The non-syndromic clinical spectrums of mtDNA 3243A>G mutation

Abstract

The m.3243A >G mutation in the tRNA Leu )UUR( gene )MT-TL1( of the mitochondrial DNA is the most widely seen pathogenic mtDNA mutation which has major phenotypic variations. The clinical phenotype involves various organs such as the brain and nerves, skeletal muscles, heart, endocrine system, gastrointestinal tract, and skin. Some phenotypes conform to well established syndromes, while most of the symptoms appear individually or concomitant to other syndromes, making identification difficult. Furthermore, some progress has been made on cardiac manifestations as well as complications during pregnancy and perinatal period. This article provides a systematic review of the non-syndromic phenotypes and latest developments in m.3243A>G mutation.

Late-onset mitochondrial encephalopathy with lactic acidosis and stroke-like episodes and the role of serial imaging

“…A significant proportion of patients with the m.3243A.G mutation have a phenotype that does not meet the accepted criteria for these classical mitochondrial syndromes. These can include asymptomatic carriers, non-syndromic multisystem subtypes, isolated sensorineural hearing loss, isolated myopathy, retinopathy or nephropathy 10 13 16–20. As a result, the disease course, diagnosis and prognosis can be challenging to navigate.…”

Pathogenic mitochondrial DNA 3243A>G mutation: From genetics to phenotype

“…Mitochondrial dysfunction may be associated with insulin resistance due to increased production of reactive oxygen species (ROS) and inhibited glycolysis, leading to impairment of glucose uptake (Fazakerley et al, 2018). Other endocrine (Shen and Du, 2021).…”

“…Symptoms often affect cells and organs with high energy consumption, such as the nervous system, heart and pancreas. Categories of phenotypes include well-defined clinical syndromes, such as MELAS syndrome, myoclonic epilepsy and ragged-red fibers (MERRF) syndrome, and maternally inherited diabetes and deafness (MIDD), or non-syndromic mitochondrial disorders, such as enteromyopathy, hypertrophic cardiomyopathy, and cluster headaches ( Shen and Du, 2021 ). The syndromic phenotypic spectrum of m.3243A>G reported by the UK MRC showed that 10% of patients exhibited MELAS syndrome, 30% MIDD, and 6% MELAS/MIDD, 13% other syndromes and 28% a panoply of non-syndromic clinical features ( Nesbitt et al, 2013 ).…”

“…Mitochondrial dysfunction may be associated with insulin resistance due to increased production of reactive oxygen species (ROS) and inhibited glycolysis, leading to impairment of glucose uptake ( Fazakerley et al, 2018 ). Other endocrine glands affected include the thyroid, parathyroid, pituitary, and gonadal glands, leading to symptoms of hypopituitarism, short stature, Hashimoto thyroiditis, hypoparathyroidism, and ovarian failure ( Shen and Du, 2021 ).…”

Varied Responses to a High m.3243A>G Mutation Load and Respiratory Chain Dysfunction in Patient-Derived Cardiomyocytes

“…Heteroplasmic m.3243A>G mutation in the tRNA-Leu(UUR) gene ( MTTL1 ) is one of the most common human disease causing mtDNA mutations [ 4 , 5 ], with a prevalence of 1/6000 in the Finnish population [ 6 ] and an estimated carrier frequency of 1/400 in the Caucasian population [ 7 ]. As typical for mitochondrial disease, patients with this mutation present various clinical phenotypes.…”