CASE REPORT
published: 21 March 2019
doi: 10.3389/fimmu.2019.00412

Edited by:
Tjalf Ziemssen,
Zentrum für Klinische
Neurowissenschaften (ZKN), Germany
Reviewed by:
Silvia Corrochano,
Medical Research Council, United
Kingdom
Maria Cano Cano-Abad,
Autonomous University of Madrid,
Spain
*Correspondence:
Dominique Endres
dominique.endres@
uniklinik-freiburg.de
Specialty section:
This article was submitted to
Multiple Sclerosis and
Neuroimmunology,
a section of the journal
Frontiers in Immunology
Received: 24 December 2018
Accepted: 15 February 2019
Published: 21 March 2019
Citation:
Endres D, Süß P, Maier SJ, Friedel E,
Nickel K, Ziegler C, Fiebich BL,
Glocker FX, Stock F, Egger K,
Lange T, Dacko M, Venhoff N, Erny D,
Doostkam S, Komlosi K, Domschke K
and Tebartz van Elst L (2019) New
Variant of MELAS Syndrome With
Executive Dysfunction, Heteroplasmic
Point Mutation in the MT-ND4 Gene
(m.12015T>C; p.Leu419Pro) and
Comorbid Polyglandular Autoimmune
Syndrome Type 2.
Front. Immunol. 10:412.
doi: 10.3389/fimmu.2019.00412

New Variant of MELAS Syndrome
With Executive Dysfunction,
Heteroplasmic Point Mutation in the
MT-ND4 Gene (m.12015T>C;
p.Leu419Pro) and Comorbid
Polyglandular Autoimmune
Syndrome Type 2
Dominique Endres 1,2*, Patrick Süß 1,2 , Simon J. Maier 1,2 , Evelyn Friedel 1,2 , Kathrin Nickel 1,2 ,
Christiane Ziegler 2 , Bernd L. Fiebich 2 , Franz X. Glocker 3 , Friedrich Stock 4 , Karl Egger 5 ,
Thomas Lange 6 , Michael Dacko 6 , Nils Venhoff 7 , Daniel Erny 8,9 , Soroush Doostkam 8 ,
Katalin Komlosi 10 , Katharina Domschke 2 and Ludger Tebartz van Elst 1,2
1
Section for Experimental Neuropsychiatry, Department of Psychiatry and Psychotherapy, Medical Center-University of
Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany, 2 Department of Psychiatry and Psychotherapy,
Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany, 3 Department of
Neurology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany, 4 Institute of
Human Genetics, University Hospital Muenster, Muenster, Germany, 5 Department of Neuroradiology, Medical
Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany, 6 Department of Radiology,
Medical Physics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany,
7
Department of Rheumatology and Clinical Immunology, Medical Center-University of Freiburg, Faculty of Medicine,
University of Freiburg, Freiburg, Germany, 8 Institute of Neuropathology, Medical Center-University of Freiburg, Faculty of
Medicine, University of Freiburg, Freiburg, Germany, 9 Berta-Ottenstein-Programme, Faculty of Medicine, University of
Freiburg, Freiburg, Germany, 10 Institute of Human Genetics, Medical Center-University of Freiburg, Faculty of Medicine,
University of Freiburg, Freiburg, Germany

Background: Mitochondrial diseases are caused by dysfunctions in mitochondrial
metabolic pathways. MELAS syndrome is one of the most frequent mitochondrial
disorders; it is characterized by encephalopathy, myopathy, lactic acidosis, and
stroke-like episodes. Typically, it is associated with a point mutation with an
adenine-to-guanine transition at position 3243 of the mitochondrial DNA (mtDNA;
m.3243A>G) in the mitochondrially encoded tRNA leucine 1 (MT-TL1) gene. Other point
mutations are possible and the association with polyglandular autoimmune syndrome
type 2 has not yet been described.
Case presentation: We present the case of a 25-year-old female patient with
dysexecutive syndrome, muscular fatigue, and continuous headache. Half a year ago,
she fought an infection-triggered Addison crisis. As the disease progressed, she had two
epileptic seizures and stroke-like episodes with hemiparesis on the right side. Cerebral
magnetic resonance imaging showed a substance defect of the parieto-occipital left
side exceeding the vascular territories with a lactate peak. The lactate ischemia test
was clearly positive, and a muscle biopsy showed single cytochrome c oxidase-negative

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New Variant of MELAS Syndrome

muscle fibers. Genetic testing of blood mtDNA revealed a heteroplasmic base exchange
mutation in the mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit
4 (MT-ND4) gene (m.12015T>C; p.Leu419Pro; heteroplasmy level in blood 12%, in
muscle tissue: 15%). The patient suffered from comorbid autoimmune polyglandular
syndrome type 2 with Hashimoto’s thyroiditis, Addison’s disease, and autoimmune
gastritis. In addition, we found increased anti-glutamic acid decarboxylase 65, anti-partial
cell, anti-intrinsic factor, and anti-nuclear antibodies.
Conclusion: We present an atypical case of MELAS syndrome with predominant
symptoms of a dysexecutive syndrome, two stroke-like episodes, and fast-onset fatigue.
The symptoms were associated with a not yet described base and aminoacid exchange
mutation in the MT-ND4 gene (m.12015T>C to p.Leu419Pro). The resulting changed
protein complex in our patient is part of the respiratory chain multicomplex I and might
be the reason for the mitochondriopathy. However, different simulations for pathogenetic
relevance are contradictory and rather speak for a benign variant. To our knowledge
this case report is the first reporting MELAS syndrome with comorbid polyglandular
autoimmune syndrome type 2. Screening for autoimmune alterations in those patients is
important to prevent damage to end organs.
Keywords: MELAS, mitochondrial disease, polyglandular autoimmune syndrome, ND4 gene, dysexecutive
syndrome

