SCARB2 – Action Myoclonus-Renal Failure Syndrome

Action myoclonus-renal failure (AMRF) syndrome is an autosomal recessive progressive myoclonus epilepsy with renal failure, characterized by myoclonus, ataxia, generalized seizures, renal insufficiency and peripheral neuropathy. Biallelic loss-of-function variants in SCARB2, encoding the lysosomal integral membrane protein LIMP-2, underlie this syndrome (PMID:22032306).

In the original German family, three affected homozygous siblings segregated a novel SCARB2 frameshift variant c.111del (p.Ile37MetfsTer7) (PMID:22032306). Autosomal recessive segregation has since been confirmed in at least four additional pedigrees—including two Chinese brothers (PMID:29941711), two Iranian siblings (PMID:33772352), and multiple Turkish relatives (PMID:35346091)—totaling nine affected relatives.

Over 30 AMRF probands have been reported harboring diverse SCARB2 null alleles, including frameshifts, nonsense and splice-site mutations such as c.1270C>T (p.Arg424Ter) (PMID:24485911) and c.40dup (p.Asn45MetfsTer?) (PMID:33343627). Phenotypic expansion encompasses cases with AMRF-like neurologic features without renal compromise, demyelinating polyneuropathy, dilated cardiomyopathy, hearing impairment and cognitive decline.

Cellular studies demonstrate that mutant LIMP-2 proteins are truncated, mislocalized to the endoplasmic reticulum or cytosol, and fail to incorporate into lysosomal membranes, leading to autophagosome accumulation in patient-derived lymphocytes (PMID:23515316).

LIMP-2 deficiency abolishes lysosomal glucocerebrosidase trafficking, resulting in near-absent enzyme activity in fibroblasts and elevated plasma glucosylsphingosine, distinguishing AMRF from Gaucher disease (PMID:24212238).

While heterozygous carriers may occasionally exhibit isolated polyneuropathy or seizures, mutation screening in cohorts with isolated epilepsy, renal failure or cardiomyopathy revealed no pathogenic SCARB2 variants, arguing against a significant dominant effect.

Definitive genetic and functional concordance—biallelic LOF variants in >30 probands, segregation in multiple families and consistent cellular phenotypes—establish SCARB2 as the causal gene for AMRF. Key Take-home: Genetic testing for SCARB2 guides diagnosis and differentiation of AMRF from other lysosomal disorders.

References

• BMC neurology • 2011 • Novel SCARB2 mutation in action myoclonus-renal failure syndrome and evaluation of SCARB2 mutations in isolated AMRF features. PMID:22032306
• Journal of the neurological sciences • 2014 • A novel SCARB2 mutation in progressive myoclonus epilepsy indicated by reduced β-glucocerebrosidase activity PMID:24485911
• Frontiers in genetics • 2020 • Case Report: Distinctive EEG Patterns in SCARB-2 Related Progressive Myoclonus Epilepsy. PMID:33343627
• BioResearch open access • 2013 • Abnormal Processing of Autophagosomes in Transformed B Lymphocytes from SCARB2-Deficient Subjects. PMID:23515316
• Journal of lipid research • 2014 • Action myoclonus-renal failure syndrome: diagnostic applications of activity-based probes and lipid analysis. PMID:24212238

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