Avoid common mistakes on your manuscript.
With interest we read the article by Zhu et al. about a 54yo male with MELAS due to the mutation m.3243A > G in the tRNA (Leu) gene manifesting as short stature, stroke-like episodes (SLEs), and macroangiopathy (Zhu et al. 2017). We have the following comments and concerns.
Macroangiopathy is a typical phenotypic feature of mitochondrial disorders (MIDs) but is even more frequently not attributed to the underlying metabolic defect (Finsterer and Zarrouk-Mahjoub 2016). Macroangiopathy in MIDs may manifest as atherosclerosis, ectasia of arteries (aortic root, intracerebral arteries, abdominal aorta) (Finsterer and Zarrouk-Mahjoub 2016), aneurysm formation (intracerebral arteries) (Zhu et al. 2017), as arterio-venous malformation (Scuderi et al. 2015), or as reversible vasoconstriction (Yoshida et al. 2013) (Table 1). The reason why macroangiopathy is not more frequently attributed to a MID is due to the fact the MIDs go frequently undetected for years and is often misdiagnosed and mistreated. Particularly in case of atherosclerosis but absence of classical risk factors or frequent sport activity a mitochondrial defect must be considered.
Macroangiopathy in MIDs may be complicated by dissection (internal carotid artery) or spontaneous rupture (aorta) (Table 1). Spontaneous rupture of intracerebral arteries may cause intracerebral bleeding (Fujitake et al. 2002) or sudden death in case of aortic rupture. An argument in favour of a MID manifesting as cerebral aneurysm is that in patients with subarachnoid bleeding intracerebral microdialysis was indicative of mitochondrial dysfunction in 29/55 patients with subarachnoid bleeding (Jacobsen et al. 2014).
mtDNA mutations are usually maternally inherited and only rarely occur spontaneously. Was the family history positive for MELAS, in particular, did the mother present with any features typical for MELAS? Did the mother or other first degree relatives carry the same mutation as the proband? Were other family members investigated for cerebral aneurysms? Was the family history positive for subarachnoid bleeding?
Severity of clinical manifestations may depend on the amount of mutation present within a tissue. Was the heteroplasmy rate determined and was there a difference between tissues such as hair follicles, buccal cells, fibroblasts, muscle cells, urine bladder epithelial cells, or lymphocytes? Was the heteroplasmy rate determined from a biopsy of an artery?
The patient was obviously admitted because of a SLE, manifesting as epilepsy, visual impairment, and headache (Zhu et al. 2017). Which type of headache did the patient present with? Was it migraine or migraine-like headache? What type of therapy did he receive for cephalalgia? NO-precursors have been shown beneficial for SLEs. Did the patient receive L-arginine or L-citrulline in addition to coenzyme-Q and levetiracetam? Was the patient put on a ketogenic diet, which has been shown to be beneficial particular for mitochondrial epilepsy and migraine-like headache?
Since cerebral aneurysms may increase in diameter over time we should be informed if follow-up investigations were carried out and if there were dynamic changes of the aneurysm over time.
Overall, the report would profit from an extensive family history and genetic investigations of first degree relatives. Macroangiopathy is not restricted to MELAS but has to be regarded as a phenotypic manifestation in other MIDs as well. Patients with subarachnoid bleeding should be investigated for MID.
JF: design, literature search, discussion, first draft, SZ-M: literature search, discussion, critical comments.
