Abstract
Mitochondrial disorders are the most common inherited conditions, characterized by defects in oxidative phosphorylation and caused by mutations in nuclear or mitochondrial genes. Due to its high energy request, skeletal muscle is typically involved. According to the International Workshop of Experts in Mitochondrial Diseases held in Rome in 2016, the term Primary Mitochondrial Myopathy (PMM) should refer to those mitochondrial disorders affecting principally, but not exclusively, the skeletal muscle. The clinical presentation may include general isolated myopathy with muscle weakness, exercise intolerance, chronic ophthalmoplegia/ophthalmoparesis (cPEO) and eyelids ptosis, or multisystem conditions where there is a coexistence with extramuscular signs and symptoms. In recent years, new therapeutic targets have been identified leading to the launch of some promising clinical trials that have mainly focused on treating muscle symptoms and that require populations with defined genotype. Advantages in next-generation sequencing techniques have substantially improved diagnosis. So far, an increasing number of mutations have been identified as responsible for mitochondrial disorders. In this review, we focused on the principal molecular genetic alterations in PMM. Accordingly, we carried out a comprehensive review of the literature and briefly discussed the possible approaches which could guide the clinician to a genetic diagnosis.
Highlights
Received: 8 December 2021According to the International Workshop of Experts in Mitochondrial Diseases held inRome in 2016, Primary Mitochondrial Myopathies (PMMs) can be defined as disorders that lead to defects in oxidative phosphorylation (OXPHOS) and that mainly, but not exclusively, affect skeletal muscle [1]
Mitochondrial DNA maintenance defects are a group of diseases caused by pathogenic variants in the nuclear genes involved in mitochondrial DNA (mtDNA) maintenance, resulting in impaired mtDNA synthesis leading to quantitative and qualitative defects in mtDNA
Several mutations in SLC25A4 have been linked to mitochondrial disorders and fall into two distinct clinical phenotypes: (1) Autosomal dominant CPEO [119,120] or (2) a slow progressive mitochondrial myopathy with cardiomyopathy characterized by fatigue and exercise intolerance and an autosomal recessive trait of inheritance [121]
Summary
According to the International Workshop of Experts in Mitochondrial Diseases held in. Rome in 2016, Primary Mitochondrial Myopathies (PMMs) can be defined as disorders that lead to defects in oxidative phosphorylation (OXPHOS) and that mainly, but not exclusively, affect skeletal muscle [1]. Myopathy can be isolated but more frequently is associated with other clinical manifestations [2]. More than 350 genes in both mitochondrial and nuclear genomes are known to cause primary mitochondrial diseases [4]. In the present review we will give an overview of the principal molecular genetic defects linked to PMM (Table 1). Mutations causing mitochondrial disease: What is new and what challenges remain?. Human diseases associated with defects in assembly of OXPHOS complexes. Nuclear genes involved in mitochondrial diseases caused by instability of mitochondrial DNA
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