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

Rodriguez-Budelli, M.; Kark, Pieter

doi:10.1212/wnl.28.12.1283

Cited by 21 publications

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“…We have therefore undertaken a "blind" study with samples from two previous patients. Technical personnel were different from those involved in prior work.The patients were brothers: [3] except that the p H was 7.3, and in the forward direction with 250 p M nicotinamide-adenine dinucleotide at p H 8.0. The changes from prior conditions were to ensure optimal circumstances for the assays.…”

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confidence: 98%

Reduced enzyme activities in inherited ataxia

Kark¹,

Becker²,

Perlman³

1980

Annals of Neurology

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Our group and colleagues have reported partial diminution in activities of the enzyme lipoamide dehydrogenase (LAD) in peripheral tissues of some patients with recessively inherited ataxia [ l , 31. This result extended findings of low activities of the pyruvate and the a-ketoglutarate dehydrogenase complexes (PDH and KGDH) [l] and is a possible explanation for the decreased oxidation of [2-*4C]pyruvate to 14C02 in tissues of some of the same patients. Others have not been able to find these changes in their patients [2, 41, though a recent report can be interpreted as confirming our findings with respect to P D H [5]. We have therefore undertaken a "blind" study with samples from two previous patients. Technical personnel were different from those involved in prior work.The patients were brothers: [3] except that the p H was 7.3, and in the forward direction with 250 p M nicotinamide-adenine dinucleotide at p H 8.0. The changes from prior conditions were to ensure optimal circumstances for the assays. Heat inactivation was expressed as the time taken to decrease the activity to half the initial value (t5& Cytochrome c oxidase and protein were assayed as before [3], each sample in duplicate to quadruplicate. The results are given in the Table. We have previously reported that patients could be distinguished from controls by these methods on the basis of average values from assays on three to six separate platelet samples. We believe multiple samples need to be assayed despite the lack of overlap in some of the simultaneous assays indicated in the Table. These findings confirm previous reports of abnormalities of LAD and P D H in the patients [l,

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confidence: 98%

Reduced enzyme activities in inherited ataxia

Kark¹,

Becker²,

Perlman³

1980

Annals of Neurology

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“…With the activation procedures, the deficiencies appear to be much more severe because of the much higher control values. The problem of detection of PDC deficiencies in untreated fibroblasts may become much more difficult in cases where the deficiency is less severe, e.g., in Friedreich's ataxia where PDC activities of 40-50% of normal have been reported (34,49,58,59) by some investigators and normal activities by others (60). Results obtained with the familial study of patient B.J.R.…”

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confidence: 99%

“…Blass et al (21) have correlated the severity of clinical symptoms and the age of onset with the residual PDC activity found in cultured fibroblasts. Various attempts have also been made to measure the activities of the component enzymes of PDC, and the deficiencies in overall pyruvate oxidation have been attributed to defects in specific enzymes, including abnormalities in kinetic parameters (21,(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38).…”

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Pyruvate Dehydrogenase Complex Activity in Normal and Deficient Fibroblasts

Sheu¹,

Hu²,

Utter³

1981

J. Clin. Invest.

140

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A B S T R A C T Pyruvate dehydrogenase complex (PDC) activity in human skin fibroblasts appears to be regulated by a phosphorylation-dephosphorylation mechanism, as is the case with other animal cells. The enzyme can be activated by pretreating the cells with dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase, before they are disrupted for measurement of PDC activity. With such treatment, the activity reaches 5-6 nmol/min per mg of protein at 37°C with fibroblasts from infants. Such values represent an activation of about 5-20-fold over those observed with untreated cells. That this assay, based on [1-_4C]pyruvate decarboxylation, represents a valid measurement of the overall PDC reaction is shown by the dependence of 14CO2 production on the presence ofthiamin-PP, coenzyme A (CoA), Mg++, and NAD+. Also, it has been shown that acetyl-CoA and '4CO2 are formed in a 1:1 ratio. A similar degree of activation of PDC can also be achieved by adding purified pyruvate dehydrogenase phosphatase and high concentrations ofMg++ and Ca++, or in some cases by adding the metal ions alone to the cell homogenate after disruption. These results strongly suggest that activation is due to dephosphorylation. Addition of NaF, which inhibits dephosphorylation, leads to almost complete loss of PDC activity.Assays of completely activated PDC were performed on two cell lines originating from patients reported to be deficient in this enzyme (Blass, J. P.,

