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Copper and zinc levels in familial amyotrophic lateral sclerosis patients with cuznsod gene mutations.

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to worsening of parkinsonian symptoms. Because Verhagen
and co-workers [3] do not provide confirmation of their lesion locations, it is conceivable that their lesions encroached
on the GPe.
The second point raised by Krack and colleagues, is not
really relevant, since it seems to apply solely to DBS and not
to pallidotomy. The mechanism underlying the effect of
DBS on akinesia is unclear. The worsening of akinesia from
ventral pallidal stimulation could be secondary to increased
pallidal (inhibitory) output.
The authors’ third point, that DBS permits optimization
of stimulation and location parameters is true, but it does
not necessarily follow that DBS is therefore superior to pallidotomy. Of concern is the apparent limited benefit of DBS
for tremor and drug-induced dyskinesias. Moreover, the results of bilateral DBS (5 of 8 were bilateral procedures) cannot be compared directly with those of unilateral pallidotomy. The benefits of pallidotomy versus DBS can only
be addressed in a randomized controlled clinical trial that
compares unilateral and bilateral procedures in comparable
populations.
Departments of *Neuroloa, fNeurosurgery, and $Psychiaty,
Ern0 y Universiq School of Medicine, Atlanta, GA
References
1. Lozano AM, Lang AE, Galvez-Jimenez N , et al. Effect of GPi
pallidotomy on motor function in Parkinson’s disease. Lancet
199j;346:1383-1387
2. Dogali M, Fazzini E, Kolodny E, et al. Stereotactic ventral pallidotomy for Parkinson’s disease. Neurology 1995;45:753-761
3. Verhagen L, Mouradian M, Chase T. Altered levodopa doseresponse profile following pallidotomy. Neurology 1996;46:
A416-A417 (Abstract)
Copper and Zinc Levels in Familial Amyotrophic
Lateral Sclerosis Patients with CuZnSOD Gene
Mutations
A. RadunoviC, MD, PhD,* H. T. Delves, PhD,t
W. Robberecht, MD, PhD,$ P. Tilkin, RN,$
Z. E. Enayat, MSc,* C. E. Shaw, FRACP,*
Z. Stevii-, MD, PhD,s S. Apostolski, MD, PhD,$
J. F. Powell, DPhil,* and P. N. Leigh, PhD, F R O *
The identification of mutations in the CuZn superoxide dismutase (CuZnSOD) gene in patients with the autosomal
dominant familial form of amyotrophic lateral sclerosis
(FALS) [ l ] suggests a prominent role for CuZnSOD in the
pathogenesis of ALS. FALS is clinically and pathologically
almost identical to the sporadic form of ALS (SALS), and it
is likely that both forms could share a common underlying
mechanism(s) leading to motor neuron degeneration. Although some FALS-associated CuZnSOD mutants appear to
lose their primary dismutation activity, disease pathogenesis
appears to be related to a gain of toxic function that may
lead to cell death. It has recently been proposed that disrup-
130 Annals of Neurology
Vol 42
No 1 July 1997
tion of the intracellular homeostasis of C u and/or Zn could
lead to motor neuron degeneration in CuZnSOD-associated
FALS [2].
W e have determined the concentrations of total C u and
Zn by flame atomic absorption spectrometry (FAAS) after
dilution with 6% (vol/vol) butan-1-01, as well as the concentration of loosely bound “free” C u using copper phenanthroline-dependent degradation of DNA in blood, plasma,
and red blood cells (RBCs) of 12 FALS patients (mean age,
50.5 years; range, 25-72 years; males/females = 6:6) with
seven different CuZnSOD gene mutations (L38V, n = 1;
D90A, n = 3; G93C, n = 4; ElOOG, n = 1; DlOlG, n =
1; L144F, n = 1; and I149T, n = l ) , 7 FALS patients
without CuZnSOD gene mutations (mean age, 55.9 years;
range, 41-73 years; males/females = 4:3), 34 patients with
SALS (mean age, 57.1 years; range, 32-81 years; males/
females = 21:13), 23 patients with Parkinson’s disease
(mean age, 63.7 years; range, 33-74 years; males/females =
14:9), and 31 spouse controls (mean age, 56.8 years; range,
31-80 years; males/females = 1417). Furthermore, levels of
both metals in RBCs have been correlated to the activity of
CuZnSOD.
