Eur J Pediatr (1994) 153:598-603
© Springer-Verlag 1994

Louis Vall6e
Monique Fontaine
Jean-Pierre Nuyts
Guy Ricart
Ivan Krivosic
Priscille Divry
Christine Vianey-Saban
Michel Lhermitte
Joseph Vamecq

Received: 1 July 1993
Accepted: 18 January 1994
L. Va116e • M. Fontaine • J.-P. Nuyts
J. Vamecq (W~)
North France Center
for the Study of Childhood Epilepsy,
Service des Maladies Infectieuses
et de Neurologie Infantiles, HSpital B,
Centre Hospitalo-Universitaire de Lille,
F-59037 Lille Cedex, France
M. Fontaine
Laboratoire de Biochimie, HSpital Huriez,
Centre Hospitalo-Universitaire de Lille,
Place de Verdun,
F-59037 Lille Cedex, France
G. Ricart
Laboratoire de Spectrom~trie de Masse,
Universit6 des Sciences de Lille I,
F-59655 Villeneuve d'Ascq, France
I. Krivosic
Laboratoire de Neuropathologie,
H6pital B, Centre Hospitalo-Universitaire
de Lille, F-59037 Lille Cedex, France
P. Dirty • C. Vianey-Saban
Service de Biochimie, HSpital Debrousse,
29, rue Soeur-Bouvier,
F-69322 Lyon Cedex 05, France
M. Lhermitte
Laboratoire de Biochimie, H6pital Calmette, Centre Hospitalo-Universitaire de
Lille, F-59037 Lille Cedex, France

ORIGINAL

PAPER

Stroke, hemiparesis
and deficient mitochondrial -oxidation

A b s t r a c t We describe on a 3-yearold child referred for evaluation and
therapy of a cerebral vascular accident with residual hemiplegia and
partial epilepsy. Metabolic investigations initially showed normal urinary
organic acids as well as normal
blood and urinary amino acids.
Blood carnitine fractions had been
pathological and a secondary carnitine deficiency was diagnosed and
treated by oral L-carnitine supplementation. During carnitine treatment, abnormal urinary acylcarnitine
profiles were noticed with excessive
amounts of several carnitine esters
including propionylcarnitine, butyryl- and/or isobutyryl-carnitine,
isovaleryl- and/or 2-methylbutyrylcarnitine, hexanoylcarnitine and octanoylcarnitine. Subsequently, an
urinary organic acid profile suggestive of glutaric aciduria type II was
recorded during a clinical decompensation crisis. Morphological and biochemical studies on skeletal muscle
and skin fibroblasts were performed
and confirmed the existence of a defect of the mitochondrial [~-oxidation pathways with lipidic myopathy,

Introduction
Incidence of brain stroke episode in the young subject is
approximated to 2.52/100000 [32]. Its characterization
exceeds the classical determination of vessel integrity, extent of cerebral lesions and blood coagulation factors [32]

reduced palmitate and octanoate oxidation rates in cultured fibroblasts.
Glutaric aciduria type II increases
the list of metabolic disorders characterized by hemiplegia and other sequelae of brain ischaemia such as
stroke-like episode, seizures, aphasia, ataxia and myoclonia, similar to
those seen in MELAS.
Key words Mitochondrial myopathy
Encephalopathy • Glutaric aciduria
A b b r e v i a t i o n s ETF electron
transfer flavoprotein • ETF:QO
electron transfer flavoprotein:
ubiquinone oxidoreductase. MADD
multipe acyl-CoA dehydrogenase
deficiency (glutaric aciduria type II)
MELAS mitochondrial myopathy,
encephalopathy, lactic acidosis and
stroke-like episodes

because of its occasional association with metabolic disorders [1, 29] including hypoglycaemia [4, 27] and deficient pyruvic acid metabolic pathways [29]. In metabolic
disorders, hemiplegia which may be either isolated or related to brain stroke episode is exceptionally present at
onset and occurs rather during adolescence or late childhood [1].

599

Fig. 1 CT scan in the patient
showing atrophy of the left
hemisphere

In a 3-year-old girl previously u n d e r g o i n g cerebral
vascular accident and subsequent epilepsy refractory to
drug therapy, mild glutaric aciduria type II, a m i t o c h o n drial ~-oxidation deficiency disorder, was found. The present observation originally reports o n cerebral vascular
accident or h e m i p l e g i a in t~is pathology, and increases the
list of metabolic disorders i n v o l v e d in brain ischaemia accident with stroke-like episode.

