Background Gross Pathology Histopathology & Immunohistochemistry Reference

BACKGROUND AND CLINICAL INFORMATION: Head

Summary: Pelizaeus-Merzbacher disease is an X-linked disease with female patients occasionally found. It is resulted from mutation of the proteolipid protein (PLP) gene that leads to abnormal PLP and DM20 protein. Clinically, it is characterized by X-linked inheritance, abnormal eye movement, and slowly progressive clinical course. Pathologically, this is a sudanophilic demyelinating and dysmyelinating disease with relative preservation of axons. There is gross reduction or absence of myelin in the white matter of the brain but peripheral nerves are not involved. A typical tigroid pattern of myelin stain is present in the centrum ovale. At the molecular level, Pelizaeus-Merzbacher disease is heterogeneous and such heterogeneity may produce clinical conditions of different

Clinical features: There are two main forms: the classical type and the connatal variant of Seitelberger. Onset on both type are in the first few months of life but the rate of progression and severity of the clinical picture is different. Both types can co-exist in the same family.

Connatal type: the disorder begins in the neonatal period with abnormal eye movements, micropthalmia, optic atrophy, head titubation, and hypotonia. There is severe feeding problems and extrapyramidal symptoms. This form is rapidly progressive, leading to involuntary movements, spasticity of the legs, and intellectual failure. The infant has no or little development and death occurs within months to several years.
Classical type: Roving eye movements or rotatory nystagmus usually appear within 3 months birth. Nystagmus disappears before age 2 years in 20% of patients. Hypotonia is present but is variable. Some children may even start walking and develop some meaningful language before slow regression starts. There is dystonic pyramidal and cerbellar signs and optic atrophy. The spectrum of clinical presentation varies from mild X-linked spastic paraparesis without other minor to moderate neurological impairment to severe quadriparesis and essentially a stage of helplessness and decortication. The most consistent features include spasticity, a lack of evidence of male-to-male transmission, and generalized leukodystrophy on MRI. However, some patients with mild symptomatology may lack these features.

Six different types were recognized in the old time before PLP gene was identified.

Type I Classic
Type II Seitelberger (connatal or congenital type)
Type III Transitionalb
Type IV Adult
Type V Atypical
Type VI Cockayne (The Cockayne type has photosensitivity of the skin similar to Cockayne syndrome.)

Genetics: X-linked pattern of inheritance but female heterozygote patients have also been recognized.

Molecular biology of myelin proteolipid protein (PLP) gene:

The gene is located on Xq21.33-22. The mRNA is alternatively spliced to produce two mRNA products that encode two transmembrane proteins, namely PLP and DM20, that comprise about 50% of protein in the myelin sheath. They are the most abundant protein in the CNS. The PLP gene is identical in mouse, rat, and human and is highly conserved among other vertebrates.
DM20 and PLP: DM20 differs from PLP by an internal deletion of 35 amino acids encoded by exon 3B of the gene. The amino acid sequences of DM20 and PLP are highly conserved among different species. The function of PLP and DM20 is not clearly known.
Expression: in addition to the myelin-forming cells in the CNS, expresion of PLP and DM20 has also been shown in the PNS, embryonic CNS, the heart, and probably also in the thymus, spleen, lymph nodes.

Pathogenesis: mutations that affect the folding and transport to the cell surface of both PLPO and DM20 are associated with the most severe phenotypes and alos cause increased oligodendrocyte cell death. Three possible mechanisms,

Loss of function due to deletion or mutation, probably lead to mild clinical pheotype.
Gain of toxic function due to mutation, probably lead to most severe clinical phenotype. The abnormal protein may not be exported to the cell membrane and is entrapped within the cells. Toxicity due to accumulation possibily lead to death of oligodendrocytes and loss of myelination. Depending on the amino acid being substituted, the clinical presentation may change.
Over expression. The most common type of Pelizaeus- Merzbacher disease caused by PLP duplication corresponds to the classic type.

Molecular pathology of PLP gene: Three types of abnormalities are most common,

Duplication of a portion of the PLP gene accounts of 50-75% of the cases.
Mutations have been found in 15-20% of cases. More than 60 point mutations in the PLP coding region have been identified.
No abnormality identified in the coding region are seen in some cases. There may be potential abnormalities in the non-coding and regulatory regions.

GROSS PATHOLOGY: Head

Tigroid pattern: The white matter has patchy brown grayish areas, the so-called tigroid pattern. The brain is atrophic with sulcal widening and ventricular enlargement. The corpus callosum is thin and hypoplastic. There is also heterotypia, microgyria, and narrowing of the subcortical white matter. Tigroid pattern of myelin lost can also be seen in Cockayne syndrome.

Cerebellar degeneration.

Polymicrogyria may be seen.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head

Characteristic features of Pelizaeus-Merzbacher disease include:

Wide spread myelin loss with preserved myelin islets, subcortical arcuate fibers are also affected. Axons are relatively preserved. White matter contains small amount of sudanophilic lipid products.]
Cerebellar degeneration with loss of Purkinje cells. Surviving Purkinje cells have abnormal dendritic swellings (“asteroid” bodies) and axonal torpedoes. Ectopically placed Purkinje cells with “weeping willow” dendrites may also be present.
Normally myelinated peripheral nerves.

Connatal type: There is a diffuse lack of myelin staining. Rare islands of preserved myelin give a tigroid pattern to the widespread demyelination. Axons are relatively preserved and the severity of the astrocytic gliosis contrasts with the discrete macrophage reaction. The PNS is spared.

The so-called classic type and connatal type has similar age of onset. The connatal type progress much faster. In addition, the connatal type has virtually no myelin and the amount of fat in the white matte is reduced, suggesting absence of myelination rather than myelin destruction.

REFERENCES: Head

Garbern J, Cambi F, Shy M, Kamholz J.The molecular pathogenesis of Pelizaeus-Merzbacher disease. Arch Neurol. 1999 Oct;56(10):1210-4.

Osaka H, Kawanishi C, Inoue K, Onishi H, Kobayashi T, Sugiyama N, Kosaka K, Nezu A, Fujii K, Sugita K, Kodama K, Murayama K, Murayama S, Kanazawa I, Kimura S. Pelizaeus-Merzbacher disease: three novel mutations and implication for locus heterogeneity. Ann Neurol. 1999 Jan;45(1):59-64.

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Background Gross Pathology Histopathology & Immunohistochemistry Reference