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Pelizaeus–Merzbacher disease

Pelizaeus–Merzbacher disease (PMD) is a rare central nervous system disorder in which coordination, motor abilities, and intellectual function are delayed to variable extents.[1]

Frequency of Occurrence Pelizaeus - Merzbacher disease [PMD] affects 1 per 200,000 to 500,000 males

Penetrance Males will display the gene. The disease is X-linked (common form). X-linked means that the affected gene or mutation is on the x chromosome, and will affect the X chromosome of the two chromosome pairs.[1]

Since females have two X genes, they are carriers of the gene. In males, having only one X gene, will cause an expression of the genetic disorder.

Mode Of Inheritance There are four types of PMD inheritance patterns. These are genetic mutations due to either environmental factors or through family genetics (passing down the gene). The most common form of PMD is Classic PMD. As all PMD inheritance patterns are X linked, Classic PMD is an X-linked recessive inheritance. Classic PMD is an early onset genetic disorder, meaning that symptoms of the disease will occur early in age. The most severe form of PMD is called Connatal PMD. Connatal PMD is present at birth or two to three months after birth, and most children do not live past the first decade of their lives.  The disease affects mostly male, whereas females are rarely affected. The third type of PMD is autosomal dominant PMD.  This type of PMD is passed down from one generation to the next but is not expressed in many individuals who have this type PMD. The fourth type of PMD is Transitional form. The transitional form of PMD is sporadic, meaning that the mutations that occur are isolated (occurs in few places on the affected chromosome). These mutations are not inherited from parents, and are caused only by mutation. Transitional PMD accounts for 15% of all cases and predominantly affects males.

Classification[edit | edit source] 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 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 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. There are several forms of Pelizaeus-Merzbacher disease including classic, connatal, transitional, and adult (uncomplicated SPG2) variants. Each form results in varying degrees of severity. Individuals with Severe conatal PMD present before birth, never achieve ambulation, and usually die before 30. On the other end of the spectrum is uncomplicated SPG2, with individuals presenting as late as 40 and achieving a normal lifespan. The majority of disease-causing mutations result in duplications of the entire PLP1 gene. 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 exons and neighboring intronic regions of the gene. Among these is a new genetic disorder (discovered in 2003,[2] 2004[3]) 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. Pelizaeus-Merzbacher disease is a type hypomyelinating leukodystrophy which results from more than 100 different mutations in the PLP1 gene . This gene is on the twenty-second band of the long arm of the X chromosome in humans and contains the code for the large PLP1 and small DM20 proteins. These proteins lead to myelination of oligodendrocytes, with PLP1 accounting for more than half of the protein which functions as the building blocks of the myelin sheath. The PLP1 protein has four transmembrane domains and when spliced, develops the DM20 protein which lacks thirty-five amino acids from exon three that PLP1 includes. When PLP1 and DM20 are incapable of folding correctly, oligodendrocytes are not properly myelinated and ultimately die. The known types of mutations in the PLP1 gene causing Pelizaeus-Merzbacher disease are duplications, missense mutations, deletions, and null mutations with the different types of mutations leading to a spectra of severity of the disorder. Gene duplications are the most common cause of the disease and are found to be present in 60-70% of patients. Duplications lead to an excess of PLP1 protein being degraded by lysosomes and a greater frequency of oligodendrocyte apoptosis. Point mutations have also been determined to have a 20% prevalence in patients. Pelizaeus-Merzbacher disease is caused by mutations in the PLP1 gene which codes for the proteolipid protein 1. Many different types of mutations have been identified to cause this disease such as missense, nonsense, addition, deletion, and complete gene duplications. The most common type of mutation causing this disease are duplications of the gene coding for the plp1 protein which account for 60-70% of cases. Missense and point mutations account for roughly 15% of cases and are the second most common type of mutation. These types of mutations cause hypomyelination of neurons leading to cell death .Most duplications of the PLP gene occur in germ cells during meiosis in the grandfathers of the affected patient. Point mutations arise due to random mutation and are more likely to occur in the gametes of the mother, grandfather, or grandmother of the patient. Non-symmetrical sister chromatid exchange between gametes, which may indicate why there is a male bias present in the duplication of the PLP gene. Around 23% of patients with PMD do not have any indication of a PLP mutation.

