Unverricht-Lundborg Disease

Mendelian MONDO:0009698 Pathograph 16 Show in embeddings browser Progressive Myoclonus Epilepsy

Unverricht-Lundborg disease (ULD), also called progressive myoclonic epilepsy type 1 (EPM1) or Baltic myoclonus, is an autosomal recessive neurodegenerative progressive myoclonus epilepsy caused by biallelic loss-of-function of CSTB, the gene encoding cystatin B. Cystatin B is a ubiquitously expressed intracellular inhibitor of the cysteine cathepsins (thiol proteases). In the great majority of patients the causal lesion is an unstable expansion of a dodecamer (12-mer) repeat in the CSTB promoter that reduces CSTB transcription; a minority carry point/indel loss-of-function variants, often in compound heterozygosity with the repeat expansion. Onset is typically between 6 and 16 years with stimulus-sensitive (action) myoclonus and generalized tonic-clonic seizures; over the following years progressive cerebellar signs (ataxia, incoordination, intention tremor, dysarthria) develop, together with emotional lability, depression, and a mild decline in cognition, while patients remain largely mentally alert. It is one of the most common progressive myoclonus epilepsies and is markedly enriched in Finland, the Baltic region, and the western Mediterranean through founder effects. EPM1 is distinguished from the other classic progressive myoclonus epilepsies (notably Lafora disease) by its slower course and relative preservation of cognition. Treatment is symptomatic; importantly, phenytoin can aggravate neurologic symptoms and may accelerate cerebellar degeneration, while several sodium-channel-blocking, GABAergic, and gabapentinoid antiseizure drugs can aggravate myoclonus and are avoided.

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1
Inheritance
8
Pathophys.
9
Phenotypes
2
Gaps
16
Pathograph
1
Genes
5
Medical Actions
2
Differentials
2
Trials
1
Models
17
References
👪

Inheritance

1
Autosomal Recessive HP:0000007
EPM1 is inherited in an autosomal recessive manner; affected individuals carry biallelic CSTB loss-of-function alleles (most commonly two dodecamer repeat expansions, or a repeat expansion in compound heterozygosity with a CSTB point/indel variant).
Autosomal recessive inheritance
Show evidence (2 references)
PMID:8596935 SUPPORT Human Clinical
"Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) is an autosomal recessive inherited form of epilepsy, previously linked to human chromosome 21q22.3."
Establishes the autosomal recessive inheritance and 21q22.3 localization of EPM1.
PMID:20301321 SUPPORT Other
"EPM1 is inherited in an autosomal recessive manner."
The GeneReviews chapter confirms autosomal recessive inheritance.
?

Discussions and Knowledge Gaps

2
Is the primary neurodegenerative driver in EPM1 the dysregulation of lysosomal cysteine cathepsins released from cystatin B inhibition, or the loss of cystatin B's oxidative-stress/mitochondrial protective function, and how do these two arms interact to cause selective neuronal death?
OPEN QUESTION OPEN gap_epm1_cathepsin_vs_oxidative_primary_driver
Attached to
pathophysiology#Cathepsin B-Dependent Oxidative Stress Vulnerability pathophysiology#Cerebellar Granule Neuron Death and Degeneration
Cystatin B is defined biochemically as a cathepsin inhibitor, yet cystatin B-deficient neurodegeneration is demonstrably coupled to oxidative stress and is mediated, at least in part, by cathepsin B. Whether the disease is driven primarily by unrestrained cathepsin proteolysis, by failed antioxidant/ mitochondrial protection, or by an obligate interaction of the two is unresolved, and the answer determines whether cathepsin inhibition or antioxidant strategies are the more rational disease-modifying target.
Proposed experiments
Cathepsin-inhibition versus antioxidant rescue in cystatin B-deficient neurons
pharmacologic and genetic rescue experiment Relation: this experiment is of type this experiment type This experiment is of type pharmacologic and genetic rescue experiment.
exp_epm1_cathepsin_vs_antioxidant_rescue
In cystatin B-null cerebellar granule neurons and mice, compare selective cathepsin B inhibition, genetic cathepsin B reduction, and antioxidant/ mitochondrial-protective treatment for their ability to prevent neuronal apoptosis, cerebellar degeneration, and myoclonus, to determine which arm is the dominant driver.
Perturbations
Cathepsin B inhibition or knockdown versus antioxidant treatment
pathophysiology#Cathepsin B-Dependent Oxidative Stress Vulnerability
Apply selective cathepsin B inhibition or genetic cathepsin B reduction, versus antioxidant/mitochondrial-protective treatment, on the cystatin B-deficient background.
CSTB hgnc:2482 HUGO Gene Nomenclature Committee (hgnc) Relation: this perturbation targets this gene This perturbation targets CSTB (hgnc:2482). hgnc:2482 is a gene from the HUGO Gene Nomenclature Committee.
Readouts
Neuronal apoptosis and cerebellar degeneration
pathophysiology#Cerebellar Granule Neuron Death and Degeneration
neuron apoptotic process GO:0051402 Gene Ontology (GO) Relation: this readout reports on this biological process This readout reports on increased neuron apoptotic process (GO:0051402). GO:0051402 is a biological process from the Gene Ontology. ↑ INCREASED
TUNEL apoptosis assay Relation: this readout is measured by this assay This readout is measured by TUNEL apoptosis assay. cerebellar histopathology Relation: this readout is measured by this assay This readout is measured by cerebellar histopathology.
Direction: NEGATIVE
Controls
Untreated cystatin B-deficient neurons
Cystatin B-deficient neurons/mice receiving vehicle only.
Wild-type neurons
Cystatin B-sufficient neurons/mice.
Decision criterion
The arm whose targeted correction most fully prevents apoptosis, cerebellar degeneration, and myoclonus is the dominant driver; comparable partial rescue by both, with additivity, supports an obligate interaction.
Would support
pathophysiology#Cathepsin B-Dependent Oxidative Stress Vulnerability pathophysiology#Cerebellar Granule Neuron Death and Degeneration
Show evidence (2 references)
PMID:19420257 SUPPORT In Vitro
"The Cystatin B deficiency-induced predisposition to oxidative stress in neurons is mediated by the lysosomal protease Cathepsin B."
Shows the two candidate arms are mechanistically linked (cathepsin B mediates the oxidative-stress vulnerability), framing the primary-driver question.
PMID:38247861 SUPPORT Other
"protection against oxidative stress, likely through regulation of mitochondrial function."
Highlights the parallel oxidative/mitochondrial-protective role of cystatin B whose loss is the alternative primary driver. Evidence source is OTHER because this is a review article.
Does the cystatin B-null mouse, which shows early and prominent cerebellar granule cell apoptosis, faithfully capture the human EPM1 trajectory — in which action myoclonus and cortical GABAergic dysfunction dominate and cognition is relatively preserved — or does it over-represent cerebellar degeneration relative to the human cortical-hyperexcitability phenotype?
HUMAN MODEL MISMATCH OPEN gap_epm1_cstb_mouse_fidelity
Attached to
pathophysiology#Cerebellar Granule Neuron Death and Degeneration pathophysiology#Cortical Hyperexcitability
Model evidence clearly exists: the Cstb-null mouse reproduces myoclonus, ataxia, cerebellar granule cell apoptosis, cortical GABAergic interneuron loss, and cerebellar oxidative damage. The open translational question is fidelity of emphasis — human EPM1 is dominated by disabling, treatment-resistant cortical action myoclonus with relatively preserved cognition, whereas the mouse phenotype foregrounds cerebellar granule cell death; whether the model's cell-type and regional emphasis matches the human disease gates its use for preclinical testing of cortically targeted therapies.
Proposed experiments
Cross-species cortical-versus-cerebellar contribution mapping in EPM1
cross-species regional phenotyping experiment Relation: this experiment is of type this experiment type This experiment is of type cross-species regional phenotyping experiment.
exp_epm1_cortical_vs_cerebellar_mapping
Quantitatively compare the temporal and regional sequence of cortical GABAergic interneuron loss versus cerebellar granule cell apoptosis in Cstb-null mice against human EPM1 natural-history imaging/neurophysiology and post-mortem tissue, and against EPM1 patient iPSC-derived cortical interneuron and cerebellar models, to test whether the mouse over-weights the cerebellar arm.
Perturbations
Cystatin B loss of function
pathophysiology#Cerebellar Granule Neuron Death and Degeneration
Cstb-null mice and CSTB-deficient human iPSC-derived cortical interneuron and cerebellar neuron models compared against controls.
CSTB hgnc:2482 HUGO Gene Nomenclature Committee (hgnc) Relation: this perturbation targets this gene This perturbation targets CSTB (hgnc:2482). hgnc:2482 is a gene from the HUGO Gene Nomenclature Committee.
Readouts
Regional GABAergic versus cerebellar granule cell loss over time
pathophysiology#Cortical Hyperexcitability
neuron apoptotic process GO:0051402 Gene Ontology (GO) Relation: this readout reports on this biological process This readout reports on increased neuron apoptotic process (GO:0051402). GO:0051402 is a biological process from the Gene Ontology. ↑ INCREASED
quantitative immunohistochemistry Relation: this readout is measured by this assay This readout is measured by quantitative immunohistochemistry. electrophysiological recording Relation: this readout is measured by this assay This readout is measured by electrophysiological recording.
Direction: POSITIVE
Controls
Wild-type littermates
Age-matched cystatin B-sufficient mice.
Isogenic-corrected human neurons
Patient iPSC lines with the CSTB lesion corrected.
Decision criterion
The mouse is a faithful EPM1 model if the relative timing and magnitude of cortical GABAergic versus cerebellar granule cell involvement matches human data; a mismatch is supported if the mouse disproportionately foregrounds cerebellar granule cell death relative to the human cortical phenotype.
Would support
pathophysiology#Cerebellar Granule Neuron Death and Degeneration pathophysiology#Cortical Hyperexcitability
Show evidence (2 references)
PMID:9806543 SUPPORT Model Organism
"The principal cytopathology appears to be a loss of cerebellar granule cells, which frequently display condensed nuclei, fragmented DNA and other cellular changes characteristic of apoptosis."
Establishes that the model's principal lesion is cerebellar granule cell apoptosis, confirming model evidence exists for the mismatch question.
PMID:22538221 SUPPORT Human Clinical
"A marked reduction in VGAT labeling was found in the cortex of both CSTB knockout mice and an ULD patient."
Documents the cortical GABAergic phenotype in human ULD tissue, the human arm whose murine emphasis is the open question.
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Pathophysiology

