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Folia Neuropathologica
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vol. 49

Original article
Increased reactive oxygen species (ROS) production and low catalase level in fibroblasts of a girl with MEGDEL association (Leigh syndrome, deafness, 3-methylglutaconic aciduria)

Agnieszka Karkucinska-Wieckowska
Magdalena Lebiedzinska
Elzbieta Jurkiewicz
Magdalena Pajdowska
Joanna Trubicka
Tamara Szymanska-Debinska
Jan Suski
Paolo Pinton
Jerzy Duszynski
Maciej Pronicki
Mariusz R. Wieckowski
Ewa Pronicka

Folia Neuropathol 2011; 49 (1): 56-63
Online publish date: 2011/03/31
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Originally Leigh syndrome (LS, OMIM#256000) was a characteristic pathological gross and microscopic pattern of brain damage in autopsy study [13,25], now also detectable in vivo by computed tomography, magnetic resonance imaging and spectroscopy (MRI and MRS) [31]. In humans LS occurs almost exclusively in primary mitochondrial disorders, irrespective of the location of the defect in the process of oxidative phosphorylation, or of the type of the responsible gene mutation [14,16,28,30]. The changes are always of a similar location and nature, although they show varying degrees of severity and different age of appearance. The anatomical extent of involvement is progressive with time. LS is relatively frequent in the paediatric population in the country [18-21].

Non-specific 3-methylglutaconic aciduria (3-MGCA type IV, OMIM#250951) is a heterogeneous bioche­mical finding of unexplained pathogenesis [1,4,34,35]. This type of aciduria may occur in the course of mitochondrial diseases [9,15,23,33]. Careful analysis of the similarity of clinical presentation in a subgroup of chil­dren with 3-MGCA recently helped to identify a new gene, TMEM70 [5]. Its mutations are responsible for mitochondrial cardiomyopathy and a deficit of mitochondrial ATP synthase (complex V) activity.

In 2006, another clinical subgroup of 3-MGCA type IV was identified [33]. These four children de­monstrated a special association of symptoms, cal­led MEGDEL association (methylglutaconic aciduria, deafness, Leigh syndrome). Only a few more similar cases can be found in the literature [6,9].

Retrospective analysis of our own material (over 300 patients with mitochondrial diseases including LS) showed that in the years 1995-2010, only a few could correspond to MEGDEL association. The aim of this study was to broaden knowledge about the pathogenesis of the defect on the basis of proteomic and functional studies of muscle and fibroblast mitochondria obtained from the girl with such an association.

Material and methods

Patient – case report

The 4.5-year-old girl, the daughter of healthy unrelated parents, was born on time (40 hbd) by Caesa­rean section, small for gestational age (weight 2200 g, Apgar score 10). Transient adaptation troubles and liver dysfunction were observed at 4-7 days of life (symptomatic hypoglycaemia 1.5 mmol/l, lactic aci­demia 11.4, 13.4, 7.1 mmol/l, ATIII 41%, 61%, INR 2.08, 2.07). Neonatal test for phenylketonuria was false positive (normal serum Phe level and oral Phe loading excluded PKU). Blood amino acids and acylcarnitine profiles were normal with the exception of mild in­crease of methionine. Urinary profile of organic acids revealed increased excretion of 3-methylglutaconic, lactic, and p-hydroxypyruvic acids.

During early infancy her psychomotor development seemed normal; only mild hypotony was seen. Glucose concentration normalized, lactate concen­tration decreased (to 3.5, 3.2 mmol/l) ammonia level was in the normal range. A tendency to respiratory alka­­losis was found in capillary blood (pH 7.47, pCO2 28.6 mmHg, pO2 55.6 mmHg, HCO3 20.5 mmol/l, BE –3.0 mmol/l, saturation 91.3%).

