Mitochondrial genome disorder panel

Mitochondrial diseases due to pathogenic mtDNA variants display a broad clinical spectrum spanning single-organ and multisystem presentations. Some entities affect one organ in isolation, such as in the eye or mitochondrial nonsyndromic hearing loss in the ear, whereas many forms involve multiple organ systems with prominent neurologic and myopathic features. Common clinical features include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. Central nervous system manifestations are often encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity. Many affected individuals show a cluster of features that fall into a discrete clinical syndrome, while others present with overlapping or atypical combinations. Onset spans any age from early infancy through late adulthood, with characteristic mtDNA syndromes showing typical ranges: Leigh syndrome with infantile onset, Kearns-Sayre syndrome with progressive external ophthalmoplegia before age 20 years, and Leber hereditary optic neuropathy with median onset around 24 years.

An important point concerning pathogenic mtDNA variants is that the clinical relevance of a variant is dependent not only on the pathogenicity of the variant but also on the heteroplasmic state of this variant in the affected tissue. Because each cell has not only two copies of a gene, as it is usually the case for nuclear genes, but many copies (~1000), the variant can be present in a certain amount (heteroplasmy) in a cell. This heteroplasmy can be different in distinct groups of cells, e.g., tissues. For each pathogenic mtDNA variant there is a threshold of clinical relevance in each potentially affected tissue. This is the reason for the principle of “any symptom, any organ, any age” applying to primary mitochondrial diseases.

The estimated prevalence is approximately 1/5,000 in adults. This represents a minimum prevalence rate from a Northeast England adult cohort.

A large number of mtDNA loci have been associated with primary mitochondrial disease. The genetic forms group into point-variant encephalomyopathies and single-organ or rearrangement syndromes. The most common pathogenic mtDNA variant is the so-called MELAS variant m.3243A>G, located in MT-TL1 gene. MELAS is an acronym standing for stroke-like episodes, seizures, ragged-red fibres. But presence of this variant can also manifest in diabetes mellitus and migraines, for example. MELAS can be associated also to different mtDNA variants. The phenotypic spectrum of mtDNA associated diseases is very broad, as mentioned above.

Homoplasmatic mtDNA variants are in most cases not pathogenic. The reason is that homoplasmatic variants cannot be removed from the gene pool, all maternal relatives will harbour this variants. If the variant is associated with severe mitochondrial disease all carriers should be affected and would not reproduce, so that the variant is eliminated from the gene pool. An exception is Leber hereditary optic neuropathy, associated to several mtDNA variants and presenting with subacute painless bilateral visual failure. LHON variants are usually found in homoplasmatic state in affected patients. The penetrance of these variants is incomplete (male ca. 50%, female ca. 20%, depending on the variant).

Kearns-Sayre syndrome (external ophthalmoplegia, ptosis, multisystem features; mtDNA deletions) is associated with deletions of mtDNA. The severity of symptoms is depending on size and heteroplasmic state of the deletions in affected tissue.

The genetic conditions covered on this page predominantly follow mitochondrial (maternal) inheritance, as documented in the current overview literature. Both syndromic and nonsyndromic forms occur across the mtDNA disease spectrum. Single large-scale mtDNA deletions, which underlie Kearns-Sayre syndrome, Pearson syndrome, and a subset of chronic progressive external ophthalmoplegia, are typically sporadic rather than maternally inherited.

• Where mitochondrial disease is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

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