Mitochondrial DNA deletion syndromes include three overlapping phenotypes: Kearns-Sayre syndrome (KSS), Pearson syndrome, and progressive external ophthalmoplegia (PEO).  These three phenotypes may be observed in different members of the same family or may evolve in a given individual over time.

KSS is a multisystem disorder defined by three key signs and symptoms: onset before age 20 years (typically in childhood), pigmentary retinopathy, and PEO.  Affected individuals must also have at least one of the following: cardiac conduction block, cerebrospinal fluid protein concentration >100 mg/dL, or cerebellar ataxia.  Other findings may include short stature, hearing loss, dementia, limb weakness, diabetes mellitus, hypoparathyroidism, and growth hormone deficiency.

Pearson syndrome includes the findings of sideroblastic anemia and exocrine pancreas dysfunction. It is usually fatal in infancy. Those surviving into childhood develop features of KSS.  Symptoms may first occur between the first and fifth decade of life and may not appear in any particular order.

PEO is a mitochondrial myopathy characterized by findings including drooping of the eyelids (ptosis), paralysis of the extraocular muscles (ophthalmoplegia), and variably severe proximal limb weakness.  Rarely Leigh syndrome can manifest due to a mtDNA deletion which is characterized by basal ganglia and brain stem lesions.

These conditions are caused by pathogenic variants in mitochondrial DNA (mtDNA). Pathogenic variants can be sporadic (not inherited) or maternally inherited.  A female who carries the mtDNA mutation at high mutation load will typically pass it on to all of her children. A male who carries the mtDNA mutation cannot pass it on to his children.

Guidelines and Evidence

• No specific evidence-based U.S. testing guidelines were identified.
• Case reports and a limited number of case series is the primary evidence base available for the diagnosis of mitochondrial disease. There are few prospective studies. The Mitochondrial Medicine Society developed consensus recommendations using the Delphi method and published them in 2015.
  • Recommendations for DNA testing;
    • “Massively parallel sequencing/NGS of the mtDNA genome is the preferred methodology when testing mtDNA and should be performed in cases of suspected mitochondrial disease instead of testing for a limited number of pathogenic point mutations.”
    • “Patients with a strong likelihood of mitochondrial disease because of a mtDNA mutation and negative testing in blood, should have mtDNA assessed in another tissue to avoid the possibility of missing tissue-specific mutations or low levels of heteroplasmy in blood; tissue-based testing also helps assess the risk of other organ involvement and heterogeneity in family members and to guide genetic counseling.”
    • “Heteroplasmy analysis in urine can selectively be more informative and accurate than testing in blood alone, especially in cases of MELAS due to the common m.3243 A>G mutation.”
    • “When considering nuclear gene testing in patients with likely primary mitochondrial disease, NGS methodologies providing complete coverage of known mitochondrial disease gene is preferred.  Single-gene testing should usually be avoided because mutations in different genes can produce the same phenotype. If no mutation is identified via known NGS panels, then whole exome sequencing should be considered.”
• A workshop of the National Institute of Neurological Disorders and Stroke (2008) summarizes:
  • "The diagnosis of mitochondrial diseases is complicated by their heterogeneous presentations and by the lack of screening procedures or diagnostic biomarkers that are both sensitive and specific.  The workshop panelists explained that diagnosis is often a lengthy process beginning with a general clinical evaluation followed by metabolic screening and imaging and finally by genetic tests and more invasive biochemical and histological analyses. The identification of known mitochondrial mutations in tissue has greatly aided diagnosis. However, even when clinical features and family history strongly suggest mitochondrial disease, the underlying genetic mutation can elude detection, and there is no current screening procedure that would be practical for all cases of suspected mitochondrial disease."
• The European Federation of Neurological Sciences (2009) provided molecular diagnostic evidence-based guidelines for these conditions:
  • "If the phenotype suggests syndromic MID [mitochondrial disorders] due to mtDNA deletion (mtPEO, KSS, Pearson's syndrome), mtDNA analysis starts with RFLP or Southern-blot from appropriate tissues. mtDNA deletions with low heteroplasmy rate may be detected only by long-range PCR.  If neither a single deletion nor multiple deletions are found, mtDNA sequencing is recommended."