 mutated
male subjects". Ann. Neurol. 65 (1):
- The Stennis Foundation -
Registered charity committed to raising awareness and funds for
- The Stennis Foundation's
Disease. NINDS/National Health Institutes.
- pmd at NIH/UW GeneTests
- Uhlenberg B, Schuelke M,
Rüschendorf F, Ruf N, Kaindl A, Henneke M, Thiele H,
Stoltenburg-Didinger G, Aksu F, Topaloğlu H, Nürnberg P, Hübner C,
Weschke B, Gärtner J (2004). "Mutations in the gene encoding gap
junction protein alpha 12 (connexin 46.6) cause
Pelizaeus-Merzbacher-like disease". Am J Hum Genet
75 (2): 251–60. doi:10.1086/422763. PMID 15192806.
- PMD foundation web site. PMD Foundation
Pathology of the nervous system, primarily CNS (G04–G47,
, Neuromyelitis optica
) · hereditary
) · Central pontine
myelinolysis · Marchiafava-Bignami
disease · Alpers'
|central nervous system navs: