MELAS Syndrome

MELAS is an acronym for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke. It is a progressive neurodegenerative disorder. Other clinical features include diabetes mellitus, deafness, episodic vomiting, seizures, and cortical blindness.

In the US adult population, the frequency is approximately 16.3:100,000. Internationally, the prevalence is approximately 10.2:100,000 in the Finnish population. Affects males and females between the ages of 4 and 15 years.

Mitochondrial; the incidence of affected children is dependent upon maternal mutant load. It is a large heterogeneic syndrome with possible mutation of many genes such as MTTL1, MTND6, and MTTQs.

Multiple organ systems involved are the central nervous system, skeletal muscle, eye, cardiac muscle, and, more rarely, the gastrointestinal system. Approximately 80% of patients with the clinical characteristics of MELAS have a heteroplasmic A-to-G point mutation in the dihydrouridine loop of the tRNALeu (UUR) gene at base pair 3243 (i.e., A3243G mutation). Mitochondrial angiopathy of a small vessel is responsible for contrast enhancement of affected regions and mitochondrial abnormalities of endothelial cells and smooth muscle cells of blood vessels. The multisystem dysfunction may be a result of both parenchymal and vascular oxidative phosphorylation defects. The effect of potent vasodilators (e.g., nitric oxide) may be offset by increased production of free radicals in association with an oxidative phosphorylation defect leading to vasoconstriction. Defect of the respiratory chain enzymes, mainly the reduced form of nicotinamide adenine dinucleotide (NADH)-cytochrome c reductase (complex I).

Usually based on clinical criteria; lactate levels are elevated at rest and increase further with minimal exercise. Demonstration of ragged-red fibers on muscle biopsy. Electronic microscopy may show abnormal mitochondria and mitochondrial DNA (mtDNA) testing (80% have a mutation at base 3243 and 10% at base 3271). The stroke-like episodes usually are associated with infarcts exhibited on head CT scan or MRI. These infarcts have been hypothesized to be nonvascular and caused by transient oxidative phosphorylation dysfunction within the brain parenchyma.

These children have normal early development. Onset is most often during the second decade but can be seen as early as age 4 years. The severity and form of presentation vary considerably and depend on maternal mutant mitochondrial load. The main features include subsequently poor growth and fatigability with muscle weakness. There is progressive episodic vomiting, seizures, and recurrent cerebral insults mimicking strokes and causing hemiparesis, hemianopsia, or cortical blindness. The most frequent symptom is episodic sudden headaches with vomiting and convulsions. Myopathy is associated with lactic acidosis in blood and cerebrospinal fluid. Most of the allelic variants are described with atrioventricular block, Wolff-Parkinson-White syndrome, or cardiomyopathy. Multihormonal hypopituitarism may be present. Alterations of the skin (purpura and hirsutism) occur in 45% of cases. The clinical diagnosis is based on five cardinal manifestations: clinical stroke, seizures, lactic acidosis, ragged-red fibers, and exercise intolerance.

The diagnosis of mitochondrial disease should be considered in any child with a multisystem neurologic disorder or who is being investigated for hypotonia. Anesthesia-related morbidity and mortality risk is essentially linked to the preoperative status of the child, that is, the number and extent of organ dysfunction. A preoperative electrocardiogram should be considered at any age. The elevated serum lactate resulting from defects in the respiratory chain necessitate maintenance of a normal glucose level, normothermia, normocapnia, and more stable possible cardiovascular function. Allelic variants are diabetic, so serum glucose must be closely measured. Avoid any elective anesthesia/ surgery in the presence of infection or raised temperature because cytokines (mainly tumor-necrosis factor) inhibit some complex of the respiratory chain. The following should be checked: central nervous system (seizures, myoclonus, strokes, swallowing problems); metabolic (usual venous or arterial concentration of lactates and glucose); muscles (hypotonia, contractures, scoliosis); cardiac (even if the child is asymptomatic, ECG and echocardiography to exclude conduction disorders and cardiomyopathy, respectively; check functioning of pacemaker, if present); pulmonary (frequent infections, chronic aspiration, pulse oximetry breathing room air, obstructive and/or central apnea; reduced ventilatory drive is common and many patients have an abnormal response to both hypoxia and hypercarbia, and deaths have been reported following sedation with chloral hydrate or diazepam); hepatic and renal function; and nutritional status and diet (glucose and/or lipid-rich, tolerance to fasting and treatment [carnitine, vitamin Q, antiepileptic drugs]).

