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Coenzyme QЦ responsive Leigh's encephalopathy in two sisters.

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Coenzyme Q– Responsive Leigh’s
Encephalopathy in Two Sisters
Lionel Van Maldergem, MD,1 Frans Trijbels, PhD,2 Salvatore DiMauro, MD,3 Pavel J. Sindelar, PhD,4
Olimpia Musumeci, MD,3 Antoon Janssen, MD,2 Xavier Delberghe, MD,5 Jean-Jacques Martin, MD, PhD,6
and Yves Gillerot, MD, PhD1
A 31-year-old woman had encephalopathy, growth retardation, infantilism, ataxia, deafness, lactic acidosis, and increased
signals of caudate and putamen on brain magnetic resonance imaging. Muscle biochemistry showed succinate:cytochrome c
oxidoreductase (complex II–III) deficiency. Both clinical and biochemical abnormalities improved remarkably with coenzyme Q10 supplementation. Clinically, when taking 300mg coenzyme Q10 per day, she resumed walking, gained weight,
underwent puberty, and grew 20cm between 24 and 29 years of age. Coenzyme Q10 was markedly decreased in cerebrospinal fluid, muscle, lymphoblasts, and fibroblasts, suggesting the diagnosis of primary coenzyme Q10 deficiency. An older
sister has similar clinical course and biochemical abnormalities. These findings suggest that coenzyme Q10 deficiency can
present as adult Leigh’s syndrome.
Ann Neurol 2002;52:750 –754
Leigh’s syndrome (LS; OMIM 256000) is a genetically
heterogeneous condition characterized by developmental delay or regression, lactic acidosis, and symmetrical
lesions in the basal ganglia,1 which are considered the
neuroradiological or neuropathological signature of LS.2,3
Primary coenzyme Q10 (CoQ10) deficiency causes a
mitochondrial encephalomyopathy that can be dominated by myopathic or cerebellar involvement and is
responsive to CoQ10 administration.4 – 8
Here, we describe two sisters with LS and widespread CoQ10 deficiency, who responded drastically to
CoQ supplementation.
Patients and Methods
Patient 1
The proposita was born at term after an uneventful pregnancy.
There was no consanguinity and no history of neuromuscular
disorders in the family. At 6 months, she was noted to have
axial hypotonia and failure to thrive. At 19 months, her weight
was 8,700gm (⫺2.5 standard deviation [SD]), and her height
was 79cm (25th percentile). She had unsteady gait, bilateral ptosis, and dysmorphic features, including narrow bifrontal diameter, flat philtrum, and thin upper vermilion border. Visual contact was poor and funduscopy revealed tortuous retinal vessels.
Plasma lactic acid was elevated (3.8mmol/L) whereas pyruvic
acid was normal (0.47mmol/L). A diagnosis of LS was sug-
From the 1Centre de Génétique Humaine, Institut de Pathologie et
de Génétique, Loverval, Belgium; 2Center for Mitochondrial Disorders, Clinical Genetics Center, University of Nijmegen, Nijmegen,
The Netherlands; 3Columbia University College of Physicians and
Surgeons, Department of Neurology H. Houston Merritt Clinical
Research Center, New York, NY; 4Department of Biochemistry and
Biophysics, Stockholm University, Stockholm, Sweden; 5Institut
Medico-Pedagogique Montfort, Herseaux, Belgium; and 6Department of Neuropathology, Born-Bunge Foundation, University of
Antwerp, Antwerp, Edegem, Belgium.
© 2002 Wiley-Liss, Inc.
gested. At age 4 years, she had marked muscle wasting and
moderate spasticity, but she was still ambulant with the aid of
orthopedic shoes for calcaneovalgus deformity. She became deaf
and failed to undergo puberty.
At age 19 years, she had ataxia with wide-base gait and
slow, uncoordinated movements. Moderate spasticity of
lower limbs, brisk knee jerks, atrophy of leg muscles, and
distal contractures were suggestive of a pyramidal syndrome.
A quadriceps muscle biopsy showed fiber-type disproportion but no lipid storage or ragged-red fibers. The activities
of pyruvate dehydrogenase, PC, cytochrome oxydase (COX),
succinate–cytochrome c reductase, and citrate synthase and
lactate to pyruvate ratio were normal in cultured skin fibroblasts (B. H. Robinson, Hospital for Sick Children, Toronto,
Ontario, Canada; C. Marsac, Paris, France, data not shown).
The only abnormality in fibroblasts was a mild complex I
deficiency (L. De Meirleir, University of Brussels, Belgium).
No mtDNA point mutation was detected.
A brain magnetic resonance imaging showed symmetrical
bilateral T2 hypersignals in the caudate and putamen. In addition, there was a white matter hypersignal in the left frontal subcortical region (Fig 1).
