Dysmyelination

The importance of P0 in PNS myelin has been clearly demonstrated. In P0 gene knockout experiments in mice [40], severe hypomyelination and a virtual absence of compact myelin in the PNS is observed. In humans, there are two disease states associated with mutations in the P0 gene Charcot-Marie-Tooth type I disease (see Ch. 38) and Dejerine-Sottas disease, both dysmyelinating diseases that exhibit a spectrum of severity depending on the particular mutation. 

Yandava, B. D., Billinghurst, L. L. and Snyder, E. Y. Global cell replacement is feasible via neural stem cell transplantation evidence from the dysmyelinated shiverer mouse brain. Proc. Natl Acad. Sci. U.S.A. 96 7029-7034,1999. 

Familial demyelinative/dysmyelinative neuropathies may be caused by impaired peroxisomal lipid metabolism. 

Adrenoleukodystrophy is an X-linked dysmyelinative disorder caused by mutations in the ABCD1 gene, which encodes the peroxisomal integral membrane ALD protein, a member of the ATP binding cassette transporter family. These mutations result in impaired clearance of plasma very-long-chain fatty acids. Affected males may present with symmetrical distal axonal polyneuropathy, adrenocortical insufficiency or CNS demyelination, while occasional heterozygous women demonstrate deficits suggestive of multiple sclerosis [56]. Manipulation of dietary fatty acid intake has some minimal therapeutic effect, while bone marrow transplantation has diminished deficits in a few patients. (See in Ch. 41.)... 

Familial demyelinative/dysmyelinative and axonal neuropathies may also be caused by impaired lysosomal lipid metabolism. Metachromatic leukodystrophy (sulfatide lipidosis) results from mutations of the arylsulfatase A gene, which encodes a lysosomal enzyme required for sulfatide turnover. Myelin is affected in both CNS and PNS, though dysfunction is restricted to the PNS in some patients, and the onset of symptoms can occur at any time between infancy and adulthood. Bone marrow transplantation can slow disease progression and improve nerve conduction velocities [57]. (See in Ch. 41.)... 

Heurteaux C, Baumann N, Lachapelle F, et al Lithium distribution in the brain of normal mice and of quacking dysmyelinating mutants. J Neurochem 46 1317-1321, 1986... 

Sunada, Y., Bernier, S. M., Utani, A., Yamada, Y. and Campbell, K. P. (1995) Identification of a novel mutant transcript of laminin a2 chain gene responsible for muscular dystrophy and dysmyelination in dy2J mice. Hum Mol Genet 4, 1055-1061. 

Neuromotor disorders, including paresthesia of the hands and feet, hyperactive deep tendon reflexes and muscle weakness. These can be explained by the role of acetyl CoA in the synthesis of the neurotransmitter acetylcholine and the impaired formation of threonine acyl esters in myelin. Dysmyelination may explain the persistence and recurrence of neurological problems many years after nutritional rehabilitation in people who had suffered from burning foot syndrome. 

A genetic disease, the 18q-syndrome is a rare leukodystrophy presenting a genomic deletion that includes the MBP gene. Proton magnetic resonance data indicate demyelination or increased myelin turnover rather than dysmyelination (Hausleretal., 2005). 

Eftekharpour E, Karimi-Abdokezaee S, Sinha K, Velumian AA, Kwiecien JM, FehUngs MG (2005) Structural and functional alterations of spinal cord axons in adult Long Evans Shaker (LES) dysmyelinated rats. Exp Neurol 193 334—349... 

Espinosa-Jeffrey A, Zhao P, Awosika W, Wu N, Macias F, Cepeda C, Levine M, De Velhs J (2006) Activation, proliferation and commitment of enogenous stera/progenitor cells to the oligodendrocyte lineage by TSl in a rat model of dysmyelination. Dev Neurosci 28 488 98... 

Readhead C, Hood L (1990) The dysmyelinating mouse mutations shiverer (shi) and myelin deficient (shimld). Behav Genet 20 213-234. 

