Gene analysis using next-generation sequencing technology has revealed many new mitochondrial disorders that involve disturbances in the interaction between nuclear and mtDNA. Mitochondrial cytopathies of Mendelian inheritance include a wide variety of conditions classified as mitochondrial DNA maintenance defects (Viscomi, 2016).
Weakness of limb muscles is often associated with CPEO in addition to other neurological abnormalities including ataxia, hearing loss, parkinsonism, peripheral neuropathies, and psychiatric disturbances. Muscle biopsy shows RRF and decreased COX activity in some fibers. Multiple deletions in the mtDNA are usually observed, and mutations in the following nuclear genes are identified: SLC25A4, TWNK, POLG, RRM2B, DNA2, and RRM2B. The SLC25A4 gene encodes adenine nucleotide translocator 1 (ANT1), and the TWNK gene encodes Twinkle protein that is involved in the production of mtDNA and RNA helicase, which is involved in replication of mtDNA.
Some patients with this condition show ataxia. Multiple DNA deletions in mtDNA have been reported in mutations in the following nuclear genes: SLC25A4, POLG, MGME1, RNASEH1, TK2, MPV17, SPG7, and AFG3L2.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is characterized by progressive external ophthalmoplegia, severe gastrointestinal dysmotility, cachexia, peripheral neuropathy, diffuse leukoencephalopathy, and evidence of mitochondrial dysfunction (Hirano, 1994). It shows an AR inheritance pattern. Examination of post-mortem samples revealed selective mtDNA depletion with multiple deletions. Mutations in the gene encoding thymidine phosphorylase (TYMP) have been identified (Hirano, 1998) as an etiological factor (Nishino, 1999). Defects in TYMP, an enzyme that catabolizes thymidine, cause dysfunction of thymidine kinase 2, which catabolizes thymidine in the mitochondria, thereby disturbing nucleotide metabolism and mtDNA replication. Thymidine accumulates in the peripheral nerves, small intestine, and cerebral white matter.
This condition is also referred to as Alpers-Huttenlocher hepatopathic poliodystrophy. It is one of the many conditions caused by mutations in the polymerase gamma (POLG) gene located on chromosome 15q. POLG plays a pivotal role in replication and repair of mtDNA; therefore, a mutation of this vital gene results in multiple deletions and depletion of mtDNA.
This condition shows an AR inheritance pattern and is often fatal. Infants commonly develop hepatic failure, intractable seizures, and global neurological deterioration. Administration of valproic acid is contraindicated to avoid the risk of acute hepatic failure. Sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO) is known to be associated with this condition in a few families.
Mitochondrial DNA depletion syndrome (MTDPS), in a narrow sense, includes conditions in which the quantity of mtDNA is decreased, although the remaining mtDNA is structurally normal without mutations or deletions. This group includes heterogeneous conditions, which usually show an AR inheritance pattern.
The myopathic type of MTDPS is characterized by weakness of the limbs and arthrogryposis, ophthalmoplegia, and respiratory failure. Severity of the clinical symptoms and degree of histopathological changes observed in a muscle biopsy vary greatly. Some infants may show dystrophic changes and lack COX activity in the muscle. It is noteworthy that serum CK levels are often increased in these infants, in contrast to mitochondrial myopathies in which this finding is relatively uncommon. Mutations have been reported in the following nuclear genes: SLC25A4, RRM2B, and TK2.
The encephalomyopathic type of MTDPS includes a subtype that is associated with the gene encoding ATP-dependent succinyl-CoA ligase subunits (SUCLA2) and another subtype associated with the gene encoding the GTP-dependent succinyl-CoA ligase subunit (SUCLG1). Clinically, the former category includes patients with high blood lactate levels, hypotonia, seizures, and joint contractures. The latter subtype includes patients with lactic acidosis and dysmorphic features, and these infants usually die on the first day of life.
The hepatocerebral type includes infants with persistent vomiting, failure to thrive, and hypotonia. Histopathological changes in the liver include hepatocyte degeneration and fibrosis along with DNA depletion. Mutations occur in the DGUOK gene, encoding mitochondrial deoxyguanosine kinase and in the MPV17 gene, encoding a small protein of the inner mitochondrial membrane, of unknown function.
Conditions associated with mitochondrial dysfunction have been recognized in recent years.
A small percentage of infants who are born as floppy infants and in whom muscle biopsies reveal RRF and fibers with decreased COX activity, tend to recover after several months and show corresponding improvement in histopathological features observed in muscle specimens. Reports have shown that genetic analysis of mtDNA in these patients revealed point mutation of m.14674T>C or T>G mttRNAGlu (Horvath, 2009; Mimaki, 2010). Although Northern blot analysis showed decreased levels of mitochondrial tRNA-glutamate molecules, respiratory chain enzyme activity in naïve myoblasts was normal. The mechanism of recovery remains unclear; however, a compensatory role of nuclear factors is considered a possible contributor.
A previous study has reported a mutation in mtDNA contributing to exercise-induced hyper-CKemia and myalgia in a patient with RRF on muscle biopsy (Nishigaki, 2002). Episodic hyper-CKemia is usually attributed to drugs or viral infections. Among these cases of episodic hyper-CKemia, single nucleotide polymorphism (SNP) in mtDNA has been implicated as an important factor (Okamoto, 2011).