BACKGROUND

stroke-like episodes, and other organ-related complications such
dementia, epilepsy, headache, hearing impairment, short stature,
or type 1 diabetes mellitus (3, 4).
Autoimmune polyendocrine syndromes (APS) are a
heterogeneous family of autoimmune diseases. The two
major types, APS-1 and APS-2 are both associated with adrenal
cortex insufficiency (Addison’s disease). While APS type 2 is most
frequently associated with diabetes mellitus and/or autoimmune
thyroiditis, APS type 1 is often characterized by the coexistence
of hypoparathyroidism and mucocutaneous candidiasis, a
condition which is also called autoimmune polyendocrinopathy
candidiasis ectodermal dystrophy (APECED). Both types can be
associated with other autoimmune diseases (5, 6).

Mitochondrial diseases are caused by malfunctions surrounding
the mitochondrial metabolic pathways. They are clinically,
genetically, and biochemically heterogeneous, can occur at
any age, often involve the central nervous system (CNS),
and are usually associated with multiorgan involvement
(1, 2). Mitochondria produce energy for the cell in form
of adenosine triphosphate (ATP) generated by oxidative
phosphorylation within the respiratory chain. The respiratory
chain is composed of five enzymatic multiprotein complexes
(I, II, III, IV, and V). Four of these complexes contain both
proteins encoded by nuclear DNA (nDNA) and proteins
encoded by mitochondrial DNA (mtDNA). Therefore, mutations
in nuclear and mitochondrial DNA may affect the respiratory
chain function resulting in impaired ATP synthesis and
cellular dysfunction or death (3). The mtDNA mutations can
be divided into structural rearrangements (e.g., deletions),
quantitative disturbances of mtDNA also being called mtDNA
depletion (reduction of the mtDNA copy number), and
point mutations (base exchange mutations) (1). Some known
inherited mitochondrial disorders are MELAS (Mitochondrial
Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes),
LHON (Leber hereditary optic neuropathy), or MERRF
(myoclonic epilepsy and ragged red fibers) (1, 2). Because of the
mixed genetics and the broad spectrum of biochemical functions
of mitochondria the clinical manifestations of mitochondrial
disorders are very heterogeneous. Typically, post-mitotic
long-living cells like neurons, muscle cells or retinal cells are
predominantly affected by these diseases. MELAS, one of the
most common mitochondrial disorders, is characterized mainly
by symptoms of myopathy, encephalopathy, lactic acidosis,

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Mitochondrial Diseases and Autoimmunity
The most prevalent immunological alteration in mitochondrial
disease is type 1 diabetes mellitus, which is associated with
the point mutation m.3243A > G and is frequently found
in patients with mitochondrial disease (7, 8). Autoimmune
polyglandular syndrome type 2 (with Addison’s disease,
autoimmune thyroiditis, diabetes mellitus, and primary ovarian
failure) was reported once in a patient with mitochondrial
disease, more specifically in a female patient with KSS and
a consistent 2,532-bp deletion of her mtDNA, and—beyond
that—with a heteroplasmic m.3243A > G mutation (9)—but not
in patients with MELAS syndrome.

CASE PRESENTATION
We present the case of a 25-year-old female German patient with
dysexecutive syndrome (affective instability, sensory overload,

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FIGURE 1 | Hyperpigmentation and skinny figure due to Addison’s disease.

discrete hemiparesis on the right side. Treatment was started
with a glucocorticoid (hydrocortisone) and a mineralocorticoid
(fludrocortisone). Later, the patient developed two grand
mal seizures, for which she was admitted to an intensive
care unit. An anti-epileptic treatment with levetiracetam
was initiated. While being on intensive care treatment,
she developed progressive disorientation, reduced vigilance,
headache, coordination disturbances and, again, hemiparesis on
the right side. The MRI showed a subacute left parieto-occipital
cortical/subcortical lesion involving the precentral gyrus with T2weighted FLAIR signal increase and diffusion restriction without
respecting vascular territories and the multiple right-hemispheric
chronic posttraumatic lesions. There was a clear lactate peak in
the lesion (Figure 2). The EEG showed an intermittent slowing
temporoparietal on both sides (stronger on the left) and singular
spike-wave complexes temporal (once temporoparietal) on the
left. During her subsequent stay in a neurological rehabilitation
clinic, her neurological deficits receded almost completely. On
occasion her right hand may feel clumsier than her left, but this
occurs rarely. Following the grand mal seizures symptoms of
sensory overload and affective instability evolved and persisted
ever since. She has not experienced any further early morning
nausea following treatment with hydro- and fludrocortisone.
Several attempts to reduce levetiracetam led to an exacerbation
of cognitive deficits.

concentration, and impulse control problems), rapid-onset
physical fatigue, and continuous headache.

