196

Journal of Neurology, Neurosurgery, and Psychiatry 1997;63:196–203

Late onset familial dystonia: could mitochondrial
deficits induce a diVuse lesioning process of the
whole basal ganglia system?
D Caparros-Lefebvre, A Destée, H Petit

Department of
Neurology, CHU
Pointe à Pitre,
Guadeloupe, French
West Indies, France
D Caparros-Lefebvre
Departement of
Neurology, CHU Lille,
France
A Destée
H Petit
Correspondence to:
Dr D Caparros-Lefebvre,
Head of the Department of
Neurology, University
Hospital, route de Chauvel,
F-97159 Pointe à Pitre
cedex, Guadeloupe, French
West Indies, France.
Received 8 November 1996
and in revised form
17 March 1997
Accepted 25 March 1997

Abstract
Background—Striatal necrosis has been
related to various clinical syndromes, with
acute or chronic progression, and juvenile
or late occurrence, but the most common
type is Leigh’s encephalopathy.
Methods—Between 1967 and 1995, six out
of seven related patients with chronic
familial dystonia were examined. MRIs
were performed in four, between 19921994. The seven members, aVected over
three generations, were the father, three
daughters (one surviving), and three surviving grandsons.
Results—The leading symptoms were gait
disorders and dystonia in all, dysarthria in
six, verbal and motor stereotypies in two,
and parkinsonian and cerebellar signs in
three. Optic neuropathy was found in
three. A frontal lobe syndrome without
amnesia occurred in two. Symptoms occurred between the second and the fifth
decade, with progressive deterioration.
Magnetic resonance imaging, performed
in four, showed in the two patients with
severe neurological signs diVuse striatopallidal abnormal hyposignal (comparable with CSF signal) in T1 weighted
images, suggesting extensive necrosis of
the striatum and pallidum, associated
with thalamo-subthalamo-rubro-dentatonigral and substantia innominata hypersignals in T2 weighted images suggesting
gliosis in these respective areas. The same
images were described to a lesser extent in
a third patient. Concentrations of lactate
in CSF and serum were normal in three.
Muscle biopsy, performed in four, was
shown to be normal. Enzyme histochemistry showed complex I, III, and IV
deficiency in surviving patients.
Conclusion—This familial dystonia of
chronic progression may be related to
basal ganglia necrosis or gliosis, associated with alterations in the respiratory
chain. These metabolic alterations probably play a part in the pathophysiology of
these unusual brain lesions.
(J Neurol Neurosurg Psychiatry 1997;63:196–203)
Keywords: striatal necrosis; familial dystonia; dysarthria; mitochondrial disorders

Familial dystonia is often essential but the
occurrence of striatal lucencies suggests other

entities including a large group of metabolic
disorders, including mitochondrial defects.1 2
Striatal necrosis was first described by Paterson
and Carmichael, in young children.3 Later,
some reports have described similar lesions in
adults,4 5 associated with diVerent clinical
pictures.6 7 Striatal necrosis had appeared as a
common feature of subacute encephalopathy
of Leigh’s type.5 8 Its relation to mitochondrial
disorder has been ascertained,2 but mitochondrial diseases which represent a chemically
defined entity, correspond, in fact, to an
association of very diVerent clinical syndromes,
including pure encephalopathy, neuropathy,
myelitis, or myopathy.6 9 To our knowledge,
familial late onset dystonia with diVuse lesions
of the basal ganglia has not previously been
reported in mitochondrial diseases. Analysis of
the current literature disclosed only one family
of late onset dystonia with dysarthria and striatal hypodensities, reported by Druschky10;
however, he did not study the respiratory chain
complexes, nor the muscle biopsy. We report
seven family members with dystonia. Six of
these have been examined or followed up by
one of us between 1967 and 1995.
Case reports
Figure 1 gives the relation between each
relative, and table 1 summarises the main clinical features.
CASE 1: PROPOSITUS I.4

His daughter (case 4) and grandson (case 5)
remember that he had an abnormal gait, with
probable dystonia in lower limbs. In 1914, he
became divorced after his wife gave birth to a
daughter (case 2). He was the father of a
second daughter (case 3), before he married
again. Later, he had five other children. The
diVerent family names of his children explain
the delay before recognising that they were
Table 1

