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Complex I function in familial and sporadic dystonia.

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556 Annals of Neurology Vol 41
No 4
April 1997
Complex I Function in
Famiiial and
Sporadic Dystonia
A. H. V. Schapira,*t 7’. Warner,* M. T. Gash,’
M . W. J. Cleeter,+ C. F. M. Marinho.*$ and J. M. C o o p e r
A significant proportion of patients with inborn errors of
the mitochondrial respiratory chain exhibit movement
disorders, particularly dystonia. Point mutations of mitochondrial DNA (mtDNA) are usually expressed systemically, and defects of platelet respiratory chain function
have been described in patients with mtDNA mutations
and Leber’s hereditary optic neuropathy (LHON). Recent
reports have documented families with dystonia in association with LHON and mtDNA complex I gene mutations. We have examined mitochondrial function in
platelet mitochondria from patients with familial generalized dystonia (linked or not linked to 9q34) and sporadic focal dystonia. We confirm a previous report of a
specific complex I defect in patients with sporadic focal
dystonia but could not find any abnormality in patients
with familial generalized dystonia, linked or not to 9q34.
These results support the existence of a mitochondrial deficiency in sporadic focal dystonia and provide a biochemical dimension to the clinical and genetic distinction
between focal and generalized familial dystonia.
Schapira A H V , W a r n e r T, Gash M T ,
Cleeter MWJ, M a r i n h o CFM, C o o p e r JM.
C o m p l e x I function in familial a n d sporadic
dystonia. A n n Neurol 1997;41:556-559
Idiopathic torsion dystonia (ITD) is the commonest
form of primary dystonia. Genetic analysis suggests
that the majority of patients with segmental, multifocal, and generalized ITD are affected through the presence of an autosomal dominant gene(s) with reduced
penetrance and variable expression [ 11. The gene
mapped to 9q34 (DYTI) [2] appears responsible for
the majority of patients with childhood and generalized
ITD in the Ashkenazi Jewish population and in approximately 50% of non-Jewish familial I T D [ 3 , 41.
Focal ITD is usually of adult onset and sporadic, al-
From the ‘Department of Clinical Neurosciences, Royal Free Hospital School of Medicine, and tUniversiry Departinent of Clinical
Neurology, Institute of Neurology, London. UK.
$ Permanent address: Department of Physiological Chemistry,
School of Medicine, Universiry of Oporto. 4200 Oporto, Portugal.
Received July 16, 1996, and in revised form Sep 25. Accepted for
publication Sep 26. 1996.
Address correspondencc to Prof Schapira, Department of Clinical
Neurosciences. Royal Free Hospital School of Medicine, Rowland
Hill Street, London NW3 2PF, UK.
though familial cases have been described [ 5 ] .No linkage to a focal ITD gene has been described to date;
DYTl has been excluded in two families with dominantly inherited cervical dystonia [6].
Although the pathology of dystonia is thought to reside in the basal ganglia, no information is yet available
o n the biochemical abnormalities that cause dystonia.
In 1992, Benecke and colleagues [7] reported a specific
deficiency of nicotinamide adenine dinucleotide (reduced form) (NADH) coenzyme Q1 (CoQ,) reductase
(complex I), the first protein of the mitochondrial respiratory chain, in platelets from patients with focal
segmental and generalized ITD. There was some correlation between the reduction in complex I activity
and the severity of the dystonia in that there was a
more severe defect in generalized dystonia. Complex I
comprises 41 subunits of which seven are encoded by
mitochondrial DNA (mtDNA) and the remainder by
nuclear DNA. T h e finding of mitochondrial complex I
deficiency in I T D raised the possibility that it may be
linked to the molecular genetic basis of this disorder.
Whereas the chromosome 9-linked families might be
associated with a nuclear encoded complex I gene defect, the sporadic forms of ITD might be caused by
mutations in either the nuclear or mitochondrial genomes.
To investigate this further, we have analyzed mitochondrial respiratory chain function in patients with
familial generalized and sporadic focal ITD. T w o
groups of families with generalized I T D were studied,
ie, Ashkenazi patients known to carry the haplotype of
chromosome 9q34 markers associated with DYT1, and
non-Jewish patients with familial ITD in whom linkage to 9q34 had been excluded.