History of Illness
The patient’s history was negative for in-utero or birth
complications, inflammatory brain diseases, or febrile
convulsions. She reported cognitive deficits (memory difficulties
and needing more time to learn than her siblings) and impulsive
behaviors (especially when things change) since her first decade
of life. Both symptoms were mild and did not meet the diagnostic
criteria for attention-deficit/hyperactivity disorder or autism.
The subject did not encounter tics, or extraordinary personality
traits, though she had known a physical lack of energy for as long
as she could remember. She was easily exhausted in sports at
school and could not keep up with her family on hikes. She had to
go to bed early, upon which she fell asleep swiftly. Since she was
6 years old, she experienced repeated syncopations which based
on history probably represented vasovagal pathomechanisms.
There was no history of increased frequency of infections,
especially no signs of mucocutaneous candidiasis. Dental history
was unremarkable.
When she was seventeen, she fell off her bike in an unclear
way and suffered brain trauma with cerebral hemorrhage.
The cerebral magnetic resonance imaging (MRI) showed left
hemispheric subdural hemorrhage and “contre-coup” right
fronto-opercular as well as multiple right temporal cerebral
contusions. Neither a subsequent change of personality nor
other neurocognitive or psychomotor symptoms were observed
by the patient or her family. Five years ago, she noticed
hyperpigmentation (Figure 1). Four years ago, she developed
early morning nausea that occurred almost on a daily base. She
had no appetite and could eat very little. At age 25 (half a year
before presentation in our clinic), she developed an infectiontriggered Addison crisis with hypotension, diarrhea/vomiting,
hypoglycemia, vigilance reduction, and metabolic acidosis.
The diagnosis of Addison’s disease was suspected due to
the Addison crisis, anti-adrenal cortex autoantibodies (titer
of 1:100; reference <1:10) and indicative laboratory values
(ACTH increased, 71.4 pg/ml; reference: 5–50 pg/ml). During
her inpatient stay, the patient already noticed a self-limiting,

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Somatic and Family History
The patient suffered from Hashimoto’s thyroiditis for years
(substituted with L-thyroxine) and, as already mentioned,
Addison’s disease. When being diagnosed for the Addison
crisis normochromic, normocytic anemia was recognized
(hemoglobin: 10.4 g/dl; reference 12–16 g/dl). Two years prior
to present admission a gastroscopy was done revealing mild to
moderate antrum gastritis suspicious of chronic toxic (type C)
gastritis. Her mother, sister, and maternal grandfather all suffered
from type 1 diabetes mellitus, while another sister is healthy.

Genetic Investigations
Analysis of the complete mitochondrial genome from peripheral
blood leukocytes showed a heteroplasmic base exchange
mutation in the mitochondrially encoded NADH:ubiquinone

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FIGURE 2 | Cerebral magnetic resonance imaging (MRI) findings during the stay in the intensive care unit because of stroke like episodes. The MRI showed a
subacute left parieto-occipital cortical/subcortical lesion involving the precentral gyrus with T2-weighted FLAIR signal increase and diffusion restriction without
respecting vascular territories and the multiple right-hemispheric chronic posttraumatic lesions. The former subdural hemorrhage showed complete resolution. In the
lesion, an increased lactate peak was registered (uncorrected data).

oxidoreductase core subunit 4 (MT-ND4) gene (m.12015T>C;
p.Leu419Pro). Heteroplasmy level for the mutation in blood
showed 12%, in muscle tissue 15%. This point mutation was not
detected in the blood of the patient’s mother, no other tissues were

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analyzed in the mother. No other pathogenic or likely pathogenic
alteration was detected in the mtDNA of the patient.
In MITOMAP, the human mitochondrial genome database
(www.mitomap.org/MITOMAP) the alteration is only

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reported as a mtDNA coding region sequence variant and
has not been reported in association with disease yet. Several
simulations (prediction tools) assume a benign change (fathmm,
MutationTaster, PROVEAN), according to SIFT it is a pathogenic
variant (Table 1). Besides the mtDNA analysis, only the nuclear
DNA polymerase subunit gamma (POLG) gene was analyzed
in the patient. In the POLG gene (part of mitochondria-related
nDNA) no pathogenic variant (mutation), but the well-known
polymorphism c.156_158delGCA; p.Q55del (rs727504102)
was detected in heterozygous state. For this deletion, an
association with diabetes mellitus has been reported in the
Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/
ac/index.php). It is classified as a clearly benign polymorphism

in several databases (https://www.ncbi.nlm.nih.gov/clinvar/
variation/167521/).

Psychiatric Examination and Somatic
Investigations
The psychiatric investigation showed attention and
concentration deficits, memory difficulties, affective instability,
impulsive behaviors and sensory overload. Cognitive
performance showed partially below-average results (Figure 3).
The lactate ischemia test revealed a more than three-fold increase
in lactate levels compared to resting state values. The lactate
concentration in the cerebrospinal fluid (CSF) was not increased.
In the muscle biopsy, single cytochrome c oxidase (COX)negative muscle fibers were identified. In the immunological
screening, increased anti-thyroglobulin, increased anti-thyroid
peroxidase, anti-adrenal cortex, anti-glutamic acid decarboxylase
(GAD-65), anti-partial cell, anti-intrinsic factor, and anti-nuclear
antibodies (ANAs) were discerned. Serum concentration for
immunoglobulin (Ig)G, IgM and especially IgA were within
normal range. The B-cell panel showed clearly increased number
of IgD-CD27+B-cells, IgA+CD27+memory B-cells, and
IgM+/–CD38++plasma blasts of B-cells. The urine analyses
revealed only slightly increased albumin-creatinine quotient and
therefore no typical signs of focal segmental glomerulosclerosis
(10). A current gastroscopy showed signs of autoimmune
gastritis. The examination’s findings are summarized in Table 2.