At the age of 7 mo she was admitted to a regional hospital because of failure to thrive (weight 5600 g) and enlarged liver (9 cm below costal margin). Laboratory data showed markedly increased transaminases (AspAT up to 1108 U/l), glucose level in the lower normal range, elevated plasma lactate (2.1-7.1 mmol/l), and com­pensated respiratory alkalosis (pH 7.429, pCO2 18.1 mmHg, pO2 90.3 mmHg, HCO3 13.4 mmol/l, BE –10.0 mmol/l). GC-MS analysis revealed mild 3-me­thyl­glutaconic aciduria, and increased excretion of lactic, p-hydroxypyruvic and 3-hydroxydicarboxylic acids.

At the age of 13 mo she did not sit and showed marked deficits in weight and growth (anthropometric measurements were from –2.0 SD to –3.0 SD). The liver was slightly enlarged. Sensorineural deafness (detected at 13 mo) was treated with a hearing aid device. Her emotional contact was preserved. Investigations revealed pigmentary degeneration of retina and Leigh syndrome features with lactate accumu­lation on brain magnetic resonance spectroscopy (Fig. 1). Cardiological examination was normal. Laboratory data showed increased plasma and cerebrospinal con­centrations of lactate (4.7 mmol/l and 3.9 mmol/l) and alanine (621.1 mol/l and 56.6 mol/l, respecti­vely), liver dysfunction (AspAT/AlAT 140/102 U/l) and a switch from respiratory alkalosis to metabolic acidosis (pH 7.309, pCO2 37.2 mmHg, HCO3 18.4 mmol/l, BE –7.0 mmol/l).

Muscle biopsy performed at the age of 2 show­ed only a mild degree of lipid accumulation. Otherwise the biopsy was unremarkable. Histology and histochemistry revealed no features characteristic of mitochondrial disease/myopathy. Cytochrome oxidase ac­ti­vity was positive at the histochemical level. Spec- ­tro­photometric assay of muscle biopsy sample showed only unspecific changes of complex II/III activities (not shown). The search for known mitochondrial and nuclear gene mutations leading to LS was negative.

Mitochondrial disorder presenting as MEGDEL association of unknown biochemical and molecular background was diagnosed. Careful physical rehabilitation, stress avoidance and antioxidant preparations were administered.

From 17 months of life the girl demonstrated neurological deterioration, extrapyramidal signs and dystonic movements, as well as episodes of respiratory insufficiency.

At the age of 4 her status is relatively stabilized, she is fed through PEG, she breathes spontaneously, periodically receiving oxygen.

Histology, histochemistry and spectrophotometry

Histology, histochemistry and spectrophotometry of the muscle were performed according to the procedure described earlier [26,27].

Blue Native PAGE and in-gel activity assay

Samples for Blue Native electrophoresis from muscle biopsies were isolated as previously described [10,11]. Mitochondria were solubilized with 1.5 M 6-ami­nocaproic acid, 50 mM Bis-Tris pH 7.0, 1% dodecylmaltoside, combined with 0.5% Serva Blue G and separated on a 5-12% acrylamide gel. To visualize activity of individual mitochondrial respiratory chain complexes adequate parts of the Blue Native gel were incubated in the appropriate solutions as described [10,11].

Fibroblast cultures

Human skin fibroblasts were grown in Dulbecco modified Eagle's medium with glucose (4.5 g/l), 5 mM sodium pyruvate and 2 mM L-glutamine (Lonza), supplemented with 10% (v/v) fetal bovine serum (Gibco), and 1.2% antibiotic, antimycotic solution (Sigma Al­drich) in an atmosphere of 5% (v/v) carbon dioxide in air at 37°C. The cells were grown in 100 mm culture dishes. Three days before measurement of mitochondrial parameters cells were plated and grown in 24-well plates (Costar).

