Founder variant. Specific language impairment (SLI) is a common neurodevelopmental disorder, presenting as delays in acquiring language skills in children who have no hearing loss or other developmental delays. There is a strong genetic component, but the genetic architecture of SLI is entirely unknown. In a recent publication in PLOS Genetics, exome sequencing is performed in the founder population of the Robinson Crusoe Island where SLI is common. Using a combination of exome sequencing and association study, the autors identify a variant In NFXL1 as a plausible candidate for language delay. Continue reading
Crompton and colleagues recently published the clinical and genetic description of a large family with Familial Adult Myoclonic Epilepsy (FAME). This phenotype is particularly interesting since it provides some insight into how neurologists conceptualize twitches and jerks. It is also a good example that large families do not necessarily result in a narrow linkage region, particularly when centromeric regions are involved.
What is myoclonus? Despite usually mentioned in the context of epilepsy, most people are inherently familiar with myoclonus. Most of us “twitch” when we fall asleep and sometimes experience this twitch as part of a dream. These episodes are entirely normal and are called hypnic jerks, but they give people a good idea of what a sudden, brief, shocklike, involuntary movement caused by muscular contraction or inhibition would feel like. Myoclonus in the setting of epilepsy is usually mentioned as part of a Juvenile Myoclonic Epilepsy (JME) or Progressive Myoclonus Epilepsy (PME). Please note that both epilepsies use different endings to describe the twitch (“-us” vs. “–ic”). This is mainly convention. Basically, myoclonus is a brief shock-like twitch, which can affect almost every part of the body and can be due to dysfunctions in various regions in the Central Nervous System.
The neuroanatomy of twitching. A motor command from the cerebral cortex has to pass through several steps prior to execution. For example, the simple command of tapping a finger on the table surface is prepared by the cortex through several loops before being sent down your spine. Accordingly, myoclonus can arise from different parts in the brain. (1) The cortical myoclonus is due to a purely cortical source and can be seen in many forms of symptomatic myoclonus. (2) The cortico-subcortical myoclonus is due to feedback from the cortex to other brain areas. This is the myoclonus we see in patients with JME. Both variants may be seen on EEG since the cortex is involved. (3) The subcortical-supraspinal myoclonus is generated in the brain stem or below and is responsible for phenomena such as hyperekplexia or startle disease. Some forms of hyperekplexia, literally “exaggerated surprise”, are due to mutations in genes involved in glycinergic transmission and can be found in some isolated communities such as the Jumping Frenchmen of Maine. (4) Finally, there is also spinal and peripheral myoclonus.
FAME – epilepsy or movement disorder? Familial Adult Myoclonic Epilepsy (FAME) is an enigmatic familial disorder with the triad of myoclonus, tremor and seizures. Several families have been described and two loci on 8q23.3-8q24.11 and 2p11.1-q212.2 for FAME have been established. The underlying genes are still unknown. Crompton and colleagues no describe a large six-generation family with FAME in Australia/New Zealand. The familial disease usually starts with tremor in early adulthood in the affected family members, even though a wide range of age of onset is observed. Interestingly, only a quarter of all affected family members had seizures, which is in contrast to previous studies. Therefore, FAME may actually be better characterized as a movement disorder with concomitant seizures rather than a familial epilepsy syndrome. The authors also point out the difficulties distinguishing FAME from the much more common essential tremor (ET). In particular, the well-described response to β-blockers seen in patients with ET can also be observed in some family members.
The genetics of FAME. Crossovers during meiosis usually lead to a progressive narrowing of the linkage interval in familial disorders. However, the lack of crossover events leads to very large linkage intervals even in very extended families. The family described by Crompton et al. links to the pericentromeric region of chromosome 2. Pericentromeric regions usually have a low frequency of crossover events, and this phenomenon has also delayed the identification of other familial epilepsies such as Benign Familial Infantile Seizures with mutations in PRRT2. The linkage region contains almost 100 genes and Figure 1 shows the “candidate gene landscape” in this region. While some genes clearly classify as top candidate genes, the majority of the genes in this region are unknown in the context of epilepsy. Therefore, identification of the FAME gene will be exciting and provide us with novel insight on how genetic alterations may produce combined neurological phenotypes.