TABLE 1 | Upper part: Different in silico prediction scores for the pathogenic
relevance of the novel base exchange variant in the MT-ND4 gene of our patient.
Pathogenicity
prediction tool

Transcript

Prediction

FATHMM

ENST00000361381

Tolerated

MutationTaster

ENST00000361381

Polymorphism

Provean

ENST00000361381

Neutral

SIFT

ENST00000361381

Damaging

mtDNA databases

Allele frequency

Prediction

MITOMAP

2/46,092 mtDNA
sequences

Coding region
sequence variant

HmtVar

Healthy total: 0.000048

Likely polymorphic

Magnetic Resonance Imaging
The follow-up cMRI 6 months after the stroke like events showed
a chronic cortical to subcortical parieto-occipital brain lesion
on the left side involving the posterior margin of the precentral

Lower part: Information on the present sequence variant from two mitochondrial
DNA (mtDNA) databases; MITOMAP: www.mitomap.org; HmtVar: www.hmtvar.uniba.it/
varCard/22365.

FIGURE 3 | Neuropsychological findings showed significant impairments in divided attention for visual and auditory stimuli combined. The recorded intelligence level
was in the lower normal range (IQ = 86), which appeared discrepant with the patient’s educational background (this may also be attributed to fluctuations in attention).
A detailed description of all test results can be found in Table 2 in the bottom column on neuropsychological test results.

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TABLE 2 | Psychiatric examination, family history, somatic and neuropsychological findings.
Psychiatric examination

• Attention and concentration deficits, memory difficulties, affective instability, impulsive behaviors and sensory overload.
• No depressiveness, no anxiety, no delusions/hallucinations, no suicidal tendencies, no sleep disorders, normal appetite.

Physical examination

• Internal: Normal internal investigation.
• Dermatological: Diffuse hyperpigmentation, periorbital melasma, discreet acne (most likely steroid-triggered), xerosis skin, secondary
hair was reduced.
• Neurological: Monopod right somewhat plumped up, muscle self-reflexes at the upper and lower extremities right-emphasized, the
remaining neurostatus was inconspicuous.

Family history

• Mother, sister, and maternal grandfather suffered from type 1 diabetes mellitus. Maternal grandfather died of kidney failure.
• Several family members suffer from hearing impairments (paternal great-grandmother, paternal grandfather and grandmother, father;
no investigations for underlying reason carried out). Paternal grandfather developed dementia in old age and presently suffers from
bronchial carcinoma in his advanced age.
• In terms of body height our patient was 172 cm tall but still the shortest in her family, her one sister is 174 cm (24 years), her other
sister is 180 cm (22 years). Her parents are measuring both about 180 cm.

Genetic testing*

• Heteroplasmic base exchange mutation in the MT-ND4 gene (m.12015T>C; p.Leu419Pro); MAF >0.01%; heteroplasmy level in the
blood: 12%, in the muscle tissue 15%.
• In the POLG gene, the well-known polymorphism c.156_158delGCA; p.Q55del (rs727504102) was found in heterozygous state.

Basic blood/urine
analyses

• Blood cell count, electrolytes, liver/kidney/pancreas values, HbA1c, and folic acid were normal. Vitamin B12 was elevated under
substitution (3,106 pg/ml; reference 197–771 pg/ml). Selenium was slightly reduced (68 µg/l; reference: 75–140 µg/l)
• Thyroid-stimulating hormone and triiodothyronine levels were in normal ranges. Thyroxine was slightly increased under substitution:
22.2 pmol/l; reference: 12–22 pmol/l).
• Normal blood glucose day profile.
• Testosterone was not measurable (<0.087 nmol/l).
• ACTH in the morning (at 8 o’clock) was increased (243 pg/ml, reference: 10–60 pg/ml).
• The urine analyses showed slightly increased albumin creatinine quotient (29 mg/g creatine). The urine-stix was slightly positive for
protein (+) and negative for blood.

Immunological blood
testing

• No antibodies against the intracellular onconeural antigens Yo, Hu, CV2/CRMP5, Ri, Ma1/2, SOX1 or the intracellular synaptic antigen
amphiphysin were found. Anti-GAD65 antibodies were positive (quantification with ELISA-technique showed concentrations of 113
U/ml; reference < 2 U/ml).
• Antibodies against neuronal cell surface antigens (NMDAR, AMPA-R, GABA-B-R, VGKC-complex [LGI1, Caspr2]) were negative.
• Autoantibodies against thyroglobulin (329.3 IU/ml; reference < 115 IU/ml) and thyroid peroxidase (401 IU/ml; reference: < 34 IU/ml)
were increased. Antibodies against the TSH receptor were normal. Adrenal cortex antibodies were increased (1:30; reference <
1:10).
• Anti-partial cell and anti-intrinsic factor antibodies were positive. Anti-insulin and anti-IA2 antibodies were not increased.
• Screening for antinuclear antibodies (ANA) in IIF showed a homogeneous nuclear fluorescence with a chromosomal pattern (1:200).
Testing for extractable nuclear antibodies (ENA) showed no antibody specificity including anti-DFS-70 antibodies. Anti-neutrophil
cytoplasmic antibodies, antiphospholipid antibodies, rheumatoid factor, and anti-mitochondrial antibodies were negative.
• No changes in the complement system (C3, C4, CH50, C3d) were observed.
• Serum immunoglobulin concentrations: 10.4 g/L IgG (reference 7.00–16.00 g/L), 1.05 g/L IgM (reference 0.7–4.0 g/L), 1.75 g/L IgA
(reference 0.4–2.3 g/L). Immunofixation showed no monoclonal antibody production.
• Lymphocyte and B-cell panel showed slightly increased levels of CD3+t-cells (84.1% reference: 55–83%), CD3+CD4+t-cells
58.2% (reference: 28–57%), clearly increased number of IgD-CD27+B-cells (29.88%, reference 5.7–24%), IgA+CD27+memory
B-cells (14.72%, reference 2.8–10.9), and IgM+/-CD38++plasma blasts of B-cells (8.75%, reference 0.2–3.4%).
CD65+CD16+natural killer cells (72/micro l, reference: 90–600/micro l) and CD56+CD16+natural killer cells (4.5%, reference:
7–31%) were reduced. All other cells were in the normal range.

