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Sulaiman et al. J Transl Genet Genom 2020;4:159-87 I https://doi.org/10.20517/jtgg.2020.27 Page 169

Another PMD with eye disorder is the Kern-Sayre syndrome (KSS), which is characterized by a progressive
external ophthalmoplegia, a condition that causes eye muscle paralysis. The patients may also have other
symptoms such as cardiac conduction defect, ataxia, and abnormalities in protein levels of the cerebrospinal
fluid. The disease affects 1-3 in 100,000 individuals, and most KSS cases are due to mtDNA mutations. Some
of the mutations that have been identified in KSS are the deletion of 3,236 bp of mitochondrial chromosome
[35]
[36]
[37]
from 10,170 , mtDNA duplication , a mtDNA point mutation in the MTTL2 gene , and a large mtDNA
[38]
deletion . Mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease affects several parts of the
[39]
body, mostly the digestive and nervous systems . It is caused by a mutation in the thymidine phosphorylase
[40]
gene (TYMP) that leads to decreased enzyme activity and increased thymidine levels . MNGIE is a
progressive multi-system disorder with various symptoms, including dysphagia, gastroesophageal reflux
disease, gastroparesis, intestinal pseudo-obstruction, muscle weakness, ptosis, and ophthalmoparesis.
This condition affects intra-mitochondrial nucleoside levels leading to mtDNA depletion and secondary
[41]
mtDNA mutations . Mutations in the POLG and RRM2B genes have also been described in MNGIE-type
phenotypes [42,43] .
Another PMD is Alpers disease, which is a childhood progressive neurological disorder that affects 1 in
100,000 individuals. The clinical characteristics of Alpers disease include recurrent seizures, mental loss,
movement disabilities, and liver disease with clinical symptoms of spasticity, seizures, and dementia.
POLG gene mutations occur in 13% of Alpers cases, resulting in reduced DNA replication, mtDNA depletion,
[44]
and subsequently reduced ATP production . mtDNA depletion syndrome (MDDS) is an autosomal
recessive disease that is characterized by severe depletion of mtDNA in tissues. MDDS disease is clinically
heterogeneous, in which affected tissues can be in a single organ or multiple organs, including liver, brain,
kidney, and muscles. The known cause of MDDS is due to mutations in nuclear genes (nDNA) that affect
mtDNA maintenance [Table 2]. The known genes are those that encode thymidine kinase 2 (TK2), guanosine
diphosphate (GDP)-forming succinyl CoA ligase alpha subunit (SUCLG1), adenosine diphosphate (ADP)-
forming succinyl CoA ligase beta subunit (SUCLA2), RRM2B, TYMP and deoxyguanosine kinase (DGUOK).
[45]
All of these genes are responsible for maintaining the mitochondrial dNTP pools during mtDNA synthesis .
In some cases, mutations in POLG and Twinkle (TWNK) that are involved in mtDNA replication will also
result in insufficient mtDNA synthesis [45,46] . Similar to MDDS, ataxia neuropathy spectrum (ANS) is also due
to mutations in nuclear genes (nDNA), namely POLG and TWNK genes. Patients with ANS typically have
symptoms involving nerve, brain, and muscle dysfunctions. Currently, patients with mitochondrial recessive
ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO) are
considered having ANS. Mutations in POLG are often inherited via an autosomal recessive pattern, whereas
[47]
mutations in TWNK are often inherited in an autosomal dominant pattern .

Secondary mitochondrial diseases
Secondary mitochondrial diseases (SMD) constitute a group of complex disease manifestations that can
be caused by genetic as well as environmental factors. From a genetic point of view, SMD could be due to
pathogenic mutations in other genes that are not related to OXPHOS components, but these mutations
disrupt mitochondrial function. Also, adverse environmental effects or other factors such as oxidative
stress, aging, drug mitotoxicity, and inflammation are some of the processes that could alter mitochondrial
functions. If PMD is inherited, then SMD could be inherited and acquired. Typically, SMD occur after
conception, which could result in dysfunction in mitochondrial ATP and also non-ATP (mitochondrial
fission and fusion) producing capabilities. Mitochondria are highly dynamic organelles and undergo
mitochondrial fission and fusion processes regularly [119] . Fission is a process of making short, rod- or sphere-
shaped mitochondria controlled by DRP1, which is a large GTPase of the dynamin superfamily [119] . In
contrast, fusion leads to the formation of long and filamentous mitochondria, involving MFN1, MFN2, and
OPA1 [119] . In normal conditions, mitochondrial dynamics are well-maintained; however, oxidative stress
(intra- and extracellular stresses) could disrupt this balance, generating fragmented mitochondria.