Metab Brain Dis (2012) 27:217–220
DOI 10.1007/s11011-012-9277-y

SHORT COMMUNICATION

Mimicry between mitochondrial disorder
and multiple sclerosis
Josef Finsterer & Romana Höftberger &
Claudia Stöllberger & Boris Rolinski

Received: 27 August 2011 / Accepted: 24 January 2012 / Published online: 5 February 2012
# Springer Science+Business Media, LLC 2012

Abstract Under certain conditions or at certain stages of
the disease course, multiple sclerosis (MS) and mitochondrial disorder (MID) may be differential diagnoses and thus
may be confused with each other. In a 30 years old female
MS was diagnosed at age 16 year upon recurrent sensory
disturbances of the right lower leg, an “inflammatory” cerebrospinal fluid, and a cerebral MRI with multiple nonenhancing white matter lesions. Steroids were repeatedly
given but because of rapid deterioration treatment was
switched to interferon and mitoxantrone, without improvement. Fourteen years after onset the patient additionally
presented with a history of rhabdomyolysis, hypothyroidism, ophthalmoparesis, anarthria, tetraspasticity, tetraparesis, and joint contractures. After MID had been diagnosed in
her mother she was re-evaluated and elevated resting lactate,
axonal polyneuropathy, and empty sella were additionally
found. Muscle biopsy revealed myophagy, fat deposition,
J. Finsterer
Danube University Krems,
Krems, Austria
R. Höftberger
Clinical Institute of Neurology, Medical University Vienna,
Vienna, Austria
C. Stöllberger
2. Medical Department, Krankenanstaltung Rudolfstiftung,
Vienna, Austria
B. Rolinski
Institute of Clinical Chemistry,
Academic Hospital München-Schwabing,
München-Schwabing, Germany
J. Finsterer (*)
Postfach 20 Europe,
1180 Vienna, Austria
e-mail: fifigs1@yahoo.de

and type-II predominance, and biochemical investigations
showed a deficiency of complex I and IV of the respiratory
chain. MID was diagnosed also in the index patient. It is
concluded that even if CSF investigations or imaging studies suggest MS, differentials such as MIDs need to be
excluded before prescribing medication possibly toxic to a
MID. An “inflammatory CSF” may also occur in MIDs.
Keywords Multiple sclerosis . Metabolic defect .
Respiratory chain . Mitochondrial dysfunction . Metabolic
myopathy . Leucencephalopathy

Introduction
Though of completely different etiology and following different pathomechanisms, multiple sclerosis (MS) and mitochondrial disorder (MID) may be differential diagnoses
under certain conditions or at certain stages of the disease
and thus may be confused with each other (Harding et al.
1992; Isohanni et al. 2010), as in the following case.
Case report
The patient is a 30 years old female, height 172 cm, weight
85 kg, who developed hypoesthesias and paresthesias on the
right lower limb at age 16 year. Diagnostic work-up
revealed slightly elevated kappa-light chains in the serum
and non-enhancing periventricular, deep, and subcortical
white matter lesions on MRI. MRI of the cervical spine
was normal. Cerebrospinal fluid (CSF) investigations
revealed 21/3 cells, slightly elevated IgG (85 mg/l,
n 0–70 mg/l), slightly elevated kappa-light chains, and positive oligoclonal bands. Latencies of visually-evoked potentials were prolonged. MS was diagnosed and since she