Estimation of antioxidant enzyme levels by Western blot technique

The level of antioxidant enzymes was investigated as previously described [12]. Cell lysates (35 g protein) were separated electrophoretically in 10% SDS polyacrylamide gel and transferred onto PVDF membrane (BioRad). Membranes were blocked using 2% non-fat milk (Biorad) in TBS buffer containing 0.01% Tween 20 (Sigma Aldrich) for 1 h. Proteins were detected with anti-SOD1 rabbit polyclonal antibody (1 : 5000, Santa Cruz), anti-SOD2 goat polyclonal antibody (1 : 500, Santa Cruz), anti-catalase monoclonal antibody (1 : 1000, Santa Cruz) and anti-actin antibody (1 : 10 000, Abcam) followed by appropriate secondary HRP-conjugated antibodies (1 : 5000) (Santa Cruz).

Measurement of mitochondrial membrane potential (mtΔΨ)

mt was measured using 10 M JC-1 as previously described [12].

Measurement of respiratory chain activity

The respiratory chain activity was measured in PBS containing 5 mM glucose and 6 M resazurin as previously described [12].

Measurement of cytosolic superoxide (cO2•–) production

cO2•– production was measured using 0.5 M dihydroethidium (DHE) as previously described [12].

Measurement of mitochondrial superoxide (mtO2•–) production

mtO2•– production was measured using 2.5 M MitoSox as previously described [12].

Measurement of H2O2 production

H2O2 production was measured using 2 M CM-H2DCFDA as previously described [12].

Determination of protein modifications by oxygen free radicals

The level of oxidized proteins was estimated using the OxyBlot Protein Oxidation Detection Kit (Chemicon) as previously described [12].

Statistical analysis

Data obtained from the Tecan microplate reader were calculated using Microsoft™ Excel 2005 and analysed for significance by Student's t-test.


Mitochondrial respiratory chain proteomic and bioenergetics parameters were investigated in the patient. First Blue Native electrophoresis and in-gel activity assay using muscle biopsy were performed. In-gel activity assay showed a significant decrease of complex V activity accompanied by a slight decrease of complexes II and IV activity in the female patient, which indicates a combined respiratory chain defect (Fig. 2A). Interestingly, similarly to the immunocytochemical results Western blot analysis showed no alterations in the amount of the studied respiratory chain subunits (Fig. 2B). This indicates that the mitochondrial alte­rations are connected with the defect in the enzymatic activity and not with the amount of the subunits of the mitochondrial respiratory chain complexes.

To study how these alterations affect basic mitochondrial parameters at a cellular level the fibroblast culture of the patient was investigated (Table I). In our recent paper [12] we reported that the measurement of mitochondrial membrane potential (mt) in such cells showed a significant decrease in the proton-motive force in mitochondria. Moreover, the ac­tivity of the respiratory chain measured using resazurin was reduced by ~25%.

Parameters describing intracellular oxidative stress were also assessed and found abnormal in comparison to the control fibroblasts (Table I, see also Figures for patient 2 [12]). The patient’s fibroblasts demonstrated increased production of both cytosolic and mitochondrial superoxide. Moreover, the rate of H2O2 production was even doubled. The increased level of carbonylated proteins found in the patient’s fibroblasts may also be connected with a decreased level of crucial antioxidant defence enzymes, including SOD2 and catalase.

The reduced catalase level in the patient’s fibro­­blasts seemed especially interesting because it was not observed in the reference fibroblast lines of two brothers with Barth syndrome (BS). BS remains MEGDEL association by similar presence of the 3-MGCA urinary marker.


The described patient was the first child among the dozens with Leigh syndrome with increased excretion of 3-MGCA in the urine studied in our centre. The clinical picture included progressive ence­phalopathy, liver dysfunction, dystonia, pigmentary retinal degeneration, sensorineural deafness, in­cre­ased lactate concentration in plasma, cerebrospinal fluid and urine, and 3-methylglutaconic aciduria. MEGDEL association described by Wartmann [33] was evident in the patient.