Summary of clinical presentation
Patients

Dystonia
Dysarthria
Athetoid
movements
Parkinsonism
Rest hypotonia
Cerebellar signs
Blepharospasm
Frontal syndrome
Dementia

1

2

3

4

5

6

7

+
ND

+
+

+
+

+
+

+
+

+
+

+
+

ND
ND
ND
ND
−
ND
ND

−
+
−
+
−
ND
ND

+
−
+
+
−
ND
+

−
−
−
−
−
−
−

−
+
+
−
+
−
−

+
−
+
+
−
+
−

+
−
+
−
−
+
−

ND=Not determined; +=positive; −=negative.

197

Late onset familial dystonia

1

I
1

2

II

3

4

5

2
1

3
2

6

III
1

2

3

4

7
5

6

4
3

4

11

12

5

6

7

8

5
7

8

9

10

13

14

15

16

IV
1

Figure 1

2

3

4

5

6

Family tree. ‡=Female; ß=male; /= deceased; patients are shown in black.

relatives. He died at the age of 54, from sequelae of poison gas during the first world war, and
was not necropsied. Before he died, he was able
to walk only with diYculty due to dystonia and
equinism.
CASE 2: PROPOSITUS II.2

This woman complained of gait disorders and
dystonia at the age of 46. No somatic disorder
occurred before this period, but she had
psychiatric symptoms with personality disorders. She was admitted to hospital at the age of
56. At this time, she was unable to walk,
because of pronounced dystonia and cerebellar
ataxia. Speech was slurred. At rest, a mild
hypertonia appeared in all limbs. Rigidity was
considerably increased during voluntary movement and was then associated with torsional
spasms involving both legs, with equinism.
Alternating movements of the hands disclosed
bradykinesia. No treatment had improved the
dystonia nor the rest hypertonia. The predominant features were dystonia occurring during
voluntary movements, parkinsonism, and dysarthria. She died at the age of 71. A necropsy
was not performed.
CASE 3: PROPOSITUS II.3

This woman had moderate gait disorders. She
has been examined once in 1968. At this time,
she had gait unsteadiness, with falls. Speech
was explosive. No dystonic posture occurred
but athetoid movements were seen in both
hands. Deep tendon reflexes were brisk. She
did not complain of these disorders. The axial
cerebellar syndrome and abnormal movements
were associated with mental deterioration. She

died at the age of 67. A necropsy was not performed.
CASE 4: PROPOSITUS II.8

She had been a nurse until the age of 58 but she
had complained of gait disorders at the age of
51. She was first examined at the age of 63, in
1992. The most striking feature was that she
waddled, despite the fact that there was only
mild spasticity in the legs, and mild dystonic
posture in the toes of the right foot. Strength
was slightly reduced proximally in both legs.
No parkinsonian symptoms were present.
Speech was nasal and monotonous with
normal volume. Neuropsychological studies
included the Wechsler memory scale,11 and
parts of the Wechsler adult intelligence scale
(WAIS; cubes and similitudes),12 Buschke
test,13 and digit span. They showed impairment
for recall of a list of words, improved by
indexation (Buschke test): free recall 1: 5/16,
delayed free recall: 7/16. Nerve conduction
velocities (NCV), somaesthesic evoked potentials (SEP), EMG, and EEG were normal.
Brain CT and MRI of the spine were normal.
In 1995, MRI of the brain with T2 weighted
images (1Tesla, Magnetom impact, TE = 14,
TR = 3200, slice thickness = 5 mm) showed
diVuse abnormal hypersignal of both putamen,
associated with abnormal hypersignal involving
both substantia nigra. Pallidum and red
nucleus density seemed to be normal. Muscle
biopsy was performed when she was 62 and
showed isolated ragged red fibres, corresponding to 3% of total fibres. Electron microscopy
showed normal mitochondria, without inclusions.