References
Brunetti-Pierri N, Pignatelli R, Fouladi N, Towbin JA, Belmont JW, Craigen WJ, Wong LJ, Jefferies JL, Scaglia F (2011) Dilation of the aortic root in mitochondrial disease patients. Mol Genet Metab 103:167-70
Finsterer J, Bastovansky A (2015) Dilative arteriopathy and leucencephalopathy as manifestations of a neurometabolic disease. Open Neurol J 9:28-31
Finsterer J, Stöllberger C (2015) Leriche-syndrome despite regular sport and non-compaction suggest neuromuscular disease. Int J Cardiol 191:15-17
Finsterer J, Zarrouk-Mahjoub S (2016) Mitochondrial vasculopathy. World J Cardiol 26(8):333–339
Fujitake J, Mizuta H, Fujii H, Ishikawa Y, Sasamoto K, Goto Y, Nonaka I, Tatsuoka Y (2002) Leber’s hereditary optic neuropathy with intracranial arteriovenous malformation: a case report. Acta Neurol Belg 102:82–86
Iizuka T, Goto Y, Miyakawa S, Sato M, Wang Z, Suzuki K, Hamada J, Kurata A, Sakai F (2009) Progressive carotid artery stenosis with a novel tRNA phenylalanine mitochondrial DNA mutation. J Neurol Sci 278:35-40
Jacobsen A, Nielsen TH, Nilsson O, Schalén W, Nordström CH (2014) Bedside diagnosis of mitochondrial dysfunction in aneurysmal subarachnoid hemorrhage. Acta Neurol Scand 130:156–163
Kalashnikova LA, Dobrynina LA, Sakharova AV, Chaĭkovskaia RP, Nazarova MA, Mir-Kasimov MF, Patrusheva NL, Patrushev LI, Konovalov RN, Protskiĭ SV (2012) The A3243G mitochondrial DNA mutation in cerebral artery dissections. Zh Nevrol Psikhiatr Im S S Korsakova 112:84-89
Mancuso M, Montano V, Orsucci D, Peverelli L, Caputi L, Gambaro P, Siciliano G, Lamperti C (2016) Mitochondrial m.3243A > G mutation and carotid artery dissection. Mol Genet Metab Rep 9:12-4
Noguchi A, Shoji Y, Matsumori M, Komatsu K, Takada G (2005) Stroke-like episode involving a cerebral artery in a patient with MELAS. Pediatr Neurol 33:70-1
Ryther RC, Cho-Park YA, Lee JW (2011) Carotid dissection in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. J Neurol 258:912-4
Sakharova AV, Kalashnikova LA, Chaĭkovskaia RP, Mir-Kasimov MF, Nazarova MA, Pykhtina TN, Dobrynina LA, Patrusheva NL, Patrushev LI, Protskiĭ SV (2012) Morphological signs of mitochondrial cytopathy in skeletal muscles and micro-vessel walls in a patient with cerebral artery dissection associated with MELAS syndrome. Arkh Patol 74:51-6
Scuderi C, Borgione E, Castello F, Lo Giudice M, Santa Paola S, Giambirtone M, Di Blasi FD, Elia M, Amato C, Città S, Gagliano C, Barbarino G, Vitello GA, Musumeci SA (2015) The in cis T251I and P587L POLG1 base changes: description of a new family and literature review. Neuromuscul Disord 25:333–339
Tay SH, Nordli DR, Bonilla E, Null E, Monaco S, Hirano M, DiMauro S (2006) Aortic rupture in itochondrial encephalopathy, lactic acidosis, and stroke-like episodes. Arch Neurol 63:281-3
Yoshida T, Ouchi A, Miura D, Shimoji K, Kinjo K, Sueyoshi T, Jonosono M, Rajput V (2013) MELAS and reversible vasoconstriction of the major cerebral arteries. Intern Med 52:1389–1392
Zhu K, Li S, Chen H, Wang Y, Yu M, Wang H, Zhao W, Cao Y. (2017) Late onset MELAS with m.3243A > G mutation and its association with aneurysm formation. Metab Brain Dis 21. doi:10.1007/s11011-017-9989-0
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interests
There are no conflicts of interest.
Funding
No funding was received.
Rights and permissions
About this article
Cite this article
Finsterer, J., Zarrouk-Mahjoub, S. Macroangiopathy is a typical phenotypic manifestation of MELAS. Metab Brain Dis 32, 977–979 (2017). https://doi.org/10.1007/s11011-017-0020-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-017-0020-6