Copqright 0 Munksguurd 1995

Acra Neurol Scand 1995: 92: 252-255
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ACTA NEUROLOGICA
SCANDINAVICA
ISSN 0001-6314

CPEO and carnitine deficiency overlapping
in MELAS syndrome

I

Hsu C-C, Chuang Y-H, Tsai J-L, Jong H-J, Shen Y-Y, Huang H-L, Chen
H-L, Lee H-C, Pang C-Y, Wei Y-H, Chen S-S. Overlapping Syndrome
of CPEO and Carnitine Deficiency in MELAS Syndrome
Acta Neurol Scand 1995: 92: 252-255. 0 Munksgaard 1995.

C.-C. Hsu’, Y.-H. Chuang’, J.-L.Tsai3
H.-J. Jong’, Yo-Y.Shen5, H.-L. Huanj‘,
H.-L. Chen’, H.-C. Lee‘, C.-Y.Pang ,
Y.-H. Wei‘, S . 4 . Chen’

Mitochondrial myopathy, encephalopathy with lactic acidosis and
stroke-like episodes (MELAS) syndrome is one of the mitochondrial
encephalomyopathies that has distinct clinical features including stroke-like
episodes with migraine-like headache, nausea, vomiting, encephalopathy
and lactic acidosis. We report a 27-year-old woman who presented with
partial seizure, stroke-like episodes including hemiparesis, hemianopia and
hemihypethesia, sensorineural hearing loss, migraine-like headache, and
lactic acidosis. Brain computed tomographic scan showed encephalomalacia
in the right parieto-occipital area and recent hypodensity in the left
temporoparieto-occipital area with cortical atrophy. Muscle biopsy revealed
ragged-red fibers and paracrystaline inclusions in the mitochondria.
Genetic study revealed an A to G point mutation at nucleotide position
(np) 3243 of mitochondrial DNA. External ophthalmoplegia and ptosis were
also found during two exaggerated episodes in this patient. Therefore, the
overlapping syndrome of chronic progressive external ophthalmoplegia in the
MELAS syndrome is considered in this case. Furthermore, we also found
carnitine deficiency in this patient and she was responsive well to steroid
therapy. Muscle biopsy also revealed excessive lipid droplets deposits.
Therefore, the carnitine defiency may occur in MELAS syndrome with the
A to G point mutation at np 3243. We recommend the steroid or
carnitine supplement therapy be applied to the MELAS syndrome with
carnitine deficiency.

Departments of Neurology, Pathology,
Graduate Institute of Medicine, School of
Medical Technology, Kaohsiung Medical College,
Neurology, Changhua Christian Hospital,
Biochemistry, School of Life Science, National
Yang-Ming University, Taipei, Taiwan

Mitochondrial encephalomyopathy was first introduced in 1975 by Shapira et al., to describe mitochondrial diseases in which both muscle and the
central nervous system (CNS) are involved (21). But
these disorders are obviously multisystemic and
affect a combination of the CNS, peripheral nerve,
skeletal muscle, heart, retina, liver, kidney, intestine,
endocrine gland and other organs (1, 2). The syndrome of mitochondrial myopathy, encephalopathy with lactic acidosis and stroke-like episodes
(MELAS), which was first introduced by Pavlakis
et al. in 1984, is now recognized as one of the several major distinct syndromes of mitochondrial encephalomyopathy ( 6 ) . Others include the KearnsSayre syndrome (KSS) (3, 4), myoclonic epilepsy
with ragged-red fibers disease (MERRF) ( 5 ) and
chronic progressive external ophthalmoplegia
(CPEO). A few overlapping syndromes of KSS with
MELAS, K S S with M E R R F , M E L A S with
MERRF and MELAS with CPEO have been described and reported over the past few years (7-1 1,
252

’

Key words: mitochondrial encephalomyopathy:
MELAS: CPEO: overlapping syndrome: carnitine
deficiency
Shun-Sheng Chen, Department of Neurology,
Graduate Institute of Medicine, Kaohsiung
Medical College, Kaohsiung, Taiwan
Accepted for publication January 12, 1995

