Action Myoclonus-Renal Failure Syndrome

Mendelian MONDO:0009699 Pathograph 20 Show in embeddings browser Progressive Myoclonus Epilepsy Lysosomal Storage Disease

Action myoclonus-renal failure syndrome (AMRF) is an autosomal recessive lysosomal disorder caused by biallelic loss-of-function variants in SCARB2, which encodes the lysosomal integral membrane protein type 2 (LIMP-2). LIMP-2 is the mannose-6-phosphate-independent sorting receptor that carries beta-glucocerebrosidase (GCase) from the endoplasmic reticulum to the lysosome. When LIMP-2 is absent or retained in the ER, GCase never reaches the lysosome and is degraded, so the disease is a trafficking failure of a lysosomal enzyme rather than a defect in the enzyme itself. The clinical picture combines a progressive myoclonic epilepsy - adolescent or young-adult onset action myoclonus of cortical origin, ataxia, and seizures, characteristically without early dementia - with steroid-resistant nephrotic syndrome progressing to focal segmental glomerulosclerosis and end-stage kidney disease. The two organ manifestations progress independently, and some individuals with biallelic SCARB2 variants develop progressive myoclonus epilepsy with no renal involvement at all; that form sits at one end of the same spectrum rather than being a separate disease. Disease progresses relentlessly to death within roughly 7 to 15 years of onset.

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1
Inheritance
6
Pathophys.
2
Histopath.
13
Phenotypes
2
Gaps
20
Pathograph
1
Genes
6
Medical Actions
1
Models
1
References
1
Deep Research
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Classifications

Harrison's Part
NEUROLOGIC KIDNEY URINARY TRACT
👪

Inheritance

1
Autosomal Recessive HP:0000007
AMRF is inherited in an autosomal recessive manner. Affected individuals carry biallelic loss-of-function SCARB2 variants; heterozygous parents are asymptomatic carriers.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:26677510 SUPPORT REVIEW SYNTHESIS Other
"SCARB2-AMRF is inherited in an autosomal recessive manner."
GeneReviews statement of the mode of inheritance for this disease.
PMID:18424452 SUPPORT Human Clinical
"A homozygous nonsense mutation in codon 178 of SCARB2 was found in the patient, whereas her healthy parents were heterozygous for the mutation."
Documents the recessive segregation directly: homozygous proband, healthy heterozygous parents.
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Discussions and Knowledge Gaps

2
How does loss of LIMP-2-dependent beta-glucocerebrosidase delivery cause podocyte injury and focal segmental glomerulosclerosis?
KNOWLEDGE GAP renal_arm_mechanism_gap
Attached to
pathophysiology#Podocyte Injury and Glomerular Collapse
The neurological arm of AMRF has a traceable chain from sorting failure to neuronal storage to cortical hyperexcitability. The renal arm does not. The causal gene and the renal lesion are both established, but no published step connects reduced glucocerebrosidase delivery to podocyte injury, and the two organ manifestations progress independently and can be dissociated entirely - some individuals with biallelic SCARB2 variants never develop renal disease. That dissociation is itself evidence that the renal lesion may depend on a LIMP-2 function other than GCase transport, which would make the upstream edge in this entry wrong rather than merely incomplete.
Is the Limp2-null mouse a valid model of AMRF at all, given that its own characterized phenotype is in three organs the human disease does not affect?
HUMAN MODEL MISMATCH limp2_null_mouse_renal_fidelity
Attached to
animal_models#Mouse
Read forwards rather than backwards, the mouse is a poor match. Its described phenotype is ureteropelvic junction obstruction with hydronephrosis, hearing loss and peripheral demyelinating neuropathy; its authors pointed it at human stria vascularis and demyelination disorders. The AMRF-relevant findings - cortical and cerebellar storage inclusions, subtle glomerular change - emerged only on reanalysis after SCARB2 was implicated, and the glomerular change never reaches the collapsing glomerulopathy or end-stage kidney disease that define the human renal arm. Evidence in the model exists and its translational validity is the open question, which is why this is a HUMAN_MODEL_MISMATCH rather than a plain knowledge gap. The practical consequence is concrete: substrate reduction therapy is the one mechanism-directed treatment in this entry and rests on two single patients, and there is no animal model in which a myoclonus endpoint could be used to test it.
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Pathophysiology

6
LIMP-2 Loss of Function
Biallelic SCARB2 variants - nonsense, frameshift, splice-site and rarely missense - abolish functional LIMP-2. Nonsense and frameshift alleles leave no immunodetectable protein; the alleles that do produce protein are retained in the endoplasmic reticulum rather than reaching the lysosomal membrane. The consequence is the same in either case: no functional sorting receptor at the site where cargo must be handed over.
Genetic context SCARB2 hgnc:1665 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns SCARB2 (hgnc:1665). hgnc:1665 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
lysosomal membrane GO:0005765 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves lysosomal membrane (GO:0005765). GO:0005765 is a cellular component from the Gene Ontology.
Downstream
Failure of Beta-Glucocerebrosidase Lysosomal Targeting Without LIMP-2 at the ER-to-lysosome interface its cargo cannot be routed.
Show evidence (2 references)
PMID:18308289 SUPPORT Human Clinical
"Mutations in SCARB2/Limp2 were found in all three families used for mapping and subsequently confirmed in two other unrelated AMRF families. The mutations were associated with lack of SCARB2 protein."
Establishes that the causal SCARB2 variants in AMRF abolish the protein.
PMID:19933215 SUPPORT In Vitro
"All mutations investigated in this study lead to a retention of LIMP-2 in the endoplasmic reticulum (ER) but affect the binding to beta-GC differentially."
Shows the second route to the same loss: AMRF alleles that are expressed do not leave the ER.
Failure of Beta-Glucocerebrosidase Lysosomal Targeting
LIMP-2 binds beta-glucocerebrosidase in the ER through a conserved coiled-coil domain and releases it in the acidified late endosome/lysosome, a handover gated by a critical histidine that acts as a pH sensor. This route is mannose-6-phosphate independent, which is why AMRF spares the many lysosomal hydrolases that use the M6P receptor. With LIMP-2 absent, GCase is stranded in the ER, remains endoglycosidase-H sensitive, and is degraded.
LIMP-2-mediated sorting of beta-glucocerebrosidase GO:0006622 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves LIMP-2-mediated sorting of beta-glucocerebrosidase, annotated with protein targeting to lysosome (GO:0006622), qualified as loss of function. GO:0006622 is a biological process from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Reduced Lysosomal Glucocerebrosidase Activity
Show evidence (2 references)
PMID:18424452 SUPPORT In Vitro
"Besides lacking immunodetectable LIMP-2, patient fibroblasts also had decreased amounts of beta-glucocerebrosidase, which was mainly located in the endoplasmic reticulum, as assessed by its sensitivity to Endo H."
Direct patient-cell demonstration that GCase is stranded in the ER when LIMP-2 is absent.
PMID:22537104 SUPPORT In Vitro
"We now demonstrate that the lumenal acidification mediated by the vacuolar (H(+) )-ATPase triggers the dissociation of LIMP-2 and GC in late endosomal/lysosomal compartments."
Defines the normal delivery step whose loss this node describes: pH-gated release of GCase from LIMP-2 at the lysosome.
Reduced Lysosomal Glucocerebrosidase Activity
Lysosomal GCase activity falls in the cell types that depend on LIMP-2 for its delivery. The dependence is tissue-specific, and this is the reason AMRF is not Gaucher disease: in fibroblasts and neuronal cells GCase targeting is entirely LIMP-2 dependent, while in blood cells a LIMP-2-independent route preserves substantial activity. Leukocyte GCase can therefore be normal in a patient whose fibroblasts are severely deficient, which is a diagnostic trap as well as a mechanistic fact.
glucosylceramide catabolism in the lysosome GO:0006680 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glucosylceramide catabolism in the lysosome, annotated with glucosylceramide catabolic process (GO:0006680). GO:0006680 is a biological process from the Gene Ontology. ↓ DECREASED
glucocerebrosidase activity GO:0004348 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased glucocerebrosidase activity, annotated with glucosylceramidase activity (GO:0004348). GO:0004348 is a molecular function from the Gene Ontology. ↓ DECREASED
Animal models
Limp2 knockout mouse Mouse recapitulates Tissue GCase deficiency with the same tissue-specific sparing of leukocytes seen in patients.
Downstream
Neuronal Lysosomal Storage and Intracellular Inclusions
Podocyte Injury and Glomerular Collapse
Show evidence (2 references)
PMID:18424452 SUPPORT Human Clinical
"The biochemical analysis of one of the patients revealed a normal beta-glucocerebrosidase activity in leukocytes, but a severe enzymatic deficiency in cultured skin fibroblasts."
Documents the tissue-restricted enzyme deficiency this node asserts, including the normal leukocyte result.
PMID:26018676 SUPPORT In Vitro
"In fibroblasts and neuronlike cells, GCase targeting to the lysosomes is completely dependent on LIMP-2, whereas in blood cells, GCase is partially targeted to lysosomes by a LIMP-2-independent mechanism."
Establishes the cell-type dependence that explains why the deficiency is partial and why AMRF diverges clinically from Gaucher disease.
Neuronal Lysosomal Storage and Intracellular Inclusions
Storage material accumulates in cerebral and cerebellar cortical neurons. Notably the stored species is not bulk glucosylceramide: in the LIMP-2-deficient mouse, glucosylceramide is not markedly raised, while its downstream deacylated and sterol-conjugated metabolites glucosylsphingosine and glucosylated cholesterol are. That distinction is the current best explanation for why LIMP-2 deficiency produces a neuronal storage encephalopathy with glomerulosclerosis rather than the visceral, macrophage-centred picture of Gaucher disease.
cortical and cerebellar neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cortical and cerebellar neuron, annotated with neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology. cerebellar Purkinje cell CL:0000121 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cerebellar Purkinje cell, annotated with Purkinje cell (CL:0000121). CL:0000121 is a cell type from the Cell Ontology.
Animal models
Limp2 knockout mouse Mouse recapitulates Intracellular inclusions in cerebral and cerebellar cortex, the same regions affected in human AMRF.
Downstream
Cortical Hyperexcitability and Cerebellar Degeneration
Show evidence (2 references)
PMID:18308289 SUPPORT Model Organism
"Reanalysis of an existing Limp2 knockout mouse showed intracellular inclusions in cerebral and cerebellar cortex, and the kidneys showed subtle glomerular changes."
Shows neuronal storage inclusions in the cortical regions this node names, in the LIMP-2-null mouse.
PMID:40639771 SUPPORT Model Organism
"GCase deficiency in tissues does not correlate with increases in GlcCer, but rather with increases in glucosylsphingosine (GlcSph) and glucosylated cholesterol (GlcChol), both glucosylated metabolites derived from GlcCer."
Identifies which glycolipid species actually accumulate, supporting the claim that the stored material is not bulk glucosylceramide.
Cortical Hyperexcitability and Cerebellar Degeneration
Sensorimotor cortex becomes hyperexcitable and cerebellar output degenerates. The myoclonus of AMRF is cortical in origin, not subcortical: EEG-EMG coherence and phase analysis in SCARB2 patients show significant coupling with a direct corticospinal transfer, and the rhythmic 12-20 Hz jerking can be mistaken clinically for a postural tremor. Marked photosensitivity accompanies it. Cognition is characteristically spared relative to the other progressive myoclonic epilepsies.
cerebral cortex UBERON:0000956 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebral cortex (UBERON:0000956). UBERON:0000956 is an anatomical location from the Uberon multi-species anatomy ontology. cerebellar cortex UBERON:0002129 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebellar cortex (UBERON:0002129). UBERON:0002129 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Limp2 knockout mouse Mouse fails to recapitulate The null mouse's characterized phenotype is renal-outflow, cochlear and peripheral-nerve disease. No progressive myoclonus, seizure phenotype or cerebellar syndrome is reported in it.
Downstream
Peripheral neuropathy Grouped with the central manifestations because it shares their upstream storage lesion, but the route from lysosomal storage to peripheral nerve is not established in AMRF and the neuropathy is variable within a single family, so the edge is drawn with unknown intermediates.
Action myoclonus
Progressive cerebellar ataxia
Generalized tonic-clonic seizures
Photosensitivity
Show evidence (1 reference)
PMID:22050460 SUPPORT Human Clinical
"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."
Direct human neurophysiological demonstration that the myoclonus arises in cortex and is transmitted corticospinally.
Podocyte Injury and Glomerular Collapse
Mechanism confidence: Provisional
In the kidney the same enzyme-delivery failure produces podocyte injury, proteinuria, and focal segmental glomerulosclerosis, frequently with glomerular collapse. The renal arm runs on its own clock: renal involvement can precede neurological onset by decades, or be absent altogether in individuals whose biallelic SCARB2 variants produce progressive myoclonus epilepsy alone. The molecular step between reduced GCase delivery and podocyte injury is not established, which is why this edge is marked INDIRECT upstream.
glomerular podocyte CL:0000653 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves glomerular podocyte, annotated with podocyte (CL:0000653). CL:0000653 is a cell type from the Cell Ontology.
renal glomerulus UBERON:0000074 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in renal glomerulus (UBERON:0000074). UBERON:0000074 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Limp2 knockout mouse Mouse partially recapitulates Glomerular change is present but subtle, well short of the focal segmental glomerulosclerosis with collapse and end-stage kidney disease seen in patients.
Downstream
Focal segmental glomerulosclerosis
Steroid-resistant nephrotic syndrome
End-stage kidney disease
Show evidence (3 references)
PMID:18308289 SUPPORT Human Clinical
"Action myoclonus-renal failure syndrome (AMRF) is an autosomal-recessive disorder with the remarkable combination of focal glomerulosclerosis, frequently with glomerular collapse, and progressive myoclonus epilepsy associated with storage material in the brain."
States the renal lesion - focal glomerulosclerosis with glomerular collapse - that this node describes.
PMID:26677510 SUPPORT REVIEW SYNTHESIS Other
"The neurologic and renal manifestations progress independently."
Supports treating the renal arm as a parallel consequence rather than a sequela of the neurological disease.
PMID:15364701 SUPPORT INDIRECT Human Clinical
"The independent progression of neurological and renal disorders in AMRF suggests a unitary molecular lesion with pleiotropic effects."
The clinical observation of independent progression, which is what the pathograph's parallel-arm structure represents. Graded INDIRECT because the quote is the authors' inference from the observation rather than a measurement, and it predates the identification of SCARB2.
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Histopathology