Usual treatment up to the day of surgery. Preoperative fasting as short as possible; if fasting is usually poorly tolerated, a glucose-containing solution should be started when the fasting period starts. A sedative premedication is best avoided because of the possible abnormal response to hypoxia/ hypercarbia. Induction: No contraindication to choice of anesthetic; however, the dosage of sedative agents might require reduction; sevoflurane is the best choice for inhalation induction; propofol seems the best choice for IV induction, but a 2% solution should be used to lessen the lipid load. Opiates: Dose should be carefully titrated according to the patient's needs. Muscle Relaxant: Published data are contradictory. Even in the absence of clinical myopathy, the patient's muscular response to nerve stimulation should be measured before administering a muscle relaxant. Atracurium and cis-atracurium are the best choices because of their spontaneous degradation. In case of myopathy, succinylcholine should not be used to avoid producing rhabdomyolysis. Intraoperative Fluids: Avoid infusion containing lactates, such as lactated Ringer or Hartmann solution, but the patient should receive a glucose solution (5 or 10% according to blood sugar level). Aim for normoglycemia because hyperglycemia can increase lactate production. Monitor (arterial or venous) blood gases and lactates level. In case of severe lactic acidosis, use dichloroacetate 50 mg/kg IV over 30 minutes to stimulate pyruvate dehydrogenase to metabolize lactate in pyruvate. Perimedullar locoregional anesthesia can be used, but its cost-to-benefit ratio should be evaluated, taking into account the presence of severe scoliosis or degenerative lesions in the spinal cord. Some patients with mitochondrial disease also present with axonal neuropathy of peripheral nerves; the possible effects of local anesthetics on these nerves are unknown. Prevention of hypothermia is important to avoid shivering and increased oxygen consumption upon awakening.

Patients with mitochondrial disease are very sensitive to the respiratory effects of sedatives. It also seems, according to the Bispectral index (BIS) measurement, that children with an anomaly of complex I of the respiratory chain are much more sensitive to the hypnotic effects of sevoflurane. Most studies performed on isolated mitochondria use doses of anesthetic agents far in excess of those used in daily practice; thus their clinical relevance is often dubious. The sensitivity to neuromuscular blocking agents is controversial. It would be advisable to avoid succinylcholine and to carefully monitor short-duration drugs.

Kearns-Sayre Syndrome: Mitochondrial encephalomyopathy characterized by progressive external ophthalmoplegia, atypical retinitis pigmentosa, and cardiomyopathy.

MERRF Syndrome: Mitochondrial cytopathy that stands for myoclonus epilepsy associated with Ragged-Red fibers. It is characterized by severe myoclonic seizures that are usually brief, sudden, and defined as jerking spasms that affect the limbs and/or the entire body. Severe lactate acidosis is often present. Dysarthria, ataxia, short stature, hearing loss, and dementia are also features.

Leber Hereditary Optic Neuropathy: Rare hereditary form of optic atrophy that usually affects young males. Characterized by sudden bilateral cloudiness of vision, followed by scotoma, rapid deterioration of central vision, and occasional color vision disorders. Associated with atrophy of the optic nerve fibers and the retinae. Considered a mitochondrial disease.

Alström Syndrome: Inherited syndrome with diabetes mellitus, cardiac, hepatic and renal involvement, and progressive visual and hearing loss.