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Caparros-Lefebvre, Destée, Petit

Figure 2 Case 5: MRI with T1 weighted coronal images
shows diVuse abnormal putaminopallidal low intensity
signal, comparable with the CSF signal.
CASE 5: PROPOSITUS III.10

This first son of case 3, born in 1935, had been
a draughtsman until the age of 33. Birth and
childhood had been normal. At the age of 27
years, he noted the appearance of mild gait disorders which progressively worsened. He was
admitted once in 1967, for impaired balance,
dyskinesia, dysarthria with hypophonia, and
swallowing impairment. At rest, hypotonia was
permanent. During voluntary movements,
hypertonia due to dystonia with myoclonus
occurred. Dystonic movements interfered with
the voluntary, precise, and rapid alternating
movements of the hands, performed for bread
buttering, hairdressing, drumming, or scratching. Walking was stiV, unstable, and also
impaired after a few minutes by dystonic
posture of the left foot. He was amimic, with
monotonous speech and micrographia. There
were no pyramidal signs, nor oculomotor deficit. One year later, falls occurred daily.
Dystonic dysarthria worsened until speech was
no longer understood in 1973. Aphonia
extended to severe hypophonia in 1976.
Blepharospasm occurred in 1978, and worsened progressively. It has been partly improved
by repeated injections of botulin toxin, which
have been continued. Other treatments orally
administered (dopaminergic agonists, anticholinergic drugs) were not eVective on motor
disorders and were stopped. In 1995, the
patient was still able to walk, with moderate
dystonic posture of both feet, unstable gait,
axial akinesia, taking shuZing steps, without
arm swinging. He had moderate hearing loss.
Neuropsychological evaluation was limited by
aphonia. Verbal testing was performed using a
small computer. Premorbid intelligence quotient (IQ) determined by Beauregard’s
automatisms14 was 36/40, which corresponds
to high IQ (130). Verbal memory testing from
the Signoret memory battery15 was at the lower
limit of normality (6/12, controls: 8.31 (SD

1.25)). Digit spans were normal16 (direct: 7,
inverse: 5). Progressive matrices of Raven (PM
47)17 were normal (A: 11, B: 12, C: 9, time: 9
min 48 s). EEG, EMG, and NCV were normal,
as was the muscle biopsy. Ophthalmological
examination showed normal visual acuity and
field, and a normal electroretinogram. Visual
evoked potentials (VEPs) were bilaterally
disorganised with decreased velocity, suggesting a mild optic neuropathy. T1 weighted coronal and axial images MRI on (TE = 12, TR =
400) showed diVuse putaminopallidal abnormal hyposignal, comparable with CSF signal
(fig 2), and to necrotic cavities, suggesting
extensive necrosis of the striatum and pallidum. In T2 weighted axial images (TE = 100,
TR = 2000), the putaminopallidal area appeared as a large hypersignal (similar to the
CSF signal). This intense abnormal signal
involved the whole putamen and pallidum, and
the caudate nucleus was involved to a lesser
extent. A mild high intensity signal was also
seen in both thalami (fig 3). At the level of the
brain stem, T2 weighted axial images showed
symmetric abnormal hypersignals involving the
whole substantia nigra. An abnormal hypersignal was also located in both red nuclei,
surrounded by a lower signal, bilaterally (fig 4).
The coronal plane confirmed red nuclei
lesions, and suggested symmetric implication
of subthalamic nuclei and below of both
substantia nigra (fig 5). This also showed an
abnormal hypersignal surrounded by hyposignal in the cerebellum, bilaterally, in the area of
dentate nuclei (fig 6). An abnormal signal was
located below the pallidum and above the optic
tracts in the area of the substantia innominata,
probably including the Meynert’s basalis nuclei,
according to the atlas of Nieuwenhuys et al18 (fig
7). This may suggest a gliosis in these respective
areas : substantia nigra, thalami, red nuclei, dentate, and basalis nuclei. SPECT, using 99mTc-

Figure 3 Case 5: in T2 weighted axial images, the
putaminopallidal area appears as a large high intensity
signal. The caudate nucleus is involved to a lesser extent. A
mild high intensity signal also appears in both thalami.