The types of nervous system effects described in the Minamata outbreak included mental retardation retention of primitive reflexes cerebellar symptoms dysarthria hyperkinesia hypersalivation atrophy and hypoplasia of the cerebral cortex, corpus callosum, and granule cell layer of the cerebellum dysmyelination of the pyramidal tracts and an abnormal neuronal cytoarchitecture. It has been suggested that the widespread damage involved derangement of basic developmental processes, such as neuronal migration (Choi et al. 1978 Matsumoto et al. 1965) and neuronal cell division (Sager et al. 1983). 

Loevner LA, Shapiro RM, Grossman RI, Overhauser J, Kamholz J 1996 White matter changes associated with deletions of the long arm of chromosome 18 a dysmyelinating disorder Am J Neuroradiol 17 1843—1848... 

SAolecular plasticity of Na channel gene expression the dysmyelinating shiverer mouse... 

Kim, S., Tuck, M., Kim, M., Campagnoni, A. T., Paik, W. K. (1984). Studies on myelin basic protein-specific protein methylase 1 in various dysmyelinating mutant mice. Biochem. Biophys. Res. Commun. 123, 468 74. 

The microlocalisation technique with the stable isotope Li uses a beam of neutrons in an atomic reactor. The Li nucleus absorbs a neutron and immediately undergoes fission to produce an a-particle and a H atom, which create tracks in a suitable detector placed in contact with Li-containing tissue. The tissue distribution in the rat, brain lithium distribution in the mouse " and the rat, ° distribution in the mouse embryo, kinetics in the mouse brain, and distribution in mutant strains of mice with dysmyelination have been studied. 

The clinical manifestations of X-ALD vary widely but can be categorized into three distinct phenotypes based on age of symptom onset (Table 15.1). First, the most severe form, cerebral X-ALD (CCALD) appears most commonly during early childhood (3-10 years old). The characteristic rapid demyelination is associated with a large inflammatory response in the cerebral white matter (Powers, 1985 Schaumburg et al., 1975). The demyelination and inflammation are associated with oligodendrocyte cytolysis, rather than apoptosis. This raises the question as to whether the inflammatory reaction is the primary cause of demyelination or a secondary immune system response to an initial dysmyelination of neurons (Bezaire et al., 2001). These patients suffer from behavioral disturbances as well as auditory... 

Microscopic examination of brain tissue from affected patients has revealed demyelination/dysmyelination and severe vacuolation in the cerebral cortex and the subcortical white matter (Adachi et al., 1966, 1967). Additionally, vacuoles were observed within the myelin sheaths, between the wraps at the major dense lines. There was also an increased number of astrocytes containing large nuclei and abnormal mitochondria in the cerebral cortex and cerebellum (Adachi et al., 1973 Adachi and Volk, 1968). 

Results of relaxometry indicate a dysmyelination , as originally described by Hommes and Matsuo (1987) in the hyperphenylalaninemic rat, namely that the decreased synthesis of sulfatides and other myelin compartments is associated with an increased myelin turnover, leading to disruption splaying of myelin lamellae associated with increased water content. 

According to Dyer et al., white matter pathology in untreated PKU is a developmental process, whereby elevated phenylalanine concentrations arrest the myelination causing reduced myeUn formadon and hypomyelination. In early treated patients, myelin lesions reflect demyelination or dysmyelination and represent loss or impairment of previously assembled myelin [50] (Box 9.5). 

Structural manifestations of phenylalanine neurotoxicity include dysmyelination in the white matter of the brain, revealed with MRl as intense lesions and cortico-subcortical atrophy on T2-weighted images with specifically high-signal intensity in periventricular white matter. White matter abnormaUties may be explained by cytotoxic edema and dysmyelination changes with increase in free water trapped in myeUn sheaths [44]. The size and distribution of WMA vary between patients with locahzation in the white matter of temporal and occipital lobes as the most common areas affected [42] (Figs. 9.5 and 9.6). 

SATURATED AND MONO-UN SATURATED FATTY ACID BIOSYNTHESIS IN BRAIN RELATION TO DEVELOPMENT IN NORMAL AND DYSMYELINATING MUTANT MICE... 

---