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Cerebellar -Ketoglutarate dehydrogenase activity is reduced in spinocerebellar ataxia type 1.

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Cerebellar a-Ketoglutarate
Dehvdrogenase Activitv Is
AtaxiaType 1
Frank Mastrogiacomo, BSc, and Stephen J. Kish, PhD
We measured the activity of the thiamine pyrophosphate-dependent enzyme a-ketoglutarate dehydrogenase complex in postmortem brain of 12 patients with
the spinocerebellar ataxia type 1form of olivopontocerebellar atrophy. a-Ketoglutarate dehydrogenase complex
activity measured in the absence of thiamine pyrophosphate was markedly reduced ( - 72%) in olivopontocerebellar atrophy cerebellar cortex. Decreased activity of
this key rate-limiting Krebs cycle enzyme could compromise cerebellar energy metabolism and excitatory amino
acid synthesis and thereby contribute to the brain dysfunction of olivopontocerebellar atrophy.
Mastrogiacomo F, Kish SJ. Cerebellar
a-ketoglutarate dehydrogenase activity is
reduced in spinocerebellar ataxia type 1.
A n n Neurol 1974;35:624-626
Reduced levels of thiamine and its phosphates have
been reported in cerebrospinal fluid of patients with
spinocerebellar damage, including patients with dominantly inherited olivopontocerebellar atrophy (OPCA;
cf. [I}). Experimental animal data suggest that the
mechanism by which thiamine deficiency produces
brain dysfunction and damage could involve depletion
of energy stores consequent to diminished activity of
thiamine pyrophosphate (TPP)-dependent enzymes,
including especially a-ketoglutarate dehydrogenase
complex (aKGDHC), a key rate-limiting enzyme of
the Krebs cycle [2]. To our knowledge, no information is available on the status of a K G D H C in brain
of patients with OPCA. Therefore, we measured
a K G D H C activity, both in the presence and absence
of TPP, in brain of 12 patients with the spinocerebellar
ataxia type I form of OPCA.
Patients and Methods
Autopsied brain was obtained from 12 clinically end-stage
patients with the spinocerebellar ataxia type 1 form [ 3 ] of
OPCA and 13 neurologically normal control subjects
From the Human Neurochemical Pathology Laboratory, Clarke Institute of Psychiatry, Toronto, Ontario, Canada.
Received Sep 2, 1993, and in revised form Oct 4. Accepted for
publication Oct 5 , 1993.
Address correspondence to Dr Kish, Human Neurochemical Pathology Laboratory, Clarke Institute of Psychiatry, 250 College Street.
Toronto, Ontario, Canada M5T 1R8.
624 Copyright 0 1994 by the American Neurological Association
aKGDHC activity in the absence of TPP was significantly reduced ( - 65%))with a nonsignificant trend for
reduction ( - 39%) when measured in the presence of
TPP ( p > 0.05 for other brain areas). The mean difference between aKGDHC or CS-corrected aK GDHC
activity in the presence versus absence of TPP (i.e.,
TPP effect and CS-corrected TPP effect, respectively)
was significantly greater in both cerebellar and occipital
cortices of the OPCA patients compared with the controls, with the exception of the TPP effect in OPCA
cerebellar cortex, which just missed statistical significance ( p = 0.062). In frontal cortex, neither the TPP
nor CS-corrected TPP effect between the OPCA and
control patients was significantly different ( p > 0.05).
Levels of aspartate and, to a lesser extent, glutamate,
were significantly reduced in all three brain areas with
the greatest reductions occurring in cerebellar cortex.
matched ( p > 0.05) with respect to age (OPCA, 40 3 yr;
controls, 40 2 5 yr), postmortem interval (OPCA, 9 ? 2
hr; controls, 13 -t 1 hr), and, as an index of premortem
agonal status (cf. [4]),
cerebral (frontal) cortical p H (OPCA,
6.2 ? 0.1;controls, 6.2 2 0.1). The affected gene for this
form of OPCA contains an unstable CAG trinucleotide repeat on chromosome 6 [3}. The diagnosis of OPCA was
based upon the presence of clinical signs (limb and gait ataxia,
dysarthria, dysphagia) and characteristic neuropathological
changes, severe in all of the cases, consisting of neuronal cell
loss and gliosis in the Purkinje cell and molecular layers of
the cerebellar cortex, basal pontine nuclei, and inferior olives.