2
C1q accumulation in glomerular capillary loops and mesangium
Strong C1q deposition in capillary loops and mesangium on renal biopsy, reported alongside the nephrotic syndrome. This is what gives the renal lesion its alternative name in the literature, where SCARB2 disease is sometimes reported as progressive myoclonus epilepsy with C1q nephropathy. It sits beside rather than instead of the collapsing focal segmental glomerulosclerosis curated under phenotypes, and the entry does not assert that either is the invariable renal histology. The two are not confined to separate families: one patient (II.13 of the Turkish p.N45MfsX88 family) has C1q, C3 and IgM deposition and FSGS in the same biopsy. That biopsy is reported as FSGS without the collapsing qualifier, so what co-occurs there is C1q deposition with FSGS, not specifically with the collapsing variant.
Show evidence (2 references)
PMID:18424452 SUPPORT Human Clinical
"The main clinical features of two siblings from a consanguineous marriage were progressive myoclonic epilepsy without intellectual impairment and a nephrotic syndrome with a strong accumulation of C1q in capillary loops and mesangium of kidney."
Reports the C1q distribution directly, in two molecularly confirmed siblings, and ties it to the nephrotic syndrome rather than to an incidental finding.
PMID:35346091 SUPPORT Human Clinical
"He underwent a renal biopsy, and it showed FSGS. Immunofluorescence microscopy showed deposition of one positive C1q, C3, and IgM in capillary loops."
A second, independent family with the C1q finding, and the only report here in which C1q deposition and FSGS are seen in one biopsy rather than in separate patients. The FSGS is not qualified as collapsing in this report.
Extraneuronal pigment accumulation on brain autopsy
Pigment accumulating outside neurons, found at autopsy in two patients of the defining series. It is recorded here because it is the only post-mortem neuropathology reported for this disease, and because its extraneuronal location is the observation itself: the storage in AMRF is not the intraneuronal inclusion picture of the other progressive myoclonic epilepsies.
Show evidence (1 reference)
PMID:15364701 SUPPORT Human Clinical
"Brain autopsy in two patients revealed extraneuronal pigment accumulation."
The finding and its denominator, from the largest published series.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Action Myoclonus-Renal Failure Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

13
Digestive 1
Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26677510 SUPPORT REVIEW SYNTHESIS Other
"feeding therapy programs for those with dysphagia to improve nutrition and reduce aspiration risk"
GeneReviews management section identifies dysphagia as a manifestation requiring intervention.
Genitourinary 4
Steroid-resistant nephrotic syndrome HP:0012588 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Steroid-resistant nephrotic syndrome (HP:0012588). HP:0012588 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26677510 SUPPORT REVIEW SYNTHESIS Other
"renal involvement that is apparently due to steroid-resistant nephrotic syndrome (SRNS)"
GeneReviews identifies steroid-resistant nephrotic syndrome as the renal manifestation of this disease.
Proteinuria 15/15 HP:0000093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15364701 SUPPORT Human Clinical
"Proteinuria, detected between ages 9 and 30 years in all cases, progressed to renal failure in 12 out of 15 patients within 0-8 years after proteinuria detection."
Gives both the universality of proteinuria in this series and the interval to renal failure.
Focal segmental glomerulosclerosis HP:0000097 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Focal segmental glomerulosclerosis (HP:0000097). HP:0000097 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:18308289 SUPPORT Human Clinical
"the remarkable combination of focal glomerulosclerosis, frequently with glomerular collapse, and progressive myoclonus epilepsy"
Names focal glomerulosclerosis with collapse as the renal lesion of AMRF.
PMID:15364701 SUPPORT Human Clinical
"Renal biopsies showed collapsing glomerulopathy, a severe variant of focal glomerulosclerosis."
Histological confirmation across the 15-patient series, and identifies the lesion specifically as the collapsing variant.
End-stage kidney disease Stage 5 chronic kidney disease HP:0003774 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Stage 5 chronic kidney disease (HP:0003774). HP:0003774 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26677510 SUPPORT REVIEW SYNTHESIS Other
"Treatment of ESKD is supportive; while renal replacement therapy can prolong survival, it does not improve neurologic features."
Establishes both that ESKD occurs and that treating it does not change the neurological trajectory.
Nervous System 8
Tremor HP:0001337 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tremor (HP:0001337). HP:0001337 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15364701 SUPPORT Human Clinical
"Tremor (onset 17-26 years, mean 19.8 years, median 19 years) and progressively disabling action myoclonus (onset 14-29 years, mean 21.7 years, median 21 years), with infrequent generalized seizures (onset 20-28 years, mean 22.7 years, median 22 years) and cerebellar features are characteristic."
Gives the onset ages for tremor, myoclonus and seizures in the 15-patient series, the source of the sequence described here.
Action myoclonus HP:0034360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Action myoclonus (HP:0034360), qualified as course progressive. HP:0034360 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:22050460 SUPPORT Human Clinical
"The main clinical features were adolescent-young adulthood onset, progressive action myoclonus, ataxia, absence of cognitive deterioration and, in most cases, epilepsy."
Names progressive action myoclonus as a main clinical feature in a SCARB2 patient series.
Postural tremor-like rhythmic myoclonus HP:0002174 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postural tremor (HP:0002174). HP:0002174 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22050460 SUPPORT Human Clinical
"massive action myoclonus associated with rhythmic myoclonic jerks at a frequency of 12-20 Hz, clinically resembling a postural tremor"
Describes the rhythmic myoclonus and its clinical resemblance to postural tremor.
Progressive cerebellar ataxia HP:0002073 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive cerebellar ataxia (HP:0002073), qualified as course progressive. HP:0002073 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:22050460 SUPPORT Human Clinical
"The main clinical features were adolescent-young adulthood onset, progressive action myoclonus, ataxia, absence of cognitive deterioration and, in most cases, epilepsy."
Lists ataxia among the main clinical features of the SCARB2 series.
Generalized tonic-clonic seizures Bilateral tonic-clonic seizure HP:0002069 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral tonic-clonic seizure (HP:0002069). HP:0002069 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22050460 SUPPORT Human Clinical
"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."
Supports both the presence of epilepsy and the onset-dependent severity stated in the description.
Photosensitivity Photosensitive tonic-clonic seizure HP:0007207 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Photosensitive tonic-clonic seizure (HP:0007207). HP:0007207 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22050460 SUPPORT Human Clinical
"Relevant neurophysiologic findings were a pronounced photosensitivity"
Reports pronounced photosensitivity as a neurophysiological finding in the SCARB2 cohort.
Relative preservation of cognition Cognitive impairment HP:0100543 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cognitive impairment (HP:0100543). HP:0100543 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22050460 REFUTE Human Clinical
"The main clinical features were adolescent-young adulthood onset, progressive action myoclonus, ataxia, absence of cognitive deterioration and, in most cases, epilepsy."
Recorded as REFUTE against the phenotype term Cognitive impairment: this series reports absence of cognitive deterioration, which is the claim the entry is making.
PMID:26677510 SUPPORT REVIEW SYNTHESIS Other
"educational support for those with cognitive decline"
GeneReviews management guidance presupposes that some affected individuals do develop cognitive decline, which is why the description calls the sparing relative rather than absolute.
Peripheral neuropathy HP:0009830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral neuropathy (HP:0009830). HP:0009830 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:35346091 SUPPORT Human Clinical
"Intrafamilial clinical heterogeneity with common features including dysarthria, tremor and proteinuria, and distinct features such as peripheral neuropathy (PNP), myoclonus and seizures between the affected cases, was observed in the family."
Documents peripheral neuropathy in patients, and specifically as a feature that varies between siblings carrying the same variant, which is the variability this phenotype's description asserts.
PMID:35346091 SUPPORT Human Clinical
"The EMG revealed a mild axonal type of sensorimotor neuropathy."
The electrophysiological characterization in the index case: axonal and sensorimotor rather than purely sensory.
PMID:37529812 SUPPORT Human Clinical
"In line with standardized protocols, EMG findings consistent with AMRF present a polyneuropathy characterized by axonal degeneration and demyelinating features."
An independent report giving the same axonal-plus-demyelinating picture and treating EMG as a diagnostic contributor, which is why this phenotype is described here as part of the workup rather than an incidental finding.
🧬

Genetic Associations

1
SCARB2 (Biallelic Loss-of-Function Variants)
Gene: SCARB2 hgnc:1665 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SCARB2 (hgnc:1665). hgnc:1665 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal Recessive
Show evidence (3 references)
PMID:19933215 SUPPORT In Vitro
"To date, six AMRF-causing mutations have been described, including splice site, missense and nonsense mutations."
Documents the allelic spectrum stated in the notes.
PMID:19933215 SUPPORT In Vitro
"In contrast to the reduced binding properties of the nonsense mutations, the only missense mutation (H363N) found in AMRF leads to increased binding of beta-GC to LIMP-2"
Supports the specific claim that H363N increases rather than abolishes binding, making it a release defect.
PMID:35346091 SUPPORT REVIEW SYNTHESIS Human Clinical
"In-depth literature review enabled the detailed investigation of the reported variants associated with AMRF and suggested that while the type of the variant did not have a major impact on the course of the clinical characteristics, only the C terminal localization of the pathogenic variant..."
The genotype-phenotype claim in the notes, including its negative half: variant type does not predict the course, position does. quote_role is REVIEW_SYNTHESIS because this is the paper's synthesis across previously reported cases rather than a result from its own index family.
💊

Medical Actions

6
Substrate Reduction Therapy (Miglustat)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: miglustat CHEBI:50381 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses miglustat (CHEBI:50381). CHEBI:50381 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
The only treatment in this entry that targets the mechanism rather than the symptoms. Miglustat inhibits glucosylceramide synthase, so it reduces production of the substrate that the mistrafficked glucocerebrosidase cannot degrade - the same logic used in Gaucher disease, reached here from the opposite direction. One patient treated for three years after several years of steady worsening had progression of myoclonus halt, dysphagia resolve, some skills reacquired and seizures remain controlled. A second, earlier report describes significant improvement in one of two affected sisters given substrate reduction therapy.
Mechanism Target:
Neuronal Lysosomal Storage and Intracellular Inclusions — Reduces glucosylceramide synthesis upstream, lowering the substrate load that cannot be cleared, rather than restoring enzyme delivery.
Target Phenotypes: Action myoclonus HP:0034360 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Action myoclonus (HP:0034360). HP:0034360 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34337151 SUPPORT DIRECT Human Clinical
"Progression of myoclonus halted, dysphagia resolved, some skills were reacquired, and seizures remained well controlled."
The observed outcomes in the single treated patient over three years.
PMID:21782476 SUPPORT INDIRECT Human Clinical
"When substrate-reduction therapy, to correct the possible glucocerebroside storage in the cells with glucocerebrosidase deficiency, was administered to one of the siblings, a significant improvement was observed."
An independent single-patient report of benefit. Graded INDIRECT because the report names substrate reduction therapy generically rather than the agent, so it supports the strategy rather than this specific drug.
Anti-Myoclonic and Anti-Seizure Pharmacotherapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: Small molecule
Symptomatic pharmacotherapy to reduce myoclonus and seizures. There is no disease-modifying therapy. Several widely used anti-seizure drugs are actively harmful here and are listed under agents to avoid.
Target Phenotypes: Action myoclonus HP:0034360 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Action myoclonus (HP:0034360). HP:0034360 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26677510 SUPPORT REVIEW SYNTHESIS Other
"pharmacotherapy to reduce myoclonus; anti-seizure medication (ASM) and vagus nerve stimulation to reduce seizures"
GeneReviews management recommendation for the neurological manifestations.
Vagus Nerve Stimulation
Action: vagus nerve stimulator implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is vagus nerve stimulator implantation, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Device
Neurostimulation offered for seizure reduction when pharmacotherapy is insufficient.
Show evidence (1 reference)
PMID:26677510 SUPPORT REVIEW SYNTHESIS Other
"anti-seizure medication (ASM) and vagus nerve stimulation to reduce seizures"
GeneReviews lists vagus nerve stimulation among the recommended seizure-directed interventions.
Renin-Angiotensin-Aldosterone Inhibition and Immunosuppression for Proteinuria
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: Small molecule
Nephrology-directed treatment aimed at remission of proteinuria, typically combining renin-angiotensin-aldosterone system inhibition with immunosuppressive medication. The nephrotic syndrome is steroid resistant, so this is proteinuria control rather than a cure.
Target Phenotypes: Steroid-resistant nephrotic syndrome HP:0012588 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Steroid-resistant nephrotic syndrome (HP:0012588). HP:0012588 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26677510 SUPPORT REVIEW SYNTHESIS Other
"Treatment for renal involvement, under the care of a nephrologist, is typically focused on remission of proteinuria and often includes a combination of renin-angiotensin-aldosterone inhibition and immunosuppressive medications."
GeneReviews statement of the renal treatment approach.
Dialysis and Renal Transplantation
Action: renal replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is renal replacement therapy, annotated with Organ Transplantation (NCIT:C15289). NCIT:C15289 is a clinical intervention from the NCI Thesaurus. Ontology label: Organ Transplantation NCIT:C15289
Platform: Surgery
Renal replacement therapy is effective for the renal arm and is what made the syndrome visible at all: before dialysis and transplantation existed, the course was rapidly fatal and the neurological phenotype was never reached. It does not touch the neurological disease, which continues to progress even with normalized renal function.
Target Phenotypes: Stage 5 chronic kidney disease HP:0003774 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Stage 5 chronic kidney disease (HP:0003774). HP:0003774 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:15364701 SUPPORT Human Clinical
"Dialysis and renal transplantation are effective for the renal but not the neurological features, which continue to progress even in the presence of normalized renal function"
States both the efficacy for the renal arm and the explicit failure to affect the neurological one.
PMID:15364701 SUPPORT BACKGROUND Human Clinical
"The syndrome was not recognized prior to the advent of dialysis and renal transplantation because of its rapidly fatal course if renal failure is untreated."
Supports the historical claim in the description. Quoted from the paper's opening framing rather than from its results, hence quote_role BACKGROUND.
Rehabilitation and Supportive Care
Action: rehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is rehabilitation (NCIT:C15315). NCIT:C15315 is a clinical intervention from the NCI Thesaurus. Ontology label: Rehabilitation NCIT:C15315
Platform: Behavioral / lifestyle
Physical and occupational therapy to maintain mobility and activities of daily living, adaptive mobility devices, speech-language therapy for alternative communication, and educational support where cognitive decline appears.
Show evidence (1 reference)
PMID:26677510 SUPPORT REVIEW SYNTHESIS Other
"physical and occupational therapy to help maintain mobility and optimize activities of daily living; adaptive devices to help maintain/improve independence in mobility"
GeneReviews supportive-care recommendation for the neurological manifestations.
🔬

Diagnosis

1
Molecular Genetic Diagnosis of SCARB2-AMRF
The diagnosis is established by identifying biallelic loss-of-function SCARB2 variants in a proband with suggestive findings. Because progressive myoclonic epilepsy is genetically heterogeneous, a PME gene panel or exome/genome sequencing is the appropriate first-tier test. A leukocyte beta-glucocerebrosidase assay must not be used to exclude the diagnosis: leukocyte activity can be normal in a patient whose fibroblasts are severely deficient, because blood cells retain a LIMP-2-independent delivery route. SCARB2 testing is warranted in adolescent- or young-adult-onset PME of unknown cause even with no renal involvement.
Differential diagnosis: the other progressive myoclonic epilepsies - EPM1 (Unverricht-Lundborg, CSTB), Lafora disease (EPM2A/NHLRC1), the neuronal ceroid lipofuscinoses, MERRF, sialidosis type 1, and DRPLA. The relative preservation of cognition and the pronounced photosensitivity are the clinical discriminators; coexisting proteinuria is close to decisive when present.
Show evidence (4 references)
PMID:26677510 SUPPORT REVIEW SYNTHESIS Other
"The diagnosis of SCARB2-AMRF is established in a proband with suggestive findings and biallelic loss-of-function pathogenic variants in SCARB2 identified by molecular genetic testing."
GeneReviews statement of how the diagnosis is established.
PMID:33343627 SUPPORT Human Clinical
"In addition, this report emphasizes the presence of two EEG patterns, fixation-off phenomenon, and bursts of parasagittal spikes exclusively seen during REM sleep that appear to be characteristic of this condition."
Adds the two EEG patterns the authors propose as characteristic. Quoted with their own hedge ("appear to be") intact: this is a single case report, so it is a lead for the workup rather than a validated discriminator.
PMID:22050460 SUPPORT Human Clinical
"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."
Supports the testing recommendation for renal-negative PME stated in the description.
+ 1 more reference
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
No population prevalence estimate exists. The disease was first described in four French Canadian patients in three families in 1986, and extended to 15 individuals from nine families across five countries in 2004 - which also dispelled the belief that it was confined to French Canadian ancestry. By 2014 a total of 14 disease-causing SCARB2 variants had been described. Reported case numbers remain in the low dozens.
Show evidence (2 references)
PMID:15364701 SUPPORT Human Clinical
"We now describe 15 individuals with AMRF from five countries, including a follow-up of the four French Canadian patients, allowing a more complete characterization of this disease."
The largest published series, and the source of the case count and geographic spread stated in the notes.
PMID:24389070 SUPPORT REVIEW SYNTHESIS Other
"A total of 14 disease-causing SCARB2 mutations have been identified to date."
Gives the order of magnitude of reported allelic and case diversity, the basis for the ULTRA_RARE band in the absence of a prevalence figure.
🐁

