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Issues That Affect Breathing

Abnormalities in breathing patterns are described in advanced mitochondrial disease (Flaherty, 2001; O'Brien 1998; Piper, 1994). The development of such patterns is gradual and intermittent and may initially appear during periods of increased oxidative stress (e.g., infections, following significant exercise, or during significant emotional distress), resolving as the patient recovers. The patterns may become more permanent as the disease progresses.

Significant fatigue can affect the respiratory muscles in the chest wall and diaphragm (Flaherty, 2001). This can result in tachypnea and/or a subjective inability to catch one's breath, associated with discomfort or anxiety. A drop in oxygen saturation may occur. The voice can change becoming hoarse in character. Rest and/or sleep usually help alleviate these symptoms. In more advanced disease, the symptoms can become permanent.

Disordered breathing during sleep including obstructive apnea is not an uncommon feature for patients with significant muscle weakness or fatigue or hypotonia. This can result in snoring, mouth-breathing, restlessness during sleep, a lack of feeling refreshed upon waking, and/or daytime somnolence. Aside from muscle fatigue (chest wall or upper airway), other contributing factors can include aspiration or impaired ventilatory control mechanisms due to brainstem involvement by the primary disease process (O'Brien, 1998).

Early signs of respiratory failure in the form of central hypoventilation are often seen at night during rapid eye movement (REM) sleep in individuals with neuromuscular disorders. The resultant hypoxemia contributes to depression of the respiratory drive and difficulty with arousability (Piper, 1994).

Tachypnea and/or dyspnea can occur with cardiac disease or active gastroesophageal reflux.

Weakened trunk muscles put these patients at high risk for pneumonia and its complications. With severe respiratory infections, patients may require weeks to recover to their baseline levels of function. In addition, chronic hypoventilation may lead to pulmonary hypertension and right-sided heart failure (Chinnery, 1997).

Patients whose phenotype includes significant biochemical abnormalities, particularly during periods of acute decompensation (as with intercurrent infections or seizures), may show tachypnea as a physiologic response to metabolic acidosis or hyperammonemia. In these cases, one would expect to see associated acid-base abnormalities. A primary metabolic acidosis can be associated with a secondary respiratory alkalosis; significant hyperammonemia can be associated with a primary respiratory alkalosis and secondary metabolic acidosis. Note that respiratory muscle weakness is more likely to be associated with primary respiratory acidosis and secondary metabolic alkalosis.

Mitochondrial Differential Diagnosis

1. Neurologic causes:

a. Progressive mitochondrial disease with central apnea

b. Obstructive apnea

c. Seizures

2. Respiratory causes:

a. Infection

b. Muscle weakness

3. Muscle causes:

a. Weakness

b. Deconditioning

4. Cardiac causes:

a. Cardiomyopathy with ventricular dysfunction

b. Arrhythmia

5. GI causes:

a. Gastroesophageal reflux

6. Sleep-disordered breathing

7. Metabolic abnormalities -

a. Metabolic acidosis

b. Hyperammonemia

Assessment and Recommendations

1. Considerations:

a. Determine what symptoms are associated with the breathing abnormalities/tachypnea and whether or not there are any trigger factors.

b. Assess the patient when symptoms are present (including cardiac examination, vital signs). Evaluate mental status.

c. For patients at risk for respiratory disease, vaccinations against pneumococcus and influenza are probably indicated.

2. Neurologic causes/Sleep-disordered breathing:

a. If there are any concerns about disordered sleep or apnea, a sleep study (polysomnogram) is indicated. If the patient has additional problems with sleep (e.g., difficulties initiating or maintaining sleep), a full sleep evaluation may produce additional information and benefit.

b. Evaluate oxygen saturation (when symptoms are present or during sleep).


1. Pulmonary function testing and a referral to Pulmonology as appropriate for respiratory muscle weakness or sleep apnea.

2. If seizures are a concern, a neurology referral is appropriate.

3. Respiratory and muscle causes:


1. Pulmonary function testing and a referral to Pulmonology as appropriate for respiratory muscle weakness or sleep apnea.

2. Consider pulmonary rehabilitation.

4. Cardiac causes:

a. Are there other signs of cardiac involvement?


1. Chest x-ray, EKG, especially in the setting of tachypnea.

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


5. GI causes:

a. Assess for reflux and delayed gastric emptying. Does the patient have post-prandial pain? Is the patient unable to eat a large amount at one time?

b. Is the patient a grazer (perhaps suggesting that the patient can't tolerate easting big meals) or a meal-eater?


1. Gastroenterology referral as appropriate (particularly one knowledgeable in but motility issues).

2. If reflux is present, a trial of anti-reflux medication should be considered.

6. Metabolic abnormalities -

a. Assess blood gases, electrolytes, ammonia when symptoms are present.


1. Metabolism clinic referral as appropriate for primary metabolic acidosis or hyperammonemia if present.


Flaherty KR, Wald J, Idelle M, et al. Unexplained exertional limitation: Characterization of patients with a mitochondrial myopathy. Am J Respir Crit Care Med 2001;164(3):425-32.

O'Brien A, Blaivas M, Albers J, et al. A case of respiratory muscle weakness due to cytochrome c oxidase enzyme deficiency. Eur Respir J 1998;12(3):742-4.

Piper AJ, Sullivan CE. Sleep-disordered breathing in neuromuscular disease. Dekker, New York 1994:761-86.

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