Pathophysiology Pelizaeus-Merzbacher disease is primarily characterized by a demyelination of the gray matter in the brain. This loss of protective sheathing around the axons leads to the classic characteristics of PMD. Although the severity varies, most sufferers of the disease will exhibit some form of ataxia or mild cognitive delay. This loss of muscle control may manifest as nystagmus, hypotonia and seizures in the more severe cases and spastic paraparesis or simple muscle spasms in milder ones. Symptoms can begin to show as early as three months but are generally seen before the inflicted individual reaches the age of two.The tigroid appearance of myelin in the brain is a universal trait of the disease.

Pelizaeus-Merzbacher disease manifests due to abnormal activity of PLP. This abnormal activity can vary with variations yielding highly severe phenotypes or relatively mild ones depending on the mutation present.

Most commonly, the region of the X-chromosome that contains PLP undergoes a duplication event.The severity of the disease has been shown to correlate with a greater number of duplicate copies of the PLP-gene and the amount of PLP over-expression. An accumulation of PLP due to over-expression has also been attributed to an increased severity of symptoms and may stem from this duplication mutation.The PLP that does not make it to the outer membrane via vesicular trafficking and is thought to overcrowd the ER of cells so that the organelle loses function, leading to a degradation of myelin. (This was seen in mice but may not be applicable to humans)

Aside from over-expression, PLP can also lose its function entirely or gain a new and toxic one. In null mutations, the PLP is lost entirely. Loss of PLP leads to milder forms of the disease that typically includes only mild spastic paraparesis. Toxic expression of alternative amino acids leads to a conformational change of PLP that prevents it from exportation to the membrane. This overcrowding event triggers oligodendrocyte cell death by apoptosis and degradation of myelin.

Each mechanism yields the same pattern of disorder with varying degrees of severity.

Diagnosis[edit | edit source] 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. More subtle abnormalities should be evident during the first few weeks of infancy, such as head shaking, hypotonia, and back and forth eye movements. 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. Diagnosis of PMD starts with patient and family history. If family history indicates X-linked inheritance and the patient displays the typical signs of PMD an MRI is performed. If the MRI indicates abnormal myelin then genetic testing for the PLP1 gene can be pursued. [1]

Treatment[edit | edit source] 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. Researchers are focused on developing a stem cell based therapy . Induced pluripotent cell (iPS) cells, produced by PMD patients, have been shown to differentiate into functional oligodendrocytes that continue into the process of cell death as normal cell do, in vitro. Wild-type cells are another avenue of therapy and researchers are studying ways to ‘rescue’ the phenotype using mouse models and then potentially human patients.  Other experimental strategies included investigating PLP1 gene expression . Specifically to lower the transcription and translation of PLP1 because duplications of segments of PLP1 have been seen to cause a harmful gain-of-function phenotype . Additionally researchers are considering the effects of overloading the diet with cholesterol to induce PLP introduction into the cell membrane. Others are focused on studying the mechanism of protein  misfolding and its regulation in relation to clearance of proteins that are folded incorrectly as is seen with PLP. Elizabeth Okafor (talk) 03:18, 1 December 2016 (UTC)Elizabeth Okafor

A potential avenue of treatment for PMD is the use of cell replacement therapy. Human neural precursor cell transplantation for PMD has been proven to be safe, but researchers have yet to demonstrate a significant effect on clinical recovery.  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.

3. History: Pelizaeus-Merzbacher disease is named after the two German physicians responsible for characterizing the disease, Dr. Friedrich Pelizaeus and Dr. Ludwig Merzbacher. Dr. Pelizaeus first described the disease in 1885, noting that a family of five boys all displayed similar symptoms including cognitive dysfunction and neurological impairments. Dr. Merzbacher studied the same family in 1910, which had grown to 14 affected individuals. Dr. Merzbacher’s analysis of the white matter from an affected individual showed a significant decrease in myelination. His work on the family also was the first indication Pelizaeus-Merzbacher disease is an X-linked disorder.[2] The discovery of proteolipid protein (PLP) helped increase the knowledge of the genetic aspect of PMD. PLP was noted as an important protein in the myelination of the central nervous system. An incomplete understanding of the pathogenesis still continues today. [3]

Future forms of Treatment: There is no cure. A potential avenue of treatment for PMD is the use of cell replacement therapy. Human neural precursor cell transplantation and stem cell engraftment for PMD has been proven to be safe, but researchers have yet to demonstrate a significant effect on clinical recovery.