Table 1.
Mitochondrial DNA testing for common diagnostic referral reasons.
| Phenotype/syndrome | Phenotype details | Minimum level of testing | Tissue typea | Possible further testing |
|---|---|---|---|---|
| Ataxia |
Possible diagnosis of: late-childhood or adult-onset peripheral neuropathy, ataxia, pigmentary retinopathy (NARP) OR Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Ataxia may be present in up to half of MELAS patients. |
m.8993T>G p.(Leu156Arg) m.8993T>C p.(Leu156Pro) (MT-ATP6) + m.3243A>G (MT-TL1) |
Any (e.g., blood) Muscle > Urine > Blood (a normal result in blood from individuals aged ≥18 years does not exclude presence in another tissue) |
Nuclear DNA testing may also be appropriate Large-scale mtDNA rearrangement testing Whole mtDNA sequencing (e.g., after further clinical examination and/or muscle biopsy) |
| Cardiomyopathy | Familial hypertrophic cardiomyopathy with maternal inheritance |
m.4300A>G (MT-TI) + m.3243A>G (MT-TL1) |
Any (e.g., blood) Muscle > Urine > Blood (a normal result in blood from individuals aged ≥18 years does not exclude presence in another tissue) |
Nuclear DNA testing may also be appropriate Whole mtDNA sequencing (e.g., after further clinical examination and/or muscle biopsy) |
| Diabetes and hearing loss | Diabetes mellitus and sensorineural hearing loss |
m.3243A>G (MT-TL1) |
Urine > Blood (a normal result in blood from individuals aged ≥18 years does not exclude presence in another tissue) |
Large-scale mtDNA rearrangement testing Nuclear DNA testing may also be appropriate Whole mtDNA sequencing (e.g., after further clinical examination) |
| Encephalopathy/seizures with lactic acidosis |
Possible diagnosis of: mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) OR Infantile onset subacute relapsing encephalopathy, cerebellar and brain stem signs (MILS) |
m.3243A>G (MT-TL1) + m.8993T>G p.(Leu156Arg) m.8993T>C p.(Leu156Pro) (MT-ATP6) |
Muscle > Urine > Blood (a normal result in blood from individuals aged ≥18 years does not exclude presence in another tissue) Any (e.g., blood) |
Nuclear DNA testing may also be appropriate Large-scale mtDNA rearrangement testing Whole mtDNA sequencing (e.g., after further clinical examination and/or muscle biopsy) |
| Hearing loss | Non-syndromic sensorineural hearing loss, particularly if onset following aminoglycoside exposure |
m.1555A>G (MT-RNR1) |
Any (e.g., blood) |
Nuclear DNA testing may also be appropriate Whole mtDNA sequencing may be appropriate if there is a maternal family history |
| Kearns–Sayre syndrome | Onset below the age of 20 years: PEO and pigmentary retinopathy with one of either cardiac conduction block, cerebrospinal fluid protein concentration greater than 100 mg/dL, or cerebellar ataxia |
Large-scale mtDNA rearrangements (single and multiple deletions) + m.3243A>G (MT-TL1) |
Muscle > Urine > Blood (may be detectable in blood but a normal result does not exclude presence in another tissue) Muscle > Urine > Blood (a normal result in blood from individuals aged ≥18 years does not exclude presence in another tissue) |
Nuclear DNA testing may also be appropriate Whole mtDNA sequencing (e.g., after further clinical examination and/or muscle biopsy) |
| Leber hereditary optic neuropathy, LHON, optic atrophy | Childhood or midlife (adult-onset) acute or subacute painless bilateral central vision loss |
m.3460G>A p.(Ala52Thr) (MT-ND1) m.11778G>A p.(Arg340His) (MT-ND4) m.14484T>C p.(Met64Val) (MT-ND6) |
Blood | Nuclear optic atrophy genes Whole mtDNA sequencing (e.g., after further clinical examination) |
| Myoclonic epilepsy |
Myoclonus, seizures; Cerebellar ataxia; Myopathy |
m.8344A>G (MT-TK) + m.3243A>G (MT-TL1) |
Any (e.g., blood) Muscle > Urine > Blood (a normal result in blood from individuals aged ≥18 years does not exclude presence in another tissue) |
Nuclear DNA testing may also be appropriate Whole mtDNA sequencing (e.g., after further clinical examination and/or muscle biopsy) |
| Pearson syndrome |
Sideroblastic anaemia of childhood; Pancytopenia; Exocrine pancreatic failure |
Large-scale mtDNA rearrangements |
Any (e.g., blood) |
N/A |
| Progressive external ophthalmoplegia (PEO), ptosis | Typically, adult-onset ptosis, paralysis of the extraocular muscles (ophthalmoplegia), oropharyngeal weakness, and variably severe proximal limb weakness |
Large-scale mtDNA rearrangements (single and multiple deletions) + m.3243A>G (MT-TL1) |
Muscle > Urine > Blood (blood is not suitable from patients aged >20 years) Muscle > Urine > Blood (a normal result in blood from individuals aged ≥18 years does not exclude presence in another tissue) |
Nuclear DNA testing may also be appropriate Whole mtDNA sequencing (e.g., after further clinical examination and/or muscle biopsy) |
| Stroke-like episodes | Stroke-like episodes, typically before age 40 years |
m.3243A>G (MT-TL1) |
Muscle > Urine > Blood (a normal result in blood from individuals aged ≥18 years does not exclude presence in another tissue) |
Nuclear DNA testing may also be appropriate Whole mtDNA sequencing (e.g., after further clinical examination and/or muscle biopsy) |
Guidance on the minimum recommended level of mitochondrial DNA testing for the most common diagnostic referral reasons.
a‘>’ used to indicate the order of tissue type preference if all sample types are available; in reality, blood is typically tested first as the most readily available target DNA source.