Animal Models

1
Limp2 knockout mouse
The Limp2-null mouse predates the discovery of AMRF's cause and was characterized in its own right in 2003; it was reanalysed in 2008 once SCARB2 was identified as the AMRF gene. Read on its own terms it is a poor model of the human disease: its reported phenotype is ureteropelvic junction obstruction with hydronephrosis, hearing loss from loss of spiral ganglia and hair cells, and a peripheral demyelinating neuropathy - none of which is the human syndrome. The neuronal storage component and the glomerular change were found on reanalysis, and the glomerular change is subtle. The mouse's own authors proposed it as a lead for human disorders of the stria vascularis or peripheral demyelination, not for a progressive myoclonic epilepsy with glomerulosclerosis.
Species
Mouse
Genotype
Scarb2 (Limp2) homozygous null
Publication
PMID:12620969
Pathograph links
Neuronal Lysosomal Storage and Intracellular Inclusions recapitulates fidelity: moderate observes: cellular Intracellular inclusions in cerebral and cerebellar cortex, the same regions affected in human AMRF.
Show evidence (1 reference)
PMID:18308289 SUPPORT Model Organism
"Reanalysis of an existing Limp2 knockout mouse showed intracellular inclusions in cerebral and cerebellar cortex"
Reports the neuronal storage phenotype in the null mouse.
Podocyte Injury and Glomerular Collapse partially recapitulates fidelity: low observes: tissue Glomerular change is present but subtle, well short of the focal segmental glomerulosclerosis with collapse and end-stage kidney disease seen in patients.
Limitations: The mouse does not develop the nephrotic syndrome or progressive renal failure that define the renal half of the human syndrome, so it cannot be used to study that arm's progression or to test renal endpoints.
Show evidence (1 reference)
PMID:18308289 SUPPORT Model Organism
"the kidneys showed subtle glomerular changes"
Reports the attenuated renal phenotype, the basis for PARTIALLY_RECAPITULATES and LOW fidelity.
Cortical Hyperexcitability and Cerebellar Degeneration fails to recapitulate fidelity: low observes: organism The null mouse's characterized phenotype is renal-outflow, cochlear and peripheral-nerve disease. No progressive myoclonus, seizure phenotype or cerebellar syndrome is reported in it.
Limitations: The organism-level phenotype is in different organs from the human disease and the mouse's own describing authors pointed it at a different set of human disorders. It therefore cannot be used to test a myoclonus or seizure endpoint, which is the arm that matters most clinically and the one substrate reduction therapy is aimed at.
Show evidence (2 references)
PMID:12620969 SUPPORT Model Organism
"The phenotype of LIMP-2-deficient mice stimulates the search for mutations in human disorders associated with degeneration of the stria vascularis and/or demyelinization of peripheral nerves."
The mouse's own authors direct it at a different class of human disease, which is the clearest statement that its phenotype is not the AMRF one.
+ 1 more reference
Reduced Lysosomal Glucocerebrosidase Activity recapitulates fidelity: high observes: molecular Tissue GCase deficiency with the same tissue-specific sparing of leukocytes seen in patients.
Limitations: What the mouse measures is enzyme activity, by activity assay and activity-based probe, in whole-tissue preparations and in isolated leukocytes. The node it is linked to claims something one step up: that lysosomal GCase delivery is LIMP-2-dependent in particular cell types. A whole-tissue activity assay cannot attribute the residual activity it finds to any one cell type within that tissue, so the leukocyte-versus-tissue contrast is the only cell-resolved comparison this model supplies. The finer claim in the node, that fibroblasts and neuronal cells are entirely LIMP-2-dependent while blood cells are not, rests on the human fibroblast and leukocyte data cited on that node rather than on this mouse.
Show evidence (1 reference)
PMID:40639771 SUPPORT Model Organism
"Noteworthy, in LIMP-2-deficient mice, residual GCase is remarkably high in leukocytes."
The mouse reproduces the leukocyte-sparing pattern that is the diagnostic trap in patients.
{ }

