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The identification of mitochondrial diseases, and particularly MERRF, as a cause of PME69 also led to a major controversy as to the causes and usefulness of the Ramsay-Hunt syndrome (discussed in section 1.5.) MERRF is historically unique in two senses: it was the first disease in which maternal inheritance was clearly demonstrated, indicating a defect of mitochondrial DNA, and it was also the first disorder in which a molecular defect was associated with epilepsy174.
The place of mitochondrial disorders as a cause of the PME syndrome was highlighted in a review of patients from the Montreal Neurological Institute by Berkovic47. Eighty-four cases of PME in 53 sibships were studied. Thirteen patients had MERRF comprising one family with multiple affecteds and seven sporadic cases. Myoclonus was usually the first symptom. Myoclonus and ataxia were the central features in 11 cases, these patients having all previously been diagnosed as having RHS. Clinical evidence of myopathy was usually absent or mild, but was sometimes prominent. Less frequent features included optic atrophy, hearing loss, neuropathy, pes cavus, short stature, endocrine abnormalities and subcutaneous cervical lipomas.
1.6.8.2 Inheritance
The disorder is maternally inherited.
1.6.8.3 Clinical Manifestations
Onset is usually in childhood, although adult onset is not uncommon, with the mean age being 21 years (range 5-42 years)175. Myoclonus and ataxia are constant features of MERFF, and tonic-clonic seizures are usual, with other features including short stature, hearing loss, optic atrophy, neuropathy, and migraine176 177-179.
The prognosis of the disorder is variable, and mildly affected cases may not progress 174. Although dementia may occur, and significant neurological deficits such as cortical blindness are described, MERRF usually has a relatively long course and only mild behavioural and cognitive deficits 175. The disease may vary in its extent in particular families, and otherwise asymptomatic older relatives may, for example, only have hearing loss174.
It is possible that some reports of PME associated with Friedreich’s ataxia represent cases of MERRF. Prominent amongst these are the twins originally reported by Ramsay-Hunt, who had myoclonus, ataxia, absent reflexes, pes cavus and loss of sensation in the legs (see Section 1.5.1). Similarly, a report by Ziegler et al entitled Myoclonic Epilepsia Partialis Continua and Friedreich Ataxia describes a patient who had myoclonus, generalized seizures and spike and wave discharges on EEG180.
Similarly, the May-White Syndrome is a familial disorder with variable penetrance which causes PME associated with deafness and ataxia 54;181, and has been associated with a mitochondrial myopathy69.
1.6.8.4 Special Investigations
Lactate levels in serum or CSF may be elevated69, and skeletal muscle classically shows ragged-red fibers. However, the latter are not a reliable marker and are not invariably found in affected members of well-studied families174.
1.6.8.5 Pathology
Baraitser reported on a 74 year old patient with a history of myoclonus, ataxia and deafness181. The basal ganglia and brainstem were normal, apart from some gliosis of the inferior olive; there were foci of laminar necrosis in the pericallosal gyrus and loss of the pyramidal cells in Ammon’s horn. In the cerebellum, there was neuronal loss in the dentate nucleus, reduction in white matter volume and mild reduction in Purkinje cells. There was moderate pallor of the gracile tract in the spinal cord.
Skre reported on a family with myoclonic epilepsy and dementia, associated with peripheral neuropathy and external ophthalmoplegia. There was diffuse atrophy of the cerebral cortex182. There was diffuse atrophy of the cerebral cortex, with demyelination of white matter, sponginess of the thalamus and minor changes in the striatum. In the brainstem, there was degeneration of the pontine and red nuclei. The cerebellum showed loss of Purkinje cells, myelin loss in the white matter and some atrophy of the dentate nucleus. In the spinal cord, there was marked atrophy of the dorsal columns, with atrophy of anterior horn cells and Clarke’s columns. Berkovic reported findings from three cases of MERRF: the cortex was normal, but the brainstem showed diffuse gliosis, and neuronal loss in the red nucleus and inferior olive47. In the cerebellum, there was mild loss of Purkinje cells, considerable loss of neurons in the dentate nucleus and astrocytic gliosis throughout the white matter, densely around the dentate nucleus. In the spinal cord, there was pallor of the dorsal columns.
1.6.8.6 Genetics
Molecular defects include the A8344G mutation of the tRNALys gene of mitochondrial DNA 183. This mutation is also sometimes a cause of Leigh’s syndrome. Two other mutations associated with MERRF are also in the tRNALys gene (T8356C and G8363A)139. The gene symbol is MTTK (previously MERRF). Mutations associated with myoclonic seizures are also found in the tRNALeu gene, which is usually linked with mitochondrial encephalopathy, lactic acidosis and strokes184.
174. Rosing HS, Hopkins LC, Wallace DC, Epstein CM, Weidenheim K. Maternally inherited mitochondrial myopathy and myoclonic epilepsy. Ann.Neurol. 1985;17:228-37.
175. DiMauro S, Hirano M, Kaufmann P, Tanji K, Sano M, Shungu DC, Bonilla E, DeVivo DC. Clinical features and genetics of myoclonic epilepsy with ragged red fibers. Adv.Neurol 2002;89:217-29.
176. Tsairis, P., Engel, W. K., and Kark, P. Familial myoclonic epilepsy syndrome associated with skelatal muscle mitochondrial abnormalities. Neurology 23, 408. 1973.
Ref Type: Abstract
177. Fukuhara N, Tokiguchi S, Shirakawa K, Tsubaki T. Myoclonus epilepsy associated with ragged-red fibres (mitochondrial abnormalities ): disease entity or a syndrome? Light-and electron-microscopic studies of two cases and review of literature. J.Neurol.Sci. 1980;47:117-33.
178. Fitzsimons RB, Clifton-Bligh P, Wolfenden WH. Mitochondrial myopathy and lactic acidaemia with myoclonic epilepsy, ataxia and hypothalamic infertility: a variant of Ramsay-Hunt syndrome? J.Neurol.Neurosurg.Psychiatry 1981;44:79-82.
179. Sasaki H, Kuzuhara S, Kanazawa I, Nakanishi T, Ogata T. Myoclonus, cerebellar disorder, neuropathy, mitochondrial myopathy, and ACTH deficiency. Neurology 1983;33:1288-93.
180. Ziegler DK, Van Speybroech NW, Seitz EF. Myoclonic epilepsia partialis continua and Friedreich Ataxia. Archives of Neurology 1974;31:308-11.
181. Baraitser M, Gooddy W, Halliday AM, Harding AE, Rudge P, Scaravilli F. Autosomal dominant late onset cerebellar ataxia with myoclonus, peripheral neuropathy and sensorineural deafness: a clinicopathological report. J.Neurol.Neurosurg.Psychiatry 1984;47:21-5.
182. Skre, H and Loken, A. C. Myoclonus epilepsy and subacute presenile dementia in heredoataxia- A clinical, electroencephalographic and pathological study with a discussion of classification and etiology. Acta Neurol Scand 46, 18-42. 1970.
Ref Type: Journal (Full)
183. Shoffner JM, Lott MT, Lezza AM, Seibel P, Ballinger SW, Wallace DC. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell 1990;61:931-7.
184. Hosford DA, Caddick SJ, Lin FH. Generalized epilepsies: emerging insights into cellular and genetic mechanisms. [Review] [64 refs]. Current Opinion in Neurology 1997;10:115-20.