Semiquantitative histopathological analysis of cerebral cortex
showed no evidence of neuronal cell loss or gliosis with the
exception of slight neuronal cell loss and gliosis in parietal
cortex only of 2 OPCA patients. Most of the OPCA patients
had died of bronchopneumonia and had likely received antibiotics and corticosteroids just prior to death. Activities of
a K G D H C and citrate synthase (CS), a marker of rnitochondrial mass, and brain p H were determined as previously described [ 4 ] . Aspartate and glutamate levels, previously reported on 6 of the 12 OPCA patients [5), were determined
by a high-performance liquid chromatographic-fluorometric
procedure [ S ] .
Our observation that TPP produced in OPCA above
normal stimulation of aKGDHC and CS-corrected
aK GDHC activity in both occipital and cerebellar cortices provides some indirect support for the presence
of lowered endogenous levels of TPP in OPCA brain.
This possibility is consistent with the report of decreased thiamine levels in cerebrospinal fluid of patients with OPCA El]. Although this TPP effect could
be explained by reduced dietary thiamine intake in the
end-stage OPCA patient, the finding that, in OPCA,
blood thiamine levels (which should reflect dietary
changes) are normal [l} argues against this interpretation. The observation that aKGDHC activity in
OPCA cerebellum remained below normal even in the
presence of a maximally stimulatory concentration of
TPP could be explained by irreversible inactivation of
the enzyme due to chronic deficiency of its cofactor
TPP, which has been postulated to have an enzyme
As shown in the Table, a KGDHC activity determined
in the presence of a maximally stimulatory concentration of TPP was markedly reduced ( - 50%) in OPCA
cerebellar cortex (just missing statistical significance; p
= 0.058) but was normal in both frontal and occipital
cortices. In the absence of TPP, (YKGDHClevels were
significantly and more markedly reduced ( - 7 2 g b )in
cerebellar cortex with a nonsignificant trend for decreased ( - 33%) levels in occipital cortex ( p > 0.05
for frontal cortex). Mean CS activity was slightly but
significantly decreased in OPCA frontal (~ 6%), occipital ( - 2393, and cerebellar ( - 20%) cortices. In
OPCA cerebellar cortex, activity of CS-corrected
Mitochondria1 Enzyme ActivitieJ and Amino Acid Levels in Postmortem Brain of Conlrol Subjec-tJ and
Patients with OlivopontocevebellarAtrophy
TPP Effccr
5 33 2 1 4 9
1 4 8 f 0.24a
- 72
1.01 f 0.12
1 7 2 i 0 27
206 i i
165 i 3"
6.92 f 1.21
59 t 2.2s
5.09 2 0.96
7 8 0 2 1.13
8.31 ? 1.30
7.12 t 1 36
7.42 I1.52
TPP Effect
0.005 0.001
0.010 z i)002'
Cerebellar cortex
ci of change
occlpltd iurrex
6 of change
Frontal conex
$$ ot change
6 34
3.20 ? 0.4.i
7 20
0 68 f 0.12
0 89 i 3.49
0 00'
- 19
0.026 z 0.00:
0.009 2 0.001
- 65
I 9
164 2 4'
- 23
0.034 z 0.010
0.041 I0.00'
188 i 1
176 I 2'
0.042 t 0.006
0 035 I0.908
z 0011
0.030 0.005
- 18
(!.Oil 3
0.004 f 0.002
(j.004 2 0.002
3 Ra
- 44
- 66
- 1'
4 ? 0.Y
20.2 t 2 2
75.5 z 4.1
12.4 3 l.>a 58.8 2 5.3b
- 39
- 22
16.6 f 1.6
12.11 2 i . i b
88.1 f 3.2
3 . ~
- 28
Valuer represenr mean f SE of 13 control rublcctr and 12 parienrs wirh dominanrly inherited olivopontocerebellar armphv (OPCA) for enzyme acti>ities and 8 to 11 OPCA patients for aminn acid levelc,
in lrcntal cortex (Brodmann uea lo), occipital correx (area 171, and cerebellar currex. uKGDHC + TPP = acrivir) (nmollmmlrng of proiem) of u-kemglutardtr dchydrogmasc complch laKGDHC) in the
presence of thiamine pgrophosphare iTPP1 added to rhe reacrion mixture; aKGDHC - TPP = activity ofaKGOHC in the absence ofTPP; TPP Effect = mean diffcrrnie between mKGDHC acrivirg m
the presence vs absence of TPP CS = acrivity (nmollminimy: of prore~nlof titrate rynthase ICS), iolKGDHC + TPPYCS = artiwy of uKGDHL in the prrsentc of TPP corrected for CS activity,
(aKGDHC - TPP1:CS = activity of aKGDHC In the abrencr uf TPP corrected for CS acnviry. CSXorrecred" TPP Lfferr = mean ddfcrcnce k t w c c n Cb corrcired aKGDHC amvxy ~n rhe presence
vs absence of TPP; apartate a d gluramate valuer (pmol'gm of protein) represenr levels ot the rerpectlw amino a d 5
'p < 0.02, ' p < 0.05 (two-railed Studenr's f resr).
