Symptomatic Localization-Related Epilepsy associated with a mitochondrial disorder, MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes).
This patient presented with a history of infrequent focal seizures and was initially evaluated at an outside hospital with work-ups only significant for a right occipital lesion of unclear significance. The patient then enjoyed seizure freedom as well as absence of obvious neurological deficits over the next three years. His seizures subsequently remerged and were associated with persistent hearing and speech difficulties. He also displayed sustained memory and coordination deficits after one of his seizure episodes. Repeat MRI brain showed a large acute-to-subacute lesion over the right parietal-occipital-temporal region that was suspicious for focal encephalitis vs. inflammatory process vs. ischemia (though not following any vascular territory). Extensive work-ups including serum and CSF studies with eventual brain biopsy were only significantly for an elevated CSF lactate. He was placed back on anti-epileptics for which his seizures demonstrated improved control. However, an etiology was still elusive. Given the patient's age, MRI findings and a high CSF lactate, an underlying metabolic versus mitochondrial abnormality was high within the differential diagnosis. His DNA analysis was positive for MELAS A3243G mitochondrial tRNA mutation.
The differential diagnosis for MELAS and mitochondrial disorders is broad, and several key alternative diagnoses should include:
MELAS was first described in 1984 as a syndrome characterized by mitochondrial encephalopathy, lactic acidosis and stroke-like episodes. It is the most common genetic mitochondrial disorder of maternal inheritance. As is known of the mitochondria, its genetic make-up codes for processes primarily related to oxidative-phosphorylation that allow for efficient energy production to the cells in the human body.[1] Since the initial description of pathogenic mitochondrial mutations, many mutations have since been described in the literature (a continuously updated number may be viewed at www.mitomap.org). The most common point mutation (responsible for ~80% of cases) in MELAS is the adenine-to-guanine point mutation at base pair 3243 of the mitochondrial tRNA gene.[2]
The pathogenesis of mitochondrial disorders derives from the inability of the mitochondria to provide the energy needs of the cell. Consequently, the cell shunts pyruvate to lactate away from the oxidative-phosphorylation pathway and manifests systemically as lactic acidosis. Consequently, mitochondrial disorders frequently present with involvement of multiple organ systems, particularly organ systems with high energy needs (i.e., brain, muscle, and peripheral nerves).[1] The exact mechanisms through which specific phenotypes of MELAS are derived remain uncertain, especially considering the varying phenotypes that can be seen in patients with the same genetic mutation.
When mutated mitochondria enter the female germ cell line, random migration of mitochondria during cell division within the developing embryo can lead to varying concentrations of normal and mutant mitochondrial DNA (i.e., heteroplasmy). Over time, these differences can evolve to varying extent between tissues/organs of the same patient, leading to the multiple phenotypes seen in mitochondrial diseases—including between siblings with the same genetic mutation. Symptoms of mitochondrial disorders frequently do not appear until adulthood because many cell divisions and necessary amount of time are required for a cell to receive enough mitochondria containing the mutant alleles to cause symptoms.
The hallmark signs of MELAS include stroke-like episodes before the age of 40, encephalopathy characterized by seizures, cognitive impairments, and lactic acidosis in serum or CSF. Ragged-red fibers on muscle biopsy may or may not be present. Stroke-like episodes is used as a term to describe the non-vascular origin of symptoms. These lesions do not tend to demonstrate the typical cerebrovascular distribution, and preferentially involves the cerebral cortex with relative sparing of the subcortical white matter. Henceforth, the most common clinical deficits include aphasia, hemianopsia, and cortical blindness. These deficits from each discreet attack can eventually show either complete or partial recovery of the prior function. Over the long term, however, patients can progressively deteriorate from the accumulation of less-reversible neurological deficits and radiographic lesions. Other common neurologic features of MELAS include sensori-neural hearing loss, migraine headaches, peripheral neuropathy, depression, learning disabilities, and diabetes. Another manifestation seen in families includes short stature possibly related growth hormone deficiency or a chronically energy-starved state. Cardiomyopathy and conductions deficits with Wolff-Parkinson-White syndrome and conduction block can be seen. Myopathy with exercise intolerance is commonly seen as well. Renal diseases with glomerular and nephritic syndromes have also been reported. Gastrointestinal effects seen include pseudo-obstruction from constipation/diarrhea, gastric dysmotility, and cyclic vomiting.
Diagnostic evaluation for MELAS initially involves laboratory testing for lactic acidosis which is a nonspecific finding for any metabolic derangement and is seen commonly in other mitochondrial disorders. However, the demonstration of increased lactic acid in the CSF will further narrow the clinical suspicion towards a MELAS diagnosis. Brain MRI upon presentation of stroke-like episodes tends to show diffusion-restriction similar to ischemic lesions, but of a nonvascular distribution that primarily affects the cortex and sparing the deep cortical white matter.[3] These lesions tend to be asymmetric and primarily involve the parietal and occipital lobes. Angiographic imaging will demonstrate normal cerebral vasculatures. Over time, it is also not unusual to observe fluctuations of lesion burden upon serial brain imaging. Magnetic resonance spectroscopy (MRS) can also be used which would show a lactate peak that can be both a sensitive marker as well as a confirmatory test for elevated CSF lactate. Furthermore, the N-acetylaspartate/creatine would be decreased in the stroke-like regions on MRS. Muscle biopsy of MELAS characteristically shows ragged red fibers, but can also be seen in other mitochondrial disorders. Vacuolated with basophilic inclusions that are reflective of mitochondrial proliferation can also be present. Molecular testing for mitochondrial mutations using various PCR techniques can be performed on serum leukocytes, muscle biopsy, urine sediment, cheek mucosa, and skin fibroblasts.
There is presently no curative treatment to mitochondrial diseases. Treatment is centered on symptomatic management aimed toward any of the varied manifestations described above. Supplementation designed to treat the disordered oxidative-phosphorylation pathway includes creatine, coenzyme Q10, L-carnitine, and α-lipoid acid.[4] Anecdotal studies with L-arginine have shown improvement in stroke-like episodes both acutely and possibly overtime.[5] Further studies are ongoing and advances in genomics and proteomics have the potential to yield more effective treatments.
Discussion regarding transmission of this disease to future generations is an important topic which frequently concerns patients who have been diagnosed with MELAS. Therefore, genetic counseling is indicated, particularly since mitochondrial DNA originates from the maternal oocyte and is exclusively transmitted from the mother to any of her offspring. Accordingly, males diagnosed with MELAS should be reassured that their progeny have no chance of acquiring this disease from them. On the other hand, females diagnosed with MELAS should be counseled regarding the chance of transmitting this condition to the next generation. In such situations, adoption rather than conceiving progeny can guard against recurrence of this disease. Alternatively, recent advances in techniques of in vitro fertilization allow the harvesting of core genetic information from mother and father, which can then be placed into a donor egg that contains healthy mitochondria (i.e., Three-Person IVF). Ethical dilemmas regarding creating children with three genetic parents are being actively debated.[6]
The patient's recent clinical course was protracted, requiring multiple hospital admissions related to aspiration pneumonia and status epilepticus. After optimization of levetiracetam and phenytoin, his seizures became well controlled. Unfortunately, despite being seizure free, his condition has slowly deteriorated. He now has minimal communicative skills due to severe cognitive and language impairment. Compounding his communication difficulties are his severe hearing loss and marked mood lability. Furthermore, due to his progressive appetite loss and severe malnutrition, a PEG tube became necessary to facilitate supplementation of his caloric intake.
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