At age 24 years, her general condition worsened, she refused feeding, became less social, developed generalized muscle
hypertonia and trismus, and lost 2kg in 3 months. She became
bedridden. No infections or nutritional defects were detected
to explain the global regression observed. She was given
Received Aug 10, 2001, and in revised form Apr 29 and Jul 25,
2002. Accepted for publication Jul 27, 2002.
Address correspondence to Dr Van Maldergem, Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Allée des
Templiers 41, B-6280 Loverval, Belgium. E-mail:
Table 1. Biochemical Measurements in a Frozen Muscle
Specimen from Patient 1 before CoQ10 Supplementation
Enzyme activities in
600gm supplementation
(mU.mU COX⫺1)
NADH: Q1 oxidoreductase
(complex I)
Decylubiquinol: cytochrome c
oxidoreductase (complex III)
Cytochrome c oxidase (complex IV ⫽ COX) (
Succinate: cytochrome c oxidoreductase (SCC) (
Succinate: cytochrome c oxidoreductase ⫹ decylubiquinone ( protein⫺1)
SCC: stimulation by decylubiquinone: 8.0 ⫻ (n ⬍ 3)
Control Range
CoQ10 ⫽ coenzyme Q10; NADH ⫽ nicotinamide adenine dinucleotide; n.d. ⫽ not determined.
Fig 1. Magnetic resonance imaging brain imaging of Patient 2
at 20 years. Putamen and caudate T2 hypersignals are evident.
There is also a small frontal white matter hypersignal on the left.
300mg CoQ10 (Medgenix, Wevelgem, Belgium) per day.
Within 15 days, both trismus and hypertonia decreased, and
she resumed eating and recovered her ability to walk. She
gained 7.6kg in 6 months and grew 20cm between 24 and 29
years of age. Puberty occurred at 26 years. A psychological
assessment at age 29 years showed improved social interaction.
She was better coordinated and fell less frequently.
A muscle specimen taken before CoQ10 supplementation
and stored at ⫺80°C then was analyzed for respiratory chain
activities and for CoQ content. It showed decreased complex
II ⫹ III (succinate–cytochrome c reductase) activity, which
increased eightfold after in vitro addition of CoQ10. The
content of CoQ10 was markedly decreased (Table 1).
Patient 2
The older sister of our index patient was born after normal
pregnancy and delivery, but at 1 month of age, she developed chronic diarrhea, axial hypotonia, limb hypertonia, and
failure to thrive.
At age 6 months, she had poor visual contact and upper
limb dystonia. She started walking at 18 months but failed
to acquire any language skills. At 3 years of age, she was
small (height, 92.5cm; weight, 11.100gm) and had spasticity
and choreoathetotic movements. Serum lactic acid was
8mmol/L (normal, ⬍2mmol/L) and pyruvic acid was
2mmol/L (normal, ⬍0.67mmol/L). Fundoscopy showed tortuous and enlarged retinal vessels. Electroencephalogram and
alanine loading test were unremarkable. Pyruvate dehydrogenase and pyruvate carboxylase activities in a liver biopsy were
normal (C. Marsac, Faculté de Medecine Necker, Paris,
France). The clinical course was characterized by marked
growth delay, severe mental retardation, ataxia, and deafness.
At the age of 7 years, her bone-age was that of a 4-year-old
child and she had persistent lactic acidosis. She was placed in
an institution for the mentally retarded. Pyramidal and extrapyramidal symptoms worsened and she became wheelchair
bound at age 15 years. At age 21 years, she had permanent
dystonic movements, inappropriate laughing, and mild facial
dysmorphism, with a narrow forehead and flat philtrum (Fig
2). Deep tendon reflexes were brisk and there was generalized muscle atrophy. Height was 131cm (⫺5 SD) and
weight 29kg (⫺5 SD). Lactic acid was 6.47mmol/L in
plasma and 3.9mmol/L in the cerebrospinal fluid (normal,
⬍2.5mmol/L). A quadriceps muscle biopsy showed selective
hypotrophy of type 2 fibers, normal amounts of subsarcolemmal mitochondria (oxidative enzymes stainings), and
no ragged-red fibers. Urinary organic acids showed large
amounts of lactic, pyruvic, parahydroxyphenyllactic, and
parahydroxyphenylpyruvic acids. There was a generalized increase in plasma amino acids, including alanine.
Echocardiography and eye slit-lamp examinations were
normal. Fundoscopy showed tortuous retinal vessels (Fig 3).
At age 31 years, CoQ10 was started (300mg/day) but discontinued after 6 weeks for unknown reasons. A muscle biopsy showed fiber type disproportion without ragged-red fiber.