Brief Communication: Mastrogiacomo and Kish: Brain aKGDHC in OPCA
stabilization role (cf. {GI). Decreased activity of
aKGDHC, a mitochondrial enzyme, is unlikely to be
due in toto to loss of mitochondrid mass, since the
degree of enzyme deficiency greatly exceeded the
slight reduction in activity of CS, a marker of mitochondrial content, and cerebellar cortical a KGDHC
levels in OPCA, corrected for CS, still showed a statistically significant reduction. Reduced clKGDHC levels
could be explained at least in part by neuronal loss,
since enzyme activity was markedly reduced only in
cerebellar cortex, with a slight and nonsignificant decrease (occipital cortex) or no reduction (frontal cortex)
in the morphologically spared cerebral cortex; this pattern is not observed in Alzheimer’s disease brain,
which is characterized by markedly reduced cerebral
cortical a K G D H C activity (cf. {4}).Should a KGD HC
be preferentially contained in a subgroup of neurons
more severely affected in OPCA (eg., Purkinje cell
neurons), then neuronal loss could, in fact, account for
the enzyme reduction.
Reduced a K G D H C activity in OPCA cerebellum
could have important functional consequences involving both brain energy metabolism and excitatory amino
acid production. A 72% reduction in cerebellum of
aKGDHC, a rate-limiting Krebs cycle enzyme, might
lead to depletion of energy stores, which could affect
both brain function and susceptibility to excitotoxic
neuronal damage { i } .Although no information appears to be available in the adult, a 7 5 to 95% and
apparently biochemically restricted a K G D H C deficiency (assessed in cultured fibroblasts) is associated
with severe central nervous system developmental abnormalities in humans 18, 91. Since normal activity of
the Krebs cycle is necessary for excitatory amino acid
synthesis, a chronic deficiency of a KGDHC might also
affect excitatory amino acid levels and neurotransmission. Although we could not detect by regression analysis any statistically significant correlation ( p > 0.05)
in OPCA brain between enzyme activity and either
aspartate or glutamate levels, our observation that,
among the three brain regions examined, aspartate and
aKGD H C levels (without TPP) were reduced generally in parallel (see Table) supports this possibility.
In conclusion, we have demonstrated a marked reduction in the activity of a thiamine-dependent Krebs
cycle enzyme in cerebellum of patients with one form
of OPCA. Further studies will be required to provide
the neuronal/biochemical basis for this finding.
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I .
Absence of Postoperative
Hyponatremia Syndrome
in -Young, Healthy Females
Eelco F.
M. Wijdicks, MD, and Timothy S. Larson, MD
Young and previously healthy females have been reported to develop severe postoperative hyponatremia
with a fatal outcome. The clinical presentation is dramatic, with seizures, respiratory arrest, and permanent,
often catastrophic, brain damage. The true incidence is
unknown. We report a survey of 290,815 surgical procedures on females at the Mayo Clinic from 1976 to 1772.
Postoperatively 1,498 females had cardiopulmonary arrest, 255 had a metabolic encephalopathy, 32 had newonset seizures, and 6 had central pontine myelinolysis.
We failed to identify any association of respiratory arrest
with postoperative hyponatremia. Our findings indicate
that the postoperative hyponatremia syndrome in
young, healthy females with respiratory arrest is extremely uncommon.
Wijdicks EFM, Larson TS. Absence of postoperative
hyponatremia syndrome in young, healthy
females. Ann Neurol 1994;35:626-628
Of the numerous postoperative complications, hyponaThis study was supported by US N I H NINDS grant no. NS26034.
tremia is common and is most often associated with
From the Mayo Clinic, Rochester, MN.
1. Pedraza OL, Botez MI. Thiamine scatus in inherited ataxias.
J Neurol Neurosurg Psychiatry 1992;55:136-137
2. Butterworth RF, Heroux M. Effect of pyrithiamine treatment and
subsequent thiamine rehabilitation on regional cerebral amino
Received Oct 6, 1093, and in revised form Nov 16. Accepted for
publication Nov 18, 1993.
Address correspondence to Dr Wijdicks, Department of Neurology
(Neurology Critical Care Service), Mayo Clinic and Mayo Foundation, 200 First Street, SW, Rochester, MN 55905.
626 Copyright 0 1994 by the American Neurological Association
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ataxia, cerebellar, spinocerebellar, ketoglutarate, activity, dehydrogenase, typed, reduced
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