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“…This sudden arrest of movement after about 0.25 second cannot be attributed to weakness of the triceps muscle, but rather to an excessive braking force exerted by the flexor group. After the initial arrest, extension was completed in a series of smaller accelerations, shown by rise and fall of the velocity curve.Since only the faster movements were arrested in this way, we suspected that the phenomenon was related to the rate sensitivity of antagonist muscle spindles [4]. Accordingly, the patient's right elbow was subjected to a series of Alto.…”

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confidence: 99%

“…Since only the faster movements were arrested in this way, we suspected that the phenomenon was related to the rate sensitivity of antagonist muscle spindles [4]. Accordingly, the patient's right elbow was subjected to a series of Alto.…”

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Impairment of voluntary movement by spasticity

Mizrahi

Angel

1979

Annals of Neurology

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Sahrmann and Norton [ 51 have questioned the prevalent belief that hyperactive stretch reflexes are directly related to impairment of movement in patients with the upper motor neuron syndrome: "though the premise is widely accepted that spasticity limits voluntary movement, there are no critical data to test its validity." We have recently examined a hemiparetic man whose clinical presentation and electromyographic findings provide some relevant data.A 46-year-old man had a four-year history of right hemiparesis due to a left hemisphere oligodendroglioma. H e complained that he could not use a hammer to drive nailsor to flatten objects such as aluminum cans. He had moderate weakness of the right upper limb, more pronounced distally. Tendon jerks were hyperactive on the right side. Slow movements of the elbow were done without difficulty, but rapid extensions were checked abruptly en route to the desired position. When the patient tried to strike with a hammer, movement was arrested about halfway to the target and then completed in a series of short, jerky movements.We surmised that his inability to extend the forearm rapidly was caused by hyperactivity of the stretch reflex in the elbow flexors. To test this possibility, EMG tracings were obtained from the right biceps and triceps during movement of the elbow at various rates. Action potentials, detected by means of Beckman skin electrodes, were fullwave rectified and processed by an averaging filter [21; the apparatus used to record position and velocity of the hand has been described elsewhere [l]. Signals representing the two EMGs, as well as the kinetic variables, were recorded with an Ampex tape recorder, then played back at reduced tape speed and displayed by means of a Grass polygraph.The patient was asked to extend his elbow repeatedly at various speeds, ranging from the slowest to the fastest possible. Slow movements were completed without difficulty, but faster ones were interrupted in midcourse, as seen in Figure 1. This sudden arrest of movement after about 0.25 second cannot be attributed to weakness of the triceps muscle, but rather to an excessive braking force exerted by the flexor group. After the initial arrest, extension was completed in a series of smaller accelerations, shown by rise and fall of the velocity curve.Since only the faster movements were arrested in this way, we suspected that the phenomenon was related to the rate sensitivity of antagonist muscle spindles [4]. Accordingly, the patient's right elbow was subjected to a series of 4 0 passive extensions at various rates. For each movement, the peak of the filtered EMG activity was measured as millimeters of deflection on the strip-chart recording and compared with the maximal hand velocity (Fig 2 ) . Statistical analysis showed that the two variables were positively related, the coefficient of correlation being 0.77 (Fig 3). This means that the faster the elbow was extended, the more powerfully the biceps contracted. At the highest speeds, flexor activity was strong enough to stop t...

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

Cited by 21 publications

References 0 publications

Reduced enzyme activities in inherited ataxia

Reduced enzyme activities in inherited ataxia

Pyruvate Dehydrogenase Complex Activity in Normal and Deficient Fibroblasts

Impairment of voluntary movement by spasticity

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