Epilepsy & Tremor. The familial occurrence of epileptic seizures and chronic, non-progressive myoclonic tremor represents a peculiar genetic epilepsy syndrome for which the gene still remains elusive. Several families have been reported with autosomal dominant inheritance, and linkage to chromosomes 2, 5 and 8 have been reported. Now, the story regarding this familial syndrome gets even more enigmatic. In a recent paper in Brain, Stogmann and collaborators identify CNTN2 as the causative gene for a recessive form of cortical myoclonic tremor with epilepsy.
Myoclonic tremor. A tremor is an involuntary rhythmic muscle contraction and relaxation of one or more body parts. There are many causes of tremor that arise from different regions of the Central Nervous System. In some forms of tremor, an EEG correlate can be identified through back-averaging, using the average of multiple event to extract an EEG signature that would otherwise not be noticeable. The existence of such an EEG correlate suggests a cortical origin for the tremor in these patients. Therefore, the tremor variant is referred to as cortical (myoclonic) tremor. With respect to treatment, antiepileptic drugs may work in these rare forms of tremor, while they are often not the first choice in more common tremor variants such as the essential tremor (ET). When cortical tremor occurs alongside epileptic seizures in the same patient, a common cause underlying this hyperexcitability is assumed. If both conditions run in families, this cause is thought to be genetic.
Familial myoclonic tremor with epilepsy. Over the years, more than 60 families have been described with a combination of cortical tremor and epilepsy and this familial condition has been referred to by various acronyms including FCMTE, ADCME, BAFME, Crt Tr, FCMT, FEME, FMEA, HTE or FCTE. In a post last year, we referred to this familial syndrome as FAME (Familial adult myoclonic epilepsy) and there is an ongoing discussion whether these syndromes represent a single disease or not.
A recessive form of a dominant disease. Ethnicities with a high degree of consanguinity lend themselves to gene discovery in recessive diseases. Furthermore, if recessive variants of common diseases can be identified, they might provide insight into the underlying pathophysiology. Stogmann and collaborators performed homozygosity mapping and exome sequencing in a consanguineous pedigree with five individuals affected by cortical tremor and epilepsy. They identified a homozygous deletion within the CNTN2 gene in all affected individuals while the two unaffected siblings and the parents were carriers.
Contactin 2, axonal. Even though CNTN2 coding for contactin 2 has not yet been reported in the context of human epilepsy, it is no stranger. CNTN2 is a cell adhesion molecule implicated in axonal guidance during development and has been reported as a binding partner of contactin associated protein-like 2 (CNTNAP2). The CNTNAP2 gene, in addition to being the gene covering the longest genomic region in the human genome, is a known susceptibility gene for epilepsy and neurodevelopmental disorders. In particular, microdeletions in CNTNAP2 are known risk factors for a broad range of neurodevelopmental disorders including epilepsy. In addition, when recessive, mutations may results in a severe, early-onset epileptic encephalopathy.
Implications for EuroEPINOMICS. Recessive disorders are rare and time will tell whether another family or additional cases with recessive CNTN2 mutations and epilepsy with cortical myoclonic tremor will be identified. In cases like this, functional studies sometimes remain the only possibility to tell causative genetic variation from genomic noise. In the case of CNTN2, a mouse model has been reported with spontaneous seizures, highlighting the potential pathogenic role of the mutation. A similar situation is likely to arise with many of our families that are currently being investigated using genome sequencing. Most of these families will have private mutations and functional studies will be necessary to prove pathogenicity.