Cerebrospinal fluid
analyses

• Normal white blood cell count (1/µL; reference < 5/µL).
• Normal protein concentration (247 mg/L; reference < 450 mg/L), and normal age-corrected albumin quotient: 2.5; age-dependent
reference <6.5 × 10−3 ).
• No CSF specific oligoclonal bands; IgG index not increased (0.6; reference < 0.7).
• CSF lactate normal (1.87 mmol/l; reference 1,5-2,1 mmol/L).
• Antibodies against neuronal cell surface antigens (NMDAR, AMPA-R, GABA-B-R, VGKC-complex [LGI1, Caspr2]) were negative.

Cerebral magnetic
resonance imaging
(Figure 2)

• Substance defect of the parietooccipital left side exceeding the vascular territories with signs of chronic hemorrhagic transformation.
• Small cortical/subcortical defects right temporal and frontoinsular. Cortical siderosis of a defect in the praecentral gyrus on the right
and parietooccipital left.

Magnetic resonance
spectroscopy**
(Figure 5)

• Single-voxel magnetic resonance spectroscopy results show slightly higher Lac+/Cr concentration ratio compared to control
subjects: In the orbitofrontal cortex (OFC), a Lac+/Cr concentration ratio of 0.182 was found compared to a control group (males:
N=5, females: N=1; 28 ± 2 years; Figure 5) with 0.159 ± 0.01, in the dorsal anterior cingulate cortex (dACC) 0.202 compared to
0.188 in one control subject (male, 31years) and in the dorsolateral prefrontal cortex (DLPFC) 0.172 compared to 0.168 in one
control subject (male, 27years).

Electroencephalography

Alpha-rhythm, intermittent slowing accentuated left parieto-occipital; no epileptic patterns (under the treatment with high dose
levetiracetam).

Electromyography

In the right anterior tibial muscle insertion activity was normal. No spontaneous activity. Evaluation of motor unit potentials revealed
mild myopathic changes.
(Continued)

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TABLE 2 | Continued
Lactate ischemia test

• Aerobic continuous load on the bicycle ergometer for 15 min at 30 watts: Resting lactate: 0.84 mmol/l, after 5 min: 2.35 mmol/l,
after 10 min: 3.04 mmol/l, and after 15 min 3.25 mmol/l.
• There was a continuous increase in heart rate over the course of 15 min.

Magnetic resonance
imaging of thigh and
lower leg

• Normal muscle signals.

Muscle biopsy

• Discrete substrate redistribution with partly sub-sarcolemmal, cap-like substrate propagation in the oxidative enzyme reactions,
however, clear “ragged red/blue fibers” cannot be detected here. However, single COX-negative muscle fibers can be detected.
• Ultrastructurally, small mitochondrial accumulations with individual, partly swollen, mitochondria can be found, but paracrystalline
inclusions cannot be detected here. In addition, a discrete type 2 fiber atrophy can be detected.

Ophthalmological
examinations

• Clinical ophthalmological examination was inconspicuous.
• Macular scans were performed using spectralis optical coherence tomography device (spectral-domain OCT). Both eyes showed
normal retinal volume and normal full retina thickness in all subfields with reference to normative data given by Nieves-Moreno et al.
(11).
• For visual electrodiagnostic testing light adapted electroretinogram was recorded from both eyes using RETeval device from
LKC-Technologies. Both eyes showed normal cone function in response to the photopic-flash protocol and normal ganglion cell
function with the stimulation protocol for the photopic negative response. Normative data were provided by
LKC-Technologies (https://www.lkc.com/reteval-device-normative-data/).

Heart examinations

• Inconspicuous resting electrocardiography (ECG). The long-term ECG measurement showed a sinus rhythm with intermittent
tachycardic pulse; no relevant pauses.
• No ischemic changes and no load-inducible rhythm disturbances occur in the ECG during the lactatischemia test.
• Transthoracic echocardiography was normal.
• The external CT angiography of the thorax showed no detection of coronary anomalies***.

Otorhinolaryngologic
examination

• Normal findings, no hearing impairment.

Ultrasound of the
carotides

• Only increased flow velocities are noticeable in the arteria cerebri media and anterior cerebral artery on the right side****.

Thyroid sonography

• Echo-poor parenchyma and inhomogeneous perfusion. No noddings. Compatible with autoimmune thyroiditis*****.

Gastroscopy

• Mild chronic, inactive antral gastritis with foveolar hyperplasia. Clear chronic, moderately active corpus gastritis with intestinal
metaplasia of the paneth- and bursa cell type.