8
CSTB Dodecamer Repeat Expansion and Cystatin B Deficiency
The initiating lesion is biallelic loss-of-function of CSTB. In most patients an unstable expansion of a dodecamer (12-mer) repeat in the CSTB promoter reduces transcription; a minority carry loss-of-function point/indel variants (e.g., a splice-site or nonsense variant), frequently in compound heterozygosity with the repeat expansion. The shared consequence is markedly reduced cystatin B, an intracellular thiol (cysteine) protease inhibitor.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
CSTB hgnc:2482 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CSTB (hgnc:2482). hgnc:2482 is a gene from the HUGO Gene Nomenclature Committee.
cysteine-type endopeptidase inhibitor activity GO:0004869 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased cysteine-type endopeptidase inhibitor activity (GO:0004869). GO:0004869 is a molecular function from the Gene Ontology. ↓ DECREASED
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cathepsin B-Dependent Oxidative Stress Vulnerability
Cortical GABAergic Input Loss
Early Microglial Activation
Altered Cortical Progenitor Proliferation and Interneuron Migration
Show evidence (4 references)
PMID:9126745 SUPPORT Human Clinical
"the majority of EPM1 alleles contain expansions of a dodecamer (12-mer) repeat located about 70 nucleotides upstream of the transcription start site"
Identifies the promoter dodecamer repeat expansion as the predominant EPM1 lesion.
PMID:9126745 SUPPORT Human Clinical
"Normal alleles contain 2 or 3 copies of this repeat whereas mutant alleles contain more than 60 such repeats and have reduced levels of CSTB messenger RNA in blood but not in cell lines."
Shows the expansion reduces CSTB mRNA, establishing the loss-of-expression mechanism.
PMID:8596935 SUPPORT Human Clinical
"Two mutations, a 3' splice site mutation and a stop codon mutation, were identified in the gene encoding cystatin B in EPM1 patients"
Documents the minority loss-of-function point-variant class of CSTB alleles.
+ 1 more reference
Early Microglial Activation
In the Cstb-deficient mouse, localized microglial activation appears before myoclonia and before selective neuron loss in the same vulnerable brain regions. The temporal sequence supports an early neuroinflammatory arm, while its causal contribution and human generalizability remain unresolved.
microglial cell CL:0000129 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves microglial cell (CL:0000129). CL:0000129 is a cell type from the Cell Ontology.
microglial cell activation GO:0001774 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased microglial cell activation (GO:0001774). GO:0001774 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Selective Cortical and Thalamic Neuron Loss
Show evidence (1 reference)
PMID:22157618 SUPPORT Model Organism
"Microglial activation precedes the emergence of myoclonia and is followed by successive astrocytosis and selective neuron loss."
Establishes the temporal order of microglial activation, myoclonia, astrocytosis, and selective neuron loss in the knockout model.
Selective Cortical and Thalamic Neuron Loss
The Cstb-deficient mouse develops selective neuron loss first in cortex and subsequently in the corresponding thalamic relay nucleus. This is kept separate from cerebellar granule-cell death because the affected regions and evidence base differ.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
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. thalamus UBERON:0001897 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in thalamus, annotated with dorsal plus ventral thalamus (UBERON:0001897). UBERON:0001897 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:22157618 SUPPORT Model Organism
"These changes are most pronounced in the thalamocortical system, with neuron loss occurring first within the cortex and only subsequently in the corresponding thalamic relay nucleus."
Defines the anatomic distribution and sequence of selective neuron loss in the knockout model.
Altered Cortical Progenitor Proliferation and Interneuron Migration
Patient-derived cerebral organoids with low functional CSTB show reduced or altered neural-progenitor proliferation, premature differentiation, and impaired interneuron migration. These developmental changes provide a human-cell-derived route from CSTB deficiency toward reduced cortical inhibitory-neuron recruitment.
neural progenitor cell CL:0011020 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural progenitor cell (CL:0011020). CL:0011020 is a cell type from the Cell Ontology. GABAergic neuron CL:0000617 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves GABAergic neuron (CL:0000617). CL:0000617 is a cell type from the Cell Ontology.
neural precursor cell proliferation GO:0061351 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neural precursor cell proliferation (GO:0061351). GO:0061351 is a biological process from the Gene Ontology. ↓ DECREASED neuron migration GO:0001764 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neuron migration (GO:0001764). GO:0001764 is a biological process from the Gene Ontology. ↓ DECREASED
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.
Downstream
Cortical GABAergic Input Loss
Show evidence (1 reference)
PMID:32378798 SUPPORT In Vitro
"Our results indicate that physiological levels of CSTB are essential for correct cell proliferation and interneurons migration both in vivo and in vitro. On the contrary, lower levels of functional CSTB in patient-derived hCOs result in a reduction of progenitor cell proliferation, premature..."
Human patient-derived cerebral organoids directly demonstrate the proliferation and interneuron-recruitment abnormalities represented here.
Cathepsin B-Dependent Oxidative Stress Vulnerability
Cystatin B deficiency impairs neuronal redox homeostasis and sensitizes cerebellar granule neurons to oxidative-stress-induced death. Knockdown experiments identify lysosomal cathepsin B as a mediator of this vulnerability; the node does not claim that every cysteine cathepsin is globally overactive in patients.
cerebellar granule cell CL:0001031 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cerebellar granule cell (CL:0001031). CL:0001031 is a cell type from the Cell Ontology.
