SCARB2 – Progressive myoclonus epilepsy

SCARB2 encodes lysosomal integral membrane protein-2 (LIMP-2) and is established as an autosomal recessive cause of progressive myoclonus epilepsy ([PMID:19847901]). Progressive myoclonus epilepsy (PME) presents with action myoclonus, epileptic seizures, and ataxia, sometimes accompanied by peripheral neuropathy or dysarthria, without cognitive decline or renal failure in many patients. Loss-of-function and splice‐site variants in SCARB2 disrupt mannose‐6‐phosphate–independent trafficking of β-glucocerebrosidase, a mechanism shared across AMRF and PME phenotypes.

SCARB2‐related PME follows autosomal recessive inheritance. Case‐level data include truncating, splice site, and frameshift mutations (e.g., c.862C>T (p.Gln288Ter)) in unrelated individuals. Five patients were reported in a cohort without renal failure ([PMID:19847901]); five more in an Italian series ([PMID:22050460]); and additional single‐case reports in [PMID:21670406], [PMID:24485911], and [PMID:29605618]. Two families demonstrate co‐segregation of homozygous or compound heterozygous variants with disease in siblings.

Phenotypic spectrum encompasses action myoclonus (HP:0001336), generalized myoclonic seizures (HP:0002123), and progressive cerebellar ataxia (HP:0001251). Some patients exhibit demyelinating peripheral neuropathy or dysarthria, whereas renal function remains normal in many PME‐only cases. Brain MRI frequently shows cortical and cerebellar atrophy, and neurophysiologic studies reveal pronounced photosensitivity and rhythmic myoclonus of cortical origin.

Segregation analysis supports pathogenicity: two families (Chinese and Iranian) each with two affected siblings carrying homozygous or compound heterozygous SCARB2 variants. Affected relatives co‐segregate variants consistent with autosomal recessive inheritance.

Functional studies demonstrate that mutant LIMP-2 fails to traffic to lysosomes and impairs autophagosome processing in patient‐derived lymphoblasts, resulting in accumulation of autophagic vesicles ([PMID:23515316]). In LIMP-2–deficient mouse models, reduced β-glucocerebrosidase lysosomal activity leads to glucosylceramide accumulation and α-synuclein aggregation, recapitulating neurodegenerative features ([PMID:25316793]).

No conflicting evidence has been published disputing SCARB2’s role in PME; all identified variants are loss‐of‐function or disrupt splicing and are absent in controls.

Integration of clinical, genetic, and functional data yields a Strong gene–disease association: multiple unrelated probands, familial segregation, and concordant mechanistic studies. Genetic testing for SCARB2 is critical in PME patients, even in the absence of renal involvement.

Key Take-home: SCARB2 should be included in diagnostic panels for autosomal recessive PME to enable precise genetic counselling and facilitate early intervention.

References

• Annals of neurology • 2009 • SCARB2 mutations in progressive myoclonus epilepsy (PME) without renal failure [PMID:19847901]
• Epilepsia • 2011 • Clinical and neurophysiologic features of progressive myoclonus epilepsy without renal failure caused by SCARB2 mutations [PMID:22050460]
• Archives of neurology • 2011 • Mutation of SCARB2 in a patient with progressive myoclonus epilepsy and demyelinating peripheral neuropathy. [PMID:21670406]
• Journal of the neurological sciences • 2014 • A novel SCARB2 mutation in progressive myoclonus epilepsy indicated by reduced β-glucocerebrosidase activity [PMID:24485911]
• Seizure • 2018 • Progressive myoclonus epilepsy without renal failure in a Chinese family with a novel mutation in SCARB2 gene and literature review. [PMID:29605618]
• BioResearch open access • 2013 • Abnormal Processing of Autophagosomes in Transformed B Lymphocytes from SCARB2-Deficient Subjects. [PMID:23515316]
• Proceedings of the National Academy of Sciences of the United States of America • 2014 • LIMP-2 expression is critical for β-glucocerebrosidase activity and α-synuclein clearance [PMID:25316793]

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