199

Late onset familial dystonia

Figure 4 Case 5: T2 weighted axial images show
symmetric abnormal high intensity signals involving both
substantia nigra (left arrow), and both red nuclei (right
arrow), which are surrounded by a lower intensity signal.

Figure 5 Case 5: the coronal plane confirms the
involvement of red nuclei, medially to the subthalamic
nuclei and above both substantia nigra, which were also
damaged.

hexamethyl-propylene-amine-oxime (Hm-PaO)
showed severe symmetric striatal hypoperfusion with bilateral prefrontal hypoperfusion.

Figure 6 Case 5: posterior coronal plane shows an
abnormal signal surrounded by low intensity signal in the
cerebellum, bilaterally, in the area of the dentate nuclei
(arrow).

sive development of cognitive disorders with a
frontal lobe syndrome. In the 1980s, stereotypies developed and progressively worsened. The
patient was admitted in 1994, after dystonia
worsened. Dystonic postures prevented the
patient from walking further than 10 m. The
frontal lobe syndrome worsened with permanent palilallia, and verbal and motor automatisms involving mainly the upper limbs. Speech
was dystonic with stuttering. Writing was dystonic and macrographic. Longlasting treatment
using anticholinergic drugs and dopaminergic
agonists did not modify the motor status. The
mini mental state examination result19
(MMSE) was 28/30. Neuropsychological study
showed mild impairment in verbal and visual
memory (low recall of a list of words from the
Signoret memory battery:15 6/12, impairment
of Rey figure recall:20 10/36), whereas visuoconstructional abilities were normal (Rey
figure copy). Premorbid IQ14 was 125.
Fluency21 22 was low (category: 10, letter (C):
5). The results of the Wisconsin card sorting
test23 (WCST) were abnormal: only two
categories were defined, with 32 errors (including 24 perseverative errors). EEG, EMG, and
NCV were normal, as was the muscle biopsy.

CASE 6: PROPOSITUS III5

This third child of case 2, born in 1944, had
been an engineer until the age of 32. He complained of gait disorders at the age of 24 years.
In 1970, at the age of 26, neurological examination showed dystonia. At rest, there was no
abnormal posture. Walking induced progressive distorted posture of the feet, with equinism, whereas hypotonia was seen at rest.
During movement or posture of the arms,
athetoid movements involved the left hand.
Handwriting cramps were also noted. These
disorders worsened very slowly during the next
five years, with gait impairment and progres-

Figure 7 Case 5: an abnormal signal is located below the
pallidum and above the optic tracts in the area of the
substantia innominata (arrow).

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Caparros-Lefebvre, Destée, Petit

Figure 8 Case 6: T1 images show diVuse abnormal
striatopallidal low intensity signal.

Figure 9 Case 7: one year after clinical onset, the
lenticular hyperintense signals are increased in size,
involving the pallidum and the putamen, although the
dorsal portion of the right putamen appears less involved.

define concepts was reduced. The trail making
test was impaired in time (A: 56 s, B: 185 s),
whereas the results of the Wisconsin card sorting test (WCST) were normal. EEG, EMG,
and NCV were normal, as was the muscle
biopsy. Visual evoked potentials were altered.
Brain CT showed small bilateral hypodensities
in both the putamen and pallidum, prevailing
in the left. T2 weighted MRI of the brain
showed abnormal hypersignal in the striatum,
and in the right substantia nigra. After one
year, hyperintensities had increased in both
pallidoputaminal areas (fig 9). Bilateral abnormal hyperintensities also involved the substantia nigra and the red nuclei in which a punctiform hypersignal was seen (fig 9). SPECT
showed prefrontal hypoperfusion, prevailing in
the medial regions, bilaterally.

Visual evoked potentials were altered, with
increased latency. Brain CT disclosed bilateral
hypodensities involving the whole putamen
and pallidum. Density analysis, using a workstation (IBM compatible computer, PIP, and
SM matrox cards, original software of density
analysis) showed that both striatopallidal hypodensities had the same density as the CSF in
the ventricles (89 density units (DU)/ 255
DU). T1 MRI showed diVuse striatopallidal
abnormal hyposignal (fig 8). In T2 images,
abnormal hypersignals were seen in both
substantia nigra and red nuclei, as in patient 5.
Despite sedation, the patient had moved
during the MRI study. The poor quality of
images did not allow assessment of other
abnormalities. SPECT with HmPaO showed
diVuse prefrontal and lenticular hypoperfusion.

