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Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40 Page 395

67 patients, 40% had a 5-kb deletion in muscle samples. In those patients less than six years of age, 85%
had various sizes of deletion other than the 5 kb seen in older patients. The location varied within the
mtDNA and was higher in heteroplasmy in this younger population. Further studies have shown that,
even though most deletions occur sporadically during early development, the identical deletion is found
in all affected tissues [103] . Affected patients are always heteroplasmic and a fraction of > 60% mutant load is
required to impair mitochondrial protein translation [104] . The exact mechanisms of producing single large
deletions during development remain unclear. Recently, an inherited autosomal recessive variant in the
mitochondrial single-stranded DNA-binding protein 1 (SSBP1) has been shown to produce a single large
mtDNA deletion [105] . Duplications of mtDNA have not, to date, been reported to cause disease with the
exception of a single case report [106] .

Single large deletions in mtDNA can induce one of three classic clinical syndromes: Pearson syndrome,
Kearns-Sayre syndrome, and CPEO [Table 1]. Some patients with large deletions also demonstrate Leigh
syndrome, hearing loss, myopathy, retinitis pigmentosa, diabetes, pancreatitis, cardiomyopathy, and ataxia.

Pearson syndrome onset is during infancy presenting as refractory sideroblastic anemia with vacuolization
[107]
of bone marrow precursor cells and co-morbid pancreatic failure . On genetic testing, these children have
a single mtDNA deletion; as with the other syndromic single deletion disorders, the most common size of
deletion is 5 kb. The vast majority of patient have a de novo deletion with maternal inheritance very rare.
Interestingly, the deletion is found in most tissues, and the most logical assumption is that this event is very
early in embryogenesis [108] . Since most tissues are affected, blood leukocyte testing is routinely positive. The
multiple tissue involvement creates a multisystem disease with short stature, proximal renal tubulopathy,
skin rash, liver failure, and chronic diarrhea. The clinical course is progressive with most having death
during childhood. Those patients who survive childhood develop Kearns-Sayre syndrome. The progression
of the disease has a high correlation with size of deletion, heteroplasmy level in muscle, and location of
mutation in the mtDNA [109] .

Kearns-Sayre syndrome is classically a triad of onset before 20 years of age, CPEO, pigmentary retinopathy,
and at least one of the following: cardiac conduction block, cerebrospinal fluid protein concentration
greater than 0.1 g/L, and/or cerebellar ataxia [110] . Other frequent clinical findings include short stature,
cognitive impairment, sensorineural hearing loss, renal tubular acidosis, seizures, progressive myopathy,
and endocrinopathies. The retina displays a “salt and pepper” retinopathy of the posterior fundus and does
not produce visual field defects. MRI of the brain usually demonstrates cerebral and cerebellar atrophy
[93]
and leukodystrophy . Even though only approximately 57% of patients with Kearns-Sayre syndrome
have cardiac conduction defects, 20% of these patients die of sudden cardiac death [111] . Due to selective
elimination of deleted mtDNA in proliferating leukocytes, the older age of Kearns-Sayre presentation
requires sampling from muscle tissue, and it is required for accurate heteroplasmy [112] . Accuracy in
heteroplasmy determination combined with gene deletion containing at least one of the MT-CO1, MT-
CO2, or MT-CO3 genes is related to disease progression [108] .

CPEO generally develops in mid-adulthood, but a significant correlation exists between size of deletion,
heteroplasmy, and age of onset [113,114] . Early age of onset is associated with small deletion size and higher
heteroplasmy. Characteristically, there is eyelid ptosis and a slowly progressive paralysis of the eye muscles
leading to impaired eye movements. As paralysis continues, often compromised upgaze is the first symptom
noted. Muscle weakness, sensorineural hearing loss, diabetes mellitus, proximal muscle weakness, and
progressive dysphagia are often co-morbid symptoms. In both CPEO and Kearns-Sayre syndromes, hearing
loss and diabetes mellitus can precede onset of muscle involvement [115] .

Multiple mtDNA deletions can also give rise to CPEO. The etiology of multiple mtDNA deletion are caused
by pathological variants in nuclear DNA-encoded genes (see section below). In a large cohort of 136