Neuropsychological
tests

• Test for attention performance: Borderline average/below average tonic alertness. Phasic alertness was found to be ordinary, the
ability to increase response readiness was uncompromised. She exhibited an ordinary set-shifting ability/cognitive flexibility in the
presence of an above average speed-accuracy trade-off index (T=64) indicating a slowing in response times to increase response
accuracy. She showed significant impairments in divided attention (visual and auditory stimuli combined) and working memory
functions (2-back task). Performance was ordinary in both the simple (1 out of 2) and the complex (2 out of 5) go/no-go task.
• Culture Fair Intelligence Test-20: Results suggested an intelligence level in the lower normal range (IQ = 86) which appeared
discrepant with the patient’s educational background (may also be attributed to fluctuations in attention).
• Route learning task: She was able to spontaneously recall the learned route correctly. She did not deviate from the route and therefore
required no assistance by the experimenter. In the route recognition trial, she correctly identified the previously learned route as such.
When asked to recall the designated landmarks, she spontaneously recalled eight out of the ten landmarks. In the cued condition,
she recalled nine out of ten landmarks correctly. In the image-based recognition trial, she identified all landmarks as such. None of
the distractor items were erroneously labelled as landmarks, resulting in a recognition accuracy of 100%. When tested 1 week later,
she still recalled the route without error.
• Verbal fluency: Was found to be below average in all subtests (words with S, category animals, alternating words with G-R, alternating
categories sports-fruits).
• Zoo map test: Revealed impairments in spontaneous planning ability. She was able to solve the given task correctly but only after
amount of time (∼8 min). When provided with a strategy (i.e., the correct sequence of stops on the map), she solved the task correctly
in under 2 min.
• Verbal learning and memory test: She showed ordinary verbal learning performance (T = 48) reproducing a total of 55 words (7-1013-13-12) over the course of the five learning trials. Relative delayed recall performance (-2 words, T = 55) and passive recognition
performance (T = 53) were ordinary.
• Visual reproduction task: She exhibited quantitatively normal visual learning performance. Immediately after the learning trial, she
recalled all geometric figures (38/41 points, T = 58). Delayed recall performance was similar (37/41 points, T = 49). Despite
ordinary quantitative results, she made errors only with regard figure proportions but not figure components or their placement.

The investigations were performed in August /September 2018 (a half year after the stroke like episodes and the Addison crisis). * The following regions were analyzed (in an external
laboratory for human genetics): MT-ATP6, MT-ATP8, MT-CO1, MT-CO2, MTCO3, MT-CYB, MT-ND-1, MT-ND2, MT-ND3, MT-ND4, MT-ND4L, MT-ND5, MT_ND6, MT-RN1, MT-RNP2,
MT-TA, MT-TC, MT-TD, MT-TE, MT-TK, MT-TL1, MT-TL2, MT-TM, MT-TN, MT-TP, MT-TQ, MT-TR, MT-TS1, MT-TS2, MT-TT, MT-TV, MT-TW, MT-TY (mitochondrial DNA) and POLG
(mitochondria-related nuclear DNA). ** Single-voxel magnetic resonance spectroscopy (MRS) examinations were performed in three prefrontal regions (orbitofrontal cortex [OFC], dorsal
anterior cingulate cortex [dACC] and dorsolateral prefrontal cortex [DLPFC]) using a MEGA-sLASER difference editing sequence (12, 13), which is suitable for more robust lactate (Lac)
quantification than is achievable with standard MRS protocols. Spectral quantification was performed with LCModel (14), using numerically simulated metabolite basis spectra, and Lac
concentrations were reported as ratios to creatine (Cr). Since the Lac quantification results are slightly biased due to spectral overlap with coedited macromolecular resonances, the
Lac concentration was denoted by Lac+ (15). The measured Lac+/Cr concentration ratios were compared with ratios obtained from healthy control subjects with the same protocol.
*** Already performed outside in October 2017. **** Already performed outside in February 2018. ***** Already performed outside in March 2018.

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FIGURE 4 | Magnetic resonance imaging findings a half year after the stroke-like episodes showed a chronic cortical to subcortical parieto-occipital brain lesion on
the left side involving the posterior margin of the precentral gyrus with signs of chronic hemorrhagic transformation.

FIGURE 5 | Single-voxel magnetic resonance spectroscopy imaging. Presented is a MEGA-sLASER difference spectrum from the orbitofrontal cortex (OFC) of the
patient, with indicated lactate (Lac)+ resonance. In the OFC, a Lac+/Creatine concentration ratio of 0.182 was found compared to a control group (N=6; 5 males and
1 female; 28 ± 2 years) with 0.159 ± 0.01.

DISCUSSION

gyrus with signs of chronic hemorrhagic transformation and
the known multiple post-traumatic right hemispheric lesions
(Figure 4). Single-voxel magnetic resonance spectroscopy results
show slightly increased lactate (Lac)+/creatine ratios in the
dorsal anterior cingulate cortex (dACC), dorsolateral prefrontal
cortex (DLPFC), and orbitofrontal cortex (OFC; Figure 5).

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In this paper, we present the case of a female patient with a
new variant of MELAS with the clinical phenomenology of a
dysexecutive syndrome and a history of two stroke-like episodes,
“novel” heteroplasmic base exchange mutation in the MT-ND4

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immunological activation with antibodies against GAD-65
(without clear signs for APECED), intrinsic factor, and nuclear
antigens with negative DFS70 testing. Currently, the patient
was not experiencing manifest type 1 diabetes. The finding of
an ANA with homogeneous nuclear staining pattern in indirect
immunofluorescence was suspicious for connective tissue disease
like systemic lupus erythematosus. Because of the low ANA titer
(1:200), no specificity in ENA-testing, unremarkable complement
diagnostics, and no clinical symptoms indicative of a connective
tissue disease (such as joint pain) this diagnosis was excluded.

gene (m.12015T>C; p.Leu419Pro), and comorbid polyglandular
autoimmune syndrome type 2.