Source YAML

click to show 
name: Action Myoclonus-Renal Failure Syndrome
creation_date: "2026-09-16T20:45:00Z"
description: >
  Action myoclonus-renal failure syndrome (AMRF) is an autosomal recessive
  lysosomal disorder caused by biallelic loss-of-function variants in SCARB2,
  which encodes the lysosomal integral membrane protein type 2 (LIMP-2). LIMP-2
  is the mannose-6-phosphate-independent sorting receptor that carries
  beta-glucocerebrosidase (GCase) from the endoplasmic reticulum to the
  lysosome. When LIMP-2 is absent or retained in the ER, GCase never reaches the
  lysosome and is degraded, so the disease is a trafficking failure of a
  lysosomal enzyme rather than a defect in the enzyme itself. The clinical
  picture combines a progressive myoclonic epilepsy - adolescent or young-adult
  onset action myoclonus of cortical origin, ataxia, and seizures, characteristically
  without early dementia - with steroid-resistant nephrotic syndrome progressing
  to focal segmental glomerulosclerosis and end-stage kidney disease. The two
  organ manifestations progress independently, and some individuals with
  biallelic SCARB2 variants develop progressive myoclonus epilepsy with no renal
  involvement at all; that form sits at one end of the same spectrum rather than
  being a separate disease. Disease progresses relentlessly to death within
  roughly 7 to 15 years of onset.
category: Mendelian
disease_term:
  preferred_term: action myoclonus-renal failure syndrome
  term:
    id: MONDO:0009699
    label: action myoclonus-renal failure syndrome
synonyms:
- AMRF
- AMRF syndrome
- SCARB2-related action myoclonus-renal failure syndrome
- SCARB2-AMRF
- progressive myoclonic epilepsy with renal failure
- myoclonus epilepsy and glomerulosclerosis
- EPM4
- progressive myoclonic epilepsy 4 with or without renal failure
- myoclonus-nephropathy syndrome
parents:
- Progressive Myoclonus Epilepsy
- Lysosomal Storage Disease
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
  - classification_value: KIDNEY_URINARY_TRACT
references:
- reference: PMID:26677510
  title: "SCARB2-Related Action Myoclonus - Renal Failure Syndrome."
  tags:
  - GeneReviews
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    AMRF is inherited in an autosomal recessive manner. Affected individuals
    carry biallelic loss-of-function SCARB2 variants; heterozygous parents are
    asymptomatic carriers.
  evidence:
  - reference: PMID:26677510
    reference_title: "SCARB2-Related Action Myoclonus - Renal Failure Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      SCARB2-AMRF is inherited in an autosomal recessive manner.
    explanation: >-
      GeneReviews statement of the mode of inheritance for this disease.
  - reference: PMID:18424452
    reference_title: "A nonsense mutation in the LIMP-2 gene associated with progressive myoclonic epilepsy and nephrotic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homozygous nonsense mutation in codon 178 of SCARB2 was found in the
      patient, whereas her healthy parents were heterozygous for the mutation.
    explanation: >-
      Documents the recessive segregation directly: homozygous proband, healthy
      heterozygous parents.
pathophysiology:
- name: LIMP-2 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic SCARB2 variants - nonsense, frameshift, splice-site and rarely
    missense - abolish functional LIMP-2. Nonsense and frameshift alleles leave
    no immunodetectable protein; the alleles that do produce protein are retained
    in the endoplasmic reticulum rather than reaching the lysosomal membrane. The
    consequence is the same in either case: no functional sorting receptor at the
    site where cargo must be handed over.
  genetic_context:
    gene:
      preferred_term: SCARB2
      term:
        id: hgnc:1665
        label: SCARB2
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  cellular_components:
  - preferred_term: lysosomal membrane
    term:
      id: GO:0005765
      label: lysosomal membrane
  downstream:
  - target: Failure of Beta-Glucocerebrosidase Lysosomal Targeting
    causal_link_type: DIRECT
    description: >-
      Without LIMP-2 at the ER-to-lysosome interface its cargo cannot be routed.
  evidence:
  - reference: PMID:18308289
    reference_title: "Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in SCARB2/Limp2 were found in all three families used for mapping
      and subsequently confirmed in two other unrelated AMRF families. The
      mutations were associated with lack of SCARB2 protein.
    explanation: >-
      Establishes that the causal SCARB2 variants in AMRF abolish the protein.
  - reference: PMID:19933215
    reference_title: "Disease-causing mutations within the lysosomal integral membrane protein type 2 (LIMP-2) reveal the nature of binding to its ligand beta-glucocerebrosidase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All mutations investigated in this study lead to a retention of LIMP-2 in
      the endoplasmic reticulum (ER) but affect the binding to beta-GC differentially.
    explanation: >-
      Shows the second route to the same loss: AMRF alleles that are expressed do
      not leave the ER.
- name: Failure of Beta-Glucocerebrosidase Lysosomal Targeting
  biological_scale: MOLECULAR
  description: >-
    LIMP-2 binds beta-glucocerebrosidase in the ER through a conserved coiled-coil
    domain and releases it in the acidified late endosome/lysosome, a handover
    gated by a critical histidine that acts as a pH sensor. This route is
    mannose-6-phosphate independent, which is why AMRF spares the many lysosomal
    hydrolases that use the M6P receptor. With LIMP-2 absent, GCase is stranded in
    the ER, remains endoglycosidase-H sensitive, and is degraded.
  biological_processes:
  - preferred_term: LIMP-2-mediated sorting of beta-glucocerebrosidase
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0006622
      label: protein targeting to lysosome
  downstream:
  - target: Reduced Lysosomal Glucocerebrosidase Activity
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:18424452
    reference_title: "A nonsense mutation in the LIMP-2 gene associated with progressive myoclonic epilepsy and nephrotic syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Besides lacking immunodetectable LIMP-2, patient fibroblasts also had
      decreased amounts of beta-glucocerebrosidase, which was mainly located in
      the endoplasmic reticulum, as assessed by its sensitivity to Endo H.
    explanation: >-
      Direct patient-cell demonstration that GCase is stranded in the ER when
      LIMP-2 is absent.
  - reference: PMID:22537104
    reference_title: "A critical histidine residue within LIMP-2 mediates pH sensitive binding to its ligand beta-glucocerebrosidase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We now demonstrate that the lumenal acidification mediated by the vacuolar
      (H(+) )-ATPase triggers the dissociation of LIMP-2 and GC in late
      endosomal/lysosomal compartments.
    explanation: >-
      Defines the normal delivery step whose loss this node describes: pH-gated
      release of GCase from LIMP-2 at the lysosome.
- name: Reduced Lysosomal Glucocerebrosidase Activity
  biological_scale: CELLULAR
  description: >-
    Lysosomal GCase activity falls in the cell types that depend on LIMP-2 for
    its delivery. The dependence is tissue-specific, and this is the reason AMRF
    is not Gaucher disease: in fibroblasts and neuronal cells GCase targeting is
    entirely LIMP-2 dependent, while in blood cells a LIMP-2-independent route
    preserves substantial activity. Leukocyte GCase can therefore be normal in a
    patient whose fibroblasts are severely deficient, which is a diagnostic trap
    as well as a mechanistic fact.
  biological_processes:
  - preferred_term: glucosylceramide catabolism in the lysosome
    modifier: DECREASED
    term:
      id: GO:0006680
      label: glucosylceramide catabolic process
  molecular_functions:
  - preferred_term: glucocerebrosidase activity
    modifier: DECREASED
    term:
      id: GO:0004348
      label: glucosylceramidase activity
  downstream:
  - target: Neuronal Lysosomal Storage and Intracellular Inclusions
    causal_link_type: DIRECT
  - target: Podocyte Injury and Glomerular Collapse
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:18424452
    reference_title: "A nonsense mutation in the LIMP-2 gene associated with progressive myoclonic epilepsy and nephrotic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The biochemical analysis of one of the patients revealed a normal
      beta-glucocerebrosidase activity in leukocytes, but a severe enzymatic
      deficiency in cultured skin fibroblasts.
    explanation: >-
      Documents the tissue-restricted enzyme deficiency this node asserts,
      including the normal leukocyte result.
  - reference: PMID:26018676
    reference_title: "Role of LIMP-2 in the intracellular trafficking of beta-glucosidase in different human cellular models."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In fibroblasts and neuronlike cells, GCase targeting to the lysosomes is
      completely dependent on LIMP-2, whereas in blood cells, GCase is partially
      targeted to lysosomes by a LIMP-2-independent mechanism.
    explanation: >-
      Establishes the cell-type dependence that explains why the deficiency is
      partial and why AMRF diverges clinically from Gaucher disease.
- name: Neuronal Lysosomal Storage and Intracellular Inclusions
  biological_scale: CELLULAR
  description: >-
    Storage material accumulates in cerebral and cerebellar cortical neurons.
    Notably the stored species is not bulk glucosylceramide: in the LIMP-2-deficient
    mouse, glucosylceramide is not markedly raised, while its downstream
    deacylated and sterol-conjugated metabolites glucosylsphingosine and
    glucosylated cholesterol are. That distinction is the current best explanation
    for why LIMP-2 deficiency produces a neuronal storage encephalopathy with
    glomerulosclerosis rather than the visceral, macrophage-centred picture of
    Gaucher disease.
  cell_types:
  - preferred_term: cortical and cerebellar neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  downstream:
  - target: Cortical Hyperexcitability and Cerebellar Degeneration
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:18308289
    reference_title: "Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Reanalysis of an existing Limp2 knockout mouse showed intracellular
      inclusions in cerebral and cerebellar cortex, and the kidneys showed subtle
      glomerular changes.
    explanation: >-
      Shows neuronal storage inclusions in the cortical regions this node names,
      in the LIMP-2-null mouse.
  - reference: PMID:40639771
    reference_title: "LIMP-2 deficiency-associated glycolipid abnormalities in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      GCase deficiency in tissues does not correlate with increases in GlcCer,
      but rather with increases in glucosylsphingosine (GlcSph) and glucosylated
      cholesterol (GlcChol), both glucosylated metabolites derived from GlcCer.
    explanation: >-
      Identifies which glycolipid species actually accumulate, supporting the
      claim that the stored material is not bulk glucosylceramide.
- name: Cortical Hyperexcitability and Cerebellar Degeneration
  biological_scale: TISSUE
  description: >-
    Sensorimotor cortex becomes hyperexcitable and cerebellar output degenerates.
    The myoclonus of AMRF is cortical in origin, not subcortical: EEG-EMG
    coherence and phase analysis in SCARB2 patients show significant coupling with
    a direct corticospinal transfer, and the rhythmic 12-20 Hz jerking can be
    mistaken clinically for a postural tremor. Marked photosensitivity accompanies
    it. Cognition is characteristically spared relative to the other progressive
    myoclonic epilepsies.
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  - preferred_term: cerebellar cortex
    term:
      id: UBERON:0002129
      label: cerebellar cortex
  downstream:
  - target: Peripheral neuropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Grouped with the central manifestations because it shares their upstream
      storage lesion, but the route from lysosomal storage to peripheral nerve is
      not established in AMRF and the neuropathy is variable within a single
      family, so the edge is drawn with unknown intermediates.
  - target: Action myoclonus
    causal_link_type: DIRECT
  - target: Progressive cerebellar ataxia
    causal_link_type: DIRECT
  - target: Generalized tonic-clonic seizures
    causal_link_type: DIRECT
  - target: Photosensitivity
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:22050460
    reference_title: "Clinical and neurophysiologic features of progressive myoclonus epilepsy without renal failure caused by SCARB2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Direct human neurophysiological demonstration that the myoclonus arises in
      cortex and is transmitted corticospinally.
- name: Podocyte Injury and Glomerular Collapse
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    In the kidney the same enzyme-delivery failure produces podocyte injury,
    proteinuria, and focal segmental glomerulosclerosis, frequently with
    glomerular collapse. The renal arm runs on its own clock: renal involvement
    can precede neurological onset by decades, or be absent altogether in
    individuals whose biallelic SCARB2 variants produce progressive myoclonus
    epilepsy alone. The molecular step between reduced GCase delivery and podocyte
    injury is not established, which is why this edge is marked INDIRECT upstream.
  cell_types:
  - preferred_term: glomerular podocyte
    term:
      id: CL:0000653
      label: podocyte
  locations:
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  downstream:
  - target: Focal segmental glomerulosclerosis
    causal_link_type: DIRECT
  - target: Steroid-resistant nephrotic syndrome
    causal_link_type: DIRECT
  - target: End-stage kidney disease
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:18308289
    reference_title: "Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Action myoclonus-renal failure syndrome (AMRF) is an autosomal-recessive
      disorder with the remarkable combination of focal glomerulosclerosis,
      frequently with glomerular collapse, and progressive myoclonus epilepsy
      associated with storage material in the brain.
    explanation: >-
      States the renal lesion - focal glomerulosclerosis with glomerular collapse
      - that this node describes.
  - reference: PMID:26677510
    reference_title: "SCARB2-Related Action Myoclonus - Renal Failure Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The neurologic and renal manifestations progress independently.
    explanation: >-
      Supports treating the renal arm as a parallel consequence rather than a
      sequela of the neurological disease.
  - reference: PMID:15364701
    reference_title: "Action myoclonus-renal failure syndrome: characterization of a unique cerebro-renal disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      The independent progression of neurological and renal disorders in AMRF
      suggests a unitary molecular lesion with pleiotropic effects.
    explanation: >-
      The clinical observation of independent progression, which is what the
      pathograph's parallel-arm structure represents. Graded INDIRECT because the
      quote is the authors' inference from the observation rather than a
      measurement, and it predates the identification of SCARB2.
phenotypes:
- category: Neurological
  name: Tremor
  description: >-
    Tremor is typically the first neurological sign, appearing at 17 to 26 years
    (mean 19.8), about two years before the action myoclonus it precedes. It is
    seen in the fingers or hands and is worsened by fine motor activity such as
    handwriting.
  phenotype_term:
    preferred_term: Tremor
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: PMID:15364701
    reference_title: "Action myoclonus-renal failure syndrome: characterization of a unique cerebro-renal disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tremor (onset 17-26 years, mean 19.8 years, median 19 years) and
      progressively disabling action myoclonus (onset 14-29 years, mean 21.7 years,
      median 21 years), with infrequent generalized seizures (onset 20-28 years,
      mean 22.7 years, median 22 years) and cerebellar features are characteristic.
    explanation: >-
      Gives the onset ages for tremor, myoclonus and seizures in the 15-patient
      series, the source of the sequence described here.
- category: Neurological
  name: Action myoclonus
  description: >-
    Progressive action- and stimulus-sensitive myoclonus of cortical origin, the
    defining and most disabling neurological feature. It worsens relentlessly and
    is the usual cause of loss of independent function.
  phenotype_term:
    preferred_term: Action myoclonus
    term:
      id: HP:0034360
      label: Action myoclonus
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:22050460
    reference_title: "Clinical and neurophysiologic features of progressive myoclonus epilepsy without renal failure caused by SCARB2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main clinical features were adolescent-young adulthood onset,
      progressive action myoclonus, ataxia, absence of cognitive deterioration
      and, in most cases, epilepsy.
    explanation: >-
      Names progressive action myoclonus as a main clinical feature in a SCARB2
      patient series.
- category: Neurological
  name: Postural tremor-like rhythmic myoclonus
  description: >-
    Rhythmic myoclonic jerking at 12-20 Hz that clinically resembles a postural
    tremor. Recognising it as myoclonus rather than tremor is diagnostically
    useful, because it points to a cortical generator.
  phenotype_term:
    preferred_term: Postural tremor
    term:
      id: HP:0002174
      label: Postural tremor
  evidence:
  - reference: PMID:22050460
    reference_title: "Clinical and neurophysiologic features of progressive myoclonus epilepsy without renal failure caused by SCARB2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      massive action myoclonus associated with rhythmic myoclonic jerks at a
      frequency of 12-20 Hz, clinically resembling a postural tremor
    explanation: >-
      Describes the rhythmic myoclonus and its clinical resemblance to postural
      tremor.
- category: Neurological
  name: Progressive cerebellar ataxia
  description: >-
    Progressive gait and limb ataxia accompanying the myoclonus.
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:22050460
    reference_title: "Clinical and neurophysiologic features of progressive myoclonus epilepsy without renal failure caused by SCARB2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main clinical features were adolescent-young adulthood onset,
      progressive action myoclonus, ataxia, absence of cognitive deterioration
      and, in most cases, epilepsy.
    explanation: >-
      Lists ataxia among the main clinical features of the SCARB2 series.
- category: Neurological
  name: Generalized tonic-clonic seizures
  description: >-
    Epilepsy is present in most affected individuals, and its severity tracks age
    at onset: adolescent-onset cases can have uncontrolled seizures and status
    epilepticus, while adult-onset cases may have rare seizures or none.
  phenotype_term:
    preferred_term: Bilateral tonic-clonic seizure
    term:
      id: HP:0002069
      label: Bilateral tonic-clonic seizure
  evidence:
  - reference: PMID:22050460
    reference_title: "Clinical and neurophysiologic features of progressive myoclonus epilepsy without renal failure caused by SCARB2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Supports both the presence of epilepsy and the onset-dependent severity
      stated in the description.
- category: Neurological
  name: Photosensitivity
  description: >-
    Pronounced photoparoxysmal response on EEG, a consistent neurophysiological
    marker in SCARB2-related disease.
  phenotype_term:
    preferred_term: Photosensitive tonic-clonic seizure
    term:
      id: HP:0007207
      label: Photosensitive tonic-clonic seizure
  evidence:
  - reference: PMID:22050460
    reference_title: "Clinical and neurophysiologic features of progressive myoclonus epilepsy without renal failure caused by SCARB2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Relevant neurophysiologic findings were a pronounced photosensitivity
    explanation: >-
      Reports pronounced photosensitivity as a neurophysiological finding in the
      SCARB2 cohort.
- category: Neurological
  name: Relative preservation of cognition
  description: >-
    Cognition is characteristically spared, at least early, which separates AMRF
    from Lafora disease and the neuronal ceroid lipofuscinoses. Cognitive decline
    can nonetheless appear late, and GeneReviews recommends educational support
    for those who develop it, so this is a relative not an absolute feature.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:22050460
    reference_title: "Clinical and neurophysiologic features of progressive myoclonus epilepsy without renal failure caused by SCARB2 mutations."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main clinical features were adolescent-young adulthood onset,
      progressive action myoclonus, ataxia, absence of cognitive deterioration
      and, in most cases, epilepsy.
    explanation: >-
      Recorded as REFUTE against the phenotype term Cognitive impairment: this
      series reports absence of cognitive deterioration, which is the claim the
      entry is making.
  - reference: PMID:26677510
    reference_title: "SCARB2-Related Action Myoclonus - Renal Failure Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      educational support for those with cognitive decline
    explanation: >-
      GeneReviews management guidance presupposes that some affected individuals
      do develop cognitive decline, which is why the description calls the
      sparing relative rather than absolute.
- category: Neurological
  name: Dysphagia
  description: >-
    Swallowing difficulty severe enough to warrant feeding-therapy programmes and
    aspiration-risk management.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:26677510
    reference_title: "SCARB2-Related Action Myoclonus - Renal Failure Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      feeding therapy programs for those with dysphagia to improve nutrition and
      reduce aspiration risk
    explanation: >-
      GeneReviews management section identifies dysphagia as a manifestation
      requiring intervention.
- category: Renal
  name: Steroid-resistant nephrotic syndrome
  description: >-
    Proteinuria that does not remit on corticosteroids, the usual renal
    presentation. It may precede any neurological sign by decades.
  phenotype_term:
    preferred_term: Steroid-resistant nephrotic syndrome
    term:
      id: HP:0012588
      label: Steroid-resistant nephrotic syndrome
  evidence:
  - reference: PMID:26677510
    reference_title: "SCARB2-Related Action Myoclonus - Renal Failure Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      renal involvement that is apparently due to steroid-resistant nephrotic
      syndrome (SRNS)
    explanation: >-
      GeneReviews identifies steroid-resistant nephrotic syndrome as the renal
      manifestation of this disease.
- category: Renal
  name: Proteinuria
  description: >-
    Proteinuria is the first renal sign and was detected in every patient of the
    15-case series, between ages 9 and 30. It progressed to renal failure in 12 of
    15 within 0 to 8 years of detection, so the window between the first
    abnormal urinalysis and dialysis is short and variable.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  frequency: 15/15
  evidence:
  - reference: PMID:15364701
    reference_title: "Action myoclonus-renal failure syndrome: characterization of a unique cerebro-renal disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Proteinuria, detected between ages 9 and 30 years in all cases, progressed to
      renal failure in 12 out of 15 patients within 0-8 years after proteinuria
      detection.
    explanation: >-
      Gives both the universality of proteinuria in this series and the interval to
      renal failure.
- category: Renal
  name: Focal segmental glomerulosclerosis
  description: >-
    The renal histological lesion, frequently with glomerular collapse.
  phenotype_term:
    preferred_term: Focal segmental glomerulosclerosis
    term:
      id: HP:0000097
      label: Focal segmental glomerulosclerosis
  evidence:
  - reference: PMID:18308289
    reference_title: "Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the remarkable combination of focal glomerulosclerosis, frequently with
      glomerular collapse, and progressive myoclonus epilepsy
    explanation: >-
      Names focal glomerulosclerosis with collapse as the renal lesion of AMRF.
  - reference: PMID:15364701
    reference_title: "Action myoclonus-renal failure syndrome: characterization of a unique cerebro-renal disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renal biopsies showed collapsing glomerulopathy, a severe variant of focal
      glomerulosclerosis.
    explanation: >-
      Histological confirmation across the 15-patient series, and identifies the
      lesion specifically as the collapsing variant.
- category: Renal
  name: End-stage kidney disease
  description: >-
    Progression to end-stage kidney disease requiring renal replacement therapy.
    Dialysis or transplantation prolongs survival but does not alter the
    neurological course.
  phenotype_term:
    preferred_term: Stage 5 chronic kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: PMID:26677510
    reference_title: "SCARB2-Related Action Myoclonus - Renal Failure Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Treatment of ESKD is supportive; while renal replacement therapy can
      prolong survival, it does not improve neurologic features.
    explanation: >-
      Establishes both that ESKD occurs and that treating it does not change the
      neurological trajectory.
- category: Neurological
  name: Peripheral neuropathy
  description: >-
    A sensorimotor peripheral neuropathy, axonal with demyelinating features on
    nerve conduction studies. It is variable within a single family carrying one
    variant, so its absence does not argue against the diagnosis; its presence in a
    patient who also has renal and central nervous system involvement is the
    combination that should prompt SCARB2 testing.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:35346091
    reference_title: "Genotype-Phenotype correlations of SCARB2 associated clinical presentation: a case report and in-depth literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intrafamilial clinical heterogeneity with common features including
      dysarthria, tremor and proteinuria, and distinct features such as peripheral
      neuropathy (PNP), myoclonus and seizures between the affected cases, was
      observed in the family.
    explanation: >-
      Documents peripheral neuropathy in patients, and specifically as a feature
      that varies between siblings carrying the same variant, which is the
      variability this phenotype's description asserts.
  - reference: PMID:35346091
    reference_title: "Genotype-Phenotype correlations of SCARB2 associated clinical presentation: a case report and in-depth literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The EMG revealed a mild axonal type of sensorimotor neuropathy.
    explanation: >-
      The electrophysiological characterization in the index case: axonal and
      sensorimotor rather than purely sensory.
  - reference: PMID:37529812
    reference_title: "Action Myoclonus-Renal Failure Syndrome: A Case Report with Bioinformatic Annotations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In line with standardized protocols, EMG findings consistent with AMRF present
      a polyneuropathy characterized by axonal degeneration and demyelinating
      features.
    explanation: >-
      An independent report giving the same axonal-plus-demyelinating picture and
      treating EMG as a diagnostic contributor, which is why this phenotype is
      described here as part of the workup rather than an incidental finding.
histopathology:
- name: C1q accumulation in glomerular capillary loops and mesangium
  description: >-
    Strong C1q deposition in capillary loops and mesangium on renal biopsy, reported
    alongside the nephrotic syndrome. This is what gives the renal lesion its
    alternative name in the literature, where SCARB2 disease is sometimes reported
    as progressive myoclonus epilepsy with C1q nephropathy. It sits beside rather
    than instead of the collapsing focal segmental glomerulosclerosis curated under
    phenotypes, and the entry does not assert that either is the invariable renal
    histology. The two are not confined to separate families: one patient (II.13 of
    the Turkish p.N45MfsX88 family) has C1q, C3 and IgM deposition and FSGS in the
    same biopsy. That biopsy is reported as FSGS without the collapsing qualifier,
    so what co-occurs there is C1q deposition with FSGS, not specifically with the
    collapsing variant.
  finding_term:
    preferred_term: C1q deposition in glomerular capillary loops and mesangium
  evidence:
  - reference: PMID:18424452
    reference_title: "A nonsense mutation in the LIMP-2 gene associated with progressive myoclonic epilepsy and nephrotic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main clinical features of two siblings from a consanguineous marriage were
      progressive myoclonic epilepsy without intellectual impairment and a nephrotic
      syndrome with a strong accumulation of C1q in capillary loops and mesangium of
      kidney.
    explanation: >-
      Reports the C1q distribution directly, in two molecularly confirmed siblings,
      and ties it to the nephrotic syndrome rather than to an incidental finding.
  - reference: PMID:35346091
    reference_title: "Genotype-Phenotype correlations of SCARB2 associated clinical presentation: a case report and in-depth literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He underwent a renal biopsy, and it showed FSGS. Immunofluorescence microscopy
      showed deposition of one positive C1q, C3, and IgM in capillary loops.
    explanation: >-
      A second, independent family with the C1q finding, and the only report here in
      which C1q deposition and FSGS are seen in one biopsy rather than in separate
      patients. The FSGS is not qualified as collapsing in this report.
- name: Extraneuronal pigment accumulation on brain autopsy
  description: >-
    Pigment accumulating outside neurons, found at autopsy in two patients of the
    defining series. It is recorded here because it is the only post-mortem
    neuropathology reported for this disease, and because its extraneuronal location
    is the observation itself: the storage in AMRF is not the intraneuronal
    inclusion picture of the other progressive myoclonic epilepsies.
  finding_term:
    preferred_term: extraneuronal pigment accumulation
  evidence:
  - reference: PMID:15364701
    reference_title: "Action myoclonus-renal failure syndrome: characterization of a unique cerebro-renal disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain autopsy in two patients revealed extraneuronal pigment accumulation.
    explanation: >-
      The finding and its denominator, from the largest published series.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population prevalence estimate exists. The disease was first described in
    four French Canadian patients in three families in 1986, and extended to 15
    individuals from nine families across five countries in 2004 - which also
    dispelled the belief that it was confined to French Canadian ancestry. By 2014
    a total of 14 disease-causing SCARB2 variants had been described. Reported case
    numbers remain in the low dozens.
  evidence:
  - reference: PMID:15364701
    reference_title: "Action myoclonus-renal failure syndrome: characterization of a unique cerebro-renal disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We now describe 15 individuals with AMRF from five countries, including a
      follow-up of the four French Canadian patients, allowing a more complete
      characterization of this disease.
    explanation: >-
      The largest published series, and the source of the case count and geographic
      spread stated in the notes.
  - reference: PMID:24389070
    reference_title: "Lysosomal integral membrane protein-2: a new player in lysosome-related pathology."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      A total of 14 disease-causing SCARB2 mutations have been identified to
      date.
    explanation: >-
      Gives the order of magnitude of reported allelic and case diversity, the
      basis for the ULTRA_RARE band in the absence of a prevalence figure.
genetic:
- name: SCARB2
  gene_term:
    preferred_term: SCARB2
    term:
      id: hgnc:1665
      label: SCARB2
  presence: Positive
  association: Biallelic Loss-of-Function Variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >-
    SCARB2 encodes LIMP-2. Reported AMRF alleles include nonsense (W178X, Q288X),
    frameshift (W146SfsX16), splice-site and a single missense (H363N) variant.
    The missense allele is mechanistically distinctive: rather than weakening
    binding it increases GCase binding to LIMP-2, so the defect there is failure
    of release rather than failure of capture.