GENERAL STATUS

CASE 7: PROPOSITUS III.7

Of the six patients examined, none had somatic
evidence of mitochondrial disorders: there was
no cardiac or respiratory failure, no auditory or

This sixth child of case 2, born in 1949, was a
highschool teacher, until the age of 45. In
1993, he complained of writing impairment
associated with abnormal movements of the
right hand, dysarthria, and dysphagia.
Neurological examination disclosed permanent athetoid movements of the right hand and
fingers. There was right hypotonia at rest, and
dystonia with hypertonia during movements.
Writing was micrographic. There was left adiadocokinesia. Speech was slurred and dystonic.
Constant grimacing occurred because of permanent dystonic movements of the face. Walking was slightly impaired by dystonic posture in
the right foot. Symptoms worsened progressively during the next year, with the development of permanent athetoid movements in the
right hand. The patient was administered levodopa with decarboxylase inhibitor (DCI), and
dopaminergic agonists but no change occurred. Neuropsychological study showed normal verbal and visual memory. Fluency was low
(letter: 9; category: 14). The Mattis results
were low: 122/144. The patient failed to
perform motor sequences, and the ability to

Figure 10 Case 7: nigral high intensity signals are
bilateral, associated with a punctiform high intensity signal
in the red nuclei.

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Late onset familial dystonia
Table 2

Studies of respiratory chain compounds and mitochondrial DNA

Complex

Controls (n = 29)
(mean (SD))

Patient II-8
(case 4)

Patient III-5
(case 6)

Patient III-7
(case 7)

Patient III-10
(case 5)

Total I
I (with rotenone)
II + III
III antim
IV
Citrate synthetase (CS)
III / CS
IV / CS
I / CS
IV / II+III
III / II+III
Mitochondrial DNA

35
(14)
24
(13)
22
(7)
127
(33)
69
(24)
140
(71)
1.08 (0.61)
0.68 (0.46)
0.21 (0.13)
3.35 (1.36)
6.34 (2.56)
—

13
7
18
71
54
105
0.53
0.51
0.07
3.60
3.94
Normal

19
5
16
57
39
196
0.32
0.22
0.03
2.44
3.56
Normal

16
10
15
57
57
144
0.40
0.40
0.07
3.17
3.17
Normal

12
—
—
87
85
97
0.90
0.90
—
—
—
Normal

Values in bold were below the lowest control value. Rotenone = rotenone dependent activity; antim = antimycine dependent
activity; — = not measured.

muscular involvement, and no ophthalmoplegia, and no hepatic or renal failure. None of the
patients had a history of toxic misuse, or
poisoning by methanol, thiocyanate, or
3-nitropropionic acid. Clinical and biological
studies failed to show symptoms suggesting
Wilson’s disease.
In all alive patients, CSF and blood studies
were normal. Lactate concentration was normal in serum and CSF at rest, but increased
abnormally in two patients (6 and 7) during
and after physical exercise. In the other
patients, physical exercise could not be performed. The methodology of muscle biopsy
and respiratory chain compound study has
been described previously.24 The assays were
performed on frozen muscle samples kept in
dry ice or at −80°C, obtained by a surgical
technique from deltoid muscle. Parts of the
muscle biopsies were serially sectioned and
then subjected to a histochemical staining battery including the modified Gomori trichrome
technique, Cytochrome oxydase (COX), nicotinamide adenine dinucleotide-tetrazolium reductase (NADH-TR), succinate dehydrogenase
(SDH),
and
myosin-adenosine
triphosphate (ATPase). The percentage of ragged red fibres or COX negative fibres recorded
for each patient was below 3% except in the
oldest patient. Electron microscopy was normal in all studied cases. Respiratory chain
compounds were detected by spectrophotometry. The analysis included NADH ubiquinone oxidoreductase (complex I) measurement
with and without rotenone in parallel cuvettes,
succinate cytochrome c oxidoreductase (complexes II + III), ubiquinol cytochrome c
oxidoreductase (complex III) measured with
and without antimycin A in parallel cuvettes,
cytochrome c oxidase (complex IV), and citrate
synthetase (DTNB as acceptor). With the parallel cuvettes, the technical conditions of analysis are identical. The results were compared
with those of 29 normal controls (table 2). The
total DNA was extracted from small parts of
frozen muscle, digested by a restriction enzyme,
run on agarose gel, and transferred to nitrocellulose. Mitochondrial DNA of muscle was analysed by Southern blot using two probes at the
same time: total mitochondrial DNA extracted
from human placenta and CDNA probe of the
human 28 S gene. In all cases, total complex I
was reduced. After the rotenone step, the complex I was below the lower value of controls in