response to oxidative stress GO:0006979 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. ⚠ ABNORMAL
cysteine-type peptidase activity GO:0008234 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased cysteine-type peptidase activity (GO:0008234). GO:0008234 is a molecular function from the Gene Ontology. ↑ INCREASED
Downstream
Cerebellar Granule Neuron Death and Degeneration
Show evidence (2 references)
PMID:19420257 SUPPORT In Vitro
"The Cystatin B deficiency-induced predisposition to oxidative stress in neurons is mediated by the lysosomal protease Cathepsin B."
Links loss of cystatin B to oxidative vulnerability through dysregulated cathepsin B activity, the coupled cathepsin/redox amplifier step.
PMID:19420257 SUPPORT Model Organism
"increased lipid peroxidation, in the cerebellum of Cystatin B knock-out mice in vivo."
Demonstrates in vivo oxidative damage in the cystatin B-deficient cerebellum.
Cerebellar Granule Neuron Death and Degeneration
Cystatin-B-deficient cerebellar granule neurons undergo oxidative-stress-linked death and degeneration. In the knockout mouse, loss of cerebellar granule cells with fragmented DNA and condensed nuclei is the principal cytopathology. This node is kept separate from cortical GABAergic terminal loss because the sources establish different cell populations and do not show that one causes the other.
cerebellar granule cell CL:0001031 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cerebellar granule cell (CL:0001031). CL:0001031 is a cell type from the Cell Ontology.
neuron apoptotic process GO:0051402 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased neuron apoptotic process (GO:0051402). GO:0051402 is a biological process from the Gene Ontology. ↑ INCREASED
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
Cstb knockout mouse Mouse (Mus musculus) recapitulates The knockout reproduces the principal apoptotic cerebellar granule-cell cytopathology used in the EPM1 causal graph.
Downstream
Progressive Cerebellar Ataxia
Dysarthria
Intention Tremor
Show evidence (2 references)
PMID:9806543 SUPPORT Model Organism
"The principal cytopathology appears to be a loss of cerebellar granule cells, which frequently display condensed nuclei, fragmented DNA and other cellular changes characteristic of apoptosis."
Establishes apoptotic cerebellar granule cell loss as the principal cytopathology in the cystatin B-null model.
PMID:9806543 SUPPORT Model Organism
"cystatin B, a non-caspase cysteine protease inhibitor, has a role in preventing cerebellar apoptosis."
Attributes the cerebellar apoptosis directly to loss of cystatin B's protease-inhibitory function.
Cortical GABAergic Input Loss
ULD cortex shows reduced vesicular GABA-transporter labeling, and the Cstb knockout model shows progressive loss of cortical GABA interneurons, reduced terminal GABA release, and reduced electrophysiologic inhibition. Human tissue evidence is limited to one reported case, which is stated explicitly rather than generalized into a population frequency.
GABAergic neuron CL:0000617 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves GABAergic neuron (CL:0000617). CL:0000617 is a cell type from the Cell Ontology.
gamma-aminobutyric acid signaling pathway GO:0007214 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased gamma-aminobutyric acid signaling pathway (GO:0007214). GO:0007214 is a biological process from the Gene Ontology. ↓ DECREASED
neocortex UBERON:0001950 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in neocortex (UBERON:0001950). UBERON:0001950 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Cstb knockout mouse Mouse (Mus musculus) partially recapitulates The knockout reproduces progressive cortical GABA-interneuron loss and reduced inhibitory input, a mechanism also observed in one human ULD cortex.
Downstream
Cortical Hyperexcitability
Show evidence (2 references)
PMID:22538221 SUPPORT Model Organism
"In CSTB knockout mice, a progressive decrease in neocortex thickness was found, associated with a prevalent loss of GABA interneurons."
The knockout model directly demonstrates progressive cortical GABA-interneuron loss.
PMID:22538221 SUPPORT Human Clinical
"A marked reduction in VGAT labeling was found in the cortex of both CSTB knockout mice and an ULD patient."
The human post-mortem case confirms reduced cortical GABA-terminal density, while the description preserves the single-case limitation.
Cortical Hyperexcitability
Loss of cortical GABAergic inhibition shifts the cortical excitation-inhibition balance toward excitation, producing latent network hyperexcitability. This manifests as the hallmark stimulus-sensitive (action- and reflex-activated) myoclonus and as generalized, including photosensitive, seizures.
GABAergic neuron CL:0000617 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves GABAergic neuron (CL:0000617). CL:0000617 is a cell type from the Cell Ontology.
gamma-aminobutyric acid signaling pathway GO:0007214 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased gamma-aminobutyric acid signaling pathway (GO:0007214). GO:0007214 is a biological process from the Gene Ontology. ↓ DECREASED
neocortex UBERON:0001950 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in neocortex (UBERON:0001950). UBERON:0001950 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Stimulus-Sensitive Action Myoclonus
Generalized Tonic-Clonic Seizures
Photosensitive Seizures
Show evidence (2 references)
PMID:22538221 SUPPORT Human Clinical
"loss of cortical GABA input occurs in a relevant animal model and in a case of human ULD, leading to a condition of latent hyperexcitability that favors myoclonus and seizures."
Directly links loss of cortical GABAergic input to the hyperexcitable state that generates myoclonus and seizures.
PMID:20301321 SUPPORT Other
"the myoclonic jerks are progressive, action activated, and treatment resistant, and can be severely disabling."
Characterizes the action-activated, progressive, treatment-resistant myoclonus that is the clinical signature of this hyperexcitable arm.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Unverricht-Lundborg Disease 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