Diagnostic Considerations
The patient suffered from myopathy with reduced physical
capacity, a positive lactate ischemia test [following the criteria
of Finsterer et al. (16)], discrete myopathic changes, and
slightly pathological muscle biopsy results with single COXnegative muscle fibers and a discrete unspecific type 2 fiber
atrophy. Myopathy clearly existed before steroid treatment
began. Moreover, she suffered from encephalopathy with
chronical dysexecutive syndrome, headache, EEG pathologies,
and epileptic seizures (successfully treated with high doses of
levetiracetam). She had two earlier stroke-like episodes with
a typical parieto-occipital lesion and a lactate peak. Lactate
levels outside the lesion (in the different prefrontal areas: ACC,
OFC, and DLPFC) were slightly higher compared with controls,
however the lactate concentration in the CSF was normal,
which might indicate to a milder form of mitochondriopathy.
Therefore, the patient fulfilled three main criteria of MELAS:
Myopathy, encephalopathy and stroke-like episodes (3). The
patient may have previously suffered from the fourth main
symptom, lactate acidosis. Currently, the subject’s serum and CSF
lactate levels were normal. However, the result of the lactate
ischemia test makes earlier episodes of lactate acidosis likely.
With a body height of 172 cm, the patient does not have a
short stature or growth hormone deficiency. However, she is the
smallest person in her family. Her testosterone concentrations
were extremely low (not measurable) and secondary hair was
reduced. In a cohort of 99 MELAS patients abnormal growth was
described in 50% of the individuals (8). No involvement of eyes,
inner ears, the heart, or kidneys was found.
A diagnosis of Hashimoto’s thyroiditis was made based
on the clinical findings of hypothyroidism combined with
increased antibodies against thyroglobulin and thyroid
peroxidase, and with typical alterations in thyroid sonography.
The findings to justify the diagnosis of Addison’s disease
were hyperpigmentation, loss of weight, gastrointestinal
symptoms, and a history of Addison crisis with hypotension,
diarrhea/vomiting, hypoglycemia, and vigilance reduction,
alongside with metabolic acidosis and compatible laboratory
findings (anti-adrenal cortex antibodies and increased ACTHlevels) and the normalization of these symptoms following
treatment with gluco- and mineralocorticoids. There might be an
overlap between Addison’s disease and MELAS syndrome leading
to the symptom of vomiting (could also be due to lactate acidosis
in the context of MELAS). IgA serum concentration was within
normal range and there was no evidence for mucocutaneous
candidiasis, enamel hypoplasia, or hypoparathyroidism in the
patients’ medical history. Therefore, the diagnosis of APECED
or autoimmune polyglandular syndrome type I (APS-I) was
very unlikely. The combination of Hashimoto’s thyroiditis,
Addison’s disease, and pernicious anemia led to the diagnosis of
the more frequent autoimmune polyglandular syndrome type II.
The course of MELAS syndrome was complicated by comorbid
Addison’s disease. Moreover, the present patient suffered from an
autoimmune gastritis with anti-partial gastric cells, and further

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Genetic Aspects
MELAS syndrome is classically (in over 80% of all cases)
associated with a point mutation with adenine-to-guanine
transition at position 3243 of mtDNA (m.3243A>G) in the
mitochondrially encoded tRNA leucine 1 (MT-TL1) gene
encoding tRNALeu(UUR) (1, 3). Further underlying mutations
were found in the mitochondrial genes MT-TL1 (in particular,
mutation 3271T>C) (17), MTTQ, MTTH, MTTK, MTTC,
MTTS1, MTND1, MTND5, MTND6, and MTTS2. One case
report describes a case of MELAS syndrome due to mutation
in the nuclear POLG1 gene (18). The present patient displayed
a heteroplasmic base exchange mutation in the MT-ND4 gene
(m.12015T>C; p.Leu419Pro). Changes in the MT-ND4 gene
were earlier published in one paper regarding two patients with
MELAS syndrome (PubMed search for “MELAS” and “ND4”
performed on December 23, 2018). An A-to-G base substitution
at 11084, which leads to a Thr to Ala amino acid substitution was
suggested to be disease-related (19). That association was later
proven wrong as this very mutation was found in 14% of Asians
(thus classifying it as a polymorphism). The point mutation
affecting the patient described here has thus far only been
detected in two of 46,092 examined sequences and has not yet
been associated with mitochondriopathy (https://www.mitomap.
org/MITOMAP and HmtVar: www.hmtvar.uniba.it/varCard/
22365. It is possible that the two subjects with the same variant,
who were documented earlier, had less-severe heteroplasmia, so
that penetrance was low, i.e., the critical threshold value, which
leads to the appearance of symptoms, was not exceeded. A very
low and therefore undetectable heteroplasmia level in blood or a
de novo mutation might explain the inconspicuous findings in the
mtDNA of the present patients’ mother. An examination of the
asymptomatic mother from a second tissue was not desired. The
resulting protein complex with the changed protein in the present
patient (see Figure 6; marked in blue) is part of the respiratory
complex I (https://www.ebi.ac.uk/pdbe/entry/pdb/5xtc/protein/
25; Figure 6), which is comparable with genetic alterations in
earlier published cases with MELAS syndrome (1). Different
simulations resulted in contradictory results (from mostly benign
to pathophysiologically relevant). From a clinical perspective, the
association seems logical (the phenotype, especially including the
results of the muscle biopsy and the MRI underline a clinical
picture of MELAS), however, currently there is not enough
evidence available to prove the association. Further data on
patients with a similar phenotype harboring the same MT-ND4
alteration are needed to evaluate the association of this novel
mtDNA point mutation and MELAS syndrome. Moreover, there

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New Variant of MELAS Syndrome

FIGURE 6 | The resulting protein complex with the changed protein (A) Structure of the human respiratory chain complex I. The protein subunit carrying the mutation
is highlighted in blue. (B) Schematic drawing of the complex I subunit altered in the patient. The site of the mutation in an extramembranous domain is indicated by an
arrow. Data are derived from https://www.ebi.ac.uk/pdbe/entry/pdb/5xtc/protein/25 (20).

