Emergency. 2017; 5 (1): e74

LE T T E R TO ED I TO R

Traumatic brain injury is unlikely precipitating Leigh syn-
drome due to the GJB2 mutation c.35delG
Josef Finsterer1∗, Sinda Zarrouk-Mahjoub2

1. Krankenanstalt Rudolfstiftung, Vienna, Austria.

2. University of Tunis El Manar and Genomics Platform, Pasteur Institute of Tunis, Tunis, Tunisia.

Received: March 2017; Accepted: June 2017; Published online: 30 June 2017

Cite this article as: Finsterer J, Zarrouk-Mahjoub S. Traumatic brain injury is unlikely precipitating Leigh syndrome due to the GJB2 mutation

c.35delG. Emergency. 2017; 5(1): e74.

Dear Editor:
With interest we read the article by Ashrafi et al. about a

14-year-old female who is regarded to have developed Leigh

syndrome (LS) after traumatic brain injury (TBI) (1). We have

the following comments and concerns:

We do not agree with the notion that traumatic brain injury

was the precipitating factor for LS. The patient had a his-

tory of hypoacusis, which is a typical clinical manifestation

of a mitochondrial disorder (MID). Hypoacusis obviously

had developed long before the TBI. Additionally, the patient

was diagnosed with neuropathy of the peripheral nerves two

months after TBI. It is rather unlikely that neuropathy was

triggered by TBI and more likely it was already present before

the trauma. Thus, the initial manifestations of LS in the pre-

sented patient were most likely hypoacusis followed by neu-

ropathy and TBI only might have triggered the seizure but

not the MID. Why was the patient put on phenytoin, which

is well-known to be mitochondrion-toxic (2)? Phenytoin may

worsen epilepsy and MID in general and it is conceivable

that in fact phenytoin was responsible for worsening of the

phenotype and not the TBI. In a 16-year-old female with

MELAS syndrome due to the mutation m.3243A>G, pheny-

toin caused intestinal pseudo-obstruction one month after

intravenous phenytoin for status epilepticus (3). In a pa-

tient with Kearns-Sayre syndrome phenytoin decreased cere-

brospinal fluid (CSF) folate levels (4). In rat hepatocytes,

phenytoin increased reactive oxygen species (ROS) forma-

tion, decreased intracellular reduced glutathione, increased

intracellular oxidised glutathione, and enhanced lipid per-

oxidation and mitochondrial damage (5). In a hepatic mi-

crosomal system, phenytoin decreased state-3 respiration,

∗Corresponding Author: Josef Finsterer; Postfach 20, 1180 Vienna, Aus-
tria, Europe. Tel: +43-1-71165-92085 / Fax: +43-1-4781711 / E-mail: fi-
paps@yahoo.de

ATP synthesis, and the mitochondrial membrane potential.

In this model, phenytoin increased state-4 respiration, im-

paired Ca++-uptake and release, and inhibited Ca++-induced

swelling (6). It would be interesting to know how the GJB2

mutation was detected. Was whole exome or panel sequenc-

ing carried out? Did the authors choose a gene by gene se-

quencing approach? Did the parents undergo genetic inves-

tigations? Did each of them carry the mutation in the het-

erozygous state? Did either of the parents manifest clinically?

We should be informed about the exact sequence of the TBI.

Is it conceivable that the fall was already due to a seizure or

syncope? Was the patient unconscious after the TBI? The au-

thors mention that basal ganglia lesions were “negative” on

DWI (1). However, basal ganglia appear hyperintense on DWI

in figure 2. What was the cause of respiratory insufficiency at

the second admission? Was it attributable to the cerebral le-

sions, to myopathy affecting the respiratory muscles, to lac-

tic acidosis, or to a pulmonary infection? Simultaneous ap-

plication of a bunch of drugs is not advisable since it cannot

be differentiated which of them is effective in case the ad-

ministration is followed by a beneficial response. Overall, the

report is not convincing with regard to TBI as the precipitat-

ing factor of LS. Most likely, worsening of LS was a random

event or triggered by phenytoin. It is also conceivable that

stress from TBI triggered the production of ROS, which were

mitochondrion-toxic to such a degree that a previously sub-

clinical condition became gradually symptomatic.

References

1. Ashrafi F, Pakdaman H, Arabahmadi M, Behnam B. Head

trauma as a precipitating factor for late-onset Leigh syn-

drome: a case report. Emergency. 2017;5(1):e43.

2. Finsterer J. Toxicity of antiepileptic drugs to mitochondria.

2016.

3. Chiyonobu T, Noda R, Yoshida M, Fujiki A, Ishii R, Nuk-

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J. Finsterer and Zarrouk-Mahjoub S 2

ina S, et al. Intestinal pseudo-obstruction in a patient with

mitochondrial myopathy, encephalopathy, lactic acidosis,

and stroke-like episodes (MELAS) associated with pheny-

toin therapy. Brain and Development. 2008;30(6):430-3.

4. Allen RJ, DiMauro S, Coulter DL, Papadimitriou A, Rothen-

berg SP. Kearns-sayre syndrome with reduced plasma

and cerebrospinal fluid folate. Annals of neurology.

1983;13(6):679-82.

5. Eghbal MA, Taziki S, Sattari MR. Mechanisms of

phenytoin-induced toxicity in freshly isolated rat hep-

atocytes and the protective effects of taurine and/or

melatonin. Journal of biochemical and molecular toxicol-

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6. Santos N, Medina W, Martins N, Mingatto FE, Curti C, San-

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	References