9
Nervous System 7
Stimulus-Sensitive Action Myoclonus HP:0001336 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Stimulus-sensitive action myoclonus, annotated with Myoclonus (HP:0001336), qualified as course progressive. HP:0001336 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:18325013 SUPPORT Other
"characterized by age of onset from 6 to 16 years, stimulus-sensitive myoclonus, and tonic-clonic epileptic seizures."
Establishes stimulus-sensitive myoclonus as a defining feature with typical 6-16 year onset.
PMID:20301321 SUPPORT Other
"the myoclonic jerks are progressive, action activated, and treatment resistant, and can be severely disabling."
Documents the progressive, action-activated, treatment-resistant character of the myoclonus.
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 Generalized tonic-clonic seizures, annotated with Bilateral tonic-clonic seizure (HP:0002069). HP:0002069 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18325013 SUPPORT Other
"characterized by age of onset from 6 to 16 years, stimulus-sensitive myoclonus, and tonic-clonic epileptic seizures."
Documents tonic-clonic epileptic seizures as a core feature.
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 (2 references)
PMID:18325013 SUPPORT Other
"Some years after the onset ataxia, incoordination, intentional tremor, and dysarthria develop."
Documents progressive cerebellar ataxia developing after onset.
PMID:9126745 SUPPORT Human Clinical
"onset between 6 and 13 years followed by variable progression to mental deterioration and cerebellar ataxia."
Independent source documenting progression to cerebellar ataxia.
Dysarthria HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18325013 SUPPORT Other
"Some years after the onset ataxia, incoordination, intentional tremor, and dysarthria develop."
Documents dysarthria as part of the delayed cerebellar arm.
Intention Tremor HP:0002080 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intention tremor (HP:0002080). HP:0002080 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18325013 SUPPORT Other
"Some years after the onset ataxia, incoordination, intentional tremor, and dysarthria develop."
Documents intention tremor within the cerebellar syndrome.
Mild Cognitive Decline Mental deterioration HP:0001268 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild cognitive decline, annotated with Mental deterioration (HP:0001268), qualified as course progressive; severity mild. HP:0001268 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE Severity: MILD
Show evidence (2 references)
PMID:18325013 SUPPORT Other
"Individuals with EPM1 are mentally alert but show emotional lability, depression, and mild decline in intellectual performance over time."
Documents the mild, slowly progressive cognitive decline with preserved alertness.
PMID:34171687 SUPPORT Human Clinical
"The cognitive performance of the EPM1 patient group was impaired."
A large neuropsychological cohort study confirms measurable cognitive impairment.
Depression HP:0000716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Depression (HP:0000716). HP:0000716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18325013 SUPPORT Other
"Individuals with EPM1 are mentally alert but show emotional lability, depression, and mild decline in intellectual performance over time."
Documents depression as a recognized feature.
Other 2
Photosensitive Seizures Photosensitive myoclonic seizure HP:0001327 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Photosensitive seizures, annotated with Photosensitive myoclonic seizure (HP:0001327). HP:0001327 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38247861 SUPPORT Other
"EPM1 patients suffer from photo-sensitive seizures, stimulus-sensitive myoclonus, nocturnal myoclonic seizures, ataxia and dysarthria."
Documents photosensitive seizures as part of the EPM1 phenotype. Evidence source is OTHER because this is a review article.
Emotional Lability HP:0000712 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Emotional lability (HP:0000712). HP:0000712 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18325013 SUPPORT Other
"Individuals with EPM1 are mentally alert but show emotional lability, depression, and mild decline in intellectual performance over time."
Documents emotional lability as a behavioral feature.
🧬

