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Page 414 Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40

DNA, RNA, protein, and lipid synthesis rests on the activity of the mitochondrial PPA2. Biallelic PPA2
variants display seizures, mildly delayed motor milestones, and cardiac arrhythmia [349] . The defining feature
was sudden death due to cardiac malfunction early in life, within the classification of an event named
sudden unexpected death in infancy. Most of the patients demonstrated a viral prodrome or a small
amount of alcohol in older patients [350,351] .

ECHS1 is a key component of the b-oxidation of short- and medium-chain fatty acids, responsible for the
second step of oxidation. It is also involved in the catabolism of isoleucine and valine. In valine catabolism,
the two intermediates methacrylyl-CoA and acryloyl-CoA are highly reactive and can react with a variety
of sulfhydryl groups containing compounds. If in excess, the random binding of sulfhydryl groups is toxic
to cells. Recessive ECHS1 variants induce leukoencephalopathy, changes in the basal ganglia consistent
with Leigh syndrome, hypotonia, global developmental delay, cardiomyopathy, and early death [352,353] .
3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) is the enzyme step, just upstream of ECHS1 activity in
valine metabolism. Biallelic variants in HIBCH manifest as neurodevelopmental delay, dystonia, and ataxia
with MRI findings consistent with Leigh syndrome [354] .

L-2 hydroxyglutarate dehydrogenase is a FAD-dependent enzyme that catalyzes the conversion of L-2-
hydroxygluratic acid to 2-ketoglutarate. L-2-hydroxyglutaric acid elevation in urine, cerebrospinal fluid,
and plasma is pathognomonic for L2HGDH-induced disease [355] . Patients with biallelic L2HGDH variants
have exclusive neurological findings of psychomotor retardation, cerebellar ataxia, macrocephaly, and
epilepsy [356] . Recessive and rare dominant D2HGDH variants in the chiral configuration enzyme, D-2-
hydroxyglutarate dehydrogenase induce D-2-hydroglutaric acid to 2-ketoglutarate, and patients present
with epilepsy, hypotonia, and psychomotor retardation [357] .

The OXPHOS generating ATP system presents a problem to the cell: the reduction of oxygen produces
superoxide, which is dismutated to hydrogen peroxide (H O ). Tight regulation of H O is critical for
2
2
2
2
physiological cell signaling and avoiding non-specific oxidative damage. The interlinkage of thioredoxin
and glutathione prevent excessive H O under normal conditions. The thioredoxin system is composed
2
2
of thioredoxin 2 (TXN2), thioredoxin 3 (PRDX3), and peroxiredoxin 5 (PRDX5), and it is responsible for
removing excess H O 2 [358] . Recessive variants in TXN2 have demonstrated microcephaly, cerebral atrophy,
2
psychomotor delay, epilepsy, optic atrophy, and retinopathy [359] .
The final pathway of sulfur containing amino acids, methionine, and cysteine occurs in the mitochondrial
matrix with the degradation of hydrogen sulfide (H S). H S is also produced by gut anaerobic bacteria
2
2
and metabolized in the matrix. Ethylmalonic encephalopathy protein 1 (ETHE1) is an iron containing
sulfur dioxygenase in the matrix pathway. Biallelic variants in ETHE1 demonstrate early onset progressive
psychomotor retardation, cerebral hemorrhagic lesions, chronic diarrhea, and early death [360] . The exact
mechanism of mitochondrial dysfunction remains unclear, but cell culture studies suggest impairments of
ATP production, dynamics, and disruption of ER-mitochondria contacts [361] .

CONCLUSIONS AND FUTURE DIRECTIONS
Mitochondrial disorders are heterogeneous in clinical presentation and genetic etiology. Individual
disorders are rare, but as a group they represent a common inborn error of metabolism. Phenotypically,
a range of organ involvement is the signature of the disease with those organs requiring the most energy
expressing a range of clinical features. However, tremendous overlap exists in the clinical features at
presentation, age of presentation, and progression of disease. Since there are no pathognomonic tests or
findings identifying a patient with mitochondrial disease, diagnosis is problematic. Previously, biochemistry
of bodily fluids, structural (muscle biopsy), neuroimaging, and clinical examination with thorough history
were required for diagnosis. In the initial thirty years after the first description, the expansion of disease