15). We report here a case whose clinical manifestations and genetic defect were compartable with
overlapping syndrome of MELAS and CPEO (9, 11,
14). Furthermore, we found a low carnitine level in
this patient. The relationship of mitochondrial encephalomyopathy and carnitine deficiency is discussed.
Case report

A 27-year-old woman had a normal birth history,
perinatal development and normal motor milestone.
She was rather healthy and had a nursing occupation. Unfortunately, at the age of 25 years, several
episodes of focal motor seizure occurred over the left
side of face marching to the left hand with an aura
of numbness followed by weakness in the left arm.
Besides she had a body weight loss of 9 kg/half
month. As a result, she was admitted to Changhua
Christian Hospital for medical treatment. After surveying for stroke and epilepsy, mitochondrial myo-

MELAS
pathy was highly suspected. Then she was transferred to our ward for muscle biopsy and further
management. During admission, episodic migrainelike headache, focal motor seizure,and vertigo with
transient blindness were noticed. Physical examination revealed short stature with a body length of 149
cm and a body weight of 29 kg. External ophthalmoplegia with episodic diplopia appeared (Fig. 1)
but there was no retinitis pigmentosa on fundoscopic
examination. On neurologic status, stroke-like episode with decreased muscle power and sensation in
the left side, dysarthria, bilateral sensorineural hearing loss and ataxia were manifested. After clinical
examination, she received a short course of steroid
therapy and anticonvulsant medication until 6
months ago. After skip medication for half a year,
the symptoms recurred unfortunately. Acute episodic onset of numbness of face and hand in the
right side followed slurred speech were found since
Sep. 23, 1994. Dysarthria, dysphagia, loss of sensation in the right side, and exacerbated hearing loss
were complained. Right hemianopia occurred after
migraine-like headeache . Mild mental insufficiency
and childhood-behavior were also found. As a result, steroid therapy and anticonvulsant medication
were re-prescribed.
Clinical biochemistry laboratory investigations revealed high serum lactate concentration (4.2 mmol/L,
normal 0.8-2.2 mmol/L) and high serum lactate dehydrogenase (556 IU/L, normal 90-200 IU/L). Normal hemogram and creatine phosphokinase were

Fig. 1. Eyelid ptosis and restriction of movemnets on both eyes
when gazing, A: natural position, B: right gazing, C: left gazing.

noted. Besides, serum cortisol, prolactin, and thyroid function were normal. An eletrocardiogram
showed sinus tachycardia but no conduction dysfunction. Chest radiogram was normal. Eletroencephalography showed intermittent epileptiform discharges over the left temporo-parietal area with a
background of slow activities. Brainstem auditory
evoked potential (BAEP) revealed bilateral cochlear
dysfunction, but somatosensory evoked potential
(SSEP) was normal. Forearm ischemia test and glucose challenge tolerance test revealed persistent high
lactate level (0’,7.7; 1’,7.6; 2‘,6.9; 4’,6.1; 5’,5.8;
lO’J.4 mmol/L and 0‘,4.62; 30’,4.14; 60‘,5.05;
120‘,5.22; 180’,5.46 mmol/L). No specific findings
were found on cerebral angiogram. Repetitive stimulation test showed no decrement of amplitude.
Nerve conductive velocity (NCV) was normal. Results of eletromyogram were consistent with myopathy. Brain computed tomographic scan showed
encephalomalacia in the right parieto-occipital area

Fig. 2. Brain computed tomographic scans (A and B) showed
encephalomalacia in the right parieto-occipital area and recent
hypodensity in the left temporoparieto-occipital area with cortical
atrophy.