Genetic Associations

1
CSTB (Loss-of-Function (dodecamer repeat expansion or point/indel variants))
Gene: CSTB hgnc:2482 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CSTB (hgnc:2482). hgnc:2482 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE
Autosomal Recessive
Show evidence (2 references)
PMID:9126745 SUPPORT Human Clinical
"Two point mutations in the cysteine proteinase inhibitor gene cystatin B (CSTB), proved that this gene is responsible for EPM1"
Establishes CSTB (a cysteine proteinase inhibitor gene) as the EPM1 gene.
PMID:8596935 SUPPORT Human Clinical
"levels of messenger RNA encoded by this gene were found to be decreased in cells from affected individuals."
Documents reduced CSTB expression in patient cells, the loss-of-function mechanism.
💊

Medical Actions

5
Valproic Acid
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: valproic acid CHEBI:39867 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses valproic acid (CHEBI:39867). CHEBI:39867 is a therapeutic agent from Chemical Entities of Biological Interest.
Valproic acid is the first drug of choice and diminishes myoclonus and the frequency of generalized seizures.
Show evidence (1 reference)
PMID:18325013 SUPPORT Other
"Valproic acid, the first drug of choice, diminishes myoclonus and the frequency of generalized seizures."
Documents valproic acid as first-line therapy reducing myoclonus and seizures.
Myoclonus-Directed Add-On Therapy
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: clonazepam CHEBI:3756 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses clonazepam (CHEBI:3756). CHEBI:3756 is a therapeutic agent from Chemical Entities of Biological Interest. piracetam CHEBI:32010 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses piracetam (CHEBI:32010). CHEBI:32010 is a therapeutic agent from Chemical Entities of Biological Interest. levetiracetam CHEBI:6437 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses levetiracetam (CHEBI:6437). CHEBI:6437 is a therapeutic agent from Chemical Entities of Biological Interest. topiramate CHEBI:63631 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses topiramate (CHEBI:63631). CHEBI:63631 is a therapeutic agent from Chemical Entities of Biological Interest. zonisamide CHEBI:10127 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses zonisamide (CHEBI:10127). CHEBI:10127 is a therapeutic agent from Chemical Entities of Biological Interest. perampanel CHEBI:71013 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses perampanel (CHEBI:71013). CHEBI:71013 is a therapeutic agent from Chemical Entities of Biological Interest.
Clonazepam and high-dose piracetam are used to treat myoclonus, while levetiracetam is used for both myoclonus and generalized seizures. Topiramate and zonisamide may also be used as add-on therapy. An open-label series supports perampanel for refractory myoclonus and seizures, but psychological or behavioral adverse effects occurred in half of the small cohort and required withdrawal or dose reduction. Brivaracetam is excluded from this treatment block because two phase III trials did not show a statistically significant action-myoclonus benefit.
Show evidence (4 references)
PMID:18325013 SUPPORT Other
"Clonazepam and high-dose piracetam are used to treat myoclonus, whereas levetiracetam seems to be effective for both myoclonus and generalized seizures."
Documents clonazepam, high-dose piracetam, and levetiracetam in myoclonus management.
PMID:20301321 SUPPORT Other
"Topiramate and zonisamide may also be used as add-on therapy."
GeneReviews supplies the clinical-management basis for these two add-on agents not named in the older clinical review.
PMID:28166365 SUPPORT Human Clinical
"Ten patients had a clear clinical response of myoclonus, and five were able to reduce concomitant therapy. Improvement was noted sometimes as soon as with 2 mg/day. Epileptic seizures stopped on PER in the six patients who still had experienced generalized tonic-clonic or myoclonic seizures (100%)."
The small open-label series supports potential efficacy against myoclonus and ongoing seizures while not implying randomized-trial certainty.
+ 1 more reference
Avoidance of Aggravating Antiseizure Drugs
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Certain antiseizure drugs worsen EPM1 and are avoided. Phenytoin aggravates the neurologic symptoms or even accelerates cerebellar degeneration; sodium channel blockers (carbamazepine, oxcarbazepine), GABAergic drugs (tiagabine, vigabatrin), and gabapentin and pregabalin may aggravate the myoclonus and myoclonic seizures.
Show evidence (2 references)
PMID:20301321 SUPPORT Other
"Phenytoin aggravates neurologic symptoms or even accelerates cerebellar degeneration; sodium channel blockers (carbamazepine, oxcarbazepine), GABAergic drugs (tiagabine, vigabatrin), and gabapentin and pregabalin may aggravate myoclonus and myoclonic seizures."
The GeneReviews agents-to-avoid guidance identifies phenytoin and sodium-channel-blocking/GABAergic drugs as harmful in EPM1.
PMID:18325013 SUPPORT Other
"phenytoin aggravating the associated neurologic symptoms or even accelerating cerebellar degeneration."
Independent clinical review confirming phenytoin aggravates EPM1 and can accelerate cerebellar degeneration.
Rehabilitation and Supportive Care
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Symptomatic pharmacologic and rehabilitative management, including physiotherapy and psychosocial support, is the mainstay of care given the disabling myoclonus and progressive cerebellar disability.
Show evidence (1 reference)
PMID:18325013 SUPPORT Other
"Symptomatic pharmacologic and rehabilitative management, including psychosocial support, are the mainstay of EPM1 patients' care."
Documents rehabilitative and psychosocial supportive care as the mainstay of management.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Genetic counseling addresses the autosomal recessive 25% sibling recurrence risk and, once both familial CSTB variants are known, carrier and prenatal testing options.
Show evidence (1 reference)
PMID:20301321 SUPPORT Other
"At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once both CSTB pathogenic variants in a family are known, carrier testing for at-risk relatives, prenatal..."
GeneReviews directly supports the recurrence-risk calculation and the reproductive-testing options stated in the treatment description.
🔬

Diagnosis

2
CSTB Molecular Diagnosis
Diagnosis is established in a proband with suggestive clinical findings by identifying biallelic CSTB dodecamer repeat expansions, or compound heterozygosity for a repeat expansion and a CSTB sequence variant, by molecular genetic testing (repeat-primed PCR sizing for the expansion plus sequencing).
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: Biallelic CSTB dodecamer repeat expansions (or a repeat expansion in compound heterozygosity with a CSTB sequence variant) confirm the diagnosis.
Show evidence (1 reference)
PMID:20301321 SUPPORT Other
"biallelic abnormal CCC-CGC-CCC-GCG dodecamer repeat expansions in CSTB or compound heterozygosity for a CSTB dodecamer repeat expansion and a CSTB sequence variant"
The GeneReviews chapter defines the molecular criteria for establishing the diagnosis.
Electroencephalography
EEG documents generalized epileptiform activity and a photoparoxysmal (photosensitive) response supporting the progressive myoclonus epilepsy phenotype.
electroencephalography NCIT:C38054 NCI Thesaurus (NCIT)
Results: Generalized spike- or polyspike-and-wave discharges and a photoparoxysmal response support the EPM1 phenotype. Both are common near onset but can diminish during long-term follow-up, so their absence later does not exclude EPM1.
Show evidence (1 reference)
PMID:17158032 SUPPORT Human Clinical
"GSWD were present in 92% of patients at the onset of the disease and gradually disappeared during the follow-up with a significant difference (p<0.001) after the 15th year of disease. PPR was present in 88% of patients at the disease onset and gradually disappeared with a significant difference..."
Longitudinal EEG review in 25 patients supports generalized spike/polyspike discharges and photoparoxysmal responses near onset while documenting their later decline.
📈

Progression

3
Onset (childhood/adolescence)
Onset is typically between 6 and 16 years with stimulus-sensitive myoclonus and generalized tonic-clonic seizures.
Show evidence (1 reference)
PMID:18325013 SUPPORT Other
"characterized by age of onset from 6 to 16 years, stimulus-sensitive myoclonus, and tonic-clonic epileptic seizures."
Documents the childhood-to-adolescent onset with myoclonus and tonic-clonic seizures.
Progression (young adulthood)
Over subsequent years the action myoclonus worsens and becomes the dominant disabling feature, while cerebellar signs (ataxia, incoordination, intention tremor, dysarthria) develop and cognition declines mildly; tonic-clonic seizures are usually well controlled.
Show evidence (1 reference)
PMID:18325013 SUPPORT Other
"Some years after the onset ataxia, incoordination, intentional tremor, and dysarthria develop."
Documents the delayed progressive cerebellar arm.
Long-term disability and survival
Course is heterogeneous: approximately 10% of Finnish registry cases remained very mild with decades of independence, but disability commonly accumulated and survival diverged from matched controls after age 40. Lower respiratory tract infection was the immediate cause in 56% of recorded deaths.
Show evidence (3 references)
PMID:32943486 SUPPORT Human Clinical
"The survival rates of the patients were comparable to matched controls up to 40 years of age, but poorer during long-term follow-up (cumulative survival 26.4% vs 78.0%), with a hazard ratio (HR) for death of 4.61."
The nationwide registry provides matched-control long-term survival data.
PMID:32943486 SUPPORT Human Clinical
"The immediate cause of death was a lower respiratory tract infection in 56% of deaths."
The registry directly quantifies the leading immediate cause of death.
PMID:32943486 SUPPORT Human Clinical
"In approximately 10% of all cases, the disease progression appeared very mild; some patients retained functional independence for decades."
This preserves the important mild-course subgroup rather than presenting the Finnish prognosis as uniform.
📊

