Pelizaeus-Merzbacher disease

The human leukodystrophies are inherited disorders of central nervous system white matter. These disorders are characterized by a diffuse deficiency of myelin caused by a variety of genetic lesions and often manifest before 10 years of age (Table 38-1). Some are caused by mutations in the PLP gene and resemble the PLP animal mutants described in Chapter 4 [ 1,23]. As with the animal models, depending on the nature of the mutation, they vary from a severe form in connatal Pelizaeus-Merzbacher disease (PMD) through an intermediate phenotype in classical PMD to a mild phenotype in spastic paraplegia. It is noteworthy that some mutations of the PLP gene also cause a peripheral neuropathy [24], very probably related to the expression of low levels of PLP in peripheral nerve (see Ch. 4). 

Pelizaeus-Merzbacher disease (classical and connatal forms) and spastic paraplegia X-linked PLP Variable hypomyelination due to different mutations in the major structural protein of CNS myelin similar to rodent mutants such as the jimpy mouse 1,23... 

Pelizaeus-Merzbacher disease p Alport-like hereditary nephritis... 

Gow A, Southwood CM, Lazzarini RA (1998) Disrapted proteohpid protein trafficking results in oligodendrocyte apoptosis in an animal model of Pelizaeus-Merzbacher disease. J Cell Biol 140 925-934... 

Pelizaeus-Merzbacher disease p Alport-like hereditary nephritis [pabry disease q Lowe syndrome Immunodeficiency, X-linked r with hyper IgM Lymphoproliterative syndrome s Hemophilia B t Albinism-deafness syndrome u Fragile X syndrome Hunter syndrome Hemophilia A... 

Other demyelinating diseases also exist, and their cause is much more straightforward. These are relatively rare disorders. In all of these diseases, there is no fully effective treatment for the patient. Inherited mutations in Po (the major PNS myelin protein) leads to a version of Charcot-Marie-Tooth polyneuropathy syndrome. The inheritance pattern for this disease is autosomal dominant, indicating that the expression of one mutated allele will lead to expression of the disease. Mutations in PEP (the major myelin protein in the CNS) lead to Pelizaeus-Merzbacher disease and X-linked spastic paraplegia type 2 disease. These diseases display a wide range of phenotypes, from a lack of motor development and early death (most severe) to mild gait disturbances. The phenotype displayed depends on the precise location of the mutation within the protein. An altered function of either Po or PLP leads to demyelination and its subsequent clinical manifestations. 

Since it has not been established whether other forms of degenerative diffuse sclerosis are also due to abnormalities of lipid metabolism, the present chapter will be restricted to a discussion of ML, although analytical findings in Pelizaeus-Merzbacher disease and in diffuse sclerosis, type Krabbe, suggest that these disorders may also be lipidoses. 

Nisenbaum, C., U. Sandbank, and R. Kohn Pelizaeus-Merzbacher disease infantile acute type . Report of a family. Ann. paediat. (Basel) 204, 365 (1965). 

We possess better information about the inheritance of the also very rare Pelizaeus Merzbacher disease, which belongs to the orthochromatic leucodystrophies. The available observations recently have been reviewed by Zerbin-Rudin and Peiffer (1964), who added a further large kindred. These authors distinguish three forms of the disease ... 

Camp, C. D., and K. Lowenberg An American family with Pelizaeus-Merzbacher disease. Arch. Neurol. Psychiat. 45, 261 (1941). 

Neurometabolite changes in leukoencephalopathy have been recorded using H MRS. Kassem et also used a battery of MRI techniques to characterise the condition of leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Mori et examined a patient with Pelizaeus-Merzbacher disease at ages 2, 6, 14, and 25 months. Finnsson et measured metabolite levels in the supraventricular white matter, which included an area under the sensory motor cortex. Absolute concentration of tNAA, Cho, and tCr, using internal water as a reference, were all reduced in patients compared to control subjects. However, there were no differences in the ratios of tNAA/ tCr or Cho/tCr between patients and controls. 

The problem of distinguishing SLD, Schilder s and Pelizaeus-Merzbacher disease has been discussed from the point of both morphology and chemical alterations [40, 81, 82, 83]. Although SLD and Schilder s disease appear to differ to a certain extent by chemical criteria [40], these two are combined and compared here. 

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