Wall Street. Between the 8th and 11th century, Haithabu (Hebedy), a Viking town in Northern Germany close to the border to Denmark was the Manhattan of its time – a flourishing trading town located at a busy shipping route at a natural short passage connecting the Eider and the Treene river, a precursor of the modern-day Kiel canal. The Vikings used this shortcut to avoid the dangerous Skagerak when heading West on their conquests. When subsequently settling down in many regions of the North Sea coast, they carried their genetic heritage with them, including a rare variant in the GOSR2 gene, which results in a devastating epilepsy when homozygous. A recent paper in Brain now delineates the phenotype of the “North Sea” progressive myoclonus epilepsy.
The progressive myoclonus epilepsies. A group of epilepsies is characterized by frequent, often therapy-resistant myoclonus in connection with generalized tonic-clonic seizures and progressive neurological symptoms. These progressive myoclonus epilepsies (PME) are usually separated into two different groups depending on the level of dementia and associated cognitive decline. Unverricht-Lundborg disease (ULD) is a PME with preserved cognitive function, while disorders such as Lafora body disease and Neuronal Ceroid Lipofuscinosis (NCL) show prominent neurological decline and dementia. Until a few years ago, the genetics of the ULD was simple, as CSTB was the only known gene for this disease. Classical ULD or “Baltic Myoclonus” is caused by an expansion of a dodecamer repeat in the 5’-UTR of the Cystatin B (CSTB) gene. However, in recent years, additional mutations in PRICKLE1, SCARB2 and GOSR2 were identified in ULD-like PME. Boisse Lomax and colleagues now report on the clinical findings in 12 patients with GOSR2-related PME.
The North Sea myoclonus. In contrast to typical ULD, GOSR2-related PME is a disease that usually starts in childhood, typically between four and twelve years. Prior to the occurrence of myoclonic seizures, patients present with ataxia, starting between the age of one to three years. More than half of the patients described were hypotonic in infancy and some showed delayed motor development, suggesting that the neurological findings in GOSR2-related PME precede the actual seizures. The course of the epilepsy in GOSR2-related PME is more severe compared to ULD. While the life expectancy in patients with classical ULD is not markedly reduced, 4/12 with GOSR2-related PME died in their third or early fourth decade. All patients showed an elevation of the creatine kinase (CK), an unusual finding that normally triggers the suspicion of a mitochondrial disorder. Neurological findings in some patients were exacerbated by febrile disease and in one patient, the initial ataxia was initially thought to be an acute viral cerebellitis. All patients were homozygous for the same variant in the GOSR2 gene (G114W p.Gly114Trp), highly indicative of a founder effect.
A SNARE, not at the synapse. GOSR2 is the Golgi SNAP receptor complex member 2, a SNARE gene of the Golgi complex. While “SNAP” and “SNARE” may remind you of the synaptic fusion machinery, this is not the case for GOSR2. GOSR2 also goes by the name of GS27, BOS1 or Membrin and is a known player in transportation of vesicles through the various compartment of the Golgi apparatus. How a defect in this transport results in progressive myoclonus epilepsy remains to be solved. At least macroscopically and histologically, there is no evidence of a storage disorder as in Lafora disease or Neuronal Ceroid Lipofuscinosis.
PME unraveled. The phenotype of the GOSR2-related PME is very instructive, particularly to people working in pediatric neurology where “ULD” is usually considered an adult phenotype that is rarely seen in children. North Sea progressive myoclonus epilepsy is a childhood onset epilepsy with several features including hypotonia, ataxia and scoliosis that might initially seem more prominent than the epilepsy itself. Therefore, it might masquerade as muscular hypotonia or fever- or infection-related epilepsies in the beginning. Given the virtually ubiquitious CK elevation and the relatively straight-forward genetics due to a founder effect, identification of further cases in Northern Europe can be expected, which –hopefully- will lead to better treatment of these patients.