Dietary carnitine supplements slow disease progression in a putative mouse model for hereditary ceroid‐lipofuscinosis

Abstract

The childhood ceroid-lipofuscinoses are a group of autosomal recessively inherited disorders characterized by massive accumulation of autofluorescent lysosomal storage bodies in neurons as well as other cell types. The storage body accumulation is accompanied by severe degeneration of the central nervous system that results in blindness, cognitive and psychomotor degeneration, and premature death. On the basis of pathologic and biochemical criteria, a hereditary disease in the mnd mouse strain has been proposed as a model for certain types of human ceroid-lipofuscinosis. Experimental evidence suggests that the storage body accumulation in humans with juvenile and late-infantile ceroid-lipofuscinosis is linked to altered carnitine biosynthesis. On the basis of the latter observation, a study was performed to determine whether dietary carnitine supplements could slow the disease progression in the mnd mouse model. Carnitine supplementation begun at 4 weeks of age did not slow the retinal degeneration that is characteristic of this disease. It did, however, significantly elevate brain carnitine levels, slow the accumulation of autofluorescent storage bodies in brain neurons, and prolong the lifespans of the treated animals. These findings suggest that there is a link between carnitine biosynthesis and the disease pathology and indicate that carnitine supplementation may be beneficial in slowing the disease progression in humans with certain types of hereditary ceroid-lipofuscinosis.

In the Rat Brain Acetyl-l-carnitine Treatment Modulates the Expression of Genes Involved in Neuronal Ceroid Lipofuscinosis

“…The changes in plasma carnitine and TML levels in the carriers are consistent with the possibility that the disease involves a defect in the carnitine biosynthetic pathway. Both TML and carnitine levels were significantly depressed in the affected individuals [7,32]. In addition, dietary supplementation with carnitine delayed the progression of cognitive decline in NCL dogs [33].…”

“…This anomalous storage of mitochondrial ATP synthase subunit c is not a result of enhanced expression of nuclear genes encoding the protein nor does the stored protein exhibit changed encoded sequences. A slower degradation of the mitochondrial carnitine biosynthesis [7]; (2) an inherited disease in the motor neuron degeneration (mnd) mouse strain has been proposed as a model for certain types of human ceroid lipofuscinosis [7,8]. In these mnd mice, it was observed that dietary carnitine supplements could slow the disease progression and reduce the accumulation of autofluorescence storage bodies in neurons prolonging their lifespan [7].…”

Vitamin E deficiency and metabolic deficits in neuronal ceroid lipofuscinosis described by bioinformatics

“…The high redox reactivity, coupled with cell membranes rich in polyunsaturated fatty lipids, predispose neuronal tissues, especially motor neurons, to free radical damage. It has been suggested that dietary supplementation with antioxidants may reverse the pathologies of these diseases (3,17,33).…”

Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice

“…Water was changed daily. For carnitine supplementation, Slc23a1 -/-females from the time of mating until delivery were supplemented with 5 g/l carnitine in drinking water, similar to amounts used by others (50).…”