Mitochondrial encephalopathy, lactic acidosis and stroke-like syndrome (MELAS): a case report, presentation, and management.

Abstract: Mitochondrial encephalopathy with lactic acidosis and stroke-like syndrome (MELAS) is a progressive neurodegenerative disorder frequently complicated by diabetes mellitus and sensory neuronal hearing loss. This syndrome tends to present initially with stroke-like symptoms. These strokes are nonvascular in nature and are linked to mitochondrial defect such as transient oxidative phosphorylation dysfunction, which in turn results in encephalopathy. The combination of lactic acidosis, multiple nonvascular strokes, encephalopathic psychosis, diabetes, and sensory neuronal hearing loss causes severe dysfunction leading to increased mental disabilities, physical disabilities, and eventually, death.

Key Words: mitochondria, encephalopathy, nonvascular, strokes, lactic acidosis

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Mitochondrial diseases are difficult to diagnose and treat. Mitochondrial inborn error syndromes are rare, inheritable disease states associated with many complications, adding to the complexity of diagnosis and management. We report on a patient in her 30s with mitochondrial encephalopathy with lactic acidosis and stroke-like syndrome (MELAS) presenting with mental disability, recurrent strokes, and diabetes.

Case Report

A 33-year-old white female presented with her third "cerebrovascular" accident within a 2-year period. Several MRIs and CT scans illustrated calcifications in the basal ganglia as well as infarcts in the cerebellum, left cerebellar hemisphere, and left parietal regions not consistent with any vascular distribution. Repeated cerebrovascular disease workups were negative. These included neurology consultations, several carotid ultrasounds showing no stenosis, a 2-D echo with no significant abnormalities, negative venous Doppler studies for deep vein thrombosis, and negative laboratory studies for hypercoaguable states. Lactic acid levels were consistently high at the initial presentation. Lab studies over the course of several admissions revealed a gammaglutamyl transferase ranging from 151 U/L to 322 U/L, alkaline phosphatase >130 U/L, and a creatine kinase ranging from 236 U/L to 2,342 U/L.

The patient was a full-term infant born via normal spontaneous vaginal delivery without complications. Family history was significant for leukemia and a premature sibling, but no mental retardation or consanguinity. Developmental milestones were reached at the appropriate ages until the first-grade level, when the patient had noticeable difficulty with schoolwork. She was diagnosed as a slow learner and placed in special education classes. She earned a high school degree and then successfully completed a vocational degree. At age 20, the patient was diagnosed with mild mental retardation. She nevertheless worked as a filing clerk for over 9 years. At age 30, she was diagnosed with diabetes mellitus and placed on insulin.

Between ages 33 and 36, the patient developed behavioral changes, refused to eat, and began injuring herself. A psychiatric evaluation was conducted and the patient was initially diagnosed with organic brain syndrome secondary to multiple strokes. By age 37, she had an abnormal EEG showing an area of focal epileptic activity. When she was 37 years old, during her admission, muscle biopsy and DNA samples were sent to a genetics lab. The muscle biopsy showed a mutation at site 3,243, confirming MELAS syndrome. DNA analysis showed a mutation in fragments 79 and 24 base pairs indicating some sort of inheritance pattern. Mitochondrial DNA analysis showed mutation in fragments 97 and 72 base pairs, confirming a maternal mitochondrial inheritance pattern.

Several years after the confirmed diagnosis of MELAS syndrome, the patient became profoundly mentally retarded and began having seizures with multiple strokes. She developed a right hemiplegia, syndrome of inappropriate antidiuretic hormone, cardiomyopathy, and numerous recurrent infections. She became malnourished despite attempts at tube feedings. She developed respiratory distress due to several infections and metabolic acidosis, and passed away four months before her 40th birthday.