Biochemical analysis showed a mild decrease in oxidation rates
and in complexes I, III, and IV (Table 2). Respiratory chain
complexes were normal in Epstein–Barr virus–transformed
lymphoblasts (P. Rustin, INSERM, U393, Hospital Necker–
Enfants Malades, Paris, France; data not shown).
When her sister benefited from CoQ10 therapy, she also
received CoQ10 (300mg/day) and improved in both growth
parameters and behavior.
The activities of respiratory chain enzymes in muscle were
measured by standard methods.9,10 CoQ10 in muscle and
lymphoblasts was measured by the method of Lang and colleages11 and Podda.12
Van Maldergem et al: Leigh’s Encephalopathy
Fig 3. Eye fundus of Patient 2 at 28 years. There is marked
tortuosity and enlargement of retinal vessels.
Fig 2. (a) Facial appearances of the two patients (at the ages
of 19 and 21 years): note gelastic facies, ptosis of the eyelids,
thin vermilion border, and flat philtrum. (b) Patients 1
(right) and 2 (left) at the ages of 28 and 31 years. Note the
growth of the younger sister after 4 years of coenzyme Q supplementation. Infantilism and short stature have regressed.
Annals of Neurology
Vol 52
No 6
December 2002
Biochemical assays in the index patient were performed
in a frozen muscle sample stored before CoQ supplementation. The activities of complex I and complex IV
were normal, but the activity of succinate: cytochrome
c oxidoreductase (a reaction including complex II,
CoQ10, and complex III) was markedly decreased. Addition of exogenous decylubiquinone to the incubation
mixture stimulated complex II ⫹ III activity eightfold
(normal stimulation factor, 0.9 –1.3). This finding suggested CoQ10 deficiency.
In the older sister, biochemical analyses were performed in muscle obtained during CoQ supplementation (see Table 2). The oxidation rates of several radiolabeled substrates (pyruvate, malate, and succinate)
measured in a 600g supernatant from a fresh muscle
specimen were moderately decreased. The production
rate of ATP ⫹ PCr from pyruvate oxidation was decreased. Measurements of pyruvate dehydrogenase
complex and of respiratory chain enzymes showed
mildly reduced activities of complex I, II and IV.
The concentration of CoQ10 in muscle obtained
from the proposita before CoQ10 supplementation was
approximately 5% of the normal mean (Table 3).
CoQ10 content was decreased by 40% in Patient 2
Table 2. Biochemical Measurements in a Fresh Muscle Specimen from Patient 2 during CoQ10 Supplementation
Oxidation Rates (nmol 14CO2 䡠 hr⫺1 䡠 mU CS⫺1)
[1-14C]pyruvate ⫹ malate
[U-14C]malate ⫹ pyruvate ⫹ malonate
[1,4-14C]succinate ⫹ acetylcarnitine
Production rate of ATP ⫹ PCr from pyruvate (nmol 䡠 hr⫺1 䡠 mU CS⫺1)
Enzyme activities in 600g supernatant (mU 䡠 mU CS⫺1)
NADH: Q1 oxidoreductase (complex I)
Decylubiquinol: cytochrome c oxidoreductase (complex III)
Cytochrome c oxidase (complex IV)
Succinate: cytochrome c oxidoreductase (SCC)
Pyruvate dehydrogenase complex (PDHc)
Citrate synthase (CS) ( protein⫺1)
SCC: stimulation by decylubiquinone: 1.1⫻ (n ⬍ 3)
even during CoQ10 supplementation. The concentration of ␣-tocopherol also was severely decreased (20%
of control). The CoQ10 content in immortalized lymphoblasts from Patients 1 and 2 was decreased to 50%
(see Table 3).
LS is caused by a variety of inborn errors of oxidative metabolism resulting in congenital lactic acidosis and severe
encephalopathy with symmetrical bilateral basal ganglia
hypersignals on brain magnetic resonance imaging.
Biochemical causes include pyruvate dehydrogenase,
pyruvate carboxylase (PC), and complex I, II, IV, and V
deficiencies, but it is likely that other biochemical defects may be involved. Recent advances in our understanding of complex IV (COX) deficiency LS illustrate
this expanding spectrum of mitochondrial cytopathies.
