MELAS Syndrome Follow-up

Admit for metabolic decompensation or signs of diabetic ketoacidosis. Diabetes appears to be the most common manifestation of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome. Admit for medical management of strokelike episodes and seizures. Admit for signs of cardiac arrhythmia (Wolff-Parkinson-White syndrome), hypertension, impending aortic root dissection, or congestive heart failure (CHF) associated with hypertrophic or dilated cardiomyopathy. Admit for signs of nephrotic syndrome that may present in association with focal segmental glomerulosclerosis. Admit if a sign of acute abdomen is present; acute abdomen may be an indication of pancreatitis.

Carefully monitor the progress of the encephalomyopathy and sequelae. Neurodevelopmental testing is appropriate because progressive intellectual deterioration follows strokelike episodes of MELAS syndrome. Neuropsychological evaluation is appropriate for presence of autism spectrum disorder (ASD).

Monitor growth curves because mitochondrial disorders such as MELAS syndrome are associated with short stature or failure to thrive.

Refer the patient to an ophthalmologist to monitor for pigmentary degeneration of the retina, which may be similar to that observed in patients with neuropathy, ataxia, and retinitis pigmentosa syndrome. Closely monitor signs (eg, ophthalmoplegia, ptosis).

Carefully monitor individuals with MELAS syndrome for hearing loss with a hearing evaluation, including distortion product otoacoustic emissions and auditory brainstem evoked responses. Carefully monitor patients for cardiomyopathy and measure Z-score for aortic root diameter with echocardiography. Request an ECG as a baseline study to monitor for conduction defects, even if patients are asymptomatic. Carefully monitor patients for type 2 diabetes, hypothyroidism, hyperthyroidism, and parathyroid dysfunction. Carefully monitor patients for the persistence of lactic acidosis.

Positron magnetic resonance spectroscopy (¹ H-MRS) of the brain may be used to monitor potential therapeutic efficacy if increased permeability of the blood-brain barrier is a concern.

Medications include the following:

• Compounds that may increase ATP production or transfer of electrons (eg, ascorbate, riboflavin, CoQ10, vitamins K-1 and K-3, nicotinamide, creatine monohydrate)
• Compounds that can be used to prevent a possible secondary carnitine deficiency or secondary dysfunction of fatty acid oxidation (eg, carnitine)
• Compounds that can be used to prevent or ameliorate the progression of strokelike episodes (eg, L-arginine): L-arginine could modulate mitochondrial energy metabolism by inhibiting glutamate uptake into mitochondria and decreasing neurotoxicity associated with nitric oxide-mediated mitochondrial dysfunction.
• Compounds that may be used to treat lactic acidosis (eg, dichloroacetate)

  • Dichloroacetate stimulates pyruvate dehydrogenase function by inhibiting pyruvate dehydrogenase kinase, the enzyme that normally phosphorylates and inactivates pyruvate dehydrogenase. Therefore, in conditions that result in the accumulation of lactate and alanine, activation of pyruvate dehydrogenase decreases the release of these compounds from peripheral tissues and enhances their oxidative metabolism by the liver.
  • This medication has been used to treat lactic acidosis in adult and pediatric patients. Anecdotal reports detail successful treatment in patients with MELAS syndrome. Dichloroacetate has been administered orally at doses of 12.5-100 mg/kg/d. This medication is available only under research protocols in the United States.

If seizures have developed as part of the condition, do not use valproic acid as an anticonvulsant, since incidents of pancreatitis following valproate administration have occurred and valproic acid has been associated with mitochondrial toxicity.

Use phenobarbital with caution, because the drug has demonstrated inhibition of the respiratory chain in vitro.

Transfer to a tertiary care center may be required to better coordinate the diagnostic evaluation to include the following:

• Muscle biopsy
• Evaluation for mitochondrial enzyme defects
• Analysis of mtDNA mutation

If diagnosis is already known and the patient has been stabilized, transfer may be required for better management of complications such as the following:

• Pancreatitis
• Cardiac arrhythmias
• Cardiomyopathy
• Ketoacidosis
• Strokelike episodes

If conditions such as cardiomyopathy are present, restrict exercise. Although the long-term effects of dietary manipulations are unknown, ensure good nutritional status, good hydration, and avoidance of fasting as part of a supportive plan. A mild degree of aerobic activity may lead to an improvement of aerobic capacity. Restrict strenuous exercise because of the possible complication of rhabdomyolysis.

Information on the therapeutic efficacy of reported compounds used as nutritional supplements are limited; however, most do not have any serious adverse effects. Nutritional supplements may help to prevent further deterioration in some individuals; however, further research is warranted.

Complications include the following:

• Failure to thrive and short stature
• Progressive intellectual deterioration and decline that eventually may lead to dementia
• Psychosis with depression, schizophrenia, or bipolar disorder
• Autism spectrum disorders (ASDs)
• Sensorineural hearing loss
• Endocrine dysfunction with hypogonadism, diabetes, hypoparathyroidism, hypothyroidism, and hyperthyroidism
• CHF from cardiomyopathy and sudden death from conduction defects
• Visual difficulties related to pigmentary degeneration of the retina or cortical blindness as one of the sequelae of progressive cortical atrophy and strokelike episodes
• End-stage renal failure as a complication of focal segmental glomerulosclerosis
• Acute renal failure secondary to rhabdomyolysis
• GI dysfunction secondary to intestinal pseudoobstruction or pancreatitis
• Aortic root dissection (reported in one kindred; requires further studies to evaluate the prevalence)

MELAS syndrome widely varies in presentation; however, patients in general tend to have a poor prognosis and outcome. The encephalomyopathy tends to be severe and progressive to dementia. The patient with MELAS syndrome may end up in a state of cachexia. Currently, no therapies have proven efficacy.

Once the diagnosis is established, refer the patient and family for genetic counseling and evaluation of other family members who may be at risk of being affected.

Educate the family concerning further deteriorations and complications (eg, cardiomyopathy, nephrotic syndrome, deafness, diabetes, GI difficulties) that may affect the proband. In general, educate the family about maintaining a good nutritional and hydration status, and discuss information concerning current trials (eg, use of dichloroacetate for persistent lactic acidosis in individuals with MELAS syndrome).

For excellent patient education resources, visit eMedicine's Stroke Center. Also, see eMedicine's patient education article Stroke.