to recognize these immunological changes to prevent end organ
damage. In our patient, gastritis or anemia could be avoided by
administering stomach protection and a vitamin B12 substitute,
Addison’s disease was successfully treated with steroids; Lthyroxin was substituted, and regular controls for early detection
of diabetes mellitus were recommended.
Autoimmune polyendocrine syndromes are frequently
associated with a broad spectrum of antibodies. In contrast,
mitochondrial disorders like MELAS are generally not
characterized by the presence of antibodies or autoimmune
phenomena. Therefore, it is most likely that the broad spectrum
of antibodies described here is part of the APS in our patient. On
the other hand, it cannot be excluded for sure that mitochondrial
disorders themselves may have impact on components of
the immune system. Like neurons, cardiac myocytes, and
skeletal muscle fibers, which are frequently affected in
mitochondrial disorders because of their postmitotic state
and longevity, antibody-producing plasma cells are postmitotic,
long-living cells and highly dependent on sufficient energy
supply by their mitochondria. A decline in ATP production
could impair the quantity of ab production and result in
hypogammaglobulinemia. An increased formation of reactive
oxygen species might result in increased mutation rates and
activation of apoptotic pathways within immune cells. Since
mitochondria also play an important role in intracellular calcium
homeostasis mitochondrial disorders might affect cellular
mobility and signaling processes (8).
In summary, to our knowledge this is the first
case presentation of a patient with atypical MELAS
syndrome presenting with a neuropsychiatric syndrome
of predominantly executive dysfunction, together with
a polyglandular autoimmune syndrome type 2, and a
heteroplasmic point mutation in the MT-ND4 gene. The
recognition of such constellations is important for further
research and clinical differential diagnosis in complex
neuropsychiatric cases.

might be further mutations or variants in the nDNA regarding
Addison’s disease or polyglandular autoimmune syndrome,
which could contribute to this complex disorder.

Immunological Aspects
The most common immunological comorbidity in MELAS
syndrome is type 1 diabetes mellitus (4), especially due to
the frequent m.3243A > G mutation in MELAS syndrome,
which is associated with diabetes mellitus (7). The present
patient had increased diabetes-associated anti-GAD65 antibodies
and a carried a polymorphism in the POLG gene, which
is known to be associated with diabetes mellitus; however,
clinically, she did not suffer from diabetes mellitus. The
prevalence of growth and sexual hormone alterations was also
high in earlier studies (8). In line with that observation, our
patient suffered from low testosterone levels and is the shortest
in her family. Hashimoto’s thyroiditis and Addison’s disease
were earlier described as comorbid disorders in patients with
mitochondriopathies; however, generally they do not seem to
occur more often in this condition (7, 8). The association between
MELAS syndrome and Addison’s disease was explored in earlier
papers (21, 22). O’Grady and colleagues presented an overview
of earlier cases with a combination of mitochondriopathy and
primary adrenal insufficiency. All the cases had manifested
in childhood and lacked predominant psychiatric symptoms
(i.e., dysexecutive symptoms), as was the case with our
patient (22).
To our knowledge, this is the first case report of a patient with
MELAS syndrome with comorbid autoimmune polyglandular
syndrome type 2. This aspect is clinically important, as shown
in the patient’s history. Addison’s disease and MELAS syndrome
(lactate acidosis/myopathy) share clinical features with respect
to weakness, fatigue, and abdominal complaints such as nausea
or diarrhea. Hence, it is important to think of both diseases
when considering the differential diagnosis. Additionally, our
patient was tested positive for further antibodies. It is important

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DATA AVAILABILITY

The patient has given her signed written informed consent for
this case report, including the presented images, to be published.

SM, KN, MD, and TL performed and interpreted the magnetic
resonance spectroscopy. FS, CZ, BF, and KK interpreted the
genetic testing. FG performed the neurological investigation
and interpretation. NV performed the rheumatological
measurements and interpreted the results. EF performed
the opthalmoscopic examinations. All authors were critically
involved in the theoretical discussion and composition of the
manuscript. All authors read and approved the final version of
the manuscript.

AUTHOR CONTRIBUTIONS

FUNDING

DoE treated the patient, performed the data research, and wrote
the paper. PS, KK, KD, and LT supported the interpretation.
SD, DaE, and PS performed the neuropathological analyses
and interpretation. KE performed and interpreted the MRIs.

The article processing charge was funded by the
German
Research
Foundation
(DFG)
and
the
University of Freiburg in the funding program Open
Access Publishing.

All datasets generated for this study are included in the
manuscript and/or the supplementary files.

ETHICS STATEMENT

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Conflict of Interest Statement: LT has received fees for lectures from Medice,
Sevier, Shire, and Actelion within the last three years.
The remaining authors declare that the research was conducted in the absence of
any commercial or financial relationships that could be construed as a potential
conflict of interest.
Copyright © 2019 Endres, Süß, Maier, Friedel, Nickel, Ziegler, Fiebich, Glocker, Stock,
Egger, Lange, Dacko, Venhoff, Erny, Doostkam, Komlosi, Domschke and Tebartz
van Elst. This is an open-access article distributed under the terms of the Creative
Commons Attribution License (CC BY). The use, distribution or reproduction in
other forums is permitted, provided the original author(s) and the copyright owner(s)
are credited and that the original publication in this journal is cited, in accordance
with accepted academic practice. No use, distribution or reproduction is permitted
which does not comply with these terms.

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