Case report
The patient is the first child of healthy non-consanguineous parents. At 22 months, she had a sudden attack with hemiplegia and
24h apyretic coma diagnosed as stroke with mild cerebral vascular
accident. Left hemisphere was atrophic (Fig. 1). Persisting right
hemiplegia was complicated by partial seizures treated with
sodium valproate (20mg/kg/d), and, later, with hydantoin (6rag/
kg/d) and clonazepam (0.1 mg/kg/d). At 3 years, the patient was
referred for resistance to antiepileptic drugs. Right versive and
tonic seizures were found besides versive movements of the head
with, firstly, hypotonia, and secondly, myoclonia. Body weight
was 13 kg (0 SD), height 98 cm (+1.5 SD), and head circumference
50cm (+0.3 SD). Motor and speech status was that of a normal 15to t8-month-old child. Neurological examination revealed right
hemiplegia with pyramidal signs, moderate static and kinetic
ataxia. Laboratory investigations including blood cell count, hepatic function and haemostasis tests, acid base balance, lactate and
pymvate levels, tactate/pyruvate ratio, blood and urinary amino
acids, and CSF protein were normal. Electroretinogram was normal.
With regard to the above-mentioned concurrence of cerebral
vascular accident and metabolic disorders, additional biochemical
and morphological investigations were perforlned (see Results section).
At 5 years of age, during a clinical decompensation crisis, the
child presented with drowsiness associated with increasing ataxia.
Routine laboratory data were pathological, including a severe decrease in blood glucose (Dextrostix zero) and abnormal disturbed
blood gas (pCO2 = 4.7kPa, p0 a = 9.9kPa, standard bicarbonate =
17.3 mM and base excess = -7.9 mM) and pH (7.30) values. Subsequent treatment combining intravenous 30% glucose solution and
1 mg glucagon resulted in full clinical recovery within a few hours.

Until now, mild delay and right hemiplegia persist while epilepsy
treated with carbamazepine (20mg/kg/d) and clobazam (0.5rag/
kg/d) in our patient supplemented with oral L-carnitine (t00mg/
kg/d) and riboflavin (20mg/kg/d) is, on the basis of clinical and
EEG criteria, adequately controlled.

Materials and methods
Organic acids were extracted, detected and quantified by gas chromatography - mass spectrometry [ 12]. Extraction of acylcarnitines
and their derivatization to lactones was performed as essentially
described by Lowes and Rose [25]. Underivatized acylcarnitines
were directly identified in a positive ion mode by fast-atom bombardment-mass spectrometry using a Kratos Concept II ItH
(Kratos analytical 2 Ltd, Urmston, Manchester, UK). Derivatized
acylcarnitines were analysed by either gas chromatography (Model
3400A, Varian [Walnut Creek, CA, USA] equipped with a 25 m x
0.25 mm [internal diameter] WCOT fused-silica capillary column
CP SIL 8 CB [Chrompack, Middelbourg, The Netherlands]) or gas
chromatography-mass spectrometry using a Nermag R 1010 B
quadrupole mass spectrometer [Delsi-Nermag, Argenteuil, France]
coupled with a Girdel 300 gas chromatograph equipped with a
30 m x 0.32mm [internal diameter] DB1 capillary column [J and
W Scientific, Rancho Cordova, CA, USA]. The latter gas chromatography parameters were needle injector temperature: 250°C,
initial column temperature: 90°C for 3rain, programm rate:
10°C/min, final temperature: 250°C, direct line interface temperature: 210°C, and reagent gas: ammonia.
Total, unesterified and esterified carnitine levels were determined by spectrophotometry [8, 30], using a Cobas Fara II centrifugal analyser [Roche Diagnostic, Basel, Switzerland].
Studies of I4C labelled fatty acid oxidation were carried out on
cultured skin fibroblasts according to Vianey-Saban et al. [38].
Electron transfer flavoprotein (ETF) activity was measured using
a dye reduction assay with dichlorindophenol as m'tificial electron
acceptor [3].

600

60

Table 1 Organic acids excreted in excessive amounts in urine
from our patient during a clinical decompensation hypoglycaemic
episode (ND not detectable)

[ ] CONTROL MEAN VALUES
M MEAN VALUES IN PATIENT

50
::t

z

_o
hi.z
uJ
o
z
0
o

IT.
LLI
U)

Metabotites

Concentrations
(rnmol/mol creatinine)

40

20

10
0

Total
carnitlne

o;!