Prevalence

2
Finland
Point Prevalence 1.91 per 100,000 1–9 per 100,000
Nationwide registry point prevalence on 2016-12-31; 105 people with EPM1 were alive in a Finnish population of approximately 5.5 million. This replaces the older 1-in-20,000 birth-incidence figure as the point-prevalence estimate.
Show evidence (1 reference)
PMID:32943486 SUPPORT Human Clinical
"A total of 135 persons with EPM1 (54% women) were identified and 105 were alive on December 31, 2016 (point prevalence 1.91/100,000 persons)."
The nationwide population-based registry directly supplies the date-specific Finnish point prevalence.
Worldwide
Point Prevalence Rare
Globally rare outside founder populations; nonetheless one of the more common progressive myoclonus epilepsies.
Show evidence (1 reference)
PMID:9126745 SUPPORT Human Clinical
"It is a rare disorder but more common in Finland (1 in 20,000) and the western Mediterranean."
Supports the overall rarity of EPM1 outside founder regions.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Unverricht-Lundborg Disease:

Lafora Disease (EPM2)
Overlapping Features Lafora disease is the other classic autosomal recessive progressive myoclonus epilepsy of adolescent onset, caused by EPM2A (laforin) or NHLRC1/EPM2B (malin). Lafora bodies may be demonstrated on skin biopsy. It follows a more rapidly progressive course with early cognitive decline and dementia, unlike the relatively preserved cognition and slower course of EPM1.
Distinguishing Features
  • Biallelic CSTB variants (dodecamer expansion) favor EPM1.
  • EPM2A/NHLRC1 variants with Lafora bodies and rapid dementia favor Lafora disease.
Show evidence (2 references)
PMID:20301563 SUPPORT Other
"Cognitive decline becomes apparent at or soon after the onset of seizures. Dysarthria and ataxia appear early, while spasticity appears late. Emotional disturbances and confusion are common in the early stages of the disease and are followed by dementia."
GeneReviews supports the early cognitive decline and dementia that help distinguish Lafora disease from the generally slower EPM1 course.
PMID:20301563 SUPPORT Other
"The diagnosis of Lafora disease is established in a proband with characteristic neurologic findings and/or biallelic pathogenic variants in one of the two known causative genes, EPM2A or NHLRC1, identified by molecular genetic testing. On rare occasion, a skin biopsy to detect Lafora bodies is..."
Supports the causal genes and the diagnostic occurrence of Lafora bodies.
Other progressive myoclonus epilepsies
Overlapping Features Other PMEs (e.g., myoclonic epilepsy with ragged-red fibers/MERRF, the neuronal ceroid lipofuscinoses, and sialidosis) overlap through action myoclonus, seizures, and progressive neurologic deterioration. Their age of onset, associated features, clinical course, inheritance, and targeted biochemical, pathologic, or genetic testing help distinguish them.
Distinguishing Features
  • A biallelic CSTB lesion favors EPM1.
  • A causal variant or storage material specific to another PME favors that diagnosis.
Show evidence (2 references)
PMID:26060909 SUPPORT Other
"The progressive myoclonus epilepsies (PMEs) comprise a group of rare and heterogeneous disorders defined by the combination of action myoclonus, epileptic seizures, and progressive neurologic deterioration."
Defines the core overlapping clinical pattern of the PME differential.
PMID:26060909 SUPPORT Other
"The specific diseases that cause PME are diagnosed by recognition of their age of onset, the associated clinical symptoms, the clinical course, the pattern of inheritance, and by special investigations such as enzyme measurement, skin/muscle biopsy, or gene testing."
Supports the clinical, biochemical, pathologic, and genetic distinctions used to separate EPM1 from other PMEs.
🔬

Clinical Trials

2
NCT00357669 PHASE_III COMPLETED
Randomized, double-blind, placebo-controlled 12-week study of adjunctive brivaracetam in genetically confirmed Unverricht-Lundborg disease in adolescents and adults aged 16 years or older. The pooled brivaracetam groups did not show a statistically significant reduction in action myoclonus versus placebo.
Show evidence (2 references)
clinicaltrials:NCT00357669 SUPPORT Human Clinical
"The study will compare the efficacy and safety of brivaracetam with placebo in patients with Unverricht-Lundborg disease."
The registry summary directly identifies the intervention, comparator, and disease population; the registry status was rechecked as COMPLETED on 2026-08-11.
PMID:26666500 SUPPORT Human Clinical
"Estimated differences versus placebo were not statistically significant."
The joint publication of both phase III trials reports that the prespecified efficacy comparisons did not reach statistical significance.
NCT00368251 PHASE_III COMPLETED
Second randomized, double-blind, placebo-controlled 12-week phase III study of adjunctive brivaracetam in genetically confirmed Unverricht-Lundborg disease in adolescents and adults aged 16 years or older. Brivaracetam did not show a statistically significant reduction in action myoclonus versus placebo.
Show evidence (2 references)
clinicaltrials:NCT00368251 SUPPORT Human Clinical
"The study will compare the efficacy and safety of Brivaracetam with placebo in patients with Unverricht- Lundborg Disease (ULD)."
The registry summary directly identifies the intervention, comparator, and disease population; the registry status was rechecked as COMPLETED on 2026-08-11.
PMID:26666500 SUPPORT Human Clinical
"Effect of BRV on action myoclonus was not statistically significant."
The joint publication reports the negative primary efficacy result while noting good tolerability and high completion.
🐁

Animal Models

1
Cstb knockout mouse
Cystatin B-null mice develop myoclonic seizures and ataxia resembling the human disease, with apoptotic loss of cerebellar granule neurons, progressive loss of cortical GABAergic interneurons, and in vivo cerebellar oxidative damage, making them a validated EPM1 model.
Species
Mouse (Mus musculus)
Genotype
Cystatin B (Cstb) knockout
Pathograph links
Cerebellar Granule Neuron Death and Degeneration recapitulates fidelity: high The knockout reproduces the principal apoptotic cerebellar granule-cell cytopathology used in the EPM1 causal graph.
Limitations: The null genotype models complete loss of Cstb rather than the residual expression typical of most human promoter-repeat alleles.
Show evidence (1 reference)
PMID:9806543 SUPPORT Model Organism
"The principal cytopathology appears to be a loss of cerebellar granule cells, which frequently display condensed nuclei, fragmented DNA and other cellular changes characteristic of apoptosis."
Directly establishes recapitulation of the graph's cerebellar granule-neuron-death mechanism.
Cortical GABAergic Input Loss partially recapitulates fidelity: moderate The knockout reproduces progressive cortical GABA-interneuron loss and reduced inhibitory input, a mechanism also observed in one human ULD cortex.
Limitations: Human tissue confirmation is limited to one post-mortem case, and the null mouse genotype is more severe than the common human promoter expansion.
Show evidence (1 reference)
PMID:22538221 SUPPORT Model Organism
"In CSTB knockout mice, a progressive decrease in neocortex thickness was found, associated with a prevalent loss of GABA interneurons."
Directly supports partial recapitulation of cortical GABAergic input loss in the knockout model.
Show evidence (2 references)
PMID:9806543 SUPPORT Model Organism
"mice lacking cystatin B develop myoclonic seizures and ataxia, similar to symptoms seen in the human disease."
The cystatin B-null mouse recapitulates the core myoclonus/ataxia phenotype and cerebellar apoptosis of EPM1.
PMID:19420257 SUPPORT Model Organism
"Cystatin B knockout in a mouse model of EPM1 triggers progressive degeneration of cerebellar granule neurons."
Confirms progressive cerebellar granule neuron degeneration in the model.
{ }

