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Re: FAME 3: A novel form of progressive myoclonus and epilepsy

We read the paper by Carr et al describing two families with an autosomal dominant form of progressive epilepsy characterized by generalized tonic-clonic seizures, myoclonus and associated neurological features. [1] The authors included this condition within the spectrum of familial cortical tremor, myoclonus and epilepsy, a genetically heterogeneous syndrome reported worldwide with different acronyms (FAME, BAFME, FCTME). [2]

Familial cortical tremor, myoclonus and epilepsy is a homogeneous clinical condition characterized by the association of cortical tremor, myoclonus and generalized seizures with benign course. [2-4] Despite the presence of affected members with partial seizures and slight mental retardation, Autosomal Dominant Cortical Myoclonus and Epilepsy [5] shows an overlapping symptomatology and is considered within the clinical spectrum of FAME as confirmed by the allelism between these two conditions. [2]

Electrophysiologically, FAME is characterized by normal or slightly slowed EEG background activity and generalized paroxysmal abnormalities especially in untreated patients. In addition, electrophysiological studies show cortical reflex myoclonus. [2] Brain MRI is generally unremarkable and neuropathological investigations are normal or demonstrate moderate cerebellar changes. [2,5] Cortical tremor responds well to anticonvulsants with antimyoclonic activity and typically show a benign course. [2]

The phenotype described by Carr et al. [1] is more severe than FAME. Affected members from the two South African families show signs of pyramidal (hyperreflexia) and cerebellar (nystagmus, abnormal pursuit, dysarthria) dysfunction, progressive dementia as well as recurrent seizures and severe EEG abnormalities. [1]

Electrophysiological features such as giant SEPs and enhanced LLRI are also found in different progressive and nonprogressive myoclonic epilepsies and are not necessarily indicative of FAME. More importantly, some of the patients died during the third decade of life and considerable neurological disability was present in several patients. Moreover, neuroimages revealed mild to severe cerebellar atrophy and other brain structural abnormalities. Neuropathologic study of a single case showed multiple abnormalities as neuronal loss and gliosis in the cerebellum as well as in the pallidum and olives. [1]

In our opinion, the neurological disorder described by Carr et al should be more appropriately placed within the group of the progressive myoclonic epilepsies as the authors discussed in their conclusion.

According to our experience the term “FAME” should be applied to the familial non-progressive form of cortical tremor and epilepsy with a more benign course, and its use should be avoided for progressive neurological disorders.

An appropriate terminology and classification is essential for the diagnosis and clinical management of these disorders.

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Re: Reply from the Authors

We appreciate Dr Striano et al’s valuable comments. In general we concur that FAME 3 does not sit comfortably within the group of patients described from Japan and Europe that have been described with various forms of familial cortical tremor.

Although some degree of progression in these families is well documented and some have cerebellar atrophy and other MRI changes, these tend to be relatively mild. On the other hand, the majority of cases of PME have severe disease leading to death or marked disability.

Although PME is usually accepted as progressive epilepsy with myoclonus, ataxia and dementia, the precise extent of the syndrome is not defined. FAME 3 appears to be neither as benign as familial cortical tremor nor as severe as classical forms of PME (MERRF, Lafora body disease, sialidoses, Unverricht-Lundborg disease and DRPLA). As we stated, FAME 3 appears to lie within the spectrum of PME, occupying a place between PME and SAME.

It should be emphasized that one patient was asymptomatic, and six patients had rare seizures. For purposes of classification, we were relatively undecided on how to classify the condition, and had originally proposed the nondescript term SAME (South African Myoclonic Epilepsy), which would have avoided the thorny issue of where to place this new syndrome.

This type of nosological difficulty is predictable given the constraints of arbitrary classification of biological conditions. The ultimate arbiter will be classification by the gold standard, which is likely to be genetic localization.

References

1. Carr JA, van der Walt PE, Nakayama J, et al. FAME 3: a novel form of progressive myoclonus and epilepsy. Neurology 2007;68:1382-1389.

2. Striano P, Zara F, Striano S. Autosomal dominant cortical tremor, myoclonus and epilepsy: many syndromes, one phenotype. Acta Neurol Scand 2005; 111:211-217.

3. Plaster NM, Uyama MD, Uchino MD, et al. Genetic localization of the familial adult myoclonic epilepsy (FAME) gene to chromosome 8q24. Neurology 1999;53:1180-1183.

4. Guerrini R, Bonanni P, Patrignani A, et al. Autosomal dominant cortical myoclonus and epilepsy (ADCME) with complex partial seizures and generalized seizures. A newly recognized epilepsy syndrome with linkage to chromosome 2p11.1-q12.2. Brain 2001;124:2459-2475.

5. van Rootselaar AF, Aronica E, Jansen Steur EN, Rozemuller-Kwakkel JM, de Vos RA, Tijssen MA. Familial cortical tremor with epilepsy and cerebellar pathological findings. Mov Disord 2004;19:213-217.