• Unestedfied '

carnitine

0

Esterifled
carnitine

ACYUFREE RATIO

F i g . 2 Serum carnitine levels and acyVt'ree carnitine ratio in our
patient. Results are expressed as mean values from six separate
measttrements on serum samples from the patient. Mean values in
control patients (n = 42) are given for reference

Results

Studies in body fluids
Urinary excretion of organic acids and amino acids were
initially normal as well as blood amino acid levels. Serum
carnitine levels, especially unesterified carnitine were
lowered ~ig. 2). An increase in the acyl/free carnitine ratio suggested secondary carnitine deficiency treated by
supplementing oral L-carnitine. Meanwhile, ethylmalonic
acid had moderately increased in the urine, a feature not
reversed by oral L-carnitine uptake. On the other hand, a
typical glutaric aciduria type II organic acid profile was
revealed during a severe hypoglycaemic episode before
starting oral L-carnitine (Table 1). Excess sarcosine was
detected in blood [79 gM] and urine [3834 gmol/g creatinine].
Urinary acylcarnitine profile was determined after Lcarnitine substitution by fast atom bombm'dment-mass
Fig, 3 Fast atom bombardment
- mass spectrometry determination of acylcarnitines in
urine samples from the patient
( Cn carnifine, Ac-Cn acetylcarnitine, But-Cn butyrylcarnifine, Isob-Cn isobutyrylcarnifine, Isov-Cn isovale12¢lcarnifine, 2-Meb-Cn 2-methylbutyrylcarnitine, He-Cn hexanoylcamitine, Oc-Cn octanoylcarnifine)

2-Ethylmalonic acid
2-Methylsuccinic acid
Glutaric acid
Adipic acid
Suberic acid
Sebacic acid
Dodecanedioic acid

Controls ~

85
12
590
2895
342
268
148

<10
ND
2-12
2-12
1-6
1-4
<0.5

Control values refer to the data published by Vianey-Liaud et at.
(Ref. [37]). Comparable values are usually recorded on our control
urine samples

spectrometry (Fig.3). This profile was distinguishable
from matched control profiles by the excessive amounts
of acylcarnitines including propionylcarnitine, butyryland/or isobutyryl- carnitine, isovaleryl- and/or 2-methylbutyryl-carnitine, hexanoylcarnitine and octanoylcamitine. Massive urinary excretion of these metabolites was
also confirmed by chemical ionization - mass spectrometry analysis of derivatized acylcarnitines (data not shown).

Studies in biopsy material
Biochemical determinations performed on cultured skin
fibroblasts disclosed reduced palmitate and octanoate 9oxidation rates besides normal succinate oxidation rates
(Table 2) whereas ETF was normally active (Table 3).
Nevertheless, lipid myopathy associated with mitochondriale proliferation was observed in skeletal muscle (Fig.
4a, b).
But-Cn/Isob-Cn
232

100

Cn
162

80
60

Patient

Ac-Cn
204

lsov-Cn/2-Meb-Cn
246

=132

143

v<

40
t74

--J

LU

0:

20
0

218

&l &l I,Jf,L,L

He-Cn
260

!
200

Oc-Cn
288

323

|

300

m/z

601

Table 2 Oxidation of 14C-labelled fatty acids in fibroblasts.
Fatty acid oxidation was determined in intact cultured skin
fibroblasts as described previously [38]. [1, 4-14C] Succinate
was used as a control substrate.
Each experimental value is the
mean of three determinations.
(PCA perchloric acid)

[1-14C] palm±tare
14CO2 + PCA
soluble compounds
(nmol/h/I06 cells)
Patient

2.33
2.18

Simultaneous controls (n = 8)
Mean _+SD
3.00 ± 0.33
(range)
(2.74-3.68)

Table 3 Activity of ETF in fibroblasts. ETF activity was measured using a dye reduction assay with dichlorindophenol as electron acceptor [3]
ETF activity
nmol reduced/min/mg protein
Patient
Controls: mean + SD (n = 15)

0.73
0.85 ± 0.08

Discussion
Our patient is characterized by the accumulation in body
fluids of metabolites of fatty acids and branched-chain
amino acids i.e. excess acylcarnitines in intercrisis periods
plus excess organic acids in percrisis periods. During a
metabolic crisis, excess sarcosine was also observed in

Fig.4 Morphological examination of skeletal muscle in the
patient: evidence of lipid storage myopathy. (a) Light microscopy (transversal section):
very large, up to 2.5 mm diameter, lipid droplets are seen in
type I fibers (Sudan black
stain). Initial magnification =
400. (b) Electron microscopy
(longitudinal section): Numerous, often irregularly shaped
intermyofibrillary clusters of
lipid microdroptets. (L lipid
microdroplets, M mitochondr±a). Initial magnification =
2,500

[1-14C] octanoate
106 cells)

[1, 4-14C] succinate
(nmo114CO2/h/
106 cells)

0.20
0.28

2.27
3.11

0.82 _+0.41
(0.40-1.42)

2.46 ± 0.38
(2,05-3.08)

