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Musumeci et al. J Transl Genet Genom 2020;4:221-37 I https://doi.org/10.20517/jtgg.2020.22 Page 231

Recently, a complex phenotype with myopathy, cerebellar atrophy and ataxia, motor developmental delay,
and pigmentary retinopathy has been associated with mutations in MSTO1, a cytoplasmic protein required
for mitochondrial fusion and network formation [114] .

Mutations in POLG1 gene encoding the catalytic subunit of mtDNA polymerase can cause either mtDNA
depletion with early childhood syndromes or mtDNA multiple deletions leading to later onset syndromes.
A wide spectrum of POLG1 mutations is reported in the literature and it is considered the main gene
responsible for inherited mitochondrial disorders; indeed, about 2% of the MD population carries these
mutations. Among POLG-related disorders, cerebellar and sensory ataxia are prominent clinical features.
Different abbreviations have been coined to distinguish POLG1-related ataxia in the context of a sensory
neuropathy: MIRAS has been used to define a mitochondrial recessive ataxia syndrome; SANDO for sensory
ataxia neuropathy, dysarthria, and ophthalmoplegia; and MEMSA for myoclonic epilepsy, myopathy, and
sensory ataxia. A different form characterized by spinocerebellar ataxia with epilepsy is known as SCAE [115] .
More than 100 mutations in POLG have been described but four common mutations (A467T, W748S, G848S,
and T251I-P587L) are frequently reported [115,116] .

Mutations in SPG7 encoding paraplegin, a component of the mitochondrial AAA protease, have been
reported both in patients with recessive hereditary spastic paraplegia and in patients with a predominant
ataxic presentation [117] . A strictly related gene to paraplegin is AFG3L2 that is highly expressed in Purkinje
neurons and is responsible of spinocerebellar ataxia type 28 (SCA28); the role of these proteins may explain
the involvement of the cerebellum in both conditions.

Finally, it is worth mentioning some rare complex forms due to mitochondrial enzymes deficiencies, such as
Aconitase 2 (ACO2) deficiency reported in severe encephalopathy with hypotonia, athetosis, seizures, optic
atrophy, and retinal and cerebellar degeneration or defect of the epimerase encoded by NAXE that results in
children with ataxia, cerebellar edema, spinal myelopathy, and skin lesions [118,119] .

A description of all genes will never be complete but the examples selected above, although arbitrary,
reinforce the concept that MoD are often combined and manifest in variable clinical scenarios that imply
diagnostic and management challenges even for physicians expert in the field.

Therapeutic interventions for MoD in MD
Over the last decades, significant progress has been achieved to improve the diagnosis of MD and to better
understand the pathogenic mechanisms underlying these disorders, but thus far therapeutic options are very
limited and mostly not specific [120] .

Among MD, some treatable disorders have to be considered and their diagnosis is critical to start early a
specific treatment. In CoQ10 deficiency syndromes, oral supplementation with high-dose CoQ10 ameliorates
the clinical condition and changes the disease progression.

Besides primary CoQ10 deficiencies, CoQ10 is largely used in combination with a variety of vitamins and
cofactors such as L-carnitine, creatine, and riboflavin, a so-called “mitochondrial cocktail”, in all patients
with MD. Although these treatments are based on the current knowledge of MD pathomechanisms, their use
is not standardized and data on clinical efficacy are quite poor.

About the management of MoD, supportive treatment of the different features (e.g., myoclonus, parkinsonism,
and dystonia) in subjects with MD is not dissimilar from the treatment of the same symptoms in the
general population but physicians should take into account some cautions because of the well-known
mitochondrial toxicity of some drugs, e.g., valproate, aminoglycosides, etc.