Friedreich's Ataxia 1980 An Overview of the Physiopathology

Abstract

SUMMARY:Phase three of the Quebec Cooperative Study of Friedreich's Ataxia was devoted to an understanding of the physiopathology of individual symptoms on the basis of previously discovered biochemical leads. The present paper attempts to pull these results together by presenting, as a hypothesis, a unifying scheme of possible interactions and relationships. The central core of this hypothesis is the demonstration in Friedreich's ataxia of a state of mitochondrial energy deprivation. This is indirectly responsible for such associated and important symptoms as muscle weakness, dying-back neuropathy, scoliosis and hypertrophic cardiomyopathy. Secondarily, and possibly as an independent but linkedevent, the entry of glucose into cells and pyruvate oxidation, are slowed down, favoring the development of diabetes. As a consequence, tissue concentrations of glutamic acid and aspartic acid are decreased, particularly in more vulnerable areas such as the cerebellum, brain stem and dorsal root ganglia. This tissue deficiency in putative excitatory neurotransmitters is directly responsible for the symptom of ataxia. This conclusion is reinforced by the correction of the ataxia in glutaexperimental animals, by the intraventricular injection of the same amino acids, and not by the injection of other stimulants of motricity. The observed mitochondrial energy deprivation could be the metabolic consequence of major changes in the linoleic acid (18:2) composition of inner mitochondrial membrane phospholipids, such as cardiolipin. Such decreases in membrane 18:2 could be the result of interference with the normal incorporation of this fatty acid to lipoproteins and/or cell membranes. It is at this level that the search for the specific enzyme defect in Friedreich's ataxia is continuing.

Mitochondrial pathophysiology in Friedreich's ataxia

“…The outstanding lesion of sensory nerves consists of a lack of myelination of axons from large sensory neurons in the DRG and axonal degeneration (Dyck et al . 1968); this axonopathy has been associated with a dying‐back mechanism (Barbeau ; Said et al . ).…”

“…The outstanding lesion of sensory nerves consists of a lack of myelination of axons from large sensory neurons in the DRG and axonal degeneration (Dyck et al 1968); this axonopathy has been associated with a dying-back mechanism (Barbeau 1980;Said et al 1986). Dying-back axonopathy should affect sensory nerves as well as central spinocerebellar and corticospinal motor tracts; however, such a mechanism has only been intensively investigated in the peripheral sural nerves, showing distal predominance of fiber loss (Hughes et al 1968;Said et al 1986;Jitpimolmard et al 1993), with data from central axons being scarce (Fig.…”

Beer and Bread to Brains and Beyond: Can Yeast Cells Teach Us about Neurodegenerative Disease?

“…Remarkably, wild-type human frataxin, but not a patient-derived point mutant, is sufficient to rescue the growth phenotype of yfh1 ⌬ cells. Clinical and pathological overlap between FRDA and mitochondrial diseases had long been appreciated [108] , but these groundbreaking studies in yeast provided the first direct link between FRDA, frataxin, iron metabolism and mitochondrial function.…”

Friedreich's ataxia: electrophysiological and histological findings

“…ation of the large myelinated sensory fibres (1,2). Disorders of glucose, bilirubin, pyruvate, lipid and taurine metabolism have been observed in most cases (3,4). However, the nature of the primary biochemical defect is still unknown.…”