Frequency of MELAS main mutation in a phenotype-targeted young ischemic stroke patient population

Abstract

Mitochondrial diseases, predominantly mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS), may occasionally underlie or coincide with ischemic stroke (IS) in young and middleaged individuals. We searched for undiagnosed patients with MELAS in a target subpopulation of unselected young IS patients enrolled in the Stroke in Young Fabry Patients study (sifap1). Among the 3291 IS patients aged 18-55 years recruited to the sifap1 study at 47 centers across 14 European countries, we identified potential MELAS patients with the following phenotypic features: (a) diagnosed cardiomyopathy or (b) presence of two of the three following findings: migraine, short stature (B165 cm for males; B155 cm for females), and diabetes. Identified patients' blood samples underwent analysis of the common MELAS mutation, m.3243A[G in the MTTL1 gene of mitochondrial DNA. Clinical and cerebral MRI features of the mutation carriers were reviewed. We analyzed blood samples of 238 patients (177 with cardiomyopathy) leading to identification of four previously unrecognized MELAS main mutation carrier-patients. Their clinical and MRI characteristics were within the expectation for common IS patients except for severe hearing loss in one patient and hyperintensity of the pulvinar thalami on T1-weighted MRI in another one. Genetic testing for the m.3243A[G MELAS mutation in young patients with IS based on phenotypes suggestive of mitochondrial disease identifies previously unrecognized carriers of MELAS main mutation, but does not prove MELAS as the putative cause.

A different pattern of clinical, muscle pathology and brain MRI findings in MELAS with mt‐ND variants

“…During follow‐up, five (27.8%) MELAS‐mtND patients died of generalized seizures. Short stature in this study was defined as male ≤ 165 cm and female ≤ 155 cm 24 at age > 16 years old. Three (3/13, 23.1%) MELAS‐mtND patients exhibited short stature.…”

Prevalence of Mutations in Mendelian Stroke Genes in Early Onset Stroke Patients

“…32 Having a "genetically" pathogenic variant of a monogenic disorder does not necessarily mean that a patient has corresponding clinical or imaging characteristics because of high variability of the penetrance and expressivity. Previous studies also reported that clinical and/or brain MR findings were not enough to specify diagnosis of monogenic disorders such as Fabry disease, 33 MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes), 34 and CADASIL. 35 For patients with CRGVs but no typical features of the corresponding disorders at stroke onset, we could not determine whether they would develop those features ultimately and how long it would take.…”

The Clinical Approach to Stroke in Young Adults

“…There are data to suggest this may be an underestimate due to lack of recognition to screen for monogenetic causes. Some studies estimate the incidence in young stroke patients could be up to 7% (144,145). To be clear, these are not "stroke genes;" rather, they are genetic conditions in which stroke is a presenting feature.…”