The expanding phenotype of MELAS caused by the m.3291T>C mutation in the MT-TL1 gene

Abstract

m.3291T > C mutation in the MT-TL1 gene has been infrequently encountered in association with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), however remains poorly characterized from a clinical perspective. In the following report we describe in detail the phenotypic features, long term follow up (> 7 years) and management in a Caucasian family with MELAS due to the m.3291T > C mutation and review the literature on m.3291T > C mutation. The clinical phenotype in the proposita included overlapping features of MELAS, MERRF (Myoclonic epilepsy and ragged-red fiber syndrome), MNGIE (Mitochondrial neurogastrointestinal encephalopathy), KSS (Kearns-Sayre Syndrome) and CPEO (Chronic progressive external ophthalmoplegia).

A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis

“…Multiple small hyperintense areas in subcortical white matter of cerebrum on T2 MRI NA NA NA Family of 5 affected individuals in 4 generations Sunami et al [ 10 ] 36 F Photo-induced myoclonus, atrophy of cerebellum, absence of tendon reflexes, truncal ataxia, normal mental status 16% (peripheral leukocytes) NA NA Family of 5 affected individuals in 4 generations Sunami et al [ 10 ] 15 F Generalized seizures, myoclonic jerks, slight cognitive decline, absence of tendon reflexes 27% (peripheral leukocytes) NA NA Family of 5 affected individuals in 4 generations Emmanuele et al [ 13 ] 43 M Progressive myoclonus epilepsy, cerebellar ataxia, cortical and cerebellar atrophy, hearing loss, myopathic weakness, ophthalmoparesis, pigmentary retinopathy, bifascicular heart block, premature graying (20 years) 92% (muscle) Elevated (serum) Normal respiratory chain enzymes. RRFs and succinate dehydrogenase reactive vessels Yarham et al [ 8 ] 51 M Bilateral sensorineural deafness, falls, speech disturbance, weight loss, diabetes mellitus, macroglossia with fatty infiltration, dysarthria, bilateral pes cavus, lipoma, low tendon reflexes, dysmetria, generalized brain atrophy 39% (muscle) Elevated (cerebrospinal fluid) Dystrophic changes and lipid infiltrates, RRFs, COX-negative fibers, succinate dehydrogenase reactive vessels Unaffected sister shows heteroplasmy levels of 6% in both urine and blood Liu et al [ 11 ] 14 F Progressive cerebellar ataxia, frequent myoclonus seizures, recurrent stroke-like episodes, migraine-like headaches with nausea and vomiting, nystagmus, basal ganglia calcification, brain atrophy, and stroke-like lesions 93% (muscle), 67% (blood), 62% (fibroblasts) Elevated (serum) RRF, COX-negative fibers, succinate dehydrogenase reactive vessels Mother of proband (phenotype: emaciation and short stature) and asymptomatic sister of proband have heteroplasmy levels of 46% and 50%, respectively Keilland et al [ 12 ] 15 F Stat...…”

Mutational Analysis and mtDNA Haplogroup Characterization in Three Serbian Cases of Mitochondrial Encephalomyopathies and Literature Review

“…Phenotype diversity of Leigh disease has been reported for m.8993T>C mutation in the same MT-ATP6 gene [81]; noticeably, other unusual presentations rather than neurological ones were found with other mitochondrial and nuclear-encoded genes, causing Leigh disease to be ocular and gastrointestinal with MT-ND mutations [82,83], cardiac with NDUF [84,85] and renal with SURF1 and ACAD9 gene defects [86,87]. Previous studies have reported many mitochondrial mutations causing classic MELAS without any detectable phenotypic specificity [88,89]; exceptional renal diseases were detected in association with m.3243 and m.13513G>A as a first manifestation of MELAS [90,91]. Furthermore, MELAS m.3243 was associated with uncommon presentations such as cardiac and ketoacidosis [92,93].…”

Response to: Letter to the Editor regarding: The expanding phenotype of MELAS caused by the m.3291T>C tRNA mutation E. Kelland, C.A. Rupar, Asuri N. Prasad, A. Downie and C. Prasad (1) by Josef Finsterer, MD, PhD [1], Sinda Zarrouk-Mahjoub, PhD [2]

“…Apparently, the m.3291T > C mutation does not manifest significantly in the heart [1] . Did the propositus undergo comprehensive cardiologic investigations, including echocardiography and long-term ECG-recordings?…”

“…The patient presented with clinical manifestations of KSS [1] . Which were the clinical manifestations of KSS?…”