Mitochondrial genome sequencing [37 genes]

This category encompasses a heterogeneous group of diseases that develop as a consequence of alterations in proteins located at the mitochondrial level. These proteins are encoded both by genes present in mitochondrial DNA and by nuclear genes.

The spectrum of clinical presentation may be very wide, from more severe forms of mitochondrial disease, generally with onset during infancy or childhood, to milder forms diagnosed in adulthood. Although some of them involve isolated organs, multisystem presentation is more common, including, among others, neurological, metabolic, myopathic, renal, and cardiac manifestations.

These diseases are clinically heterogeneous, can occur at any age, and usually can produce a wide range of clinical symptoms, being often considered multisystem diseases. Some mitochondrial diseases can be grouped into specific syndromes, such as Leigh syndrome (infantile subacute necrotizing encephalomyopathy), MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), or Alpers-Huttenlocher syndrome.

In addition to biochemical and histochemical analysis of tissue biopsy samples, diagnosis is usually based on clinical criteria.

• Childhood-onset mitochondrial diseases: 5-15/100,000 individuals
• Leigh syndrome (most common presentation): 2.5/100,000 individuals
• Adults:
  • 9.6/100,000 individuals (for diseases due to mtDNA mutations)
  • 2.9/100,000 individuals (in the case of diseases caused by mutations in nuclear genes)

Genetic testing in mitochondrial disease not only contributes to a better clinical and molecular characterization of these patients, but also enables appropriate genetic counseling for individuals and their families.

• When mitochondrial disease is strongly suspected based on clinical findings, consistent with an autosomal recessive or X-linked inheritance pattern.
• When mitochondrial disease is strongly suspected based on clinical findings and cardiovascular manifestations are absent or very mild.
• When mitochondrial disease is suspected and extracardiac manifestations (acidosis or metabolic alterations and neurological involvement, such as seizures, neuropathy, or myopathy) clearly predominate over cardiovascular ones.

Mitochondrial defects can result from mutations in genes located in nuclear DNA (nDNA) or in mitochondrial DNA (mtDNA). With regard to genetic suspicion, it is worth mentioning that 80% of adult-onset mitochondrial diseases are caused by pathogenic variants in mtDNA; however, they only account for 20-25% of childhood-onset cases, where nuclear genes are more important.