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.

Table 1 Macroangiopathy in MIDs
Full size table

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.

FormalPara Authors Contribution

JF: design, literature search, discussion, first draft, SZ-M: literature search, discussion, critical comments.