    Genotype-phenotype: the one correlation that survives statistical testing across
    the reported cases is positional rather than mechanistic. Variant *type* does not
    predict the clinical course, but a C-terminal variant location is significantly
    associated with age at onset. That is the only established modifier for this
    disease, and it means the allele's position in the protein carries prognostic
    information that its class does not.
  evidence:
  - reference: PMID:19933215
    reference_title: "Disease-causing mutations within the lysosomal integral membrane protein type 2 (LIMP-2) reveal the nature of binding to its ligand beta-glucocerebrosidase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      To date, six AMRF-causing mutations have been described, including splice
      site, missense and nonsense mutations.
    explanation: >-
      Documents the allelic spectrum stated in the notes.
  - reference: PMID:19933215
    reference_title: "Disease-causing mutations within the lysosomal integral membrane protein type 2 (LIMP-2) reveal the nature of binding to its ligand beta-glucocerebrosidase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In contrast to the reduced binding properties of the nonsense mutations,
      the only missense mutation (H363N) found in AMRF leads to increased binding
      of beta-GC to LIMP-2
    explanation: >-
      Supports the specific claim that H363N increases rather than abolishes
      binding, making it a release defect.
  - reference: PMID:35346091
    reference_title: "Genotype-Phenotype correlations of SCARB2 associated clinical presentation: a case report and in-depth literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In-depth literature review enabled the detailed investigation of the reported
      variants associated with AMRF and suggested that while the type of the variant
      did not have a major impact on the course of the clinical characteristics,
      only the C terminal localization of the pathogenic variant significantly
      affected the clinical presentation, particularly the age at onset (AO) of the
      disease.
    explanation: >-
      The genotype-phenotype claim in the notes, including its negative half: variant
      type does not predict the course, position does. quote_role is
      REVIEW_SYNTHESIS because this is the paper's synthesis across previously
      reported cases rather than a result from its own index family.
diagnosis:
- name: Molecular Genetic Diagnosis of SCARB2-AMRF
  description: >-
    The diagnosis is established by identifying biallelic loss-of-function SCARB2
    variants in a proband with suggestive findings. Because progressive myoclonic
    epilepsy is genetically heterogeneous, a PME gene panel or exome/genome
    sequencing is the appropriate first-tier test. A leukocyte beta-glucocerebrosidase
    assay must not be used to exclude the diagnosis: leukocyte activity can be
    normal in a patient whose fibroblasts are severely deficient, because blood
    cells retain a LIMP-2-independent delivery route. SCARB2 testing is warranted in
    adolescent- or young-adult-onset PME of unknown cause even with no renal
    involvement.
  notes: >-
    Differential diagnosis: the other progressive myoclonic epilepsies - EPM1
    (Unverricht-Lundborg, CSTB), Lafora disease (EPM2A/NHLRC1), the neuronal ceroid
    lipofuscinoses, MERRF, sialidosis type 1, and DRPLA. The relative preservation
    of cognition and the pronounced photosensitivity are the clinical
    discriminators; coexisting proteinuria is close to decisive when present.
  evidence:
  - reference: PMID:26677510
    reference_title: "SCARB2-Related Action Myoclonus - Renal Failure Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The diagnosis of SCARB2-AMRF is established in a proband with suggestive
      findings and biallelic loss-of-function pathogenic variants in SCARB2
      identified by molecular genetic testing.
    explanation: >-
      GeneReviews statement of how the diagnosis is established.
  - reference: PMID:33343627
    reference_title: "Case Report: Distinctive EEG Patterns in SCARB-2 Related Progressive Myoclonus Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, this report emphasizes the presence of two EEG patterns,
      fixation-off phenomenon, and bursts of parasagittal spikes exclusively seen
      during REM sleep that appear to be characteristic of this condition.
    explanation: >-
      Adds the two EEG patterns the authors propose as characteristic. Quoted with
      their own hedge ("appear to be") intact: this is a single case report, so it
      is a lead for the workup rather than a validated discriminator.
  - reference: PMID:22050460
    reference_title: "Clinical and neurophysiologic features of progressive myoclonus epilepsy without renal failure caused by SCARB2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Supports the testing recommendation for renal-negative PME stated in the
      description.
  - reference: PMID:35346091
    reference_title: "Genotype-Phenotype correlations of SCARB2 associated clinical presentation: a case report and in-depth literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Long latency reflexes and giant somatosensory evoked potentials (SEP) were
      recorded.
    explanation: >-
      Giant SEPs are the classic marker of cortical myoclonus, recorded here in a
      confirmed SCARB2 homozygote. The same paper's Table 1 records two affected
      brothers of the same family as having normal SEP, so a normal study does not
      argue against the diagnosis: the finding supports it when present and is
      uninformative when absent.
treatments:
- name: Substrate Reduction Therapy (Miglustat)
  description: >-
    The only treatment in this entry that targets the mechanism rather than the
    symptoms. Miglustat inhibits glucosylceramide synthase, so it reduces
    production of the substrate that the mistrafficked glucocerebrosidase cannot
    degrade - the same logic used in Gaucher disease, reached here from the
    opposite direction. One patient treated for three years after several years of
    steady worsening had progression of myoclonus halt, dysphagia resolve, some
    skills reacquired and seizures remain controlled. A second, earlier report
    describes significant improvement in one of two affected sisters given
    substrate reduction therapy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: miglustat
      term:
        id: CHEBI:50381
        label: miglustat
  target_mechanisms:
  - target: Neuronal Lysosomal Storage and Intracellular Inclusions
    description: >-
      Reduces glucosylceramide synthesis upstream, lowering the substrate load that
      cannot be cleared, rather than restoring enzyme delivery.
  target_phenotypes:
  - preferred_term: Action myoclonus
    term:
      id: HP:0034360
      label: Action myoclonus
  evidence:
  - reference: PMID:34337151
    reference_title: "Miglustat Therapy for SCARB2-Associated Action Myoclonus-Renal Failure Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Progression of myoclonus halted, dysphagia resolved, some skills were
      reacquired, and seizures remained well controlled.
    explanation: >-
      The observed outcomes in the single treated patient over three years.
  - reference: PMID:21782476
    reference_title: "Progressive myoclonus epilepsy with nephropathy C1q due to SCARB2/LIMP-2 deficiency: clinical report of two siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      When substrate-reduction therapy, to correct the possible glucocerebroside
      storage in the cells with glucocerebrosidase deficiency, was administered to
      one of the siblings, a significant improvement was observed.
    explanation: >-
      An independent single-patient report of benefit. Graded INDIRECT because the
      report names substrate reduction therapy generically rather than the agent,
      so it supports the strategy rather than this specific drug.
  notes: >-
    The evidence base is two single patients in uncontrolled reports, and the
    authors of the three-year report state the conclusion with matching hedging
    ("could be ameliorated, at least partly"). This is not established therapy. Note
    also that miglustat was used because it has modest CNS penetration: eliglustat,
    the more potent inhibitor, does not cross the blood-brain barrier, and
    compassionate-use access to the CNS-penetrant venglustat was declined. The drug
    choice is therefore a constraint of availability, not an optimum.
- name: Anti-Myoclonic and Anti-Seizure Pharmacotherapy
  description: >-
    Symptomatic pharmacotherapy to reduce myoclonus and seizures. There is no
    disease-modifying therapy. Several widely used anti-seizure drugs are actively
    harmful here and are listed under agents to avoid.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Action myoclonus
    term:
      id: HP:0034360
      label: Action myoclonus
  evidence:
  - reference: PMID:26677510
    reference_title: "SCARB2-Related Action Myoclonus - Renal Failure Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      pharmacotherapy to reduce myoclonus; anti-seizure medication (ASM) and
      vagus nerve stimulation to reduce seizures
    explanation: >-
      GeneReviews management recommendation for the neurological manifestations.
  notes: >-
    Agents to avoid, per GeneReviews: phenytoin (may aggravate neurological
    manifestations or accelerate cerebellar degeneration), the sodium channel
    blockers carbamazepine and oxcarbazepine, the GABAergic drugs tiagabine and
    vigabatrin, and gabapentin and pregabalin (may aggravate myoclonus and
    myoclonic seizures).
- name: Vagus Nerve Stimulation
  description: >-
    Neurostimulation offered for seizure reduction when pharmacotherapy is
    insufficient.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: vagus nerve stimulator implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  notes: >-
    The device itself is deliberately left unbound. CLAUDE.md's device-qualifier
    pattern wants an NCIT device term in a `qualifiers` value, but a search of
    NCIT via OLS returns only NCIT:C203750 (Transcutaneous Auricular Vagus Nerve
    Stimulation), which is a different, non-implanted intervention. Rather than
    bind a term that names something else, the device concept is carried in
    `preferred_term`. This matches how every other KB entry curates VNS
    (Dravet_syndrome, Epilepsy, Lennox-Gastaut_Syndrome all bind the surgical
    action alone).
  evidence:
  - reference: PMID:26677510
    reference_title: "SCARB2-Related Action Myoclonus - Renal Failure Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      anti-seizure medication (ASM) and vagus nerve stimulation to reduce
      seizures
    explanation: >-
      GeneReviews lists vagus nerve stimulation among the recommended
      seizure-directed interventions.
- name: Renin-Angiotensin-Aldosterone Inhibition and Immunosuppression for Proteinuria
  description: >-
    Nephrology-directed treatment aimed at remission of proteinuria, typically
    combining renin-angiotensin-aldosterone system inhibition with
    immunosuppressive medication. The nephrotic syndrome is steroid resistant, so
    this is proteinuria control rather than a cure.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Steroid-resistant nephrotic syndrome
    term:
      id: HP:0012588
      label: Steroid-resistant nephrotic syndrome
  evidence:
  - reference: PMID:26677510
    reference_title: "SCARB2-Related Action Myoclonus - Renal Failure Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Treatment for renal involvement, under the care of a nephrologist, is
      typically focused on remission of proteinuria and often includes a
      combination of renin-angiotensin-aldosterone inhibition and
      immunosuppressive medications.
    explanation: >-
      GeneReviews statement of the renal treatment approach.
- name: Dialysis and Renal Transplantation
  description: >-
    Renal replacement therapy is effective for the renal arm and is what made the
    syndrome visible at all: before dialysis and transplantation existed, the
    course was rapidly fatal and the neurological phenotype was never reached. It
    does not touch the neurological disease, which continues to progress even with
    normalized renal function.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: renal replacement therapy
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  target_phenotypes:
  - preferred_term: Stage 5 chronic kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: PMID:15364701
    reference_title: "Action myoclonus-renal failure syndrome: characterization of a unique cerebro-renal disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dialysis and renal transplantation are effective for the renal but not the
      neurological features, which continue to progress even in the presence of
      normalized renal function
    explanation: >-
      States both the efficacy for the renal arm and the explicit failure to affect
      the neurological one.
  - reference: PMID:15364701
    reference_title: "Action myoclonus-renal failure syndrome: characterization of a unique cerebro-renal disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      The syndrome was not recognized prior to the advent of dialysis and renal
      transplantation because of its rapidly fatal course if renal failure is
      untreated.
    explanation: >-
      Supports the historical claim in the description. Quoted from the paper's
      opening framing rather than from its results, hence quote_role BACKGROUND.
- name: Rehabilitation and Supportive Care
  description: >-
    Physical and occupational therapy to maintain mobility and activities of daily
    living, adaptive mobility devices, speech-language therapy for alternative
    communication, and educational support where cognitive decline appears.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  evidence:
  - reference: PMID:26677510
    reference_title: "SCARB2-Related Action Myoclonus - Renal Failure Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      physical and occupational therapy to help maintain mobility and optimize
      activities of daily living; adaptive devices to help maintain/improve
      independence in mobility
    explanation: >-
      GeneReviews supportive-care recommendation for the neurological
      manifestations.
animal_models:
- name: Limp2 knockout mouse
  species: Mouse
  genotype: Scarb2 (Limp2) homozygous null
  publication: PMID:12620969
  description: >-
    The Limp2-null mouse predates the discovery of AMRF's cause and was
    characterized in its own right in 2003; it was reanalysed in 2008 once SCARB2
    was identified as the AMRF gene. Read on its own terms it is a poor model of
    the human disease: its reported phenotype is ureteropelvic junction obstruction
    with hydronephrosis, hearing loss from loss of spiral ganglia and hair cells,
    and a peripheral demyelinating neuropathy - none of which is the human
    syndrome. The neuronal storage component and the glomerular change were found
    on reanalysis, and the glomerular change is subtle. The mouse's own authors
    proposed it as a lead for human disorders of the stria vascularis or peripheral
    demyelination, not for a progressive myoclonic epilepsy with glomerulosclerosis.
  modeled_mechanisms:
  - target: Neuronal Lysosomal Storage and Intracellular Inclusions
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Intracellular inclusions in cerebral and cerebellar cortex, the same regions
      affected in human AMRF.
    evidence:
    - reference: PMID:18308289
      reference_title: "Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Reanalysis of an existing Limp2 knockout mouse showed intracellular
        inclusions in cerebral and cerebellar cortex
      explanation: >-
        Reports the neuronal storage phenotype in the null mouse.
  - target: Podocyte Injury and Glomerular Collapse
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      Glomerular change is present but subtle, well short of the focal segmental
      glomerulosclerosis with collapse and end-stage kidney disease seen in
      patients.
    limitations: >-
      The mouse does not develop the nephrotic syndrome or progressive renal
      failure that define the renal half of the human syndrome, so it cannot be
      used to study that arm's progression or to test renal endpoints.
    evidence:
    - reference: PMID:18308289
      reference_title: "Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        the kidneys showed subtle glomerular changes
      explanation: >-
        Reports the attenuated renal phenotype, the basis for
        PARTIALLY_RECAPITULATES and LOW fidelity.
  - target: Cortical Hyperexcitability and Cerebellar Degeneration
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      The null mouse's characterized phenotype is renal-outflow, cochlear and
      peripheral-nerve disease. No progressive myoclonus, seizure phenotype or
      cerebellar syndrome is reported in it.
    limitations: >-
      The organism-level phenotype is in different organs from the human disease
      and the mouse's own describing authors pointed it at a different set of human
      disorders. It therefore cannot be used to test a myoclonus or seizure
      endpoint, which is the arm that matters most clinically and the one substrate
      reduction therapy is aimed at.
    evidence:
    - reference: PMID:12620969
      reference_title: "LIMP-2/LGP85 deficiency causes ureteric pelvic junction obstruction, deafness and peripheral neuropathy in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The phenotype of LIMP-2-deficient mice stimulates the search for mutations
        in human disorders associated with degeneration of the stria vascularis
        and/or demyelinization of peripheral nerves.
      explanation: >-
        The mouse's own authors direct it at a different class of human disease,
        which is the clearest statement that its phenotype is not the AMRF one.
    - reference: PMID:12620969
      reference_title: "LIMP-2/LGP85 deficiency causes ureteric pelvic junction obstruction, deafness and peripheral neuropathy in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        LIMP-2-deficient mice are also characterized by a peripheral demyelinating
        neuropathy.
      explanation: >-
        One of the three organ phenotypes that the mouse has and the human disease
        does not.
  - target: Reduced Lysosomal Glucocerebrosidase Activity
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: >-
      Tissue GCase deficiency with the same tissue-specific sparing of leukocytes
      seen in patients.
    limitations: >-
      What the mouse measures is enzyme activity, by activity assay and
      activity-based probe, in whole-tissue preparations and in isolated
      leukocytes. The node it is linked to claims something one step up: that
      lysosomal GCase delivery is LIMP-2-dependent in particular cell types. A
      whole-tissue activity assay cannot attribute the residual activity it finds
      to any one cell type within that tissue, so the leukocyte-versus-tissue
      contrast is the only cell-resolved comparison this model supplies. The finer
      claim in the node, that fibroblasts and neuronal cells are entirely
      LIMP-2-dependent while blood cells are not, rests on the human fibroblast
      and leukocyte data cited on that node rather than on this mouse.
    evidence:
    - reference: PMID:40639771
      reference_title: "LIMP-2 deficiency-associated glycolipid abnormalities in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Noteworthy, in LIMP-2-deficient mice, residual GCase is remarkably high
        in leukocytes.
      explanation: >-
        The mouse reproduces the leukocyte-sparing pattern that is the diagnostic
        trap in patients.
discussions:
- discussion_id: renal_arm_mechanism_gap
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Podocyte Injury and Glomerular Collapse
  prompt: >-
    How does loss of LIMP-2-dependent beta-glucocerebrosidase delivery cause
    podocyte injury and focal segmental glomerulosclerosis?
  rationale: >-
    The neurological arm of AMRF has a traceable chain from sorting failure to
    neuronal storage to cortical hyperexcitability. The renal arm does not. The
    causal gene and the renal lesion are both established, but no published step
    connects reduced glucocerebrosidase delivery to podocyte injury, and the two
    organ manifestations progress independently and can be dissociated entirely -
    some individuals with biallelic SCARB2 variants never develop renal disease.
    That dissociation is itself evidence that the renal lesion may depend on a
    LIMP-2 function other than GCase transport, which would make the upstream edge
    in this entry wrong rather than merely incomplete.
- discussion_id: limp2_null_mouse_renal_fidelity
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - animal_models#Mouse
  prompt: >-
    Is the Limp2-null mouse a valid model of AMRF at all, given that its own
    characterized phenotype is in three organs the human disease does not affect?
  rationale: >-
    Read forwards rather than backwards, the mouse is a poor match. Its described
    phenotype is ureteropelvic junction obstruction with hydronephrosis, hearing
    loss and peripheral demyelinating neuropathy; its authors pointed it at human
    stria vascularis and demyelination disorders. The AMRF-relevant findings -
    cortical and cerebellar storage inclusions, subtle glomerular change - emerged
    only on reanalysis after SCARB2 was implicated, and the glomerular change never
    reaches the collapsing glomerulopathy or end-stage kidney disease that define
    the human renal arm. Evidence in the model exists and its translational validity
    is the open question, which is why this is a HUMAN_MODEL_MISMATCH rather than a
    plain knowledge gap. The practical consequence is concrete: substrate reduction
    therapy is the one mechanism-directed treatment in this entry and rests on two
    single patients, and there is no animal model in which a myoclonus endpoint
    could be used to test it.
notes: >-
  Not curated: the gut-dysbiosis and FXR/vitamin E findings in Scarb2-deficient
  mice (PMID:38635907), which the deep-research report surfaced as a therapeutic
  lead. They are a mouse result with no human counterpart in AMRF, and adding a
  dysbiosis arm to this pathograph on that basis would assert more than the
  evidence carries.

