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Clinical Phenotypes

Since all organ systems are energy-dependent, any one is at risk for becoming dysfunctional in the setting of reduced energy synthesis. Theoretically then any organ system might become involved. This presents a challenge to providers who care for mitochondrial patients - the need to monitor closely an individual over the long term and screen for treatable complications. On the other hand, it is easy to understand how any new symptom could be mistakenly attributed to the underlying energy disorder if one always evaluates such a patient through a "mitochondrial disease lens." Intercurrent illnesses and unrelated medical issues in these patients can be overlooked or misdiagnosed.

The following is a list of symptoms and complications noted in or associated with mitochondrial disease by organ system (some symptoms have their source in more than one organ system):

Central nervous system:

  • seizures, myoclonus
  • ataxia
  • hypotonia, spasticity, dystonia
  • tremor, movement disorder
  • "stroke-like" events, hemiparesis
  • headaches, migraine
  • central apnea
  • developmental delays, developmental regression, dementia
  • learning disabilities
  • autism or autistic-like features
  • behavioral issues, psychiatric conditions
  • coma
  • sudden death

Peripheral nervous system:

  • numbness, paresthesiae
  • pain

Autonomic nervous system:

  • heat and cold intolerance
  • temperature dysregulation, with often abnormal (usually low) baseline temperatures
  • abnormal sweating (reduced in hot weather, present when cold or comfortable)
  • pallor, blotchiness, mottling of the skin with or without provocation
  • dizziness, fainting


  • fatigue
  • exercise intolerance
  • pain, spasms, tenderness
  • myoglobinuria


  • blurry vision, diplopia
  • diminished vision
  • ptosis
  • ophthalmoplegia
  • optic atrophy
  • pigmented retinopathy


  • hearing loss


  • dyspnea
  • obstructive sleep apnea


  • cardiomyopathy
  • arrhythmia or heart block


  • anorexia
  • easy satiety
  • failure to thrive
  • abdominal pain
  • gastroesophageal reflux
  • bloating, abdominal distention
  • pseudo-obstruction
  • constipation


  • hepatomegaly
  • dysfunction
  • fatty liver
  • cirrhosis
  • coagulopathy


  • pancreatic dysfunction


  • renal tubular dysfunction, acidosis (renal Fanconi syndrome)
  • renal failure


  • urinary retention
  • incomplete emptying
  • urinary tract infections


  • short stature
  • diabetes mellitus
  • hypothyroidism
  • hypoparathyroidism
  • adrenal insufficiency


  • pallor, blotchiness, mottling of the skin with or without provocation
  • erythromelalgia
  • easy bruising


  • anemia, sideroblastic anemia
  • neutropenia
  • thrombocytopenia


  • metabolic acidosis
  • lactic acidemia or acidosis
  • hyperammonemia
  • hypoglycemia
  • low carnitine
  • fatty acid ß-oxidation dysfunction
  • postprandial (paradoxical) ketosis
  • secondary neurotransmitter abnormalities

In this manual, many of these symptoms are explored in more detail and a "mitochondrial differential diagnosis" provided, highlighting the different pathophysiologic processes that could be producing this symptom in a mitochondrial disease patient as well as other, more common factors that can evoke or mimic the same.

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