Pelizaeus-Merzbacher disease
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.
is one in a group of genetic disorder
s collectively known as leukodystrophies that affect growth of the myelin
sheath, the fatty covering—which acts as an insulator—on nerve fiber
s 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 Pelizaeus-Merzbacher disease
including, classic, connatal, transitional, and adult variants. Interestingly, deletions at the PLP1 locus (which are rarer) 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 exon
s and neighboring intron
ic regions of the gene. Among these is a new genetic disorder (discovered in 2003, 2004) 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 signs for this disorder are as 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. Muscle contracture
s (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 bone
s.
(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 possible.
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 Hospital.http://www.stemcellsinc.com/clinicaltrials/clinicaltrials.html
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
disorder in which coordination, motor abilities, and intellectual function are delayed to variable extents.
Classification
The diseaseDisease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
is one in a group of genetic disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
s collectively known as leukodystrophies that affect growth of the myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
sheath, the fatty covering—which acts as an insulator—on nerve fiber
Nerve fiber
A nerve fiber is a threadlike extension of a nerve cell and consists of an axon and myelin sheath in the nervous system. There are nerve fibers in the central nervous system and peripheral nervous system. A nerve fiber may be myelinated and/or unmyelinated. In the central nervous system , myelin...
s in the CNS
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. PMD is generally caused by a recessive
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
mutation of the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
on the long arm of the X-chromosome (Xq21-22) that codes for a myelin protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
called proteolipid protein 1
Proteolipid protein 1
Proteolipid protein 1 is a protein associated with Pelizaeus-Merzbacher disease. It is a 4 transmembrane domain protein which is proposed to bind other copies of itself on the extracellular side of the membrane...
or PLP1. The majority of disease-causing mutations result in duplications of the entire PLP1 gene. There are several forms of Pelizaeus-Merzbacher disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
including, classic, connatal, transitional, and adult variants. Interestingly, deletions at the PLP1 locus (which are rarer) cause a milder form of PMD than is observed with the typical duplication mutations, which demonstrates the critical importance of gene dosage
Gene dosage
Gene dosage is the number of copies of a gene present in a cell or nucleus. An increase in gene dosage can cause higher levels of gene product if the gene is not subject to regulation from elsewhere in the body....
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 exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
s and neighboring intron
Intron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
ic regions of the gene. Among these is a new genetic disorder (discovered in 2003, 2004) 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
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
/floppy infants with delayed milestones). This genetic defect was known as Allan-Herndon-Dudley syndrome
Allan-Herndon-Dudley syndrome
Allan–Herndon–Dudley syndrome is a rare disorder of brain development that causes moderate to severe mental retardation and problems with movement. This condition, which occurs almost exclusively in males, disrupts development from before birth....
(since 1944) without knowing its actual cause. Some of the signs for this disorder are as follows: normal to slightly elevated TSH
Thyroid-stimulating hormone
Thyrotrophin-stimulating hormone is a peptide hormone synthesized and secreted by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid gland.- Physiology :...
, 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
Lactic acid
Lactic acid, also known as milk acid, is a chemical compound that plays a role in various biochemical processes and was first isolated in 1780 by the Swedish chemist Carl Wilhelm Scheele. Lactic acid is a carboxylic acid with the chemical formula C3H6O3...
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
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
, lack of coordination, involuntary movements, weakness, unsteady gait
Gait
Gait is the pattern of movement of the limbs of animals, including humans, during locomotion over a solid substrate. Most animals use a variety of gaits, selecting gait based on speed, terrain, the need to maneuver, and energetic efficiency...
, and over time, spasticity in legs and arms. Muscle contracture
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.For example, in the case of partial paralysis Muscle contractures can occur for many reasons,...
s (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
Scoliosis
Scoliosis is a medical condition in which a person's spine is curved from side to side. Although it is a complex three-dimensional deformity, on an X-ray, viewed from the rear, the spine of an individual with scoliosis may look more like an "S" or a "C" than a straight line...
, resulting from abnormal muscular stress on bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
s.
Diagnosis
The diagnosis of PMD is often first suggested after identification by magnetic resonance imagingMagnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
(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
Prenatal diagnosis
Prenatal diagnosis or prenatal screening is testing for diseases or conditions in a fetus or embryo before it is born. The aim is to detect birth defects such as neural tube defects, Down syndrome, chromosome abnormalities, genetic diseases and other conditions, such as spina bifida, cleft palate,...
or preimplantation genetic diagnostic testing is possible.
Treatment
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 counselingGenetic counseling
Genetic counseling or traveling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning...
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
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(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 Hospital.http://www.stemcellsinc.com/clinicaltrials/clinicaltrials.html
External links
- Pelizaeus-Merzbacher.org - Videos and information about the disorder's symptom, diagnosis, prognosis, research & potential treatment
- The Stennis Foundation - Registered charity committed to raising awareness and funds for Leukodystrophies research
- The Stennis Foundation's MySpace site
- Pelizaeus-Merzbacher Disease. NINDS/National Health Institutes.
- PMD foundation web site. PMD Foundation (US)
- PMD Clinical Trial - UCSF Neonatology Clinical Trial for PMD