  Scope: this entry covers SCARB2-related disease as a single continuum, following
  GeneReviews, which treats progressive myoclonus epilepsy without renal
  involvement as one end of the SCARB2-AMRF spectrum rather than a separate
  disease. That is why the renal phenotypes carry no frequency annotation - renal
  involvement is variable by definition here, and no published series gives a
  reliable proportion.

  Not curated: the separate role of SCARB2/LIMP-2 as the cellular receptor for
  enterovirus 71, and its presence in the cardiac intercalated disk. Both are real
  LIMP-2 biology and are described in PMID:24389070, but neither is part of this
  disease's pathophysiology. PMID:17485520 is the primary source for the cardiac
  intercalated-disc role and remains cached and uncited for the same reason: it is
  the better source for a topic this entry deliberately excludes, so it is kept
  rather than pruned in case that exclusion is ever revisited.

  PMID:33772352 is a single further case report of a novel splice-site variant. Its
  content is covered by the allelic spectrum already curated in the genetic notes,
  so it is cached and uncited rather than cited for a claim it would only
  duplicate.
📚

References & Deep Research

References

1
PMID:26677510
SCARB2-Related Action Myoclonus - Renal Failure Syndrome.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record notes

Not curated: the gut-dysbiosis and FXR/vitamin E findings in Scarb2-deficient mice (PMID:38635907), which the deep-research report surfaced as a therapeutic lead. They are a mouse result with no human counterpart in AMRF, and adding a dysbiosis arm to this pathograph on that basis would assert more than the evidence carries. Scope: this entry covers SCARB2-related disease as a single continuum, following GeneReviews, which treats progressive myoclonus epilepsy without renal involvement as one end of the SCARB2-AMRF spectrum rather than a separate disease. That is why the renal phenotypes carry no frequency annotation - renal involvement is variable by definition here, and no published series gives a reliable proportion. Not curated: the separate role of SCARB2/LIMP-2 as the cellular receptor for enterovirus 71, and its presence in the cardiac intercalated disk. Both are real LIMP-2 biology and are described in PMID:24389070, but neither is part of this disease's pathophysiology. PMID:17485520 is the primary source for the cardiac intercalated-disc role and remains cached and uncited for the same reason: it is the better source for a topic this entry deliberately excludes, so it is kept rather than pruned in case that exclusion is ever revisited. PMID:33772352 is a single further case report of a novel splice-site variant. Its content is covered by the allelic spectrum already curated in the genetic notes, so it is cached and uncited rather than cited for a claim it would only duplicate.

Review round 1: peripheral neuropathy, C1q nephropathy histopathology, C-terminal genotype-phenotype modifier · 2026-09-17T04:25:56Z · View source

Response to the ai4c-reviewer CHANGES_REQUESTED review on PR #11989, answered in one push. Three blocking content gaps, all research-backed, plus the three suggestions. Blocking 1, peripheral neuropathy. Added as a Neurological phenotype bound to HP:0009830, with three human evidence items rather than one: PMID:35346091 for its presence and for the fact that it varies between siblings carrying the same variant, the same paper's EMG characterization (mild axonal sensorimotor), and PMID:37529812 for the independent axonal-plus-demyelinating picture and the point that EMG contributes to the diagnosis. The variability is curated deliberately, because it is what makes the phenotype's absence uninformative. Wired inbound from Neuronal Lysosomal Storage and Intracellular Inclusions with INDIRECT_UNKNOWN_INTERMEDIATES and a description saying the route from lysosomal storage to peripheral nerve is not established in AMRF; the shared upstream lesion is the reason for the edge, not a demonstrated mechanism. Blocking 2, C1q nephropathy. Added a histopathology section rather than folding it into an existing node, which also let suggestion 5 be answered in the same structure. The C1q finding is quoted from PMID:18424452, already cited elsewhere in this entry, so no fetch was needed. The description states explicitly that C1q deposition sits beside rather than instead of the collapsing FSGS already curated under phenotypes: they are reported in different families, and the entry does not assert either is the invariable renal histology. Blocking 3, the genotype-phenotype modifier. PMID:35346091 was fetched by this PR and cited nowhere. The genetic notes now record that variant type does not predict the clinical course while C-terminal localization is significantly associated with age at onset, and the evidence item quotes the sentence carrying both halves. quote_role is REVIEW_SYNTHESIS because that finding is the paper's synthesis across previously reported cases, not a result from its own index family. Suggestion 4, electrophysiology. PMID:33343627 is now cited on the diagnosis record for the two EEG patterns it proposes as characteristic, fixation-off phenomenon and REM-only parasagittal spikes, quoted with the authors' own hedge intact. Giant somatosensory evoked potentials were NOT added: they are named in the deep-research report but no reference cached here states them for AMRF in quotable text. That gap is recorded in the entry notes rather than papered over, which matters in this batch because the MFF entry in the same PR set had to be corrected for making a false claim about what a cached abstract contains. Suggestion 5, histopathology. Covered by the same new section: the extraneuronal pigment accumulation on brain autopsy from PMID:15364701. Its description says why the extraneuronal location is the observation rather than incidental detail, since AMRF is not the intraneuronal inclusion picture of the other progressive myoclonic epilepsies. Suggestion 6, uncited caches. Three of the five are now consumed. The remaining two are left uncited with the reason recorded in the entry notes rather than pruned: PMID:17485520 is the primary source for the cardiac intercalated-disc role that this entry deliberately excludes, kept in case that exclusion is revisited, and PMID:33772352 is a further case report whose novel splice-site variant is already covered by the curated allelic spectrum. Validation: just validate clean, 54/54 snippets verified (up from 47/47), check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms and check-enum-values all clean.

Create: Action Myoclonus-Renal Failure Syndrome · 2026-09-16T21:33:19Z · View source

Created kb/disorders/Action_Myoclonus-Renal_Failure_Syndrome.yaml from claim issue #11960. Deep research: openscientist (17 citations, 17/17 resolved, 0 unresolved, 0 off topic, 12 of 17 weighed on topic). As with three of the other four runs in this batch, the run's term-validation step aborted on an EBI network timeout and the report carried no validation frontmatter; the ## Reference Validation section was added afterwards with just validate-research-reference. GeneReviews baseline: PMID:26677510 SCARB2-Related Action Myoclonus - Renal Failure Syndrome, found by just check-genereviews and tagged in references:. Pathograph: 6 nodes from LIMP-2 loss through failed beta-glucocerebrosidase lysosomal targeting into a neurological arm and a parallel renal arm that progresses independently. The renal arm's upstream edge is INDIRECT_UNKNOWN_INTERMEDIATES and the node is marked mechanism_confidence PROVISIONAL, because no published step joins reduced GCase delivery to podocyte injury and the two arms can dissociate entirely. The deep-research report added substantially: the 15-patient clinical series (PMID:15364701) giving onset ages, the proteinuria-to-renal-failure interval and collapsing glomerulopathy histology; miglustat substrate reduction therapy (PMID:34337151, PMID:21782476), which is the only mechanism-directed treatment and which the first draft lacked entirely; renal replacement therapy and its explicit failure to affect the neurological arm; and the primary Limp2-knockout paper (PMID:12620969), which changed the animal-model assessment. Reading that paper forwards rather than backwards shows the mouse's own characterized phenotype is ureteropelvic junction obstruction, deafness and peripheral demyelinating neuropathy, with its authors pointing it at a different class of human disease; the AMRF-relevant findings emerged only on reanalysis. The model therefore carries a FAILS_TO_RECAPITULATE link against the neurological node in addition to its partial renal one. One HGNC CURIE (hgnc:1664, SCARB1) and one NCIT CURIE (NCIT:C50083, None Device) were written from memory, were wrong, and were caught by just validate-terms and just check-qualifier-terms-online respectively; the NCIT device term was dropped rather than replaced because no implanted-VNS term exists in NCIT, with the reason recorded in the treatment notes. Validation: just validate and just validate-disorders pass (47/47 snippets verified); duplicate-key, entity-ref, causal-target, enum-value, qualifier-term gates clean; list-gene-term-mismatches clean.

OpenScientist ▸
Action Myoclonus–Renal Failure Syndrome (AMRF): A Comprehensive Disease Characteristics Report
openscientist-autonomous 17 citations 2026-09-16T21:28:33.430383

Action Myoclonus–Renal Failure Syndrome (AMRF): A Comprehensive Disease Characteristics Report

Disease: Action Myoclonus–Renal Failure Syndrome MONDO ID: MONDO:0009699 · OMIM: #254900 (EPM4) · Orphanet: ORPHA:163703 Category: Mendelian, autosomal recessive lysosomal disorder Causal gene: SCARB2 (encoding LIMP-2) · HGNC:10534 · Ensembl ENSG00000138760 · UniProt Q14108 · chr4q21.1

Summary

Action Myoclonus–Renal Failure Syndrome (AMRF) is an ultra-rare, autosomal recessive, multisystem lysosomal disorder that unites two seemingly unrelated clinical problems: a progressive myoclonus epilepsy (PME) with preserved cognition and a proteinuric collapsing focal segmental glomerulosclerosis (FSGS) that progresses to end-stage renal failure. The syndrome is caused by biallelic loss-of-function variants in SCARB2, the gene encoding lysosomal integral membrane protein type 2 (LIMP-2). LIMP-2 is the mannose-6-phosphate–independent sorting receptor that traffics β-glucocerebrosidase (GCase) from the endoplasmic reticulum (ER) to the lysosome. When LIMP-2 is absent or misfolded, GCase fails to reach the lysosome, is retained in the ER, and lysosomal GCase activity falls—producing a partial, tissue-specific enzyme deficiency and downstream glycosphingolipid dysregulation.

The mechanistic chain runs from mutation → LIMP-2 loss/ER-retention → GCase mistrafficking → partial lysosomal GCase deficiency → accumulation of the toxic glycosphingolipid glucosylsphingosine (GlcSph) and glucosylated cholesterol (rather than bulk glucosylceramide storage) → neuronal and podocyte injury → the branched clinical phenotype of cortical action myoclonus, tremor, ataxia and seizures on the neurological arm, and glomerular collapse with proteinuria and renal failure on the renal arm. Because residual GCase remains high in leukocytes but is severely deficient in fibroblasts and tissue, standard leukocyte enzyme assays are normal—a diagnostic pitfall that distinguishes AMRF from classical Gaucher disease.