Discussion

The prevalence of the MELAS mutation A3243 in the adult population is 16.3/100,000 and is the most frequent mutation in a diagnostic category of neurodegenerative diseases. There is no sex or racial difference in incidences of the disease. (1) MELAS usually presents with stroke between the ages of 4 to 15 years and up to age 40 in some patients. However, one case of MELAS has been reported in an infant at 4 months of age. (2)

In the pediatric population, it usually presents with delayed developmental milestones and learning disabilities. Patients also often present with short stature and poor nutrition. There are sensory disturbances, such as cortical blindness, ophthalmoplegia, ptosis, and sensorineural hearing loss. Cardiac manifestations include congestive cardiomyopathy and irregular heartbeat. The main neuromuscular manifestations are convulsions, numbness, hemiplegia, aphasia, and muscular weakness. Purpura, hirsutism, scaly pruritic diffuse erythema, and reticular pigmentation are some of the cutaneous manifestations. (3)

In adults, MELAS usually presents with unexplained strokes and new onset seizures. (1) Laboratory findings show lactic acidosis and increased creatine kinase levels. CT or MRI shows lucency consistent with nonvascular infarction, cerebral atrophy, and basal ganglia calcifications, while PET scans show decreased cerebral metabolic rate for oxygen with increased cerebral blood flow in the cortical regions. EEG shows epileptiform spike discharges. DNA analysis is significant for 80% mutation at position 3,243 and 8% mutation at position 3,271 in the mitochondrial DNA. The most common mutation occurs in the transfer RNA for leucine. (4)

The pathophysiology of this syndrome is the result of microdeletion or point mutation in the mitochondrial DNA at site 3,243. Mitochondrial DNA is inherited from the maternal ovum and is more prone to mutations. The syndrome of myopathy, encephalopathy, lactic acidosis, and stroke-like episodes is most likely associated with an A to G transition mutation at site 3,243. (5) This mutation causes a defect in the translation of the respiratory chain enzymes. The reduction in oxidative activity results in decreased aerobic respiration causing nonvascular infarcts within the brain parenchyma and lactic acidosis. (6)

Morbidity and mortality rates are very high. Prognosis is poor because encephalopathy tends to be severe and progresses quickly to dementia, leading to a state of cachexia. Death results rapidly secondary to cardiac failure, pulmonary embolism, or renal failure. (2)

Complications include failure to thrive and short stature, progressive intellectual deterioration, depression, schizophrenia, or bipolar disorder. Many patients have sensorineural hearing loss, endocrine dysfunction with diabetes mellitus, hypogonadism, and hypoparathyroidism. They may also have congestive heart failure with cardiomyopathy, which can progress to conduction defects causing sudden cardiac death. (4) Visual difficulties resulting from retinal pigmentary degeneration and progressive cortical atrophy causing cortical blindness are additional problems occurring in these patients. Many develop gastrointestinal dysfunction secondary to intestinal pseudo-obstruction and pancreatitis. Renal problems, such as acute renal failure resulting from rhabdomyolysis and end-stage renal failure resulting from focal segmental glomerulosclerosis, further increase morbidity. (7) Valproic acid, through an unknown mechanism, seems to exacerbate seizure-like activity and precipitate stroke-like episodes. (8) Anticonvulsants such as phenytoin, clonazepam, and zonisamide are partially effective, but case studies show that pure succinate works best in controlling and preventing seizures. (9)

Management consists solely of supportive care. Several case reports indicate that coenzyme Q10 has shown some benefit. It is theorized that it increases production of adenosine triphosphate (ATP) in the inner mitochondrial membrane. (1) However, clinical trials studying the use of coenzyme Q10 in this disorder are still in progress. Reviews of case studies reveal that IV and oral preparations of dichloroacetate used during acute stroke and prophylaxis of stroke have a decreased number and severity of strokes in patients with MELAS syndrome. (10) It seems to decrease both serum lactate and cerebrospinal fluid lactate levels. Clinical trials of IV cardiochrome, which consists of cytochrome C, vitamin [B.sub.1], and vitamin [B.sub.2], have been shown to decrease stroke-like episodes by increasing the effectiveness of the electron transport chain of the inner mitochondrial membrane. (11)

Diets rich in antioxidants, vitamins [B.sub.1] and [B.sub.2], L-arginine, uridine, coenzyme Q10, idebenone, and triglycerides have been shown to provide alternate energy sources. Thiamine has been shown in most case reports to decrease lactic acid levels. (12) There have been developments in the prenatal diagnosis of MELAS syndrome in families who may have a disposition to carry the mutation. One article reported detection of the mutation A3243G in amniotic fluid during prenatal care. (13) Risk assessment for siblings and other family members have not been clarified.

