MELAS syndrome is a rare mitochondrial disease caused by mutations in the mitochondrial DNA. It is characterized by stroke-like episodes leading to hemiplegia, hemianopsia, or cortical blindness. Other common features include focal or generalized seizures, recurrent migraine-like headaches, vomiting, short stature, hearing loss, and muscle weakness1,2. Stroke-like episodes typically present with acute onset of neurological symptoms in patients with MELAS syndrome with hyperintensities on DWI. Upon brain imaging, lesions are generally focal complying with the distribution of blood vessels. Values of apparent diffusion coefficient (ADC) do not necessarily decrease. At the acute stage, MRI signals may migrate, fluctuate, or even disappear. These changes are faster and more common than in typical ischemic stroke patients4. The patient we reported here had recurrent stroke, changeable foci, and seizures in the course of the disease. Our imaging results revealed lobar lesions that did not conform to the distribution of blood vessels. Other complementary tests did not show cerebrovascular lesions or possible cardiothrombotic diseases. Therefore, this patient is very likely to develop MELAS syndrome.
Due to the complex nature of pathogenesis and clinical manifestations, unified comprehensive diagnostic criteria have not been reached yet, rendering a likelihood of being missed or misdiagnosed for certain patients with MELAS syndrome. The initial diagnostic criteria for MELAS syndrome include: stroke-like episodes before the age of 40, encephalopathy characterized by seizures or dementia, and signs of mitochondrial myopathy evidenced by blood lactic acidosis or broken red fibers in skeletal muscle biopsy. Another two tests can be tentatively used to confirm the diagnosis, including normal early psychomotor development, recurrent headache or repeated vomiting5. Subsequent studies encompassed a wider range of phenotypes for MELAS syndrome diagnosis, a good example is clinical onset after the age of 40 years 6–8. In 2012, the Japanese MELAS Research Group Committee adopted the following diagnostic criteria requiring at least two signs of clinical criteria A – consisting of headache with vomiting, seizures, hemiplegia, cortical blindness and acute focal lesions revealed by neuroimaging, in combination with at least two positive tests in laboratory criteria B – consisting of high levels of plasma or cerebrospinal fluid (CSF) lactate, mitochondrial abnormalities in muscle biopsy, and MELAS-related gene mutations9.
The 71-year-old patient presented with recurrent cerebral infarction. However, no cardiothrombotic causes, such as atrial fibrillation or vulnerable plaques of the carotid artery, were found. The condition of this patient deteriorated though conventional treatment has been administered. Surprisingly, it was stabilized after taking coenzyme Q10 and vitamin B, both of which are used to improve metabolism. This patient presented with stroke-like episodes, aphasia, seizure, acute gyrus-like lesions in the parietal-occipital lobe on MRI, increased blood lactic acid, and a history of relatively short stature and spasmodic torticollis, which led to the suspicion of MELAS syndrome. Gene sequencing showed a 12.86% MT-TWm.5541C>T mutation in mitochondrial genes of leukocytes. Nuclear gene sequencing showed no mutations associated with mitochondrial dysfunction. A heterozygous mutation in the SLC30A8 gene was found, but it is associated with NIDDM instead of mitochondrial functions.
A number of mitochondrial tRNA mutations can cause MELAS syndrome. 80% of MELAS patients are associated with the m.3243A>G mutation, whereas 10% associated with the m.3271T>C mutation10. Interestingly, the patient reported in the present study showed MT-TWm.5541C>T mutation in mitochondrial gene sequencing. Yarham et al constructed a scoring system for mutation pathogenicity assessment which uses multiple weighted criteria including a series of molecular, functional, and genetic data11. Using an updated version of the scoring system, Blakely et al confirmed that the MT-TW m.5541C>T mutation was a "confirmed pathogenic mutation"12. Though this mutation can lead to the occurrence of clinical MELAS syndrome, there are still few reports on this mutation.
In theory, there is a threshold, also known as the threshold effect, of mtDNA mutations beyond which certain tissues or organs begin to dysfunction. However, different tissues have discrete thresholds based on their degree of energy dependence. The brain is highly dependent on energy and thus has a relatively low threshold. A male patient with a mtDNA mutation m.5541C>T showed MELAS symptoms with a mutation rate of 84% in skeletal muscles, but his mother who had a mutation rate of 51% in skeletal muscles did not show MELAS symptoms12. In the patient reported in the present study, gene sequencing showed a mutation rate of 12.86% in leucocytes, which was relatively lower than the abovementioned rates, but she had MELAS symptoms. On one hand, gene sequencing was performed on white blood cells, not muscles in the present study. On the other hand, "heterogenization" of the mtDNA disorder signifies different distribution of the mutated mtDNA in diverse tissues. For example, the mutation rate of mitochondrial gene detected in muscles is often higher than that in the blood12,13. Furthermore, individual brain tissues have different tolerance to metabolic needs, especially if there are underlying metabolic diseases that influence brain metabolism14. The patient in this study carried a SLC30A8_ex8c.973C>T missense mutation associated with NIDDM and was diagnosed with type 2 diabetes. Other mutations may result in changes in the activity or structure of other enzymes or proteins that impact brain metabolism. To date, however, specific pathophysiological mechanisms still need to be further investigated.
Due to the lack of cooperation from family members of the patient and the cost of gene sequencing, the patient did not allow to perform mitochondrial gene sequencing and biopsy on skeletal muscles. However, recurrent stroke-like episodes, MRI findings, elevated lactate in the blood, and inverted Lac/Lip peak on MRS render us to diagnose the patient with MELAS syndrome.