Total Cu concentrations in blood and plasma of FALS
patients with CuZnSOD gene mutations (FALS-1) were
13.7 2 2.2 (mean t SD) (range, 11.2-18.4) and 16.1 f
3.2 (range, 10.7-22.0) kmol/L, respectively, whereas total
Zn concentrations were 97.2 2 14.3 (range, 69-110) and
12.8 2 2.6 (range, 8.4-16.1) kmol/L, respectively. These
were not significantly different from those in FALS patients
without CuZnSOD gene mutations (FALS-0), SALS patients, Parkinson’s disease patients, and control subjects. Total Cu concentrations in RBCs were 11.7 2 1.6 (FALS-1
patients), 11.3 t 1.1 (FALS-0 patients), 12.6 t 2.1 (SALS
patients), 12.3 2 1.6 (Parkinson’s disease patients), and
12.0 -t- 1.4 (control subjects) Fmol/L. Total Zn concentrations in RBCs were 161,6 2 31.5 (FALS-1 patients),
158.3 -t- 36.3 (FALS-0 patients), 181.2 i 29.5 (SALS patients), 194.8 -C 24.8 (Parkinson’s disease patients), and
174.1 t 31.5 (control subjects) pnol/L. Cu levels in blood,
plasma, or RBCs, were not correlated to the age of onset of
ALS. No loosely bound free Cu was present in blood,
plasma, or RBCs of FALS-1 patients, FALS-0 patients, SALS
patients, Parkinson’s disease patients, or control subjects.
In FALS-1 patients, enzymatic activity of CuZnSOD in
RBCs was reduced to between 44.3% (patient with G93C
mutation) and 90.0% (patient with D90A mutation) of the
control value (Table). There was no significant correlation
between RBC CuZnSOD activity and Cu concentration
( r = 0.50, p = 0.14) or Zn concentration ( r = 0.14, p =
0.69). No correlation was found between disease duration
and C u concentration ( r = 0.271, p = 0.39) or Zn concentration ( r = 0.475, p = 0.12).
Hence, we have found no difference in copper and zinc
levels in blood, plasma, and RBCs of either FALS or SALS
patients compared with Parkinson’s disease patients and nonneurological control subjects. We have also failed to detect
any loosely bound “free” copper in blood, plasma, and RBCs
of individuals studied. These findings indicate that altered
C u and Zn levels in blood, plasma, and RBCs are not associated with ALS. However, it is possible, as in mild Menkes’
Table. Cu and Zn Concentrations and CuZnSOD Activity in RBCs of FALS Patients with CuZnSOD Gene Mutations
Age (yr)lSex
CuZnSOD
Gene Mutation
Disease
Duration
25lM
481M
441M
72/F
651F
471M
621F
40lF
70lF
451F
51/M
36lM
L38V
D90A
D90A
D90A
G93C
G93C
G93C
G93C
ElOOG
DlOlG
L144F
I149T
4 mo
44 mo
9 Y‘
32 mo
3 mo
20 mo
9 mo
14 mo
18 mo
8 mo
8 Yr
7 Yr
Cu (pmol1L)
Zn (pmol1L)
10.6
13.8
11.5
13.5
13.8
11.8
11.2
13.8
9.9
10.3
10.5
185
106
176
165
20 1
180
176
171
195
122
118
144
10.0
CuZnSOD
(Ulg of Hb)
2,952
ND
ND
5,371
3,892
2,643
4,42 1
4,074
3,281
3,194
4,501
3,167
Cu = copper; Zn = zinc; SOD = superoxide dismutase; RBCs = red blood cells; FALS = familial amyotrophic lateral sclerosis; Hb
=
hemoglobin; N D = not determined.
