Progressive Myoclonic Epilepsy, With or Without Renal Failure, via the SCARB2 Gene

The progressive myoclonic epilepsies (PMEs) are a heterogeneous group of seizure disorders characterized by myoclonus and often neurodegeneration. PME4, previously called action myoclonus-renal failure syndrome (AMRF), is a progressive epilepsy disorder in which cognition is preserved (Badhwar et al. Brain 127(Pt 10):2173-2182, 2004). PME4 usually presents in the second decade of life as tremors and myoclonic jerks which progress into clonic-tonic seizures. Seizures are sensitive to light and become intractable to anti-epileptic drugs as the disease progresses. Eventually, patients become completely bedridden due to severe action myoclonus.

In a subset of PME4 cases, seizures are accompanied by renal failure, often first detected as proteinuria. The clinical phenotype of PME4 with renal failure is similar to that of Gaucher disease type III. These two disorders can be distinguished by: 1) the absence of Gaucher cells in PME4 patients and 2) elevated Beta-glucosidase (βGC) activity in the serum of PME4 patients (Reczek et al. Cell 131(4):770-783,2007).

PME4 cases without renal failure clinically resemble Unverricht-Lundborg disease (ULD). ULD is another progressive myoclonic epilepsy with preserved intellect. The main distinction between PME4 and ULD is the average age of onset, 20 years and 10 years, respectively (Dibbens et al. Ann Neurol 66(4):532-536, 2009).

PME4 is caused by mutations in the SCARB2 gene. PME4 is largely inherited in an autosomal recessive manner, though there are reports of heterozygous carriers showing mild PME4 phenotypes (Hopfner et al. BMC Neur 11:134-141, 2011). Approximately 20 PME4-associated mutations in SCARB2 have been identified and are predicted to result in loss of SCARB2 function.

SCARB2 encodes lysosomal integral membrane protein 2 (LIMP-2). LIMP-2 acts as a sorting receptor and is required for proper localization of the enzyme βGC to the lysosome. In cells lacking LIMP-2, βGC is missorted and is secreted from the cell (Balreira et al. Hu Mol Genet 17(14):2238-2243, 2008). βGC is encoded by the GBA gene, which when mutated results in Gaucher disease (GD). Symptoms of GD type III resemble those of some PME4 cases and it is suggested that these two disorders might share an etiology. SCARB2 has also been implicated as a modifier of GD (Velayati et al. Hum Mutat 31(11):1232-1238, 2011).

PME4 is defined by the presence of a SCARB2 mutation. A study of patients with ULD-like disease found SCARB2 mutations in 5 of 41 (12%) patients (Dibbens et al. Ann Neurol 66(4):532-536, 2009). Another study identified SCARB2 as a modifier of GD in 1 of 15 (6%) of patients (Velayati et al. Hum Mutat 32(11):1232-1238, 2011).

This test provides full coverage of all coding exons of the SCARB2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.