Preclinical diagnosis and carrier detection in ataxia associated with abnormalities of lipoamide dehydrogenase.

To see whether kinetic assays of lipoamide dehydrogenase could be used for carrier detection or preclinical diagnosis, Michaelis-Menten constants (KmL and KmH) for the enzyme were determined in platelets from families with a form of recessive Friedreich ataxia and low activities of the enzyme. The KmL of patients' enzyme was 132 +/- 5 microM lipoamide (mean +/- SEM) versus 56 +/- 9 microM for controls (p less than 0.001), and KmH for the patients was 421 +/- 19 microM versus 147 +/- 14 microM for the controls (p less than 0.001). The activity and Km values of one patient's enzyme were abnormal 1 year before neurologic signs appeared. The Km values for the enzymes of the six parents were also elevated (average KmL, 105 +/- 10 microM; average KmH, 378 +/- 47 microM, p less than 0.02). The maximal activities of the parents' enzymes, relative to a mitochondrial marker, were intermediate between the mean maximal control activity and the mean activity for the affected offspring. The data suggest that the abnormalities of lipoamide dehydrogenase are inherited in a recessive pattern in these families.

Clinical correlations of partial deficiency of lipoamide dehydrogenase.

Reduced activities of lipoamide dehydrogenase (LAD) relative to cytochrome oxidase have been found in 12 or 26 patients with inherited ataxias. One of the 12 patients had adult-onset ataxia plus ragged-red muscle fibers. The other 11 had Friedreich syndrome or early-onset variants of this, as did 6 patients with normal enzyme activity. However, the 11 patients with reduced enzyme activity were clinically more homogeneous than the 6 with normal activity.

Pyruvate dehydrogenase deficiency in spinocerebellar degenerations.

To study the incidence of abnormalities of the pyruvate (PDH) or ketoglutarate (KGDH) dehydrogenase complexes in patients with spinocerebellar degenerations, we measured the activities of PDH and KGDH in platelet-enriched preparations from the blood of 14 patients. Low PDH was found in 6 of the 14 patients; low KGDH was found in 2 of the 6. PDH-normal and PDH-abnormal patients could not be distinguished by clinical criteria. These results extend previous studies, which suggested abnormalities of pyruvate oxidation in patients with hereditary ataxias. The data imply that deficient activity of the PDH complex may be associated with spinocerebellar degenerations, and that the clinical phenotypes of the inherited ataxias can be associated with several genotypes.

Kinetic evidence for a structural abnormality of lipoamide dehydrogenase in two patients with Friedreich ataxia.

Two unrelated patients with Friedreich ataxia were deficient in the activity of the enzyme lipoamide dehydrogenase (LAD). The enzymes from the patients' platelets differed significantly from controls in activity, in KM for lipoamide, and in KM for NADH. The data are consistent with a structural mutation of the gene coding for LAD.

Evidence for a primary defect of lipoamide dehydrogenase in Friedreich's ataxia.

There is now a great deal of evidence to link genetic defects of pyruvate metabolism to brain disease. Experimental evidence is reviewed in Chapter 12, and clinical evidence has been reviewed above. Severe lesions of components of the pyruvate dehydrogenase complex are associated with severe generalized brain disease, and milder defects with inherited ataxias. Nearly half of one series of our ataxic patients had deficient activity of pyruvate dehydrogenase, and 40% of another series have deficient activity of the lipoamide dehydrogenase component. This last group corresponds to 60% of the patients with Friedreich's ataxia and its clinical variants at UCLA. There is an association between defective activity of lipoamide dehydrogenase and disease, and the data suggest there is a structural mutation of the gene for the enzyme. Preliminary studies suggest that obligate heterozygotes as a group have enzyme activities between those for controls and those for patients. Moreover, the obligate heterozygotes from families in which there are kinetic defects of lipoamide dehydrogenase also appear to have kinetic abnormalities of the enzyme. The ataxic patients with reduced lipoamide dehydrogenase activity currently fall into two clinical groups. One is ragged-red ataxia, and the other is a disorder that is a subgroup of the classic Friedreich's ataxia syndrome. Studies need to be undertaken on a larger group of patients, with more diverse inherited ataxias, to test the present clinical associations of the enzyme defect. A dietary treatment derived from a knowledge of the presumed defect has modified the ataxia that is associated with defects of pyruvate decarboxylase, but the diet has not yet been tested with defects of lipoamide dehydrogenase.

Action of physostigmine on inherited ataxias.

Physostigmine improved videotape scores of ataxia in patients with various inherited ataxias. This improvement occurred in 12 out of 12 patients when the drug was given as a single dose and in nine of 11 patients when the drug and placebo were given in a long-term, double-blind randomized trial. Patients report various mild to moderate clinical benefits after the sustained use of physostigmine for 6 to 36 months. Videotape scores showed an average of 30% numerical improvement in seven patients after 6 months' sustained treatment. The acute responses are not blocked by methylscopolamine, methylscopolamine did not make ataxia more severe, nor have any patients had fasciculations or changes in strength while on physostigmine. We therefore presume that a central cholinergic mechanism plays some role in the pathophysiology of the inherited ataxias. We do not have direct data on the site or nature of this mechanism. Further studies with other cholinergic agents are now required to investigate the effects and potential clinical efficacy of this class of compounds more completely than has been done up to now.