(nmo114C02/h]

body fluids. All these findings suggest a deficiency of a
metabolic step c o m m o n to fatty acid, branched-chain
amino acid and sarcosine oxidation. This m a y be caused
by a multiple deficiency of fatty acyl-CoA, branchedchain acyl-CoA and sarcosine dehydrogenases i.e. multiple acyl-CoA dehydrogenase deficiency ( M A D D ) [6, 13,
14, 17]). Reduced 13-oxidation found in fibroblasts confirms this diagnosis whereas the normal activity o f E T F
suggests that E T F dehydrogenase might be the deficient
protein. It is noteworthy that the only positive biological
marker in intercrisis periods was occurrence o f excessive
esterification o f carnitine leading to secondary deficiency
in blood and an abnormal acylcarnitine profile in urine.
Different clinical presentations of M A D D have been
documented including two neonatal forms with and without congenital abnormalities, and a later onset f o r m with
milder clinical s y m p t o m s [14, 21, 42]. The later onset
form is characterized by neurological deterioration with

602

Table 4 Stroke, hemiplegia and metabolic disorders. Metabolic
disorders in which hemiplegia and/or stroke-like episodes have
been reported are listed in this table. Hemiplegia/hemiparesis has
also been described in heterozygotes for homocystinuria [7] and
for ornithine transcarbamylase deficiency [16], whereas metabolic
stroke was a feature of methytmalonic aciduria [18] and cerebral
damages that might have been caused by hypoglycemia have been
reported in glutaric acidufia type I [15]
Glycoregulation disorders
Diabetes mellitus [26]
Hypefinsulinism [40]
Mimchondrial respiratory chain and pyruvate metabolism defects
Leigh syndrome [1]
Pyruvate dehydrogenase deficiency [11, 41]
MELAS [291
Mitochondrial ~-oxidation defects
Multiple acyl-CoA dehydrogenase deficiency
(glutaricaciduria type II) (the present work)
Misce!tanaeous [1,331
Homocystinuria
Fabry disease
Adrenoleukodystrophy
Juvenile metachromafic leukodystrophy
Juvenile Niemann-Pick disease
Juvenile Krabbe disease
profound hypotonia, ataxia and dystonia as well as vomiting, hypoglycaemia, acidosis, lethargy episodes, and lipid
storage myopathy with carnitine deficiency [9, 10, 36,
39]. The unusual clinical presentation of our later onset
M A D D patient (i.e. at onset: coma, right hemiplegia with
secondarily epilepsy and transient aphasia, and later: intermittent attacks with coma and hypoglycaemia) has led
us to enquire about the specific mechanisms by which hypoglycaemia may cause hemiplegia as well as relationships which exist between hemiplegia and metabolic disorders in general with a special emphasis on the disorder
of mitochondrial myopathy, lactic acidosis and stroke-like
episodes (MELAS).
It is known that hypoglycaemia may mimick a stroke
or transient ischaemic attack [27]. In a series of 125 pa-

tients with hypoglycaemia, only 3 presented hemiparesis
[27]. Mechanisms for hypoglycaemia-induced hemiparesis/hemiplegia remain controversial and include selective
neuronal vulnerability [31, 40], absence of cerebral vasospasm [2], and ATP depletion with failure to maintain
cell homeostasis [34], alterations of the Na + pump and enhanced exposure of amino acid receptors at the periphery
of cells [5, 34, 35]. Although CT-scan data are usually
normal in the period following hypoglycaemia, Meet et
al. [28] have reported striatal lesions without vascular
topography. Interestingly, hemispheric atrophy was revealed by M R I in our patient, suggesting either vascular
or toxic aetiology.
Metabolic disorders in which hemiplegia and/or
stroke-like episodes may occur are listed in Table 4. Regarding these disorders, a striking finding is the clinical
analogy existing between MELAS and our later onset
M A D D patient, common features consisting of hemiplegia, brain ischaemia with stroke-like episodes, seizures,
aphasia, ataxia and myoclonia. Whereas the underlying
biochemical defect in MELAS combines partial deficiencies of complex IV, complex I and complex III of the mitochondrial respiratory chain [19, 20, 22-24], in our later
onset M A D D patient the basic defect most probably involves ETF dehydrogenase, a protein directly branched
on to the respiratory chain. The interaction of all these
proteins with the mitochondrial inner membrane is rather
tight. So, our and MELAS patients might be considered as
sharing a common pathology of the mitochondrial inner
membrane, a feature whose clinical expression could be
signs they develop in common. Although not directly determined, mitochondrial inner membrane surface, as well
as other morphological mitochondriat parameters, is
likely to be increased as inferred from mitochondrial proliferation occurring in skeletal muscle from our patient.
Acknowledgements The authors are indebted to Dr G. Sobo-Ares
for the MRI examination of the patient and acknowledge the
skilled technical assistance of Fabienne Hottevart, Camille Weller,
Chantal De Bleecker, and Jacky Izydorczak. J.V. is Charg6 de
Recherche Premiere Classe from the French INSERM (Institut National de la Sant6 et de la Recherche M~dicale).

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