Diagnosis of mitochondrial disease in the patient (with 8 points on the scale of Nijmegen according to [17]) did not pose any difficulties despite the lack of explicit enzymatic and molecular background of genetic defect. Interestingly, episodes of hyperventilation with hypocapnia and respiratory alkalosis were observed in the first phase of the illness, as we des­cribed in Leigh syndrome, independently from its mo­le­cular background [20,24,28]. According to our hypothesis, the reason for emergence of typical LS changes in the brain may be related to the subsequent increase in intracellular pH [22,24]. The current observation confirms that this phenomenon may also occur in MEGDEL syndrome.

Muscle histology and histochemistry of the patient revealed no significant pathology, and the activity of complex I and IV was in the normal range. Combined defect of respiratory chain function including decrease in the proton-motive force (mt) and low mitochondrial ATP synthase activity (with normal amount of complex V) was revealed by the expanded investigations in vitro and in vivo. Increased ROS production, decreased level of antioxidant defence, and re­markable protein carbonylation level were found [12]. There is increasing evidence that unba­lanced ROS production and defence may contribute to the neuropathology [7].

Surprisingly, the amount of catalase in the patient was selectively low (8%) in comparison with the heal­thy control (100%) and the brothers with Barth syndrome (respectively 330% and 270%) [12]. The other measured parameters did not markedly differ bet­ween MEGDEL and BS fibroblasts. BS was applied as an example, referential for the other type of 3-MGCA pathology (Table I).

Catalase [8] is a known marker of peroxisome bio­synthesis; and its lack in tissue subcellular structures is characteristic for Zellweger syndrome, a peroxi­somal defect [3]. Moreover, increased excretion of 3-MGCA may be related to impairment of peroxisomal cholesterol biosynthesis through the sterol/isoprenoid metabolic pathway [2]. Low cholesterol levels observed in Barth syndrome (type II of 3-MGCA) was attributed to that mechanism.

Moreover, the clinical phenotype observed in our patient with MEGDEL association may be related to both mitochondrial and peroxisomal defects (deafness, pigmentary retinal degeneration, impaired liver function) [29]. Unfortunately, peroxisome function was not directly assessed in our MEGDEL case, and has not been reported in the literature.

Summary: In the expanded in vitro and in vivo investigations it has been revealed that the girl with Leigh syndrome, sensorineural deafness, pigmentary retinal degeneration and 3-methylglutaconic aciduria manifests a combined defect of respiratory chain function including decrease in the proton-motive force (mt) and low mitochondrial ATP synthase activity (with normal amount of complex V subunits). Also, as was described in our recent paper, increased ROS production, decreased level of antioxidant de­fence, especially very low catalase level, and remarkable protein carbonylation level were found. We speculate that an association of the specific clinical features with low catalase level/activity and with 3-methylglutaconic acid accumulation may indicate the involvement of peroxisomal impairment in the MEGDEL syndrome, i.e. abnormalities of intracellular catalase transport.


This work was supported by the Polish Ministry of Science and Higher Education under grant NN407 075 137, by the Polish Mitochondrial Network and by the Internal Project of The Children’s Memorial Health Institute 117/09. JS was also supported by a PhD fellowship from The Foundation for Polish Science (FNP), EU, European Regional Development Fund and Ope­­rational Programme 'Innovative economy'. P.P.'s work was supported by the Italian Association for Cancer Research (AIRC), the United Mitochondrial Disease Foundation (UMDF), the Industrial Research program (PRRIITT) of the Emilia Romagna region (PRRIITT), the Italian Multiple Sclerosis Foundation (FISM), Telethon (GGP09128) and local funds from the University of Ferrara. An attempt to identify mtDNA mutations was performed in the Molecular Laboratory of the Department of Medical Genetics, Children's Memorial Health Institute (Laboratory head, Dr. Elzbieta Ciara).


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Copyright: © 2011 Mossakowski Medical Research Centre Polish Academy of Sciences and the Polish Association of Neuropathologists. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.

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