BRAIN LIPIDS OF MICE HOMOZYGOUS FOR THE GENE‘DILUTE LETHAL’(d¹)

Abstract

Abstract— The lipid composition of brains of mice homozygous for the gene‘dilute lethal’and aged 13‐26 days has been determined. This period covers the early stages of myelination up to the time of death. The brains of affected mice contained up to 8 per cent less total lipid than normal. The lipids increasing most rapidly at this age period were most affected; cerebroside, which normally increased six‐fold between the 14th and 24th days of life, was as much as 25 per cent below normal, but there was no significant reduction in non‐myelin lipids. Studies with [l‐14C]acetate suggested that the low levels of lipids reflected decreased rates of synthesis. In contrast to other reports, no myelin breakdown could be detected, either by TLC for cholesterol esters or histologically. The lowest levels of lipids and slowest rates of cerebroside synthesis occurred in the smallest affected mice; we suggest that the abnormalities in brain lipids reflect a reduced growth rate caused by poorer nutrition in the affected mice.

Some observations on the blood levels of phenylalanine in dilute mice and a comparison between human phenylketonuria and the disease of mice homozygous for the dilute lethal gene

“…In the dilute lethal mice, Kelton & Rauch (1962) found that myelination started normally, but within a few days was a degeneration of the myelin in certain welldefined tracts and areas of the brain and spinal cord as demonstrated by the Marchi method. However, Winterbourn et al (1971) could find no evidence for demyelination by this method or by tests for cholesterol esters. Instead they found a decreased rate of synthesis of cerebroside, but no reduction in non myelin lipids.…”

Myelin

“…The di lute lethal disorder is inherited as an autosomal recessive (linkage group II) and manifests clonic convulsions and opisthotonus beginning at 10 days, with death at about 3 weeks. No abnormalities have been apparent using routine myelin stains (Kelton and Rauch, 1962), but there is a lesser accumulation of cerebrosides and also of sulfatide and spingomyelin in the brain of the dilute lethai mouse (Winterbourn et al 1971). Cerebellar explants synthesize myelin in tissue culture in a manner indistinguishable from that of controls (Hamburgh and Bornstein, 1970).…”

Myelin

“…The dilute lethal disorder is inherited as an autosomal recessive (linkage group II of the mouse) and is manifested as clonic convulsions and opisthotonus beginning at 10 days with death at about 3 weeks. No abnormalities have been apparent using routine myelin stains (Kelton and Rauch, 1962), but there is a lesser accumulation of cerebrosides and also of sulfatide and sphingomyelin in the brain of the dilute lethal mouse (Winterbourn et al, 1971). Cerebellar explants synthesize myelin in tissue culture in a manner indistinguishable from that of controls (Hamburgh and Bornstein, 1970).…”