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Limb Pain and Sensory Abnormalities

Patient complaints about their arms and legs generally refer to the muscles and the peripheral nerves. Joint disease is not a common clinical feature in mitochondrial disease. Younger children may have difficulty describing abnormal sensations accurately (like numbness or tingling) and may substitute more familiar terms instead like pain instead (inaccurately).

Impaired oxidative phosphorylation not only causes muscle fatigue but also muscle cramping with or without tenderness, or a feeling of extreme heaviness in the muscles. These symptoms are especially severe in those muscle groups being used, and patients often complain of discomfort in the legs or even muscle spasms. The discomfort may be felt immediately following the activity or later on, waking up the patient from sleep. Following more prolonged or intensive activity, the pain or heaviness can persist into the next day(s) despite rest. A subset of patients has pain associated with elevations of CK and intensive exercise can lead to frank myoglobinuria; there may also be associated lactic acidemia (DiMauro, 1999).

Peripheral neuropathy can be a common and early manifestation of mitochondrial disease that is likely under-acknowledged (Stickler, 2005). It can manifest as burning pain, sharp, jabbing or "electric" pain, hyperesthesiae, tingling, or a loss of sensation. Patients can experience more than one type.

It is suggested that energy failure at the cellular level may be responsible for the development of peripheral neuropathy. The myelination of central and peripheral nerve axons requires energy; the process is inhibited in experimental situations in which ATP synthesis is decreased (Fern 1998, Zhou 2002). Impairment of oxidative phosphorylation can lead to the accumulation of lactate and free radicals with reduced synthesis of ATP (Stickler, 2005). Certain therapies specifically prescribed for patients with mitochondrial disease, such as sodium dichloroacetate for patients with lactic acidosis, are also associated with peripheral neuropathy (Kaufmann, 2006).

Abnormalities in sensation may also be a feature of complicated migraine (see HEADACHES) or seizures, or part of a complex of symptoms characterizing a stroke-like episode (see ACUTE NEUROLOGICAL DETERIORATION). If the sensations come on in the presence of light-headedness, there may be an autonomic etiology to the symptoms associated with heart rate and/or blood pressure abnormalities. Those factors that aggravate autonomic dysfunction (such as heat or fatigue) can trigger unusual sensations. Other signs of autonomic dysfunction include heat or cold intolerance, diminished sweating, spontaneous pallor/flushing/mottling without cause, or abnormal gut motility or bladder function. See AUTONOMIC DYSREGULATION (Zelnik, 1996; Axelrod, 2006).

Mitochondrial Differential Diagnosis

1. Myalgia

2. Peripheral neuropathy

3. Vascular dysautonomia

4. Migraine

5. Seizures or a stroke-like episode

Assessment and Recommendations:

1. Myalgia or peripheral neuropathy as a cause:

a. Determine what symptoms are associated with the pain or abnormal sensations and whether or not there are any trigger factors.


1. Referral to a neurologist.

2. Consider an EMG and nerve conduction studies. However, these are not necessarily sensitive tools for confirming the presence of mitochondrial myopathy or its sensory abnormalities.

3. If there is a history of intermittent frankly dark-colored urine (suggesting the possibility of myoglobinuria):

a. The following tests should be performed when symptoms are present - CPK in blood, and urinalysis and urine myoglobin.

b. If myoglobinuria is confirmed, the patient and family should be counseled about the need for assessment and management (fluids, dextrose, urine alkalinization) when rhabdomyolysis occurs.

2. Autonomic dysregulation:

a. Assess for autonomic dysfunction and those factors that can cause autonomic dysfunction: temperature dysregulation, abnormal (usually low) basal body temperature, heat and cold intolerance, abnormal sweating patterns, tachy- and bradycardia, dizziness, and bladder dysfunction.


1. Evaluate for vascular dysautonomia, and look for orthostatic changes in heart rate and blood pressure which can cause fatigue and dizziness.

2. If fluid or calorie intake is low, encourage fluids and/or calories. A trial of IV fluids might improve symptoms and support an autonomic etiology.


3. Migraine:

a. Is there a past or family history of migraine? Are episodes associated with headache or sensitivity to light or noise, or aura prior to symptoms?


1. If causes of migraine have been considered and treated without adequate benefit, consider treating the pain, or refer to a neurologist.


4. Seizures or a stroke-like episode:

a. Is there an altered mental state, loss of function, focal findings, or an asymmetry to the physical exam suggesting a neurologic event like a seizure or a stroke-like episode? Is there a history of seizures?



2. Refer to the ER or to a neurologist depending on the urgency of the situation.

5. Pain Management:

a. If migraine, seizures, and stroke-like episode have been considered and are considered unlikely, a trial of medication (like "Neurontin") is indicated.

b. Supports for living with chronic pain or discomfort include a psychologist or counselor, pacing one's lifestyle, and establishing priorities for quality of life

c. Strategies living with chronic pain include physical therapy, biofeedback, acupuncture, massage, physical therapy, and relaxation techniques


Axelrod FB, Chelimsky G, Weese-Mayer DE. Pediatric autonomic disorders. Pediatrics 2006;118:309-21.

DiMauro S. Exercise intolerance and the mitochondrial respiratory chain. Ital J Neurol Sci 1999:20:387-93.

Fern R, Davis P, Waxman SG, Ransom BR. Axon conduction and survival in CNS white matter during energy deprivation: A developmental study. J Neurophysiol 1998;79(1):95-105.

Kauffmann P, Engelstad K, Wei Y, et al. Dichloroacetate causes toxic neuropathy in MELAS; A randomized, controlled clinical trial. Neurology 2006;66(3):324-30.

Stickler DE, Valenstein E, Neiberger RE, et al. Peripheral neuropathy in genetic mitochondrial diseases. Pediatr Neurol 2005;34(2):127-31.

Zelnik N, Axelrod FB, Leschinsky E, et al. Mitochondrial encephalomyopathies presenting with features of autonomic and visceral dysfunction. Pediatr Neurol 1996;14:251-4.

Zhou CJ, Inagaki N, Pleasure SJ, et al. ATP-binding cassette transporter ABCA2 (ABC2) expression in the developing spinal cord and PNS during myelination. J Compar Neurol 2002; 451(4):334-45.

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