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Page 222 Musumeci et al. J Transl Genet Genom 2020;4:221-37 I https://doi.org/10.20517/jtgg.2020.22

INTRODUCTION
Mitochondrial diseases (MD) are the most common inherited metabolic disorders due to mitochondrial
[1]
dysfunction .

Mitochondria harbor their own DNA (mtDNA), which is a 16.6-kb double-stranded circular DNA encoding
for 13 subunits of respiratory chain (RC), whereas the nuclear DNA (nDNA) identifies about 79 subunits of
RC and several other proteins involved in the synthesis of cofactors (e.g., iron-sulfur proteins, hemes, and
copper) as well as in the assembly of the five RC complexes.

In MD, the structure and function of mitochondria are impaired due to mutations in genes encoded by
[2]
mtDNA or nDNA; for this reason, the genetics of MD is quite complex and in continuous evolution .
A genetic classification of MD distinguishes two main categories: (1) MD caused by primary mtDNA
mutations; and (2) MD due to mutations in several nDNA genes, related to mitochondria. Defects involving
these nuclear genes can be divided into five subcategories: (1) genes encoding subunits of the five complexes
of respiratory chain; (2) genes encoding assembly factors of the complexes; (3) genes responsible for mtDNA
maintenance (replication, maintenance of nucleotide pools, and mtDNA quality control); (4) genes encoding
for biosynthetic enzymes for lipids, amino acids, and cofactors; and (5) genes encoding for other proteins
that influence secondarily oxidative phosphorylation.

The oxidative phosphorylation (OXPHOS) dysfunction results in an impairment of oxidative energy
metabolism, with defective utilization of nutrients to generate energy (ATP), thereby causing an accumulation
of metabolic intermediates, increased oxidative stress, and decreased energy production. Consequently, tissues
highly energy-dependent such as skeletal muscle, central and peripheral nervous system, heart, and liver can
be affected by the bioenergetics deficiency in the same individual, explaining the multi-organ failure that is
typical of these disorders.

MD may appear at any age with a wide clinical spectrum, although some clinical syndromes have typical
[3]
infantile onset, whereas others occur later and usually have a milder course .
The nervous system and skeletal muscle, because of their high-energy dependence and susceptibility, are
invariably involved in most MD. Neurological features include epilepsy, psychomotor retardation, migraine,
[4]
stroke-like episodes, dementia, peripheral neuropathy, and sensitive and cerebellar ataxia . Movement
disorders (MoD) are defined as neurological features due to dysfunction of basal ganglia and their connections
[5]
and are common in MD, as either hyper- or hypokinetic form . Among them, dystonia, parkinsonism,
[6,7]
myoclonus, tremor, and chorea are more frequently reported . In pediatric MD patients, dystonia and chorea
[8]
are often reported, whereas parkinsonism is commonly described in adults .
Clinical presentation of movement disorders is variable; some studies report on the occurrence of either a
single type of extrapyramidal sign or a combination of two or more MoD in the same patient, usually in the
[7-9]
context of a multisystem disorder but rarely as an isolated manifestation of MD .
Diagnosis of MD is quite challenging because of the variability of the clinical presentation as well as the
presence of symptoms overlapping with other neuromuscular or neurodegenerative disorders; however,
recurrent clinical findings usually in classical syndromes associated with specific mtDNA mutations strongly
suggest the diagnosis. Laboratory investigations can help to addressed the diagnosis, being the main findings
that lead to the diagnosis: elevated lactate levels; the presence of some morphological findings on muscle
biopsy as “ragged red fibers (RRF)” on Gomori trichrome stain and/or cytochrome oxidase negative fibers
(COX-ve fibers); detection of defect of mitochondrial respiratory chain enzyme activities or CoQ levels; and
the identification of pathogenic mutations in either mtDNA or nDNA.