Clinically, AMRF typically presents in adolescence or young adulthood (tremor onset ~20 years, disabling action myoclonus ~22 years), with proteinuria often detected in childhood-to-early-adulthood and progressing to renal failure within 0–8 years. Cognition is characteristically spared. There is no approved disease-modifying therapy; management is symptomatic (antimyoclonic/antiseizure drugs, dialysis and renal transplantation). Emerging disease-modifying strategies include substrate-reduction therapy with miglustat and vitamin E repletion, the latter validated in Scarb2-knockout mice. Diagnosis rests on the combination of cortical-myoclonus electrophysiology, urinalysis/renal biopsy findings, and molecular confirmation of biallelic SCARB2 variants.

Key Findings

F001 — AMRF is caused by biallelic loss-of-function mutations in SCARB2 (LIMP-2)

Two independent 2008 studies established the genetic basis of AMRF. Berkovic and colleagues used homozygosity mapping in three unrelated families to map the disease locus to 4q13-21 and identified SCARB2/LIMP-2 by microarray expression analysis; mutations were found in all three mapping families plus two additional AMRF families, associated with an absence of SCARB2 protein. As the authors state, "The ancestral lysosomal-membrane protein SCARB2/LIMP-2 is responsible for AMRF" (PMID: 18308289). Independently, Balreira et al. identified a homozygous nonsense mutation at codon 178 (W178X), noting that "A homozygous nonsense mutation in codon 178 of SCARB2 was found in the patient, whereas her healthy parents were heterozygous for the mutation" (PMID: 18424452). Crucially, the same paper established the protein's function—SCARB2 encodes LIMP-2, "the sorting receptor for beta-glucocerebrosidase." This gene-to-function link is the foundation of all downstream mechanistic understanding of AMRF.

Ontology/annotation: Gene SCARB2 (HGNC:10534); protein LIMP-2 / SR-B2 (UniProt Q14108); MONDO:0009699; OMIM #254900.

F002 — The renal phenotype is proteinuric collapsing focal segmental glomerulosclerosis

The renal lesion of AMRF is a severe, collapsing variant of FSGS. Berkovic et al. describe AMRF as "the remarkable combination of focal glomerulosclerosis, frequently with glomerular collapse, and progressive myoclonus epilepsy" (PMID: 18308289). Balreira et al. reported nephrotic syndrome with "a strong accumulation of C1q in capillary loops and mesangium of kidney" (PMID: 18424452), a pattern designated nephropathy C1q. Chaves et al. confirmed PME with nephropathy C1q in two siblings (PMID: 21782476). The presence of collapse and podocyte injury points to the podocyte as the principal renal target cell.

Ontology/annotation: HP:0000097 (Focal segmental glomerulosclerosis); HP:0000100 (Nephrotic syndrome); HP:0000093 (Proteinuria); UBERON:0000074 (renal glomerulus); CL:0000653 (podocyte).

F003 — Limp2/Scarb2 knockout mice recapitulate multisystem AMRF-relevant pathology

The mouse model predates the human gene discovery and is central to mechanistic understanding. Gamp et al. showed that LIMP-2–deficient mice develop uni/bilateral hydronephrosis from ureteropelvic junction obstruction, serious hearing impairment (spiral ganglia and hair cell loss, stria vascularis degeneration), and a peripheral demyelinating neuropathy: "LIMP-2-deficient mice are also characterized by a peripheral demyelinating neuropathy" (PMID: 12620969). Berkovic's reanalysis of the same knockout revealed intracellular inclusions in cerebral and cerebellar cortex and subtle glomerular changes. More recently, Li et al. showed that Scarb2-deficient mice have age-dependent dietary lipid malabsorption and vitamin E deficiency via gut dysbiosis and FXR hyperactivation, and importantly that "inhibiting FXR or supplementing vitamin E ameliorates the neuromotor impairment and neuropathy in Scarb2 knockout mice" (PMID: 38635907)—a translationally significant therapeutic lead.

F004 — LIMP-2 loss disrupts glycosphingolipid homeostasis (GlcSph, GlcChol) rather than causing bulk GlcCer storage

A key refinement of the "lysosomal storage" paradigm comes from Gaspar et al., who showed that in Limp2-/- mouse tissues the only consistently deficient lysosomal enzyme was GCase, and that "GCase deficiency in tissues does not correlate with increases in GlcCer, but rather with increases in glucosylsphingosine (GlcSph) and glucosylated cholesterol (GlcChol)" (PMID: 40639771). This reframes AMRF as a disorder of toxic glycosphingolipid accumulation (GlcSph is a bioactive, cytotoxic lyso-lipid) rather than classical macromolecular storage. The same study explains a longstanding diagnostic anomaly: "residual GCase is remarkably high in leukocytes," accounting for the normal leukocyte enzyme assays seen in patients despite tissue-level deficiency.

Ontology/annotation: CHEBI:88431 (glucosylsphingosine); GO:0006687 (glycosphingolipid metabolic process).

F005 — Neurological phenotype: adolescent/young-adult onset tremor, progressive action myoclonus, ataxia, seizures — without dementia

Badhwar et al., in the landmark series of 15 patients from 9 families, quantified the neurological course: "Tremor (onset 17-26 years, mean 19.8 years, median 19 years) and progressively disabling action myoclonus (onset 14-29 years, mean 21.7 years, median 21 years), with infrequent generalized seizures (onset 20-28 years, mean 22.7 years, median 22 years) and cerebellar features are characteristic" (PMID: 15364701). The same series established the renal timeline: "Proteinuria, detected between ages 9 and 30 years in all cases, progressed to renal failure in 12 out of 15 patients within 0-8 years after proteinuria detection." Rubboli et al. emphasized the preserved cognition and cortical origin of the myoclonus: "The main clinical features were adolescent-young adulthood onset, progressive action myoclonus, ataxia, absence of cognitive deterioration and, in most cases, epilepsy" (PMID: 22050460), with rhythmic myoclonic jerks at 12–20 Hz resembling postural tremor and a demonstrated cortical origin via EEG–EMG coherence.

Ontology/annotation: HP:0001336 (Myoclonus); HP:0002345 (Action tremor); HP:0001251 (Ataxia); HP:0001250 (Seizure); HP:0007000 (Photosensitive myoclonic seizures); absence of HP:0001268 (Mental deterioration).

F006 — SCARB2 mutations cause a spectrum from AMRF to PME without renal failure; C-terminal variant location influences age of onset

The renal phenotype is not fully penetrant. Rubboli et al. described five Italian PME patients with SCARB2 mutations but without renal impairment: "We describe the clinical and neurophysiologic features of PME associated with SCARB2 mutations without renal impairment" (PMID: 22050460), indicating variable expressivity/incomplete penetrance of the renal arm. Atasu et al., in an in-depth literature review, found a genotype–phenotype correlation: "only the C terminal localization of the pathogenic variant significantly affected the clinical presentation, particularly the age at onset" (PMID: 35346091), while variant type had no major impact on the overall course. Intrafamilial heterogeneity is documented even among siblings sharing an identical truncating variant (p.N45MfsX88).

F007 — Treatment is largely symptomatic; substrate reduction therapy (miglustat) shows promise; vitamin E is a candidate

No disease-modifying therapy is approved. Management is symptomatic: antimyoclonic/antiseizure medication (valproate, levetiracetam, piracetam, clonazepam, perampanel) and renal replacement therapy. Badhwar et al. underscore the historical importance of renal support: "The syndrome was not recognized prior to the advent of dialysis and renal transplantation because of its rapidly fatal course if renal failure is untreated" (PMID: 15364701). Two lines of evidence support substrate-reduction therapy (SRT): Chaves et al. reported that "When substrate-reduction therapy, to correct the possible glucocerebroside storage in the cells with glucocerebrosidase deficiency, was administered to one of the siblings, a significant improvement was observed" (PMID: 21782476); and Quraishi et al. reported that miglustat halted myoclonus progression, resolved dysphagia, and allowed reacquisition of skills (PMID: 34337151). Vitamin E repletion or FXR inhibition ameliorated neuromotor deficits in Scarb2-knockout mice (PMID: 38635907).

Ontology/annotation: NCIT candidate terms — Miglustat (glucosylceramide synthase inhibitor / SRT), Valproate, Levetiracetam, Clonazepam, Perampanel, Renal Dialysis, Kidney Transplantation, Vitamin E supplementation.

F008 — LIMP-2 has pleiotropic non-lysosomal roles informing multisystem involvement

Beyond its GCase-sorting role, LIMP-2 has additional functions that may contribute to the multisystem phenotype. Schroen et al. showed LIMP-2 is a component of the cardiac intercalated disc that associates with cadherin; "these LIMP-2 null mice failed to mount a hypertrophic response to increased blood pressure but developed cardiomyopathy" (PMID: 17485520). Gonzalez et al. reviewed LIMP-2 as "a receptor for specific enteroviruses, two unanticipated findings that reaffirm the myriad roles of lysosomal proteins" (PMID: 24389070) (EV71, coxsackievirus A16), noting ~14 disease-causing SCARB2 mutations known as of 2014.

F009 — SCARB2 is tolerant of heterozygous loss-of-function (gnomAD), consistent with autosomal recessive inheritance

gnomAD constraint metrics for SCARB2 (ENSG00000138760, chr4:76,158,737–76,234,536, GRCh38) show the gene is not haploinsufficient: pLI = 0.0009, observed/expected LoF (oe_lof) = 0.49 with a LOEUF (90% CI upper bound) of 0.67 (observed LoF = 29 vs expected 58.6); missense Z = 1.60. This tolerance of heterozygous LoF is exactly what is expected for a recessive disease gene where a single functional allele suffices. It is consistent with the clinical observation that carriers are healthy—Balreira's "healthy parents were heterozygous for the mutation" (PMID: 18424452). The disease is catalogued as EPM4 (progressive myoclonic epilepsy-4 with or without renal failure), OMIM #254900.

F010 — Diagnosis combines cortical-myoclonus electrophysiology, renal/urinalysis findings, and SCARB2 molecular testing

AMRF diagnosis is a three-legged stool. Electrophysiology shows cortical action myoclonus: giant somatosensory evoked potentials, marked photosensitivity, and 12–20 Hz rhythmic myoclonic jerks with EEG–EMG coherence demonstrating cortical origin (PMID: 22050460). Hotait et al. highlighted distinctive EEG features: "this report emphasizes the presence of two EEG patterns, fixation-off phenomenon, and bursts of parasagittal spikes exclusively seen during REM sleep that appear to be characteristic of this condition" (PMID: 33343627). Renal workup detects proteinuria on urinalysis and collapsing FSGS on biopsy. Molecular testing is the gold standard—Yari et al. exemplify this: "Genetic analysis identified a homozygous splicing c.423+1 G>A variant in the SCARB2 gene of the proband and his affected sister" (PMID: 33772352). Critically, enzyme testing must use fibroblasts, not leukocytes: Balreira found "a normal beta-glucocerebrosidase activity in leukocytes, but a severe enzymatic deficiency in cultured skin fibroblasts" (PMID: 18424452).

F011 — Prognosis: progressive, disabling, with early mortality

Historically fatal from untreated renal failure, AMRF's prognosis is now driven by relentless neurological decline. Badhwar et al. note the disease "was not recognized prior to the advent of dialysis and renal transplantation because of its rapidly fatal course if renal failure is untreated" (PMID: 15364701). Quraishi et al. characterize AMRF as "a rare, progressive myoclonic epilepsy with early mortality" (PMID: 34337151). The trajectory is proteinuria (childhood–early adulthood) → renal failure within 0–8 years, and action myoclonus/tremor progressing to severe disability, dysphagia, and death (often from neurological complications, aspiration, or status epilepticus once renal failure is managed). Cognition is typically preserved throughout (PMID: 22050460).

F012 — Mechanistic basis: AMRF mutations cause ER retention of LIMP-2 and disrupt pH-dependent coiled-coil binding to GCase

The molecular pathology is precisely characterized. Blanz et al. showed that "All mutations investigated in this study lead to a retention of LIMP-2 in the endoplasmic reticulum (ER) but affect the binding to beta-GC differentially" (PMID: 19933215); binding occurs through a highly conserved amphipathic coiled-coil domain (segment 145–288), and its disruption abolishes GCase binding. Zachos et al. defined the release mechanism: "the lumenal acidification mediated by the vacuolar (H(+))-ATPase triggers the dissociation of LIMP-2 and GC in late endosomal/lysosomal compartments" (PMID: 22537104), with a critical histidine residue conferring pH sensitivity. In patient cells, Balreira confirmed GCase mislocalization: "decreased amounts of beta-glucocerebrosidase, which was mainly located in the endoplasmic reticulum, as assessed by its sensitivity to Endo H" (PMID: 18424452).

F013 — Anatomical involvement: cerebral/cerebellar cortex, kidney glomeruli/podocytes, peripheral nerve; lysosome the key compartment

Badhwar et al. documented the tissue-level pathology: "Brain autopsy in two patients revealed extraneuronal pigment accumulation. Renal biopsies showed collapsing glomerulopathy, a severe variant of focal glomerulosclerosis" (PMID: 15364701). Berkovic's knockout reanalysis localized storage pathology: the mice "showed intracellular inclusions in cerebral and cerebellar cortex, and the kidneys showed subtle glomerular changes" (PMID: 18308289). The cortical origin of myoclonus localizes to sensorimotor cortex; the peripheral nervous system shows axonal/demyelinating polyneuropathy; and the subcellular locus is the lysosome (LIMP-2 being a lysosomal integral membrane protein).

Ontology/annotation: UBERON:0000956 (cerebral cortex); UBERON:0002129 (cerebellar cortex); UBERON:0002113 (kidney); UBERON:0000074 (renal glomerulus); UBERON:0000044 (peripheral nerve); GO:0005764 (lysosome); GO:0005783 (endoplasmic reticulum); CL:0000653 (podocyte); CL:0000540 (neuron).

F014 — Epidemiology and etiology: ultra-rare, purely monogenic autosomal recessive; consanguinity increases risk

AMRF is ultra-rare (Orphanet ORPHA:163703; prevalence <1/1,000,000). Only ~4 patients were known before 2004; Badhwar's landmark series expanded this: "We now describe 15 individuals with AMRF from five countries" (PMID: 15364701). Since 2008, several dozen SCARB2-related cases have been reported worldwide, many from consanguineous families—Ekmekci et al. note "This study examines a consanguineous family with multiple members presenting myoclonic epilepsy" (PMID: 37529812). The etiology is entirely genetic (biallelic pathogenic SCARB2 variants); no environmental, infectious, toxic, or lifestyle cause is implicated. Sex ratio is ~1:1, as expected for an autosomal recessive disorder.

F015 — Prevention is limited to genetic counseling, carrier/cascade testing, and prenatal/PGD; secondary/tertiary prevention targets renal and nutritional complications

Because AMRF is Mendelian with no modifiable environmental cause, there is no primary prevention. Risk reduction relies on genetic counseling of at-risk and consanguineous families, carrier testing, cascade testing of relatives, and prenatal or preimplantation genetic diagnosis once the familial SCARB2 variants are known (carriers being unaffected per PMID: 18424452). Secondary prevention consists of early urinalysis surveillance for proteinuria to enable timely renal management. Tertiary prevention includes dialysis/transplant, aspiration precautions, antimyoclonic therapy, and—based on mouse data—vitamin E supplementation for the malabsorption-driven deficiency: "supplementing vitamin E ameliorates the neuromotor impairment and neuropathy in Scarb2 knockout mice" (PMID: 38635907).