COX deficiency has been attributed to mutations in at
least four genes controlling COX assembly, whereas mutations in nuclear genes encoding COX subunits have
not yet been identified.13–16
Primary CoQ deficiency has been reported in a limited number of patients and is clinically heterogeneous,
with predominant involvement of skeletal muscle4,5,8
or the central nervous system.6,7
Anecdotal benefit from CoQ10 administration has
been reported in various mitochondrial cytopathies,4,17–24 although muscle CoQ10 was only mildly
decreased in these disorders.25,26
The sisters presented here have unusual clinical presentations and remarkable responsiveness to oral CoQ
Although the index patient had the typical neuroradiological features of LS, her clinical phenotype was unusual because of long survival and coexistence of extrapyramidal and pyramidal signs. Other symptoms,
including cerebellar ataxia, deafness, and ptosis, were
more typical of mitochondrial encephalomyopathies.
However, biochemical studies documented CoQ10 deficiency. Enzyme assays in frozen muscle extracts showed
complex II ⫹ III deficiency, which was corrected by ad-
Control Range
3.61–7.48 (n⫽20)
4.68–9.62 (n⫽20)
2.54–6.39 (n⫽19)
42.1–81.2 (n⫽16)
0.07–0.25 (n⫽34)
2.50–6.61 (n⫽21)
0.81–3.12 (n⫽21)
0.30–0.97 (n⫽39)
0.034–0.122 (n⫽25)
37.4–162 (n⫽43)
Table 3. Concentrations of Coenzyme Q10 and ␣-Tocopherol
in Muscle and Cultured Lymphoid Cell Lines (values are the
means of three determinations)
Measurement Location
Older sister
Index patient
Lymphoblastoid cell lines
Older sister
Index patient
(␮g/gm protein) (␮g/gm protein)
NA ⫽ not applicable.
dition of decylubiquinone in vitro. Direct measurement
of CoQ10 in muscle homogenate confirmed profound
deficiency (5% of normal). In the older sister, biochemical studies of fresh muscle obtained during CoQ10 supplementation did not show decreased activity of complex
II–III, which is CoQ10 dependent. Her muscle CoQ10
was approximately 60% of normal despite CoQ10 supplementation (300mg/day for 30 days). Because the patient had shown striking improvement with CoQ10
supplementation, it is plausible to assume that the CoQ
content in muscle must have been even lower before
treatment. In this context, it is of interest that immortalized lymphoblasts from both patients had approximately 50% decrease in CoQ10. Because these cells
were grown in vitro for several passages, these CoQ10
levels could not have been influenced by CoQ10 administration in vivo. Patient 1 also showed a severe decrease
in ␣-tocopherol. In vitro experiments showed that the
lipid-soluble antioxidants CoQ10 and ␣-tocopherol act
synergistically in protecting membranes from reactive oxygen species.27 Other studies have shown parallel changes
in the concentrations of CoQ10 and ␣-tocopherol.
The striking growth spurt in the index patient at the
age of 24 years can be explained by her prepubertal
status when CoQ10 supplementation was started.
Van Maldergem et al: Leigh’s Encephalopathy
Of the 12 cases of primary CoQ10 deficiency reported in the literature, 10 were associated with involvement of the central nervous system. Of these, six had
cerebellar ataxia,24 whereas three siblings had progressive
encephalopathy (mental retardation, retinitis pigmentosa
with visual deficiency and deafness), hypertrophic cardiomyopathy, and a nephrotic syndrome.23
Ataxia was also seen in our patients, but magnetic
resonance imaging showed basal ganglia involvement
rather than cerebellar atrophy, setting them aside from
the patients with the cerebellar presentation of CoQ10
deficiency. The lack of retinitis pigmentosa, cardiopathy, and renal failure distinguishes also our patients
from those reported by Rötig and colleagues.6 This
wide variety of clinical presentations in primary CoQ
deficiency is suggestive of genetic heterogeneity that is
likely related to the many enzymatic steps involved in
the biosynthesis of CoQ.27,28
Our results suggest that LS also may be caused by
CoQ10 deficiency. The similar clinical presentation (and
response to CoQ10) in two siblings is compatible with
autosomal recessive inheritance. The molecular basis for
the impaired CoQ10 synthesis in these patients remains
to be identified.
This work was supported in part by a grant from the National Institutes of Health (P01 HD 32062, S.D.) and the American Muscular Dystrophy Association (S.D.).
We thank R. Van Coster (University of Ghent, Belgium), L. De
Meirleir (University of Brussels, Belgium), B. H. Robinson (Hospital
for Sick Children, Toronto, Canada), C. Marsac (Faculté de Medecine
Necker, Paris, France), and P. Rustin (INSERM U393, Paris, France)
for performing the initial evaluation of the respiratory chain, D. Sternberg (Hopital Henri-Mondor, Creteil, France) and W. Lissens (University of Brussels, Belgium) for screening the mitochondrial genome.
Part of this work was presented at the 30th annual meeting of the
Society for the Study of Inborn Errors of Metabolism, Cambridge,
United Kingdom, 9/13–17/00.
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