Bilateral deafness, diabetes, and different types of cardiomyopathy in family members with m.3243A > g mutation: a case report

Abstract

Background The point mutation at position 3243 in the mitochondrial MT-TL1 gene (m.3243A > G) is a rare cause of hypertrophic cardiomyopathy (HCM). Information about HCM progression over time and occurrence of different cardiomyopathies in m.3243A > G carriers of the same family is still lacking. Case summary A 48-year old male patient was admitted to a tertiary care hospital with chest pain and dyspnea. Bilateral hearing loss required hearing aids at the age of 40. A short PQ interval, narrow QRS complex and inverted T-waves in lateral leads were present on electrocardiogram. HbA1c of 7.3 mmol/L indicated prediabetes. Echocardiography excluded valvular heart disease and detected non-obstructive hypertrophic cardiomyopathy with slightly reduced left ventricular ejection fraction (LVEF 48%). Coronary artery disease was ruled out by coronary angiography. Myocardial fibrosis determined by repeated cardiac MRI progressed over time. Endomyocardial biopsy excluded storage disease, Fabry disease, infiltrative and inflammatory cardiac disease. Genetic testing revealed m.3243A > G mutation in the MT-TL1 gene associated with mitochondrial disease. Clinical evaluation and genetic testing of the patients’ family revealed five genotype-positive relatives with heterogeneous clinical phenotypes including deafness, diabetes mellitus, kidney disease and both hypertrophic and dilated cardiomyopathy. Discussion In patients with unexplained symmetric HCM with heterogenic clinical phenotypes at the organ levels mitochondrial disease should be taken into consideration, particularly in the context of matrilinear transmission. m.3243A > G mutation is associated with a mitochondrial disease in the index patient and five family members and leads to the diagnosis of maternal inherited diabetes and deafness (MIDD) with intra-familial variability of different cardiomyopathy forms.

Intra-familial phenotypic heterogeneity of m.3243A > G carriers remains elusive as long as heteroplasmy and mtDNA copy numbers are absent

“…The patient presented phenotypically with hearing loss, diabetes, and hypertrophic cardiomyopathy. 1 The causative variant was also detected in four first-degree relatives, who also manifested clinically but with partially different phenotypes. 1 Another family member had hypertrophic cardiomyopathy, two others dilated cardiomyopathy, and one half-brother also had renal insufficiency.…”

“… 1 The causative variant was also detected in four first-degree relatives, who also manifested clinically but with partially different phenotypes. 1 Another family member had hypertrophic cardiomyopathy, two others dilated cardiomyopathy, and one half-brother also had renal insufficiency. 1 The study is excellent but has limitations that are cause for concerns and should be discussed.…”

“…I read with interest the article by Seiler et al 1 on a 48-year-old male with a non-syndromic mitochondrial disorder (MID) due to the variant m.3243A > G in MT-TL1 . The patient presented phenotypically with hearing loss, diabetes, and hypertrophic cardiomyopathy.…”

“… 1 Another family member had hypertrophic cardiomyopathy, two others dilated cardiomyopathy, and one half-brother also had renal insufficiency. 1 The study is excellent but has limitations that are cause for concerns and should be discussed.…”

“…A limitation of the study is that heteroplasmy rates among first-degree relatives were not reported. 1 Knowledge of heteroplasmy rates of first-degree relatives is crucial not only for explaining the individual phenotype but also for predicting an individual’s progression and outcome, for explaining the intra-familial phenotypic variability, and for genetic counselling. In addition, mitochondrial DNA (mtDNA) copy numbers should be reported as they contribute to the phenotypic variability between individuals carrying the same mtDNA mutation.…”