all cases, significantly reduced in cases 4 and 6.
The complexes II, III, and citrate synthetase
results were not available in patient III.10
because of impaired conservation. Complex I
and complex III were decreased in the other
three patients, in comparison with controls.
Complex IV was decreased in two. Complexes
II + III were normal. Mitochondrial DNA study
was normal in all cases, failing to show any
deletion or known mutation.
Discussion
We have isolated a new clinical syndrome of
familial dystonia. Clinical and radiological features suggest a new entity which diVers from
previous descriptions of mitochondrial
diseases.25–28 Despite an apparent clinical heterogeneity, all of our patients were aVected by
dystonia and dysarthria. The dysarthria was
assessed in six patients. The prominent feature
was the dystonia occurring only during movements, and disappearing completely at rest.
The same biochemical disorder, and probably
the same brain lesions, had induced strikingly
diVerent clinical patterns, with various degrees
of cerebellar and parkinsonian syndromes. Of
the two most disabled patients displaying the
same MR images, parkinsonian signs were predominant in one, while dystonic and cerebellar
signs were predominant in the other. Athetoid
movements occurred in cases 3 and 7, who
were not directly related, whereas dystonia was
prominent in the others. Frontal lobe syndrome occurred in three patients, whereas
none of these patients had all of the specific
criteria for the diagnosis of dementia. A severe
behavioural impairment of the frontal lobe type
was seen in only one of the surviving patients
(case 6). The most impressive feature was his
permanent motor and verbal automatisms. In
case 7, the brother of case 6, the frontal lobe
syndrome involved only instrumental skills.
The most aVected test was the motor sequences, whereas other tests (including
WCST) were normal. Graphic sequences were
normal. The specific impairment of motor
sequences may reflect a subtle frontal lobe syndrome. Nevertheless, these dissociated results
could also be explained by a diVerent sensitivity of frontal lobe tasks. The syndromic association of action dystonia, with frontal lobe
symptoms or athetoid movements, without
dementia is uncommon in the current litera-

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Caparros-Lefebvre, Destée, Petit