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experienced several “relapses”, which responded to prednisolone, she was put on interferon (IFN) beta-1a 22 μg at age
21 year, which was increased to 44 μg a few months later. A
few weeks later IFN was discontinued by the patient herself
because of ineffectivity. After another “relapse” she was
again put on prednisolone 25 mg/day for 2 weeks but she
took the drug almost continuously during the next 2 years.
Despite this regimen sensory disturbances spreaded also to
the distal upper limbs. At age 22 year clinical neurologic
examination revealed spontaneous and gaze-dependent nystagmus, a reduced gag reflex, diffuse weakness of the right
lower limb (M3-M4), hypotonia and reduced tendon
reflexes on the lower limbs, and a positive Babinski sign
bilaterally. Since then her condition continuously deteriorated.
At age 26 year she was no longer able to ambulate and
presented with dysarthria, divergent bulbi, ophthalmoparesis,
quadruparesis, tetra-spasticity, and flexion contractures of the
right lower limb. The EDSS score was 9. Because of the
continuous deterioration, mitoxantrone was administered
three times during the next 4 months with a cumulative dosage
of 30 mg/m2, but was discontinued because of recurrent
infections. During an episode of fever at age 26 year she
developed rhabdomyolysis with complete remission.
At age 27 year the patient was re-evaluated after she had
developed immune-thyroiditis and after her mother, who
presented with metabolic myopathy, tetralogy of Fallot,
noncompaction, atrial fibrillation, heart failure, hypothyroidism, hepatopathy, anemia, hyponatremia, and short stature, was diagnosed with a MID.. Clinical neurologic
examination revealed dysarthria, torticollis, weakness (M4)
on the upper limbs, reduced tendon reflexes, bilateral ataxia,
weakness on the lower limbs (M2-3), contractures of the
hips, the right knee and the left ankle, reduced tendon
reflexes, a positive Babinski sign bilaterally, and multiple
lipomas. Cerebral MRI was similar to that at age 16 year but
additionally showed symmetric hyperintensity of the pyramidal tracts (Fig. 1). Spinal MRI showed discrete atrophy of
the cervical spinal cord. Echocardiography revealed diastolic
dysfunction exclusively. At age 28 years she had undergone
lengthening of the left Achilles tendon because of tip-toe
walking.
At age 29 year she was no longer able to speak, weakness
of the upper limbs had increased to M3-M4 and she was
plegic on the lower limbs. There was muscle hypotonia and
a foot deformity bilaterally. Resting serum lactate was
3.3 mmol/l (n, <2.0 mmol/l). Nerve conduction studies
revealed severe axonal neuropathy. In addition to the supratentorial white matter lesions cerebral MRI showed hyperintensities in the midbrain and the pons and an empty sella
(Fig. 1). Muscle biopsy revealed myophagia, fat deposition,
and type-II predominance. Biochemical investigations of the
muscle homogenate revealed respiratory chain complex I
and complex IV deficiency. Based on the history and

Metab Brain Dis (2012) 27:217–220

previous and present investigations a MID was diagnosed.
Screening for mtDNA or nDNA mutations in the POLG1,
twinkle, or ANT1 genes was proposed.

Discussion
This case is interesting for several aspects. First, the MID
remained undetected for 14 year although the individual
history, family history, occasional hyper-CK-emia, rhabdomyolysis, elevated resting lactate, leucencephalopathy,
reduced tendon reflexes, marked cerebral and discrete spinal
cord atrophy, and the unusual course, suggested a neurodegenerative disease. Second, the patient received a medication, which could have been toxic to the MID. To which
degree, however, steroids, IFN, or mitoxantrone contributed
to the progression or deterioration of the MID, remains
speculative. Third, periventricular and deep white matter
lesions together with marked diffuse supra- and infratentorial atrophy indicate rather a neurodegenerative disorder than MS. White matter lesions have a broad spectrum of
differential diagnoses, including MID. White matter lesions
in MIDs mimicking leucencephalopathy or even leucodystrophy have been particularly reported in Leber’s hereditary
optic neuropathy (LHON) (Olsen et al. 1995), mitochondrial
neuro-gastro-intestinal encephalopathy (MNGIE), leucencephalopathy with brainstem and spinal cord involvement and
lactic acidosis (LBSL) syndrome, and Leigh-syndrome
(LS). Cerebral atrophy has been particularly reported in
LS, Kearns-Sayre-syndrome (KSS), myoclonic epilepsy
with ragged-red fibers (MERRF)-syndrome, progressive
external ophthalmoplegia (PEO), and pontocerebellar hypoplasia (PCH), but also in non-syndromic MIDs (Finsterer
2006; Bargalló et al. 2000; Barragan-Campos et al. 2005;
Geldof et al. 2007; Scaglia et al. 2005; Kim et al. 2008). In
the present case reduced activity of respiratory chain complexes I and IV was attributed to either an nDNA mutation
in the POLG1, twinkle, or ANT1 gene or a mitochondrial
tRNA gene mutation.
Though it cannot be definitively excluded that the patient
suffered simultaneously from MS and MID, there are
several arguments, which favor a MID as the only underlying disease. First, all clinical and laboratory abnormalities,
including hypothyroidism, lipomas, torticollis, reduced tendonreflexes, and the “inflammatory CSF”, can be explained
by a MID. An “inflammatory” CSF does not exclude a MID
since mutated proteins in the central nervous system (CNS)
may induce an immunologic reaction by the local immune
system, and since pleocytosis (Robeck et al. 1996;
Maruyama et al. 1998), elevated protein (Chinnery and
Turnbull 1999; Marie et al. 1999), positive oligoclonal
bands (Marrie et al. 2001; Pato-Pato et al. 2006; Yiş et al.
2009), and IgG production (Finsterer 2006) have been