253

Hsu et al.
and recent hypodensity in the left temporoparietooccipital area with cortical atrophy (Fig. 2). Muscle
biopsy specimens were obtained from the left vastus
lateralis muscle and revealed myopathic changes
with ragged-red fibers, partial cytochrome c oxidase
deficiency, excessive deposits of fat droplets in some
fibers,and strongly succinate dehydrogenase-reactive
vessels (Fig. 3 ) . Under the eletron microscope,
paracrystaline inclusions with eletron dense particles
increased numbers of mitochondria and lipid droplets were found. By use of Apa I digestion of the
PCR-amplified DNA of fragment encompassing the
putative MELAS mutation, we found an A to G
point mutation at nucleotide position 3243 in the

1

2

M

115Ybp .)-

591bp
568bp

*

Fig. 4 . Molecular analysis ofthe polymerase chain reaction (PCR)
amplified DNA fragment encompassing the 3243 point mutation
in the mtDNA of this MELAS patient. Lanes 1 and 2 are the Apa
I-digested PCR products amplified from the blood cell mtDNAs
of this MELAS patient and another previously-reported MELAS
case (14). Lane M represents the BRL lOObp ladder DNA size
marker. PCR and agarose gel electrophoresis were performed
essentially according to the protocol described by Chen et al. (15),
and the amplified PCR products were digested with 10 units of
Apa I under the conditions recommended by the manufacturer.

mtDNA of the patient (Fig. 4). Most importantly, by
use of a Boehring Mannheim kit (22), we found
that serum carnitine concentration was rather low
(2.5 mg/l, normal 5-7 mg/l) in this MELAS patient.
After steroid therapy with 30mg prednisolone medication daily for one month, her condition got remarkable improvement. Two months later, she had
neither seizure nor focal sign. Her external ophthalmoplegia improved moderately and the persistent
low serum carnitine level during acute stage returned
to normal level (9.0 mg/l).
Discussion

Fig. 3. Histochemical stains of the muscle biopsy specimens
showed ragged-red fibers (A, modified Gomori trichrome stain),

increased S D H activity in the vessels (B, succinate dehydrogenase stain), and increased fat droplets in some muscle fibers (C,
Sudan black stain). Magnification 100 x .

254

The MELAS syndrome has distinct clinical features
including stroke-like episodes with migraine-like
headache, nausea and vomiting, encephalomyopathy
and lactic acidosis. Molecular analysis of mtDNA
has been well-developed for the diagnosis of mitochondrial encephalomyopathy in the past few years.
Point mutation at nucleotide position 3243 (A+G)
(80%) and 3271 (T+C) (10%) have been identified
to be associated with the MELAS syndrome (12, 13,
23). Recently, more and more overlapping syn-

MELAS
dromes have been found in mitochondrial encephalomyopathies, notably M E L A S with K S S ,
MERRF with KSS, MELAS with MERRF, and
MELAS with CPEO (7-1 1, 14-15). The patient reported here has been clearly diagnosed to be a
MELAS case both clinically and genetically. External ophthalmoplegia was also noted in this patient
while retina pigmentosa and optic atrophy were not
found. Therefore, overlapping syndrome is considered in this patient and the genetic analysis revealed
an A + G point mutation at nucleotide position 3243
of mt DNA.
Peripheral neuropathy was not found in this patient and repetitive stimulative test shows no decrement of amplitude. Therefore, no neuromuscular
junction problems are manifested in mitochondrial
encephalomyopathy of the MELAS syndrome.
Carnitine is required for the transport of long chain
fatty acids into mitochondria where beta-oxidation
occurs (17). Two types of human carnitine deficiency
were first described in 1972. Primary (systemic and
myopathic) carnitine deficiency is manifested with
skeletal myopathy, cardiomegaly, with episodic vomiting, encephalopathy, hepatomegaly and Reye's-like
syndrome (16, 18). Secondary carnitine deficiency
syndromes are now well recognized in some metabolic disorders, inadequate intake, and excessive loss
of carnitine (16). In carnitine therapy, it may have
the effects that were reported in the administration
of carnitine and corticosteroids (17). In our patient,
muscle biopsy revealed deposits of lipid droplets and
response to steroid therapy. Laboratory investigations show low serum carnitine concentration. It
may be the form of secondary carnitine deficiency
caused by defects of the mitochondrial eletron transport chain (19, 20). Therefore, further study is warranted to establish the relationship of mitochondrial encephalopathy and carnitine deficiency as
well as the possibility to apply steroid or carnitine
supplement therapy to the patient with mitochondrial encephalomyopathy such as the MELAS syndrome.
Acknowledgements
This research was supported by grants DOH83-TD-086 and
DOH84-TD-027 from Department of Health, Excute Yuan,
Taiwan.

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