Mitochondrial diseases are a group of heterogeneous disorders affecting organ systems that have high energy requirements and are dependent on aerobic metabolism. Mitochondrial DNA (mtDNA) mutations may cause mitochondrial respiratory chain dysfunction, resulting in various pathological conditions. The diseases caused by mtDNA mutations often present with prominent neurologic and myelopathic features.  These conditions are often classified as discrete clinical syndromes; however, phenotypic overlap and clinical variability may occur.

Epidemiology

• Incidence - estimated 1/8500
• Age of onset - from childhood to adult
• Sex - M:F equal

Inheritance

• Most mtDNA disorders result from de novo mutations; transmission is often maternal
• Affected individuals often have a mixture of mutant and normal mtDNA within each cell (heteroplasmy); however, homoplasmy does not rule out pathogenicity
• Disease severity may be affected by the amount of heteroplasmy and variable tissue distribution of mitochondrial mutations
• Mitochondrial disorders may be caused by defects in mtDNA or nuclear DNA
• Mitochondrial DNA mutations are transmitted by maternal inheritance
  • Clinically unaffected females with mtDNA heteroplasmy may have affected offspring
• Nuclear gene defects may be inherited in an autosomal recessive or dominant manner
• Poor genotype/phenotype correlation exists; the same mutation may cause different clinical syndromes

Pathophysiology

• Mitochondria are ubiquitous, complex intracellular organelles containing non-nuclear DNA and may be found in hundreds to thousands of copies per cell
• Mitochondria are essential in many cell processes including the generation of adenosine triphosphate (ATP) during oxidative metabolism
• Mutations in the mitochondrial genome or in nuclear genes involved in the respiratory chain principally affect tissues that are heavily dependent on oxidative metabolism (central nervous system, cardiovascular, musculoskeletal)

Clinical Presentation

• Many mitochondrial diseases can be classified as a discrete clinical syndrome based on characteristic clinical features; however, clinical overlap does occur
• Some mitochondrial disorders only affect a single organ, such as in Leber hereditary optic neuropathy (LHON) and nonsyndromic sensorineural deafness
• Presentation of mtDNA mutations typically occurs in childhood, while nuclear DNA mutations more often present in adults

Refer to Mitochondrial Diseases topic at www.arupconsult.come for a chart of Common Features of Mitochondrial DNA-associated Diseases

Refer to Mitochondrial Diseases topic at www.arupconsult.come for a chart of Features of Mitochondrial DNA-associated Diseases

Refer to Mitochondrial Diseases topic at www.arupconsult.com. for a chart of Examples of Inherited Mitochondrial Diseases

Diagnosis

• Indications for testing
  • Children with complex neurologic features or a single neurological symptom and other system involvement
  • Individuals with clinical symptoms characteristic of a specific mitochondrial disorder
  • Individuals with any progressive multisystem disorder of unknown etiology
  • Presymptomatic testing for at-risk family members
• Laboratory testing
  • Metabolic evaluation
    • Plasma or CSF lactic acid and pyruvate concentration
    • Urine organic acids
    • Ketone bodies
    • Plasma acylcarnitine
    • Analysis of respiratory chain enzymes in skeletal muscle biopsy
  • Muscle biopsy
    • Detection of ragged red fibers
  • Genetic testing
    • Mitochondrial genome mutation scanning/sequencing
    • Mitochondrial genome duplication/deletion testing
    • DNA testing for nuclear gene-associated mitochondrial disorders
    • Targeted testing for a family-specific mutation in at-risk or symptomatic family members