A MELAS phenotype is not necessarily MELAS

Letter to the editor

We read with interest the article by Macken and Birbeck about a 14-year-old Malawian boy who was suspected upon clinical presentation to have mitochondrial encephalomyopathy, lactic acidosis and stroke-like episode (MELAS) syndrome. ¹ We have the following comments and concerns.

MELAS should not be diagnosed upon clinical presentation alone. The diagnosis should be confirmed by biochemical investigations of the muscle or another clinically affected tissue. Reduced activity of any respiratory chain complex should be documented. Additionally, cerebral magnetic resonance imaging (MRI) should either document a stroke-like lesion, atrophy, basal ganglia calcification, or non-specific white matter lesions. Cerebral imaging is also essential to see if ataxia was due to a cerebellar or brainstem lesion, due to a spinal cause or due to peripheral neuropathy. Finally, the diagnosis must be confirmed by genetic studies and documentation of the m.3243A > G mutation (present in 80% of cases) or the m.3271A > C mutation (present in 10% of cases).^2,3 Confirmation of the genetic defect is essential since other mtDNA or non-mtDNA mutations may phenotypically mimic MELAS.

Cerebral imaging is inevitable since the patient presented with left-sided hemiparesis. ¹ What was the cause of left-sided hemiparesis? Had the patient experienced a stroke-like episode or a true ischemic stroke? Since MELAS is frequently associated with seizures or status epilepticus, it should be excluded that left-sided hemiparesis was due to a post-ictal condition. We should be informed after which period weakness resolved and if hemiparesis recurred after some time. Was ever atrial fibrillation documented on routine electrocardiogram (ECG)? Was carotid ultrasound normal? What were the results of the electroencephalogram (EEG)? Did the patient receive L-arginine during the acute stage or did he receive acetyl-salicylic acid or oral anticoagulation?

Since the patient presented with reduced deep tendon reflexes and ataxia, we should be informed about the results of nerve conduction studies. Did the patient suffer from diabetes, hypothyroidism, hypoparathyroidism or chronic renal failure? Were deep tendon reflexes reduced only on the left side or also on the right side? In case they occurred unilaterally, how do the authors explain this finding?

Since the patient obviously also had cardiac disease, manifesting as AV-block-1, results of a transthoracic ECG should be provided. Did the patient have a history of exertional dyspnoea, leg oedema or syncope? Was the family history positive for cardiac disease, in particular heart failure, syncope or sudden cardiac death? Cardiac involvement in MELAS includes cardiomyopathy, conduction defects, pulmonary hypertension or arrhythmias. ⁴ Since some patients may also present with non-compaction, ⁵ it is essential to know if cardiac embolism originated from intertrabecular spaces or from intra-ventricular or intra-atrial thrombus formation.

How do the authors know that the index patient’s mother had experienced a stroke-like episode? Did she undergo a cerebral MRI and was a stroke-like lesion documented? The index patient’s mother obviously died after several stroke-like episodes. ¹ Stroke-like episodes may be associated with seizures. ⁶ Did she undergo an EEG? Was a post-ictal condition in the mother excluded?

We agree with the authors that there is a strong need to investigate all first-degree relatives of the patient to see if there was familiarity of the clinical manifestations or if the suspected genetic defect was inherited or sporadic. Was there consanguinity between the parents? Were any first-degree family members other than the mother affected by a mitochondrial disorder?

Overall, this interesting case would profit from provision of supplementary data concerning the individual and family history, the ECG findings, results of nerve conduction studies and the genetic studies. A more widespread instrumental workup is essential, so as not to misinterpret MELAS-like conditions, overlap syndromes or to miss the point at which adequate treatment may be indicated and helpful.