Patients and Methods
Patients
Five Ashkenazi Jewish patients (from three families) with
childhood-onset generalized ITD were studied, as well as 2
individuals from these kindreds who were obligate gene carriers of the DYTl gene. The mean age of the DYTl-linked
patients was 46 years (range, 30-61 years) with a mean disease duration of 34.2 years (range, 17-42 years). The DYTl
obligate carriers were age 82 and 65 years. All 7 had the
haplotype associated with DYTl, demonstrated by using the
chromosome 9q34 markers D9S62, D9S63, ASS, and ABL
[3, 81. All were nonsmokers, 3 of the 5 affected patients were
not taking any medication, and the other 2 were taking Arcane 100 mg and carbamazepine 400 mg, respectively. Four
patients from two non-Jewish families with familial ITD
were also studied. Linkage analysis of these families using the
microsatellite probes listed above had previously excluded the
presence of a gene causing dystonia from the DYTl candidate interval [3]. The mean age of the non-DYT1-linked
patients was 40.5 years (range, 23-66 years) with a mean
disease duration of 28 years (range, 15-46 years). Three of
these had childhood-onset generalized and 1 had segmental
ITD. One obligate gene carrier (age, 50 years) was also studied. Non-Jewish patients with sporadic focal dystonia (n =
20) were studied and had either cervical dystonia (n = 16)
or writer’s cramp (n = 4). Results were compared with both
Ashkenazi (n = 5) and non-Jewish (n = 28, ie, 22 + 6)
age-matched controls. Thirteen of the 22 control group were
disease controls with disorders such as cervical spondylosis,
spinal cord trauma, peripheral neuropathy, and stroke. None
of the controls or patients with focal dystonia was taking
neuroleptics or other drugs known to influence platelet mitochondrial function.
Respiratoly Chain Analysis
Platelet mitochondria were prepared as previously described
[9]. Patients and control samples were prepared and assayed
simultaneously in groups of 2 or 4. After three cycles of
freeze-thawing, control and patient mitochondrial pellets
were assayed in parallel and in triplicate at 30°C on Hitachi
U3210 and Kontron 940 dual-beam spectrophotometers.
Cytochrome oxidase, succinate cytochrorne c reductase, and
citrate synthase were assayed by standard techniques [lo].
NADH CoQ, was assayed by the technique described by
Krige and associates [9]. Statistical analysis was performed
using the Mann-Whitney U test.
Results
Mitochondria1 respiratory chain activities are shown in
the Table. Activities are expressed as a ratio of citrate
synthase activity, to correct for any variation in platelet
mitochondrial yield between samples. Controls and patients were matched for age, although no correlation
between age and platelet mitochondrial function has
been demonstrated in this or other studies [7, 91.
There was n o significant difference in respiratory chain
activities between the healthy and disease controls used
for the focal dystonias, and so both groups were considered as one for comparison with this group. Assays
o n the familial dystonia groups were performed after
those on the focal group; thus, additional ethnic controls for the Ashkenazi group and non-Jewish healthy
controls were analyzed in parallel with the familial dystonics and are shown separately.
There was no significant difference from controls in
the function of complexes I to IV in patients with familial dystonia whether or not they were linked to
DYT1. Values for the obligate carriers also did not fall
outside the respective control ranges. In patients with
sporadic, focal I T D , there was a mean 22% ( p =
0.00 1) decrease in the complex Ucitrate synthase ratio,
while complexes II/III and IVlcitrate synthase ratios
were not significantly changed. There was no correlation between the age of the patient ( r = 0.109) or the
duration of disease ( r = 0.211) and complex I function.
Discussion
Abnormalities of the respiratory chain, and complex I
in particular, have been reported in patients with dys-
Copyright 0 1997 by the American Neurological Association
557
Citvate Syntbme-corrected Respiratovy Cbain Activiiies j%r Familial nnd Sporadic Bystonid Patients
Complex I
x 100
Complex IIlIII
x 10
Complex IV
x 100
2
7.5 (1.4)
7.4 (2.3)
6.8 (1.5)
1.5 (0.5)
1.9 (0.4)
1.3 (0.6)
0.8 (0.1)
1.0 (0.2)
1.2 (0.2)
6
7.6 (1.9)
4
8.5 (1.8)
6.9
1.6 (1.0)
2.0 (0.5)
1.6
1.0 (0.4)
1.1 (0.2)
1.1
2.0 (0.6)
2.1 (0.6)
0.9 (0.3)
1.0 (0.4)
Number
DYTl -linked familial dystonia
Controls
Familial ITD
Obligate carrier
Non-DYT1-linked familial dystonia
Controls
Familial ITD
Obligate carrier
Sporadic dystonia
Controls
Focal ITD
~~
~~~~
5
5
1
22
20
7.4 (1.6)
5.8 (1.0)“
~~
Enzyme activity ratios are given as mean (SD) values of activities expressed as nanomoles pcr minute per mg of protein or as K per minute per
milligram for complex IV, where k is the first-order rate constant.
“p = 0.001, compared with appropriate control group hy Mann-Whirney U test, and p = 0.0005, by Studenc t test.
