Clinical and Brain MR Imaging Features Focusing on the Brain Stem and Cerebellum in Patients with Myoclonic Epilepsy with Ragged-Red Fibers due to Mitochondrial A8344G Mutation

Abstract

SUMMARY:We report 3 patients with myoclonic epilepsy with ragged-red fibers (MERRF) diagnosed by mitochondrial A8344G mutation. Cerebellar ataxia was the first symptom in all patients. Conventional brain MR imaging showed atrophy of the superior cerebellar peduncles and the cerebellum in all patients and brain stem atrophy in 2 patients. In diffusion tensor analysis, fractional anisotropy of the superior cerebellar peduncles was mildly decreased in 1 patient. There was a discrepancy between clinical disabilities (severe) and radiologic abnormalities (mild). This discrepancy and atrophy of the superior cerebellar peduncles and the cerebellum may be important findings suggesting a diagnosis of MERRF. Myoclonic epilepsy with ragged-red fibers (MERRF) is a rare mitochondrial disorder featuring myoclonus, seizures, mental deterioration, cerebellar ataxia, hearing loss, muscular weakness, and other clinical symptoms. The A8344G or A3243G mutations of mitochondrial deoxyribonucleic acid (DNA) are the genetic causative factors.1-3 The clinical phenotype and prognosis are better for patients with the A8344G mutation than for those with the A3243G mutation.3 Mitochondrial DNA mutation is heteroplasmic, and normal DNA and mutant DNA coexist within the same individual.4 Therefore, the onset age and clinical features of MERRF vary, 5 though the onset age is usually adolescence or early adulthood. 6Neuroradiologic findings in patients with MERRF are rarely reported. Previous reports have described 1 or more brain MR imaging abnormalities, including cerebral atrophy, cerebral white matter T2 hyperintensities, striatal T2 hyperintensities, pallidal atrophy with calcification, and cerebellar atrophy. 2,3,6,7 Neuropathologic changes include degeneration of the basal ganglia (globus pallidus and substantia nigra), brain stem (pontine tegmentum, locus ceruleus, inferior olivary nucleus, and gracile and cuneate nuclei), cerebellum (dentate nucleus and cerebellar cortex), and spinal cord (posterior columns and spinocerebellar tracts).8,9 The brain stem and cerebellar degeneration might be the main feature of MERRF, but clinical and MR imaging findings focusing on brain stem and cerebellar abnormalities have not been reported. In the present study, our intent was to clarify the clinical and MR imaging features of patients with MERRF, with particular attention to the brain stem and cerebellum, by using conventional and diffusion tensor MR imaging methods. Case Reports Patient 1A 24-year-old man, who was diagnosed with MERRF with the point mutation of mitochondrial DNA A8344G, initially developed cerebellar symptoms at age 8. He also developed muscular weakness, mental deterioration, myoclonus, and ophthalmoparesis. His brain MR imaging at age 11 revealed slight enlargement of the cerebellar fissures and the fourth ventricle without obvious parenchymal signalintensity abnormalities. His symptoms gradually worsened, and at ages 22 and 24, he underwent 1.5T brain MR imaging including diffusion tensor imaging.Diffusion tensor imaging was p...

Classical MERRF phenotype associated with mitochondrial tRNALeu (m.3243A>G) mutation

“…Of note, although seizures are observed in both conditions as a sign of encephalopathy [7], our patient did not show signs of the pathognomonic stroke-like episodes. While no specific brain imaging features could be defined for MERRF, the basal ganglia lesions in our patient fit to the changes regularly described for this condition; cerebellar or brain stem changes which have been reported as well were not present in our patient [6]. This goes in line with the lack of ataxic or cerebellar symptoms in our patient, although a clear correlation of radiological and clinical expression cannot be assumed.…”

When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?

“…The presence of manifestation cerebellar ataxia is an important indicator in patients with MERRF, although it may not be present in the early phase of the disease 27,34 . However, clinical and radiological findings in patients with MERRF vary and may suggest spinocerebellar degeneration, especially in early phase of the disease 36 . Similarly, atrophy of the superior cerebellar peduncle and cerebellum, in addition to changes in the brain and basal ganglia, suggest MERRF, especially in patients with a dissociation between clinical manifestation with severe cerebellar symptoms and radiological manifestation with mild abnormalities 36 .…”

“…Conventional imaging studies of the brain, such as computed tomography or magnetic resonance imaging, have confirmed that the gray matter is altered early on in patients with MERRF, while changes in the white matter can be seen more often in the later stages of the disease and are never an isolated finding 37,38 . Cerebral, cerebellar and brainstem atrophy occurs as a result of progressive neuronal loss 4,36,39 . Thus, one expects to find in patients with MERRF frequent cortical atrophy, predominantly in the brain and cerebellum, and discrete changes in the inferior olivary nucleus, cerebellar dentate nucleus, red nucleus and pons of the brainstem.…”

Mitochondria, the Synapse, and Neurodegeneration

“…Patients with myoclonic epilepsy with ragged red fi bre (MERRF) syndrome, due to the m.8344A>G point mutation, show atrophic middle pons, cerebellar hemispheres, and middle and superior cerebellar peduncles [ 103 ]. Moreover, patients with the neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome exhibit generalized pontocerebellar atrophy [ 104 ].…”