Metab Brain Dis (2012) 27:217–220

219

Fig. 1 Cerebral MRI at age
29 years showing multiple
non-enhancing white matter
lesions periventricularly, in the
deep white matter and subcortically on axial T2 images (a).
Additionally, there was marked
atrophy of the cerebrum on
coronary T1 images (b) and the
cerebellum on sagittal T2
images (d). White matter
lesions were also found in the
cerebellum bilaterally on an
axial TIRM sequence (c)

previously reported in patients with a MID (Table 1). Elevated CSF protein is even a dominant feature of KSS (Marie
et al. 1999). Recently, it has been also found that neopterin,
interleukin-6, interleukin-8, IFN-gamma and antibodies
against the folate receptor are increased in the CSF of
patients with Alpers-Huttenlocher syndrome (Hasselmann
et al. 2010). In patients with LHON also the CSF transthyretin dimer adduct level was increased and the Apo A-IN
level increased (D’Aguanno et al. 2008). An “inflammatory
CSF” is thus not unique to MS but may be also found in
MIDs. Why an “inflammatory” CSF occurs only in single
MID patients can be explained by the variable affection of
Table 1 Mitochondrial syndromes, in which elevated CSF protein,
pleocytosis, autochthonous IgG production, or positive oligoclonal
bands have been reported
MID

Protein ↑

Pleocytosis

IgG ↑

Oligoclonal bands

MELAS
LHON
KSS
LS
NS
AHD

+ [a,b]
nr
+ [c]
nr
nr
+ [d]

+ [e,f]
nr
nr
nr
nr
nr

nr
nr
nr
nr
nr
nr

nr
+ [g,h]
nr
+ [i]
+ [j]
nr

NS non-syndromic MID, AHD Alpers-Huttenlocher disease, nr: not
reported, a (Chinnery and Turnbull 1999), b (Kihira et al. 2004),
c (Marie et al. 1999), d (Castro-Gago et al. 1999), e (Robeck et al.
1996) f (Maruyama et al. 1998), g (Pato-Pato et al. 2006), h (Parry-Jones
et al. 2008), i (Yiş et al. 2009), j (Marrie et al. 2001)

the CNS and the variable immunogenicity of mutated proteins. Second, the family history was positive for MID,
which makes it more likely that the phenotype was due to
the mitochondrial defect as well. Third, immune-modulatory
treatment did not prevent the progression of the disease. The
low therapeutic effect, however, might be also attributed to
the low compliance of the patient. Fourth, there are only few
reports about patients with a MID who also developed MS
or vice versa (Palace 2009; Parry-Jones et al. 2008). However, in a recent study on MS patients, complex I activity
was found significantly reduced in fresh skeletal muscle
(Kumleh et al. 2006). Fifth, the marked cerebral atrophy
already at an early age favors the assumption of a single
hereditary disease as the underlying cause. Definitively,
however, the coexistence cannot be excluded.
Whether the respiratory chain defect was secondary to
the immuno-suppressive treatment remains speculative.
Arguments against such a speculation are that the disorder
was most likely hereditary, that the disease progressed
already before treatment, that the abnormalities persisted
despite discontinuation of the treatment, that administration
of immune-suppressive medication was neither associated
with a clinical nor instrumental deterioration, and that mitochondrial dysfunction secondary to immune-suppressive
therapy has not been reported in MS patients receiving such
treatment. Arguments for a causal relation between the
immuno-suppressive treatment and the development of an
MID, however, are that steroids have been previously
reported to deteriorate MIDs, that the development of critical

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ill polyneuropathy may be triggered by steroids (Ahlbeck et al.
2009), that oxidation of mitoxantrone by SOD triggers the
production of ROS in yeast (Reszka et al. 1986), and that
beta-interferone blocks cytochrome-c (Kihira et al. 2004).
These arguments suggest that immune-suppressive medication
given for MS is potentially mitochondrion-toxic and if erroneously given to MID patients may contribute to their
deterioration.
Even if CSF investigations or imaging studies suggest
MS, differentials such as MIDs need to be excluded since
immune-suppressive therapy given for MS is potentially
mitochondrion-toxic. For diagnosing a MID the individual
and family history, muscle enzymes, the disease course, the
response to medication, and atypical findings on imaging
should be additionally considered. Reduced tendon reflexes
rather suggest MID than MS. Though MIDs are still frequently missed, the proportion of misdiagnosis is declining
over the last years.
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