MELAS syndrome

It is well established that mitochondrial function defects are not severe until the proportion of mutant mtDNA reaches a high level, which forms the basis of the concept of the threshold effect. In skeletal muscle, the level of the A3243G mutation is related to the severity of strokelike episodes, epilepsy, and dementia in patients with MELAS syndrome (C6, H14, PI). Similarly, the level of the A8344G mutation is correlated with the degree of cerebellar ataxia and myoclonus in patients with MERRF syndrome (C6). Thus, molecular genetic analysis of mtDNA mutations in muscle biopsies usually provides more definitive diagnosis of... 

A number of distinctive syndromes have been shown to be associated with specific point mutations of mtDNA (Table 1) (M15, S4, S14). Several point mutations have been reported to occur at tRNA genes in the mitochondrial genome. For example, the A8344G mutation is present in patients with MERRF syndrome (S9), whereas the A3243G mutation of mtDNA was first identified in a subgroup of patients with MELAS syndrome (G4). MERRF syndrome was the first... 

M2. Majamaa, K., Rusanen, H., Remes, A. M., Pyhtinen, J., and Hassinen, I. E., Increase of blood NAD+ and attenuation of lactacidemia during nicotinamide treatment of a patient with the MELAS syndrome. Life Sci. 58, 691-699 (1996). 

P6. Penn, A. M., Lee, J. W., Thuillier, P., Wagner, M., Maclure, K. M., Menard, M. R., Hall, L. D., and Kennaway, N. G., MELAS syndrome with mitochondrial tRNALeu(UUR) mutation Correlation of clinical state, nerve conduction, and muscle 3lp magnetic resonance spectroscopy during treatment with nicotinamide and riboflavin. Neurology 42, 2147-2152 (1992). 

Valanne L, Paetau A, Suomalainen A, Ketonen L, Pihko H (1996) Laminar cortical necrosis in MELAS syndrome MR and neuropathological observations. Neuropediatrics 27 154-160... 

MELAS syndrome (mitochondrial encephalopathy lactic acidosis with stroke-like episodes)... 

Driscoll, P.F., Larsen, P.D. and Gruber, A.B. (1987) MELAS syndrome involving a mother and two children. Arch. Neurol. 44 971-973. 

The clinical symptoms of mitochondrial diseases are highly varied and include seizures, vomiting, deafness, dementia, stroke-like episodes, and short stature. Although there are many types of mitochondrial disorders, four of the most common types are as follows Kearns-Sayre syndrome, Leber s hereditary optic atrophy, MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) and MERRE (myoclonic epilepsy with ragged red fibres). 

Some patients may experience hearing loss, which may accompany diabetes. Usually, type 2 diabetes is described in individuals with MELAS, although type 1 or insulin-dependent diabetes also may be observed. Palpitations and shortness of breath may be present in some patients with MELAS secondary to cardiac conduction abnormalities such as Wolff-Parkinson-White syndrome. Acute onset of gastrointestinal manifestations (e.g., acute onset of abdominal pain) may reflect pancreatitis, ischemic colitis, and intestinal obstruction. Numbness, tingling sensation, and pain in the extremities can be manifestations of peripheral neuropathy. Some patients may have the presentation of Leigh syndrome (i.e., subacute necrotizing encephalopathy). 

MELAS cases. Ragged red fibers, common to MELAS, myoclonic epilepsy with ragged red libers, Keams-Sayre, and overlap syndromes, reflect proliferation of abnormal mitochondria under the sarcolemma. However, some patients with MELAS do not develop such a proliferation of abnormal subsarcolemmal mitochondria, so a negative muscle biopsy finding, particularly early in the course of disease progression, does not preclude consideration of this syndrome. 

Medications such as P-blockers, calcium channel blockers, digoxin, and amiodarone can be used to control cardiac conduction abnormalities (arrhythmias), and a pacemaker may be inserted to combat heart failure. The general supportive care measures used in acute stroke syndromes also should be followed. Death in patients with MELAS is usually the result of cardiac failure, pulmonary embolus, or renal failure. 

Patients with mitochondrial disorders may present at any age and show variation in both the severity and kind of symptoms associated with a single genetic abnormality. For example, the tRNA mutation is predominantly associated with the neurological syndrome MELAS but may also be manifested as CPEO, myopathy, diabetes, and deafness. 

Gartaganis SP, Georgakopoulos CD, Exarchou AM, Mela EK, Lamari F, Karamanos NK. Increased aqueous humor basic fibroblast growth factor and hyaluronan levels in relation to the exfoliation syndrome and exfoliative glaucoma. Acta Ophthalmol Scand 2001 79 572-575. 

A randomized controlled trial in children with congenital lactic acidosis found that while DCA was well tolerated, it was ineffective in improving clinical outcomes. A separate trial of DCA in children with MELAS (a syndrome of inadequate mitochondrial function, leading to lactic acidosis) was halted early, as all 15 of the children receiving DCA experienced significant nerve toxicity without any evidence of benefit from the medication. A randomized controlled trial of DCA in adults with lactic acidosis found that while DCA lowered blood lactate levels, it had no clinical benefit and did not improve hemodynamics or survival. 

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