Page 126 - Read Online

Page 230 Musumeci et al. J Transl Genet Genom 2020;4:221-37 I https://doi.org/10.20517/jtgg.2020.22

In this section, we first describe the most common phenotypes associated with mtDNA mutations with early
or adult onset, and then we describe the main types of mitochondrial ataxias involving nuclear genes.

Considering primary mtDNA mutations, cerebellar ataxia is part of the phenotypic spectrum of KSS,
usually in the context of a quite heterogeneous phenotype including neurological and extraneurological
[99]
symptoms .
Early onset sensory ataxia due to a sensitive axonal neuropathy is a prominent feature of NARP (neuropathy,
ataxia, retinitis pigmentosa syndrome), a very severe syndrome characterized also by psychomotor
retardation, retinitis pigmentosa, dementia, seizures, ataxia, and proximal weakness and due to point mtDNA
mutations in the ATP6 gene, one of the two mitochondrial-encoded subunits of ATPase.

Ataxia is also a common symptom in MERRF syndrome that manifests in juveniles or adults with myoclonus,
seizures, muscle weakness, and cognitive decline. MtDNA mutation 8344A > G is the most common genetic
variant reported in MERRF and represents about 4% of all reported mtDNA mutations [100] . A review of the
clinical phenotype in a large cohort of MERFF patients revealed “myoclonus” was more frequently linked to
“ataxia” than to “generalized seizures” [101] .

Ataxia occurs in a consistent number of patients with MELAS and is associated with cortical atrophy [102] .

Pure cerebellar ataxia is one of the common features in Coenzyme Q10 (CoQ10) deficiency syndromes
caused by different defects in biosynthetic cascade of CoQ10. This cofactor has a major role in the
electron transport from complexes I and II to complex III in the respiratory chain. CoQ10 deficiency has
shown a broad spectrum of clinical manifestations ranging from severe infantile multisystemic disease
with nephrotic syndrome and encephalomyopathy to juvenile or adult cerebellar ataxia or even isolated
myopathy [103] . Several genes involved in the biosynthesis of CoQ10 are known to be responsible for primary
CoQ10 deficiency; among them, mutations in PDSS1, PDSS2, COQ2, COQ4, COQ6, COQ7, and COQ9 are
associated with different phenotypes. For example, mutations in COQ2, encoding para-hydroxybenzoate-
polyprenyl transferase, a key enzyme in the CoQ10 biosynthetic pathway, are responsible for a multisystemic
picture with muscle weakness and myoglobinuria, seizures, mental retardation, spasticity, ataxia, and
ophthalmoparesis [104] . Brain MRI usually reveals a pure cerebellar atrophy as a prominent feature [105] .

Mutations in ADCK3, an ancestral kinase with a regulatory role in ubiquinone biosynthesis, are responsible
for the most common autosomal recessive ataxia with CoQ10 deficiency (ARCA2). The main clinical features
are exercise intolerance, seizures, and mild cognitive impairment with either childhood or juvenile onset [106] .
However, some adult onset cases have also been reported with a slowly progressive cerebellar ataxia and no
additional features. A prompt diagnosis of these forms is essential because patients greatly benefit from oral
CoQ10 supplementation [107] .

Different mutations in nDNA genes controlling different mitochondrial pathways, such as TWNK, COX20,
OPA1, RR2MB, TTC19, and MSTO1 involved in mtDNA maintenance or POLG responsible of mtDNA
replication, or genes encoding some amino acyl tRNA synthetase, involved in mtDNA translation, have been
reported in MD patients with cerebellar or sensory ataxia usually as part of a complex phenotype [108-116] .

A distinctive clinical entity is infantile-onset spinocerebellar ataxia, which is frequently due to mutations
in TWNK that encodes the Twinkle mitochondrial protein, a helicase that co-localizes with mtDNA in
mitochondrial nucleoids, and causes multiple mtDNA deletions. The main clinical features are onset of ataxia
before age of 18, deafness, epilepsy, and sensory axonal neuropathy [112] .