Abstract

In a recent article, Mancuso et al. reported about a 19 years-old girl with MELAS syndrome due to the cytb mutation m.15092G>A [1]. We have the following comments and concerns.

Letter to the Editor

In a recent article, Mancuso et al. reported about a 19 years-old girl with MELAS syndrome due to the cytb mutation m. 15092G>A [1]. We have the following comments and concerns.

Mutations in the mitochondrial cytb gene may not only present as MELAS syndrome but with a large phenotypic variability (table 1). Either a single organ may be affected or several organs are involved (table 1).

Table1. Phenotypic manifestations of mitochondrial cytb mutations

Reference Patient cytb Mutation Phenotype

Mancuso 2014 19y/f m.15092G>A MELAS ( SLE, focal epilepsy)

Emmanuele 2013 15y/f m.14864T>C Migraine, neuropathy, SLE

Sobenin 2013 na m.15059G>A Essential hypertension

Zarrouk-Mahjoub 2012 na m.15434C>A Dilated cardiomyopathy

Gutierrez-Cortez 2012 na m.15077G>A Hearing loss

Sundaram 2011 na na CPEO

Ronchi 2011 15m/f m.14459G>A Leigh syndrome

Zaragoza 2011 na m.15132T>C Hypertrophic and dilated cardiomyopathy

Gil Borlado 2010 23d/m m.15533A>G Epilepsy, cognitive impairment

Kato 2010 na m.15498G>A Hearing loss

Massie 2010 18y/m m.14849T>C Myopathy, exercise intolerance

Houshmand 2004 57y/f mtDNA duplication Depression, hypoacusis, diabetes, EMP

Finsterer 2000 33y/m m.15812G>A MODS

Marin-Garcia 2000 5m/m m.15236 Hypertrophic cardiomyopathy

Marin-Garcia 2000 6m/f m.15508 Dilated cardiomyopathy

Keightley 2000 34y/f m15242G>A Exercise intolerance, lactic acidosis

De Coo 1999 young boy 4bp-deletion SLE

Marin-Garcia 1996 na m.15452C>A ischemic cardiomyopathy

Nigro 1990 18y//f na torsion dystonia, myopathy

Yo: years-old, f: female, m: male, ns: not available, SLE: stroke-like episode, CPEO: chronic progressive external ophthalmoplegia, MODS: multi-organ disorder syndrome, EMP: encephalomyopathy

The mutation is said to affect the stability of complex III. Were any animal model studies carried out to confirm the pathogenicity of the mutation? A similar effect in the animal model would confirm the pathogenicity of the mutation.

There is no need in MELAS patients to perform cerebral biopsy. Which was the indication for this invasive measure? The authors themselves mention that the tissues best suitable for genetic testing of mitochondrial disorders are the muscle and the urinary sediment. Only if there are indications for a second trouble, cerebral biopsy may be of diagnostic support. If at all cerebral biopsy was done, molecular studies should have been carried out to confirm the cytb mutation in the brain tissue.

Stroke-like lesions (SLLs) are usually not space-occupying. Is it possible that the mass effect reported was due to an ischemic stroke or focal cerebral edema from focal seizures? Were hyperintense lesions on diffusion weighted images and hypointense lesions on corresponding ADC maps observed? Is it conceivable that the SLLs actually represent an epileptic epiphenomenon? Was there focal paroxysmal EEG activity in the areas of the SLLs?

It is unusual to perform craniotomy for a SLL. For how many millimetres was the midline shifted? Were other measures, such as anti-edema therapy, applied to reduce the mass effect of SLLs? Did the mass effect occur only with one or with each SLL?

In recent studies it has been shown that L-arginine is effective to reduce duration and intensity of SLLs [ 2, 3]. Did the patient receive L-arginine or other non-specific drugs to recover from recurrent, multifocal SLLs?

Why was phenytoin applied as an antiepileptic drug? It is well-known that phenytoin reduces state-3-respiration, the mitochondrial membrane potential, and ATP-production, increases state- 4-respiration, impairs calcium uptake and release, and inhibits calcium-induced swelling, mitochondrial Na/K-ATPase, and the Mg-ATPase [ 4].

There is definitively cardiac involvement in MELAS [ 5]. Thus, one echocardiography is not enough to rule out cardiac disease. Did the patient undergo long-term ECG-recording (Holter, telemetry, reveal)? Which were the results of long-term ECG recordings? Was the individual or family history positive for syncope, fainting, or (near) sudden cardiac death (SCD)? Were ever supra-ventricular or ventricular arrhythmias, in particular atrial fibrillation or ventricular runs, recorded? Did she ever present with supra-ventricular or ventricular conduction delay?

How do the authors explain the discrepancy between MRS showing high lactate and CSF investigations showing normal CSF lactate?

Overall, this interesting case shows that extensive work-up for MELAS is not always necessary. Cerebral biopsy is not indicated in MELAS patients unless a second trouble is suspected. Mitochondrion-toxic medication should be avoided in MELAS patients. The phenotypic variability of cytb mutations is high.