Conclusion

MELAS syndrome is a complicated disease process which ultimately results in premature death. Mitochondrial diseases, as a whole, are difficult to diagnose due to the unavailability of appropriate mitochondrial DNA testing. There is presently no cure and no prospect for a cure in the short term, but recognition of the syndrome is increasing. Well-established supportive services, such as ones established for cystic fibrosis and Down syndrome for example, have not been organized. Therefore, the burden of care falls upon family and friends. All of the above factors need to be taken into consideration when caring for a patient diagnosed with MELAS syndrome. (9) When evaluating patients with cerebral infarcts not consistent with vascular distribution, our differential should include other causes of strokes including MELAS, MERRF (mitochondrial encephalopathy ragged red fiber syndrome), Leigh syndrome, and other mitochondrial inborn error syndromes. (14)

Acknowledgments

We would like to thank Mrs. Patricia Giangrosso for her help in editing and proofreading this manuscript for us.

References

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3. Textbook of Pediatrics. 16th ed. Philadelphia: WB Saunders, 2000:416, 1845-1848.

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5. Lam CW, Lau CH, Williams JC, et al. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) triggered by valproate therapy. Eur J Pediatr 1997;156:562-564.

6. Oguro H, lijima K, Takahashi K, et al. Successful treatment with succinate in a patient with MELAS. Intern Med 2004;43:427-431.

7. Singh B, Low PS, Yeo JF. MELAS: a case report. Ann Acad Med Singapore 2004;33 (Suppl):69S-71S.

8. Haslem RHA. Mitochondrial encephalomyopathies. In: Behrman RE, Kliegman R, Jenson HB, eds. Nelson.

9. Hirano M, Pavlakis SG. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): current concepts. J Child Neurol 1994;9:4-13.

10. Berbel-Garcia A, et al. Coenzyme Q 10 improves lactic acidosis, strokelike episodes, and epilepsy in a patient with MELAS. Clin Neuropharmacol 2004;27:187-191.

11. Flierl A, Reichmann H, Seibel P. Pathophysiology of the MELAS 3243 transition mutation. J Biol Chem 1997;272:27189-27196.

12. Mahoney DJ, Parise G, Tarnopolsky MA. Nutritional and exercise based therapies in the treatment of mitochondrial disease. Curr Opin Clin Nutr Metab Care 2002;5:619-629.

13. Chou YJ, Ou CY, Hsu TY, et al. Prenatal diagnosis of a fetus harboring an intermediate load of the A3243G mutation in a maternal carrier diagnosed with MELAS syndrome. Prenat Diagn 2004;24:367-370.

14. Pavlakis SG, Phillips PC, DiMauro S, et al. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol 1984;16:481-488.

Ilaben Bhagubhai Patel, MD, Mohamad Sidani, MD, MS, and Roger Zoorob, MD, MPH

From the Department of Family and Community Medicine, Meharry Medical College, Nashville, TN.

Reprint requests to Ilaben Bhagubhai Patel, MD, Meharry/Vanderbilt Assistant Professor, Meharry Medical College, Department of Family and Community Medicine, 1005 Dr. D. B. Todd Jr. Boulevard, Nashville, TN 37208. Email: [e-mail]

Accepted April 4, 2006.

RELATED ARTICLE: Key Points

* Mitochondrial encephalopathy with stroke-like syndrome (MELAS) is a progressive neurodegenerative disorder.

* MELAS strokes are nonvascular in nature.

* MELAS is an inheritable mitochondrial disease with mutation at A3243.

* MELAS is frequently complicated by diabetes and sensory neuronal hearing loss.