disease where changes in serum Cu and ceruloplasmin may
be too slight to be diagnostic [3], that analysis of copper
transport in other tissues (eg., fibroblasts and brain) may
show abnormalities. In a murine model of Menkes’ disease
where copper efflux is disrupted and there is accumulation of
copper in intestine, the excess copper is bound to metallothionein [4]. Metallothionein provides the second line of defense against zinc toxicity when zinc efflux systems are inadequate [5]. It is interesting that metallothionein has been
shown to be increased in the spinal cord of ALS patients [6].
This may reflect an increase of copper and zinc in the spinal
cord and other tissues that is not reflected in plasma or
RBCs. Thus, our findings do not entirely exclude a role for
intracellular copper and zinc toxicity in ALS, and further
studies of intracellular Cu2+ and Zn2+ homeostasis and copper and zinc concentrations in central nervous system tissue
are warranted.
Supported by the MRC(UK) and MNDA(UK).
’Department of Clinical Neurosciences, Institute of Pychiatry
and King? College School of Medicine and Dentisty,
London, UK;. ?Department of Clinical Biochemisty,
Southampton General Hospital, Southampton, U E
$Department of Neurology, University Hospital Gasthuisberg,
Leuuen, Belgium; and $Institute of Neuroloa,
Belgrade, Yugoslavia
References
1. Rosen DR, Siddique T, Patterson D, et al. Mutations in CuiZn
superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993;362:59-62
2. Brown RH. Amyotrophic lateral sclerosis: recent insights from
genetics and transgenic mice. Cell 1995;80:687-692
3. Danks DM. Disorders of copper transport. In: Scriver CR, Beaudet AL, Sly WM, Valle D, eds. The metabolic and molecular
bases of inherited disease. New York: McGraw-Hill, 1995:22112235
4. Kelly EJ, Palmiter RD. A m u r k model of Menkes disease reveals a physiological function of metallothionein. Nat Genet
1996;13:219-222
5. Palmiter RD, Findley SD. Cloning and functional characterisation of a mammalian zinc transporter that confers resistance to
zinc. EMBO J 1995;14:639-649
6. Sillevis Smith PAE, Blaauwgeers HGT, Troost D, de Jong
JMBV. Metallothionein immunoreactivity is increased in the spinal cord of patients with amyotrophic lateral sclerosis. Neurosci
Lett 1992;144:107-1 10
Acute Myopathy of Intensive Care
Nicola Latronico. MD
Lacomis and colleagues [I] described 14 critically ill patients
who had an acute thick-filament myopathy, which they attributed to the corticosteroid treatment. The authors also
stared that sepsis played a role in only a few patients. However, among the nontransplant patients (7 of 14), those who
“did not have bacteremia, had a focus of infection (most often pulmonary), leukocytosis, and usually hypotension and
multiorgan failure.” From this description, it must be inferred that all had sepsis or severe sepsis or even septic shock
if we adhere to recently proposed definitions [2]. In the
transplant group, 4 patients had fulminant hepatic failure in
their history and 1 had graft rejection in the clinical course.
Did they not have a systemic inflammatory response syndrome (SIRS) [2]? Interestingly enough, the patient with
graft rejection was described as experiencing myopathy “only
after he received high-dose IV corticosteroids (without
NMBAs) for acute graft rejection.” However, he actually had
rejection, and therefore a violent SIRS!
I suspect SIRS is poorly understood in the neurological
literature. It would be instructive, from both the human and
medical points of view, to read Bone’s paper [3] on his personal experience of SIRS. It demonstrates how violent SIRS
is, how organ dysfunctions follow, and also how transient
they can be.
Bolton [4]suggested that most patients with prolonged
( > I week) intensive care unit stay, like those in the Lacomis
study [l], actually have sepsis. My colleagues and I have re-
Annals of Neurology
Vol 42
N o 1 July 1997
131
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