Source YAML

click to show 
name: Unverricht-Lundborg Disease
creation_date: "2026-07-25T00:00:00Z"
description: >-
  Unverricht-Lundborg disease (ULD), also called progressive myoclonic epilepsy
  type 1 (EPM1) or Baltic myoclonus, is an autosomal recessive neurodegenerative
  progressive myoclonus epilepsy caused by biallelic loss-of-function of CSTB,
  the gene encoding cystatin B. Cystatin B is a ubiquitously expressed
  intracellular inhibitor of the cysteine cathepsins (thiol proteases). In the
  great majority of patients the causal lesion is an unstable expansion of a
  dodecamer (12-mer) repeat in the CSTB promoter that reduces CSTB transcription;
  a minority carry point/indel loss-of-function variants, often in compound
  heterozygosity with the repeat expansion. Onset is typically between 6 and 16
  years with stimulus-sensitive (action) myoclonus and generalized tonic-clonic
  seizures; over the following years progressive cerebellar signs (ataxia,
  incoordination, intention tremor, dysarthria) develop, together with emotional
  lability, depression, and a mild decline in cognition, while patients remain
  largely mentally alert. It is one of the most common progressive myoclonus
  epilepsies and is markedly enriched in Finland, the Baltic region, and the
  western Mediterranean through founder effects. EPM1 is distinguished from the
  other classic progressive myoclonus epilepsies (notably Lafora disease) by its
  slower course and relative preservation of cognition. Treatment is symptomatic;
  importantly, phenytoin can aggravate neurologic symptoms and may accelerate
  cerebellar degeneration, while several sodium-channel-blocking, GABAergic, and
  gabapentinoid antiseizure drugs can aggravate myoclonus and are avoided.
category: Mendelian
parents:
- Progressive Myoclonus Epilepsy
disease_term:
  preferred_term: Unverricht-Lundborg disease
  term:
    id: MONDO:0009698
    label: Unverricht-Lundborg syndrome
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    EPM1 is inherited in an autosomal recessive manner; affected individuals
    carry biallelic CSTB loss-of-function alleles (most commonly two dodecamer
    repeat expansions, or a repeat expansion in compound heterozygosity with a
    CSTB point/indel variant).
  evidence:
  - reference: PMID:8596935
    reference_title: "Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) is an
      autosomal recessive inherited form of epilepsy, previously linked to human
      chromosome 21q22.3.
    explanation: >-
      Establishes the autosomal recessive inheritance and 21q22.3 localization of
      EPM1.
  - reference: PMID:20301321
    reference_title: "Progressive Myoclonic Epilepsy Type 1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      EPM1 is inherited in an autosomal recessive manner.
    explanation: >-
      The GeneReviews chapter confirms autosomal recessive inheritance.
prevalence:
- population: Finland
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.91
  notes: >-
    Nationwide registry point prevalence on 2016-12-31; 105 people with EPM1
    were alive in a Finnish population of approximately 5.5 million. This
    replaces the older 1-in-20,000 birth-incidence figure as the point-prevalence
    estimate.
  evidence:
  - reference: PMID:32943486
    reference_title: "Unverricht-Lundborg disease (EPM1) in Finland: A nationwide population-based study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 135 persons with EPM1 (54% women) were identified and 105 were
      alive on December 31, 2016 (point prevalence 1.91/100,000 persons).
    explanation: >-
      The nationwide population-based registry directly supplies the date-specific
      Finnish point prevalence.
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: RARE
  notes: >-
    Globally rare outside founder populations; nonetheless one of the more common
    progressive myoclonus epilepsies.
  evidence:
  - reference: PMID:9126745
    reference_title: "Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is a rare disorder but more common in Finland (1 in 20,000) and the
      western Mediterranean.
    explanation: >-
      Supports the overall rarity of EPM1 outside founder regions.
references:
- reference: PMID:20301321
  title: "Progressive Myoclonic Epilepsy Type 1."
  tags:
  - GeneReviews
- reference: PMID:8596935
  title: "Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1)."
- reference: PMID:9126745
  title: "Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy."
- reference: PMID:9806543
  title: "Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice."
- reference: PMID:19420257
  title: "Cystatin B deficiency sensitizes neurons to oxidative stress in progressive myoclonus epilepsy, EPM1."
- reference: PMID:22538221
  title: "Loss of cortical GABA terminals in Unverricht-Lundborg disease."
- reference: PMID:18325013
  title: "Clinical picture of EPM1-Unverricht-Lundborg disease."
- reference: PMID:34171687
  title: "Cognitive functioning in progressive myoclonus epilepsy type 1 (Unverricht-Lundborg Disease, EPM1)."
- reference: PMID:38247861
  title: "The Roles of Cystatin B in the Brain and Pathophysiological Mechanisms of Progressive Myoclonic Epilepsy Type 1."
- reference: PMID:32943486
  title: "Unverricht-Lundborg disease (EPM1) in Finland: A nationwide population-based study."
- reference: PMID:17158032
  title: "Long-term evolution of EEG in Unverricht-Lundborg disease."
- reference: PMID:26666500
  title: "Brivaracetam in Unverricht-Lundborg disease (EPM1): Results from two randomized, double-blind, placebo-controlled studies."
- reference: PMID:20301563
  title: "Progressive Myoclonus Epilepsy, Lafora Type."
  tags:
  - GeneReviews
- reference: PMID:26060909
  title: "Progressive Myoclonus Epilepsies."
- reference: PMID:28166365
  title: "Perampanel in 12 patients with Unverricht-Lundborg disease."
- reference: PMID:22157618
  title: "Early microglial activation precedes neuronal loss in the brain of the Cstb-/- mouse model of progressive myoclonus epilepsy, EPM1."
- reference: PMID:32378798
  title: "Cystatin B is essential for proliferation and interneuron migration in individuals with EPM1 epilepsy."
pathophysiology:
- name: CSTB Dodecamer Repeat Expansion and Cystatin B Deficiency
  biological_scale: MOLECULAR
  description: >-
    The initiating lesion is biallelic loss-of-function of CSTB. In most patients
    an unstable expansion of a dodecamer (12-mer) repeat in the CSTB promoter
    reduces transcription; a minority carry loss-of-function point/indel variants
    (e.g., a splice-site or nonsense variant), frequently in compound
    heterozygosity with the repeat expansion. The shared consequence is markedly
    reduced cystatin B, an intracellular thiol (cysteine) protease inhibitor.
  role: trigger
  gene:
    preferred_term: CSTB
    term:
      id: hgnc:2482
      label: CSTB
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  molecular_functions:
  - preferred_term: cysteine-type endopeptidase inhibitor activity
    term:
      id: GO:0004869
      label: cysteine-type endopeptidase inhibitor activity
    modifier: DECREASED
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:9126745
    reference_title: "Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the majority of EPM1 alleles contain expansions of a dodecamer (12-mer)
