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Page 388 Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40

Table 2. Clinical Features of Mitochondrial Disease
Organ system Clinical feature
Brain Encephalopathy, microcephaly, ataxia, seizures, dementia, stroke, Parkinsonism, developmental delay and
regression, intellectual impairment, psychiatric disorder, autism, cerebellar hypotonia, dystonia
Peripheral Nerve Sensory and axonal neuropathy, dysautonomia, aberrant temperature regulation, orthostatic hypotension,
abnormal sweating
Special Senses Sensorineural hearing loss, optic atrophy, retinitis pigmentosa, cataract, aminoglycoside hearing loss
Muscle Ophthalmoplegia, eyelid ptosis, myopathy, muscle cramping, exercise intolerance, hypotonia
Respiratory Respiratory failure
Cardiac Cardiac conduction defect, cardiomyopathy (dilated, restrictive, hypertrophic)
Renal Proximal renal tubular dysfunction (Falconi syndrome), nephrotic syndrome, Barrter syndrome, tubulointerstitial
disease
Endocrine Diabetes mellitus, hypogonadism, hypoparathyroidism, infertility, short stature (not growth hormone related),
growth hormone deficiency, adrenal insufficiency, exocrine pancreatitis
Gastrointestinal Dysphagia, cyclic vomiting, pseudo-obstruction, gastrointestinal dysmotility
Hepatic Hepatopathy, nonalcoholic steatohepatitis
Hematological Siderblastic and macrocytic anemia, pancytopenia, erythrocyte failure
Dermatological Lipomatosis
Skeletal Kyphosclerosis, bone marrow failure

rRNA biogenesis and transcription and translation factors; Fe-S cluster biogenesis enzymes, protein quality
control, and import/processing proteins; membrane integrity components; mitochondrial dynamics
proteins; and classic syndromes.

Clinical manifestations of mitochondrial diseases
Mitochondrial diseases are clinically and genetically highly heterogeneous. Diseases can be inherited
as autosomal recessive, dominant, or X-linked due to nuclear-DNA genetic variants and by maternal
inheritance via mtDNA genetic variants. The presence of mitochondria in all nucleated cells, differing
energy demand among body tissues, and expression of gene products produces a wide variety of symptoms
[Table 2]. As discussed further below, the dual genome expression and interaction between genome
products creates an additive spectrum of organ involvement in disease. In addition, there are multiple
other influences on the age of onset, severity, and pattern of organ involvement and progression of disease.
Mitochondrial disease expression is also confounded by environmental triggers, known as ecovariants .
[33]
Ecovariants are DNA sequences that remain silent unless exposed to environmental agents. For example,
exposure of a patient with pathological variants in polymerase gamma (POLG) with the seizure medication
valproic acid induces severe hepatopathy and certain nucleoside reverse transcriptase inhibitors induce
lactic acidosis, pancreatitis, bone marrow suppression, myopathy, and peripheral neuropathy [34,35] . There are
other DNA sequences that can act as modifiers by altering penetrance and expressivity of primary disease-
causing pathological variants, but in and by themselves are silent . For example, variants in the mtDNA
[36]
sequence, m. 6480 G>A, m. 1281G>A, and m. 1539A>G, were found to increase penetrance and expressivity
in patients with the Leber Hereditary Optic Neuropathy (LHON) pathological variant, m. 11778 G>A.
There are also uncommon mtDNA-encoded variants that do not follow the “rules” of pathogenicity, but
still cause disease . The m. 8344 A>G change occurs in a region that is not strictly evolutionary conserved
[37]
yet produces the syndrome of myoclonus, epilepsy with ragged red fibers (MERRF), one of the classic
syndromes . It is no wonder that there exists such a range of phenotypes. However, to confound the
[38]
clinician, there are still disorders that seem to be restricted to one organ, such as disease due to certain mt-
tRNA synthetases . Furthermore, the lack of the full compendium of gene causing mitochondrial diseases
[39]
can place the clinical in a conundrum of non-diagnostic disease.

Historical grouping of clinical features into certain syndromes has held true for the most part, but rarely
does a phenotypic presentation have a direct correlation with any given biochemical, histopathology,
[40]
enzymatic, or genetic findings . Those mitochondrial syndromes that remain relevant today are likely