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

  1. Biallelic loss-of-function variant in SCARB2 (nonsense, frameshift, splice-site, or missense) leads to absence, truncation, or misfolding of the LIMP-2 protein. (Demonstrated — F001, F012)
  2. Mutant/absent LIMP-2 results in retention of LIMP-2 in the endoplasmic reticulum and failure of the LIMP-2–GCase complex to traffic to the lysosome. (Demonstrated — F012)
  3. ER-retained, unescorted β-glucocerebrosidase (GCase) is mistargeted and remains Endo H–sensitive in the ER instead of maturing in the lysosome. (Demonstrated in patient fibroblasts — F004, F012)
  4. Mistrafficking results in partial, tissue-specific lysosomal GCase deficiency — severe in brain, kidney, and fibroblasts, but with high residual activity in leukocytes. (Demonstrated — F004, F010)
  5. Reduced lysosomal GCase leads to dysregulated glycosphingolipid catabolism, with accumulation of the toxic lyso-lipid glucosylsphingosine (GlcSph) and glucosylated cholesterol, rather than bulk glucosylceramide storage. (Demonstrated in mouse tissue — F004; toxicity to human tissue inferred)
  6. Glycosphingolipid dysregulation and lysosomal dysfunction result in cellular injury that branches by tissue:
  7. 6a (neurological arm): Injury to cortical/cerebellar neurons leads to cortical hyperexcitability → cortical action myoclonus, tremor, ataxia, photosensitive seizures, with intracellular inclusions and extraneuronal pigment. Cognition is spared. (Demonstrated clinically/pathologically — F005, F013)
  8. 6b (renal arm): Injury to podocytes leads to collapsing focal segmental glomerulosclerosis with C1q deposition → proteinuria/nephrotic syndrome → end-stage renal failure. (Demonstrated — F002, F013)
  9. 6c (peripheral/systemic arm, partly from mouse): Leads to peripheral demyelinating/axonal neuropathy; and (mouse) gut dysbiosis → FXR hyperactivation → lipid malabsorption → vitamin E deficiency compounding neuromotor deficits. (Demonstrated in mouse; human relevance inferred — F003)
  10. Progressive neuronal and glomerular damage results in cumulative disability and early mortality — historically from untreated renal failure, now predominantly from neurological decline once dialysis/transplant manages the kidney. (Demonstrated — F011)
   SCARB2 biallelic LoF
  │
  ▼
   LIMP-2 absent / ER-retained  ──(no lysosomal sorting receptor)
  │
  ▼
   GCase mistrafficked → trapped in ER (Endo H–sensitive)
  │
  ▼
   Partial lysosomal GCase deficiency (tissue-specific;
   high residual in leukocytes → normal blood assay)
  │
  ▼
   ↑ Glucosylsphingosine (GlcSph) + glucosylated cholesterol
   (toxic lyso-lipids, NOT bulk GlcCer storage)
  │
     ┌────┴───────────────┬─────────────────────┐
     ▼                    ▼                     ▼
  NEURONS              PODOCYTES          PERIPHERAL NERVE / GUT
  cortex/cerebellum    glomerulus         + (mouse) dysbiosis→FXR
     │                    │                     │
     ▼                    ▼                     ▼
  Cortical action     Collapsing FSGS      Neuropathy; vit E
  myoclonus, tremor,  + C1q deposition     deficiency (mouse)
  ataxia, seizures    → proteinuria →
  (cognition SPARED)  renal failure
     │                    │
     └──────────┬─────────┘
        ▼
    Progressive disability + early mortality

Upstream vs downstream

  • Upstream (initiating): SCARB2 mutation → LIMP-2 loss → ER retention → GCase mistrafficking. These are the shared, obligate steps.
  • Midstream (biochemical): partial GCase deficiency → GlcSph/GlcChol accumulation.
  • Downstream (phenotypic, branched): neuronal injury (myoclonus/ataxia/seizures), podocyte injury (FSGS/renal failure), peripheral nerve and systemic/nutritional effects. The renal arm is incompletely penetrant (F006), explaining pure-PME cases; C-terminal variant location modulates age of onset (F006), the only established genotype–phenotype modifier.

Cell types and biological processes

Level Entity Ontology suggestion
Biological process Lysosomal protein transport / GSL catabolism GO:0007041, GO:0006687
Biological process ER retention / protein misfolding GO:0034976
Cell type Cortical/cerebellar neuron CL:0000540
Cell type Podocyte CL:0000653
Cell type Schwann cell / peripheral nerve CL:0002573
Compartment Lysosome GO:0005764
Compartment Endoplasmic reticulum GO:0005783
Metabolite Glucosylsphingosine CHEBI:88431

Evidence Base

PMID Study (short title) Type Supports finding(s) Contribution
18308289 Array-based gene discovery… SCARB2/LIMP-2 Human genetics F001, F002, F013 Maps AMRF to 4q13-21; identifies SCARB2 as causal; defines renal pathology
18424452 Nonsense mutation in LIMP-2 gene… Human genetics/biochem F001, F002, F009, F010, F012 W178X mutation; recessive segregation; C1q nephropathy; fibroblast vs leukocyte assay; ER localization of GCase
12620969 LIMP-2/LGP85 deficiency…in mice Mouse model F003, F013 Hydronephrosis, deafness, peripheral demyelinating neuropathy
38635907 Gut dysbiosis…Scarb2 deficiency Mouse model F003, F007, F015 FXR/vitamin E axis; therapeutic rescue
40639771 LIMP-2 deficiency…glycolipid abnormalities Mouse biochem F004 GlcSph/GlcChol accumulation; high leukocyte residual GCase
15364701 AMRF: characterization of a unique cerebro-renal disorder Human clinical series (n=15) F005, F007, F011, F013, F014 Ages of onset; renal timeline; prognosis; anatomy; rarity
22050460 PME without renal failure caused by SCARB2 Human clinical/neurophysiology F005, F006, F010, F011 Preserved cognition; cortical myoclonus; renal-sparing spectrum
35346091 Genotype-Phenotype correlations of SCARB2 Review F006, F014 C-terminal variant location affects onset age
34337151 Miglustat Therapy for AMRF Case report F007, F011 SRT halts myoclonus; early mortality framing
21782476 PME with nephropathy C1q due to SCARB2 Case report (2 sibs) F002, F007 SRT improvement; C1q nephropathy
17485520 LIMP-2…cardiac intercalated disc Mouse model F008 Non-lysosomal cardiac role
24389070 LIMP-2: new player in lysosome pathology Review F008 Enterovirus receptor; pleiotropy
19933215 Disease-causing LIMP-2 mutations…binding to β-GC In vitro F012 ER retention; coiled-coil binding domain
22537104 Critical histidine…pH-sensitive binding In vitro F012 pH-dependent V-ATPase release mechanism
33343627 Distinctive EEG Patterns in SCARB2 PME Case report F010 Fixation-off phenomenon; REM parasagittal spikes
33772352 Novel homozygous splice-site in SCARB2 Case report F010 Molecular confirmation via WES (c.423+1G>A)
37529812 AMRF Case Report with Bioinformatic Annotations Case report F013, F014 Consanguinity; polyneuropathy

Evidence source distinction: Human clinical (18308289, 18424452, 15364701, 22050460, 35346091, 34337151, 21782476, 33343627, 33772352, 37529812); mouse model (12620969, 38635907, 40639771, 17485520); in vitro (19933215, 22537104); computational/constraint (gnomAD for F009).

Section-by-Section Data Summary

1. Disease Information

AMRF is an autosomal recessive cerebro-renal lysosomal disorder combining progressive myoclonus epilepsy with collapsing FSGS/renal failure. Identifiers: MONDO:0009699; OMIM #254900 (EPM4); ORPHA:163703. Synonyms: EPM4; progressive myoclonic epilepsy 4 with or without renal failure; myoclonus-nephropathy syndrome; action myoclonus–renal failure syndrome. Information is aggregated from disease-level resources plus small clinical case series/reports (individual patients).

2. Etiology

Primary cause is purely genetic: biallelic LoF variants in SCARB2 (F001, F014). Genetic risk factor: two pathogenic SCARB2 alleles; consanguinity elevates risk (F014). No environmental, infectious, toxic, lifestyle risk or protective factors are established. C-terminal variant location is the only identified modifier of onset (F006). No meaningful gene–environment interaction is documented in humans, though the mouse gut-dysbiosis/vitamin-E axis (F003) hints at a diet-modifiable secondary pathway.

3. Phenotypes

Phenotype Type HPO Onset Progression Frequency
Action myoclonus Clinical sign HP:0001336 mean 21.7 y Progressive/disabling Near-universal
Tremor Clinical sign HP:0002345 mean 19.8 y Progressive Common (often first)
Ataxia / cerebellar signs Clinical sign HP:0001251 Young adult Progressive Common
Generalized seizures Clinical sign HP:0002197 mean 22.7 y Episodic Most cases (infrequent seizures)
Photosensitivity Neurophysiologic HP:0007000 Young adult — Pronounced
Proteinuria/FSGS Lab/pathology HP:0000097 ages 9–30 Progressive → renal failure ~universal in AMRF; absent in renal-sparing PME
Peripheral neuropathy Clinical sign HP:0009830 Variable Progressive Variable
Preserved cognition (Negative) — — Stable Characteristic

QoL impact is severe due to disabling myoclonus, dysphagia, and dialysis dependence.

4. Genetic/Molecular

Causal gene SCARB2 (HGNC:10534; OMIM *602257). Variant types: nonsense (W178X), frameshift (p.N45MfsX88), splice-site (c.423+1G>A), missense—all loss-of-function; classified pathogenic/likely pathogenic under ACMG. gnomAD: LoF-tolerant (LOEUF 0.67), consistent with recessive inheritance (F009). Germline origin. Functional consequence: loss of function via ER retention (F012). No established modifier genes beyond variant position; no epigenetic mechanism or chromosomal abnormality implicated.

5. Environmental

Not applicable—no environmental, lifestyle, or infectious cause. (Note: LIMP-2 is an enterovirus receptor, but this is unrelated to AMRF causation — F008.)

6. Mechanism

See Mechanistic Model above (F004, F012, F013).

7. Anatomical Structures

Primary organs: brain (cerebral/cerebellar cortex — UBERON:0000956/0002129) and kidney (glomerulus — UBERON:0000074). Secondary: peripheral nerve (UBERON:0000044). Cells: neurons (CL:0000540), podocytes (CL:0000653). Subcellular: lysosome (GO:0005764), ER (GO:0005783). Bilateral/symmetric involvement (F013).

8. Temporal Development

Onset: adolescence–young adulthood, insidious/chronic. Course: relentlessly progressive; proteinuria → renal failure within 0–8 years; myoclonus progressively disabling. No spontaneous remission. Lifelong (F005, F011).

9. Inheritance and Population

Autosomal recessive; ultra-rare (<1/1,000,000); ~1:1 sex ratio; consanguinity/founder effects in some kindreds. Carriers unaffected (F009, F014). Penetrance of the neurological phenotype is high; renal penetrance is incomplete/variable (F006).

10. Diagnostics

Cortical-myoclonus electrophysiology (giant SEPs, photosensitivity, EEG–EMG coherence, fixation-off phenomenon, REM parasagittal spikes); urinalysis/renal biopsy (collapsing FSGS, C1q); molecular SCARB2 testing (WES/panel/single-gene) as gold standard; fibroblast (not leukocyte) GCase assay (F010).

11. Outcome/Prognosis

Progressive, disabling, early mortality; historically fatal from renal failure, now neurological. Cognition preserved. No 5-year survival figures established for this ultra-rare disease (F011).

12. Treatment

Symptomatic: antimyoclonic/antiseizure drugs (valproate, levetiracetam, piracetam, clonazepam, perampanel), renal replacement therapy. Emerging: SRT with miglustat (F007), vitamin E repletion (F007, F015). No approved disease-modifying therapy.

13. Prevention

Genetic counseling, carrier/cascade testing, prenatal/PGD; proteinuria surveillance; dialysis/transplant; vitamin E (F015).

14. Other Species / Natural Disease

Mouse (Mus musculus, NCBI:txid10090) Scarb2 ortholog; knockout models are the principal natural/experimental analog (F003). No naturally occurring companion-animal AMRF documented in the reviewed literature.

15. Model Organisms

Mouse Scarb2/Limp2 knockout — recapitulates peripheral neuropathy, hydronephrosis, deafness, cortical inclusions, and (with aging) vitamin-E-deficient neurodegeneration; validated therapeutic rescue with vitamin E/FXR inhibition (F003). Limitation: mice show prominent hydronephrosis/deafness not central to human AMRF and less pronounced glomerulosclerosis, so the model captures the neurological and lysosomal biology better than the human collapsing-FSGS renal phenotype.

Limitations and Knowledge Gaps

  1. No natural history cohort with survival statistics. Because AMRF is ultra-rare (only dozens of reported cases), there are no Kaplan–Meier survival curves, formal prevalence/incidence figures, or validated prognostic models; prognosis is inferred from small series and case reports.
  2. Renal phenotype in the mouse is incomplete. The knockout emphasizes hydronephrosis, deafness, and neuropathy rather than the collapsing FSGS central to human AMRF, limiting mechanistic study of the podocyte injury pathway.
  3. GlcSph toxicity is demonstrated in mouse tissue, not directly in human AMRF brain/kidney. The step linking GlcSph accumulation to neuronal/podocyte death is inferred for humans (F004).
  4. Therapeutic evidence is anecdotal. Miglustat and vitamin E data derive from single case reports and mouse studies; no controlled trials exist.
  5. Incomplete penetrance of the renal arm is unexplained beyond the C-terminal variant correlation (F006); the modifiers determining whether a patient develops renal failure are unknown.
  6. Epigenetic, transcriptomic, proteomic, and single-cell profiling of human AMRF tissue is essentially absent from the reviewed literature.

Proposed Follow-up Experiments / Actions

  1. Establish an international AMRF registry to derive natural-history data (age-specific survival, renal-vs-neurological mortality, penetrance of the renal phenotype).
  2. Podocyte-specific or conditional Scarb2 knockout / patient iPSC-derived podocyte and cortical-neuron models to dissect the branched neuro-renal injury and test whether GlcSph reduction rescues each cell type.
  3. Prospective trial (or n-of-1 protocols) of miglustat SRT in genetically confirmed AMRF, with GlcSph as a pharmacodynamic biomarker in CSF/plasma.
  4. Test vitamin E repletion and FXR modulation in human patients, translating the mouse gut-dysbiosis/malabsorption finding, with serum vitamin E and neuropathy endpoints.
  5. Systematic genotype–phenotype study correlating variant position (especially C-terminal), residual GCase activity, and GlcSph levels with renal-arm penetrance and onset age.
  6. Develop plasma GlcSph as a diagnostic/monitoring biomarker, potentially resolving the leukocyte-assay pitfall and enabling earlier diagnosis.
  7. Cascade carrier screening and reproductive counseling protocols for consanguineous kindreds with known SCARB2 variants.

Report compiled from 15 confirmed findings across 5 investigation iterations and 36 reviewed papers. Evidence types are distinguished as human clinical, mouse model, in vitro, and computational throughout.

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