DYTl
=
gene mapped to 9q34; ITD = idiopathic torsion dystonia.
tonia. Complex I deficiency and mutations in complex
I mtDNA genes have been identified in three families
with Leber‘s hereditary optic neuropathy (LHON) and
dystonia. In one, a 79% deficiency in complex I activity was found in platelets in association with two coexisting mtDNA mutations in complex I genes at
14484 in ND6 and 4160 in N D 1 [ l l , 121. Normal
fibroblast complex I activity in a separate family with
the LHON 14484 mutation alone suggests that the
presence of the 4160 mutation is important in affecting enzyme function [13]. A second family with
LHON and dystonia was found to have a heteroplasmic mutation at 14453 in the mtDNA N D 6 gene
[14]. The third family had a heteroplasmic mutation at
11696 in the complex I ND4 gene, in addition to a
homoplasmic “mutation” at 14536 in N D 6 [15]. Skeletal muscle complex I activity in a patient from the
third family showed a 73% decline in complex I function, associated with less severe decrease in the activities of complexes II/III and IV. The involvement of
mtDNA was further supported by the fact that all
these three families exhibited maternal inheritance of
LHON and dystonia. Dystonia is also seen in patients
with mitochondrial encephalomyopathy more frequently than expected by chance [ 161.
Benecke and co-workers [7] reported a mean 62%
deficiency of complex I in 8 patients with segmental or
generalized dystonia and a mean 37% complex I defect
in 23 patients with focal dystonia. Activities of complexes IIlIII and IV were not significantly different
from controls. We found no abnormality in 3 patients
with familial generalized dystonia, linked or not to
9q34, but did find a mean 22% decrease of complex I
activity in patients with focal dystonia. Again, the
function of complexes II/IIl and IV was normal. ‘The
results of our focal dystonics contrast with those of
558 Annals of Neurology Vol 41
No 4
April 1997
Reichmann and collaborators [ 171, who investigated
platelet mitochondrial function in 12 patients with
spasmodic torticollis and found no significant difference from controls. However, these authors, like us,
found no abnormality in platelet mitochondrial function in 4 patients with generalized dystonia. The reason for the difference in our results on generalized dystonia with Benecke and co-workers [7] is unclear. That
all our generalized cases were familial, with defined
DYTl status, and segmental dystonia was not included
perhaps makes our group more homogeneous.
There are several examples where a defect of complex I activity in platelet mitochondria is linked to a
mutation of mtDNA, including the L H O N dystonia
families mentioned above [l 1, 151, pure L H O N associated with either the 3460 N D 1 [18, 131 or the
11778 N D 4 [13] mutations, and in patients with
mtDNA tRNA mutations and mitochondrial myopathy (Schapira AHV, unpublished data). In the case of
LHON, this provides an example of a systemically distributed mtDNA mutation, inducing a biochemical deficiency in a peripheral tissue [blood) in the context of
a specific tissue disorder (optic nerve) in the majority
of patients. It is useful to contrast the complex I defect
of the sporadic focal dystonics with the normal platelet
complex I activity that we have found in the generalized dystonics in this study and in patients with other
movement disorders including Huntington’s disease
[20] and multiple system atrophy [21]. A corollary of
these observations is whether a complex I gene defect
might underlie focal dystonia. Family studies of focal
dystonia do not reveal any clear inheritance patterns;
the majority of patients appear sporadic. This does not
distinguish between causative nuclear or mtDNA defects, as the lack of family history is common even in
the latter [22, 231. The normal complex I activity of
patients linked to DYTl would tend to exclude this
locus, involving a nuclear gene encoding a complex I
subunit. Other explanations more complex than a single gene defect cannot be excluded at this stage, including nuclear-mitochondria1 [24] or mtDNA-environmental interactions [25].
Our results provide a biochemical distinction between sporadic focal and familial generalized dystonia.
The complex I deficiency is moderate although highly
significant statistically. The presence of this defect in a
peripheral tissue would suggest a molecular genetic or
possibly environmental link to the cause of focal dystonia, at least in a proportion of cases. Like generalized
dystonia, focal dystonia is likely to be heterogeneous in
molecular genetic terms and a complex I gene defect
(nuclear or mitochondrial) may be present in only
those with the lowest respiratory chain activity. A systemically distributed mitochondrial defect is likely to
be more severe in nondividing tissues such as brain
where cell division cannot select against the deficiency
and where local biochemistry and pharmacology may
exacerbate the abnormality. We suggest that further
studies on the basis of the complex I deficiency in focal
dystonia may provide insight into the molecular mechanisms underlying this disorder.
This study was supported by grants from the Institute of Neurology,
Queen Square, and from the Parkinson’s Disease Society (UK).
9.
10.
11.
12.
13.
14.
15.
16.
17.
We are grateful to the physicians of the National Hospital for Neurology and Neurosurgery for allowing us to study their patients and
to Roche for supplying the CoQ,.
18.
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Brief Communication: Nishiyama et al: SOD1 mRNA in ALS and Controls
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