ture. We have shown evidence that this
syndrome is related to a mitochondrial cytopathy because all of our patients had a complex I
defect which appeared either alone, or associated with complex III or IV defect. These partial defects of complexes I, III and IV were
associated with a unique pattern of deep brain
lesions involving only the basal ganglia, which
may be compared only to Leigh’s disease and
related rare mitochondrial disorders.
The long-lasting course of the disease could
have suggested degenerative process such as
luysopallidonigral atrophy, which is a familial
inherited disease, disclosed by rigidity, parkinsonism, and cognitive impairment.29 Other
related syndromes, with involvement of the
pyramidal tract, thalami, or dentate nuclei,
have been described,30–32 but none of them displayed putaminal lesions, nor spongiosis (or
necrosis) of the lenticular formation. The clinical syndrome that we have described is
diVerent from previously described mitochondrial encephalopathy which usually induces
multivisceral failure. Common phenotypical
syndromes involving the CNS: Leber’s disease,
ophthalmoplegia plus syndromes, and Leigh’s
disease, could be compared with our cases, as
they displayed either parkinsonian syndrome or
striatal lesions. However, many extrapyramidal
syndromes associated with mitochondrial disorders have not been clearly classified, because
of their polymorphism.6 The long-lasting
predominance of movement disorders is unusual in mitochondrial diseases.6 27 DiVerent
symptoms of mitochondrial encephalomyopathy were missing in our patients. There was no
peripheral neuropathy, either clinically or electrophysiologically. There were no seizures, nor
ophthalmoplegia. Previous anatomical, CT, or
MRI case reports of lenticular lesions have
been reported and may be compared with our
cases. Leigh’s disease, a heterogenous entity
defined by subacute necrotising encephalomyelopathy occurring in children, has also been
reported in adults, with chronic evolution.4 5 It
is usually sporadic, but autosomal dominant
forms have been reported.33 This condition
diVers from our patients as the pallidum is
inconsistently involved, the red nuclei is
spared, and the periaqueductal grey matter is
usually destroyed.5 In Leber’s disease, which is
transmitted by females, optic atrophy is prominent, but dystonia has been reported by many
authors,
associated
with
putaminal
lucencies.34–36 However, an overlap between
these diseases is probable.37 Anatomical study
in Leigh’s disease, reported by Garcin et al,
obviously showed involvement of Meynert’s
basalis nucleus, as in our patients.38 The family
described by Druschky10 had the same clinical
features as ours: long-lasting dystonia, with
dysarthria and autosomal dominant transmission, but both MRI and anatomical study confirmed that the pallidum was not involved. In
our two most disabled patients, MRI showed
lenticular and caudate hyposignals, suggesting
necrotic cavities or spongiosis. In case 7, MRI
follow up showed that the pathological process
started probably in the pallidum, the ventral
part of the putamen and the substantia nigra,

and was asymmetric. The muscle biopsies
seemed to be normal morphologically but disclosed biochemistry abnormalities, and were
then useful. The mode of inheritance seems to
be autosomal dominant, whereas most mitochondrial diseases associated with mitochondrial DNA mutation or deletion are usually
sporadic ot transmitted by women. In our family, the transmission suggested nuclear, rather
than mitochondrial DNA alterations.
The pathogenic role of these metabolic
defects in the development of the brain lesions
remains to be proved. The implication of mitochondrial dysfunction in the pathogenesis of
movement disorders has been demonstrated in
several ways: (1) mitochondrial DNA mutations have been found in both unusual
syndromes associating chorea and dementia,39
and subacute or chronic forms of striatal
necrosis;40 (2) the dosage of respiratory chain
complexes shows a specific decrease in complex I in the substantia nigra of parkinsonian
patients,41 42 in multiple system atrophy, and
sporadic or familial cases of late onset cerebellar degeneration.6 42 This suggests that the basal
ganglia system is extremely sensitive to complex I defect. DiVerent pathogenic factors have
been discussed for the explanation of tissue
lesions in mitochondrial disorders: infarction
in anoxic tissue with secondary microangiopathy or primary involvement of small arteries. It
has also been shown that mitochondrial toxins
produce striatal excitotoxic lesions, by a mechanism involving energy depletion in vivo.43 The
delayed occurrence of symptoms with chronic
progression in our patients could be due to
both partial defects in the mitochondrial respiratory chain, and the eVect of aging. We did not
show mitochondrial DNA mutation or deletion, which is not surprising in an autosomal
dominant transmission. DiVerent mutations
have been found in Leigh’s syndrome, and
other primary dystonias.40 However, degenerative dystonia never displayed necrotic lesions
involving the lenticular formation. Mitochondrial defects might be linked to toxins such as
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,
and medications such as neuroleptic drugs.44
These causal factors could not explain the
occurrence of the striatal necrosis of our
patients, nor the clinical features, particularly
the cerebellar signs.
In conclusion, we think that we have
recognised a new clinical entity of hereditary
mitochondrial striatopallidonigral disease
which is expressed as a late onset progressive
dystonia and finally involves the entire basal
ganglia. The genetic defect underlying this disease still remains to be determined.
We are grateful to Dr A Lombes for the biological and
mitochondrial study. We thank Dr AL Benabid for valuable
comments and suggestions. We also thank Drs JP Pruvo and
MM Ruchoux for their contribution to the radiological and
pathological studies, and Dr E Boogusch for proof reading the
manuscript.
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