![]() ![]() The multi-copy nature of the mitochondrial genome leads to complicated genetics. The current accepted reference sequence is the Revised Cambridge Reference Sequence (rCRS) of the Human Mitochondrial DNA: GenBank sequence NC_012920 gi:251831106.4. Mitochondrial variants are reported using gene name and m. The nomenclature differs slightly from the standard HGVS nomenclature for nuclear genes. There are currently no standard guidelines for reporting and classifying mtDNA variants. Although mitochondrial variants are typically maternally inherited, they can be sporadic (de novo). Uniparental inheritance, cellular polyploidy and a deviation from the standard genetic code are just some of the characteristics of mitochondrial genetics. Mitochondrial genetics differ considerably from Mendelian genetics. To date, close to 400 mutations have been reported, that are known to cause a spectrum of mitochondrial diseases.Most mtDNA alterations are neutral polymorphisms, which define different population haplogroups and have been used for example in tracking human migrations. Typical early onset mitochondrial diseases include Leigh syndrome, depletions syndromes, Kearns-Sayre (KSS) and Pearson syndrome, whereas chronic progressive external ophthalmoplegia (CPEO), Leber’s hereditary optic neuropathy (LHON), neuropathy, ataxia, and retinitis pigmentosa (NARP), mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) are seen in later childhood or adult life. Common clinical features of mitochondrial disease include fatigue, weakness, metabolic strokes, seizures, cardiomyopathy, arrhythmias, developmental or cognitive disabilities, diabetes mellitus, impairment of hearing, vision, growth, liver, gastrointestinal, or kidney function, and more. Patients’ symptoms can range from mild to severe and can occur at any age. While some mitochondrial disorders only affect a single organ, many involve multiple organ systems. There are several unique properties associated with the mitochondrial genome that are important in understanding the primary mitochondrial DNA disease: 1) there are multiple copies of mtDNA in each cell 2) mtDNA is maternally inherited, 3) mutated mtDNA coexists with wild type mtDNA (heteroplasmy), 4) minimum critical proportion of mutated mtDNAs is necessary before tissue dysfunction comes apparent (threshold effect), 5) mutation load (heteroplasmy level) may vary among different tissues.Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. The vast majority of over 1000 mitochondrial proteins are encoded by nuclear genes. tRNALys), which are interspaced between the protein-encoding genes. Thirteen of these genes encode for polypeptides that form structural subunits of the respiratory chain (RC complexes I, III, IV, and V), which is functionally essential and evolutionarily constrained, and the RNA necessary for mtDNA translation, namely 2 rRNAs (MT-RNR1 and MT-RNR2, encoding 12S and 16S rRNA) and 22 transfer RNAs (tRNA, e.g. Most often the LVH of HCM becomes apparent during adolescence or young adulthood, although it may also develop later in life, in infancy, or in childhood.This panel includes the 16.5-kb mitochondrial genome (mtDNA) containing 37 genes, all of which are essential for normal mitochondrial function. Common symptoms include shortness of breath (particularly during exercise), chest pain, palpitations, orthostasis, presyncope, and syncope. Symptoms can vary from individual to individual even within the same family. SCD can be the first clinical manifestation even in patients with no clear LVH. HCM is the most common cause of sudden cardiac death under age of 30 and also the most common cause for SCD in athletes. Atrial fibrillation and atrioventricular conduction abnormalities can also manifest. The clinical manifestations of HCM range from asymptomatic LVH to progressive heart failure to ventricular arrhythmias and sudden cardiac death (SCD). Systemic diseases that can mimic HCM are for example pressure overload due to long-standing hypertension or aortic stenosis, or storage/infiltrative disorders (Fabry disease, Pompe disease) or certain syndromes (Noonan spectrum diseases, Danon disease). ![]() In HCM, LVH occurs in a non-dilated ventricle in the absence of other cardiac or systemic disease capable of producing the observed abnormal LV wall thickness. ![]() HCM is generally defined by the development of unexplained left ventricular hypertrophy (LVH) and commonly caused by mutations in cardiac sarcomere genes. It is also the most common cause for sudden cardiac death among young adults. Hypertrophic cardiomyopathy (HCM) is one of the most common human monogenic disorders with prevalence estimates of 1:500, predicting approximately 600,000 persons with HCM in the US alone. ![]()
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