Pelizaeus–Merzbacher disease

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Pelizaeus–Merzbacher disease
X-linked recessive.svg
Pelizaeus–Merzbacher disease is inherited in an x-linked recessive manner[1]
SpecialtyEndocrinology Edit this on Wikidata

Pelizaeus–Merzbacher disease is a rare central nervous system disorder in which coordination, motor abilities, and intellectual function are delayed to variable extents.[2]

Signs and symptoms[edit]

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 (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 Pelizaeus–Merzbacher disease 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.


Pelizaeus–Merzbacher disease 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 disease occurs due to changes affecting the proteolipid protein 1 gene (PLP1) located on Xq22.2 leading to decreased myelination of nerve fibers.

The majority of disease-causing mutations result in duplications of the entire PLP1 gene. Deletions at the PLP1 locus (which are rarer) 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. Some of the remaining cases of Pelizaeus–Merzbacher disease are accounted for by mutations in the gap junction A12 (GJA12) gene, and are now called Pelizaeus-Merzbacher-like disease.

Other cases of apparent Pelizaeus–Merzbacher disease 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 genetic disorder (discovered in 2003,[3] 2004[4]) 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: Normal to slightly elevated thyroid-stimulating hormone, 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,[5]) possibly with decreased mitochondrial enzyme activities, possibly with fluctuating lactate level. Patients have an alert face, a limited IQ, s may never talk/walk, 50% need a feeding tube, and have a normal lifespan. MCT8 can be ruled out with a simple TSH/T4/T3 thyroid test.


The diagnosis of Pelizaeus–Merzbacher disease is often first suggested after identification by magnetic resonance imaging 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 or GJA12 mutation is identified, prenatal diagnosis or preimplantation genetic diagnostic testing is possible.


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 central nervous system. The several forms of Pelizaeus–Merzbacher disease include classic, connatal, transitional, and adult variants.

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).


No cure for Pelizaeus–Merzbacher disease is known, nor does it have a standard course of treatment. Symptomatic and supportive treatment may include medication for seizures and spasticity. Regular evaluations by physical medicine and rehabilitation, orthopedic, developmental, and neurological 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 Pelizaeus–Merzbacher disease.

In December 2008, StemCells Inc., a biotech company in Palo Alto, received clearance from the U.S. Food and Drug Administration to conduct phase I clinical trials in Pelizaeus–Merzbacher disease to assess the safety of transplanting human neural stem cells as a potential treatment. The trial was initiated in November 2009 at the University of California San Francisco Children's Hospital, with the results published in 2012. Unfortunately, this company has since gone bankrupt, putting the future of this therapeutic modality in peril.

See also[edit]


  1. ^ "OMIM Entry - # 312080 - Pelizaeus-Merzbacher Disease; PMD". Retrieved 5 August 2017.
  2. ^ Hobson, Grace; Garbern, James (2012). "Pelizaeus-Merzbacher Disease, Pelizaeus-Merzbacher-Like Disease 1, and Related Hypomyelinating Disorders". Seminars in Neurology. 32 (1): 062–067. doi:10.1055/s-0032-1306388. ISSN 0271-8235. PMID 22422208.
  3. ^ Dumitrescu Edith; C. H. Friesema; Sumita Ganguly; Amal Abdalla; Jocelyn E.; Manning Fox; Andrew P. Halestrap; Theo J. Visser (October 2003). "Identification of Monocarboxylate Transporter 8 as a Specific Thyroid Hormone Transporter". The Journal of Biological Chemistry. 278 (41): 40128–40135. doi:10.1074/jbc.M300909200. PMID 12871948.
  4. ^ 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. PMC 1181904. PMID 14661163.
  5. ^ 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): 114–8. doi:10.1002/ana.21579. PMID 19194886.

Further reading[edit]

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