MELAS Syndrome Clinical Presentation

Onset of the disorder may be myopathic with weakness, easy fatigability, and exercise intolerance.

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome onset may occur early in infancy with a history of developmental delay and learning disabilities. Developmental delay, learning disability, or attention deficit disorder is primarily found in patients prior to the development of the first stroke. An encephalopathic picture that is progressive and leads to dementia may be present. Patients may be apathetic. The level of cognitive functioning worsens over time by Karnofsky score in fully symptomatic patients.

Failure to thrive may be the presenting feature in some patients with MELAS syndrome.

Strokelike episodes are the hallmark feature of this disorder. Initially, episodes may manifest with vomiting and headache that may last several days. These patients may also experience episodes of seizures and visual abnormalities followed by hemiplegia. Seizure types may be tonic-clonic or myoclonic.

Migraine or migrainelike headaches observed in these patients may also reflect the strokelike episodes. Pedigrees of patients with classic MELAS syndrome identify many members whose only manifestations are migraine headaches.

Patients may have visual complaints due to ophthalmoplegia, and they may experience blindness because of optic atrophy and difficulties with night vision due to pigmentary retinopathy.

Some patients may experience hearing loss, which may accompany diabetes. It may be observed in association with the classic disorder of MELAS syndrome.

Polydipsia and polyuria may be the presenting signs of diabetes; diabetes appears to be the most common manifestation of MELAS syndrome. Usually, type 2 diabetes is described in individuals with MELAS syndrome, although type 1 (formerly termed insulin-dependent diabetes) may also be observed. Guidelines for diagnosis and management of type 2 diabetes have been established.^[5]

Palpitations and shortness of breath may be present in some patients with MELAS syndrome secondary to cardiac conduction abnormalities, such as Wolff-Parkinson-White syndrome. Patients may experience shortness of breath secondary to cardiomyopathy, which is usually of the hypertrophic type; however, dilated cardiomyopathy has also been described.

Acute onset of GI manifestations (eg, 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.

Psychiatric disorders (eg, depression, bipolar disorder) have been associated with the m.3243 A → G mutation. Dementia has been another clinical manifestation. Moreover, autism spectrum disorders (ASD) have been associated with the 3243 A → G mutation.

Patients may develop features of hypothyroidism and hyperthyroidism

Some patients may develop apnea and an ataxic gait in association with neuroradiologic features of MELAS syndrome.

Oliguria can be associated with MELAS syndrome and may indicate the onset of nephrotic syndrome.

Patients with MELAS syndrome may have functional vascular involvement. Aortic root dissection has been reported in one patient with MELAS syndrome.

Patients with MELAS syndrome may exhibit hypertension.

Myopathy presents with hypotonia and weakness. Proximal muscles tend to be more involved than distal muscles. Musculature is thin, and patients may present with a myopathic face.

Strokelike episodes may present with convulsions, visual abnormalities, numbness, hemiplegia, and aphasia. Episodes may be followed by transient hemiplegia or hemianopia, which lasts a few hours to several weeks. Additional features on neurologic examination may include ataxia, tremor, myoclonus, dystonia, visual disturbances, and cortical blindness. Some patients may present with ophthalmoplegia and ptosis.

On ophthalmologic examination, patients have presented with pigmentary retinopathy.

Sensorineural deafness has been reported as part of the disorder in approximately 25% of patients with MELAS syndrome.

Cardiomyopathy with signs of congestive heart failure (CHF) may also be observed upon physical examination.^[6]

Skin manifestations of cutaneous purpura, hirsutism, and a scaly, pruritic, diffuse erythema with reticular pigmentation may be observed in patients with MELAS syndrome.

Short stature may be the first manifestation of MELAS syndrome in many patients.

MELAS syndrome has been associated with at least 6 different point mutations, 4 of which are located in the same gene, the tRNA^{Leu (UUR)}gene. The most common mutation, found in 80% of individuals with MELAS syndrome, is an A → G transition at nucleotide (nt) 3243 in the tRNA^{Leu (UUR)}gene. An additional 7.5% have a heteroplasmic T → C point mutation at bp 3271 in the terminal nucleotide pair of the anticodon stem of the tRNA^{Leu (UUR)}gene. Moreover, a MELAS phenotype has been observed associated with an m.13513G → A mutation in the ND5 gene and in POLG deficiency.

These mutations are heteroplasmic, which reflects the different percentages of mutated mtDNA present in different tissues. Variable heteroplasmy among individuals affected with MELAS syndrome reflects variable segregation in the ovum. Mutations in tRNA^Lysmay be expected to have an important effect on translation and protein synthesis in mitochondria. The MELAS disorder–associated human mitochondrial tRNA^{Leu (UUR)}mutation causes aminoacylation deficiency and a concomitant defect in translation initiation.

Abnormal calcium homeostasis resulting in neuronal injury has been suggested as another mechanism contributing to the CNS involvement observed in MELAS syndrome.

Patients with MELAS syndrome have been found to have a marked decrease in the activity of complex I. The major effects observed secondary to nt 3243 and nt 3271 mutations have been a reduction in protein synthesis and the activity of complex I. These effects have been demonstrated through studying cybrids in which human cell lines without mtDNA are fused with exogenous mitochondria containing 0-100% of the common m.3243 mutation. Cybrids with more than 95% of mutant DNA had decreased rates of synthesis of mitochondrial proteins, leading to respiratory chain defects.