Clinical and neurophysiologic features of progressive myoclonus epilepsy without renal failure caused bySCARB2mutations

Abstract

Summary Purpose: Mutations of the SCARB2 gene cause action myoclonus renal failure syndrome (AMRF), a rare condition that combines progressive myoclonus epilepsy (PME) with severe renal dysfunction. We describe the clinical and neurophysiologic features of PME associated with SCARB2 mutations without renal impairment. Methods: Clinical and neurophysiologic investigations, including wakefulness and sleep electroencephalography (EEG), polygraphic recording (with jerk‐locked back‐averaging and analysis of the EEG–EMG (electromyography) relationship by coherence spectra and phase calculation), multimodal evoked potentials, and electromyography were performed on five Italian patients with SCARB2 mutations. Key Findings: The main clinical features were adolescent–young adulthood onset, progressive action myoclonus, ataxia, absence of cognitive deterioration and, in most cases, epilepsy. The severity of the epilepsy could vary from uncontrolled seizures and status epilepticus in patients with adolescent onset to absent or rare seizures in patients with adult onset. Relevant neurophysiologic findings were a pronounced photosensitivity and massive action myoclonus associated with rhythmic myoclonic jerks at a frequency of 12–20 Hz, clinically resembling a postural tremor. The cortical origin of rhythmic myoclonus was demonstrated mainly by coherence and phase analysis of EEG–EMG signals indicating a significant EEG–EMG coupling and a direct corticospinal transfer. Significance: Our patients with SCARB2 mutations showed the clinical and neurophysiologic phenotype of PME, in which epilepsy could be extremely severe, extending the spectrum reported in the typical AMRF syndrome. Patients with PME of unknown origin of adolescent or young adult onset, with these neurophysiologic features, should be tested for SCARB2 mutations, even in the absence of renal impairment.

Lysosome sorting of β-glucocerebrosidase by LIMP-2 is targeted by the mannose 6-phosphate receptor

“…It has N- and C-terminal transmembrane helices (being a type III membrane protein) and a heavily glycosylated 400 residue luminal domain (bearing nine potential N-linked glycosylation sites)3. LIMP-2 has a major role in lysosomal and endosomal membrane organization, and LIMP-2 mutations cause several neurodegenerative and renal diseases, such as myoclonic epilepsy and nephrotic syndrome45. LIMP-2 is a member of the CD36 superfamily of scavenger receptors67, and has been identified as a receptor for Enterovirus 71 (EV71) and Coxsackievirus A16, which cause major epidemics of hand, foot-and-mouth disease in young children8.…”

Action myoclonus-renal failure syndrome: diagnostic applications of activity-based probes and lipid analysis

“…Only a few years ago, the receptor protein was identified as lysosomal integral membrane protein-2 (LIMP2), one of the integral membrane proteins of lysosomes (16). Next, mutations in the scavenger receptor class B member 2 (SCARB2) gene, encoding LIMP2 protein, were found to cause action myoclonus-renal failure syndrome (AMRF) (MIM*602257), a fatal recessively inherited disorder characterized by glomerulosclerosis, progressive myoclonus epilepsy, ataxia, and accumulation of undefined storage material in the brain (17–23). More recently it has become clear that not all AMRF patients develop renal complications (22, 23).…”

“…Next, mutations in the scavenger receptor class B member 2 (SCARB2) gene, encoding LIMP2 protein, were found to cause action myoclonus-renal failure syndrome (AMRF) (MIM*602257), a fatal recessively inherited disorder characterized by glomerulosclerosis, progressive myoclonus epilepsy, ataxia, and accumulation of undefined storage material in the brain (17–23). More recently it has become clear that not all AMRF patients develop renal complications (22, 23). Of interest, AMRF patients do not show the massive occurrence of lipid-laden macrophages and similar pathology to GD patients (24).…”

Scavenger Receptors: Structure, Function and Diversity

“…SRCL is involved in embryonic development in zebrafish (Fukuda et al, 2011). Mutations in SCARB2 can also lead to action myoclonus renal failure syndrome (AMRF) and allelic polymorphisms may contribute to Parkinson's disease (Rubboli et al, 2011;Michelakakis et al, 2012). Sperm binding to CD36 expressed on cumulus cells on the surface of the oocytes is important for sperm engulfment and fertilisation (Yang et al, 2011).…”