      repeat located about 70 nucleotides upstream of the transcription start site
    explanation: >-
      Identifies the promoter dodecamer repeat expansion as the predominant EPM1
      lesion.
  - reference: PMID:9126745
    reference_title: "Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Normal alleles contain 2 or 3 copies of this repeat whereas mutant alleles
      contain more than 60 such repeats and have reduced levels of CSTB messenger
      RNA in blood but not in cell lines.
    explanation: >-
      Shows the expansion reduces CSTB mRNA, establishing the loss-of-expression
      mechanism.
  - reference: PMID:8596935
    reference_title: "Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two mutations, a 3' splice site mutation and a stop codon mutation, were
      identified in the gene encoding cystatin B in EPM1 patients
    explanation: >-
      Documents the minority loss-of-function point-variant class of CSTB alleles.
  - reference: PMID:38247861
    reference_title: "The Roles of Cystatin B in the Brain and Pathophysiological Mechanisms of Progressive Myoclonic Epilepsy Type 1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The CSTB protein functions as an intracellular thiol protease inhibitor and
      inhibits Cathepsin function.
    explanation: >-
      Defines cystatin B as an intracellular thiol (cysteine) protease inhibitor
      of cathepsins, whose deficiency is the trigger. Evidence source is OTHER
      because this is a review article.
  downstream:
  - target: Cathepsin B-Dependent Oxidative Stress Vulnerability
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19420257
      reference_title: "Cystatin B deficiency sensitizes neurons to oxidative stress in progressive myoclonus epilepsy, EPM1."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Cystatin B knockout or knockdown sensitizes cerebellar granule neurons to
        oxidative stress-induced cell death.
      explanation: >-
        Genetic loss of cystatin B directly sensitized cerebellar granule neurons
        to oxidative-stress-induced death.
  - target: Cortical GABAergic Input Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22538221
      reference_title: "Loss of cortical GABA terminals in Unverricht-Lundborg disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In CSTB knockout mice, a progressive decrease in neocortex thickness was
        found, associated with a prevalent loss of GABA interneurons.
      explanation: >-
        The knockout model links CSTB loss to cortical GABA-interneuron loss, but
        the intervening route is unresolved and human evidence is limited to one
        post-mortem case; the edge is therefore indirect and PARTIAL.
  - target: Early Microglial Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22157618
      reference_title: "Early microglial activation precedes neuronal loss in the brain of the Cstb-/- mouse model of progressive myoclonus epilepsy, EPM1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our data reveal early and localized glial activation in brain regions
        where neuron loss subsequently occurs.
      explanation: >-
        Cstb deficiency produces early localized glial activation in the knockout
        model, but the intervening molecular route and human generalizability are
        unresolved; the edge is therefore indirect and PARTIAL.
  - target: Altered Cortical Progenitor Proliferation and Interneuron Migration
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32378798
      reference_title: "Cystatin B is essential for proliferation and interneuron migration in individuals with EPM1 epilepsy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        in patient-derived hCOs, low levels of functional CSTB result in an
        alteration of progenitor's proliferation, premature differentiation, and
        changes in interneurons migration.
      explanation: >-
        Patient-derived cerebral organoids directly connect low functional CSTB
        to altered cortical progenitor proliferation, differentiation, and
        interneuron migration.
- name: Early Microglial Activation
  biological_scale: TISSUE
  description: >-
    In the Cstb-deficient mouse, localized microglial activation appears before
    myoclonia and before selective neuron loss in the same vulnerable brain
    regions. The temporal sequence supports an early neuroinflammatory arm, while
    its causal contribution and human generalizability remain unresolved.
  role: amplifier
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  biological_processes:
  - preferred_term: microglial cell activation
    term:
      id: GO:0001774
      label: microglial cell activation
    modifier: INCREASED
  evidence:
  - reference: PMID:22157618
    reference_title: "Early microglial activation precedes neuronal loss in the brain of the Cstb-/- mouse model of progressive myoclonus epilepsy, EPM1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Microglial activation precedes the emergence of myoclonia and is followed
      by successive astrocytosis and selective neuron loss.
    explanation: >-
      Establishes the temporal order of microglial activation, myoclonia,
      astrocytosis, and selective neuron loss in the knockout model.
  downstream:
  - target: Selective Cortical and Thalamic Neuron Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22157618
      reference_title: "Early microglial activation precedes neuronal loss in the brain of the Cstb-/- mouse model of progressive myoclonus epilepsy, EPM1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our data reveal early and localized glial activation in brain regions
        where neuron loss subsequently occurs.
      explanation: >-
        Spatial and temporal ordering supports this candidate arm, but does not
        prove that activated microglia alone cause neuron loss; support is PARTIAL
        and the intermediates remain unknown.
- name: Selective Cortical and Thalamic Neuron Loss
  biological_scale: TISSUE
  description: >-
    The Cstb-deficient mouse develops selective neuron loss first in cortex and
    subsequently in the corresponding thalamic relay nucleus. This is kept
    separate from cerebellar granule-cell death because the affected regions and
    evidence base differ.
  role: effector
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  - preferred_term: thalamus
    term:
      id: UBERON:0001897
      label: dorsal plus ventral thalamus
  evidence:
  - reference: PMID:22157618
    reference_title: "Early microglial activation precedes neuronal loss in the brain of the Cstb-/- mouse model of progressive myoclonus epilepsy, EPM1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These changes are most pronounced in the thalamocortical system, with
      neuron loss occurring first within the cortex and only subsequently in the
      corresponding thalamic relay nucleus.
    explanation: >-
      Defines the anatomic distribution and sequence of selective neuron loss in
      the knockout model.
- name: Altered Cortical Progenitor Proliferation and Interneuron Migration
  biological_scale: TISSUE
  description: >-
    Patient-derived cerebral organoids with low functional CSTB show reduced or
    altered neural-progenitor proliferation, premature differentiation, and
    impaired interneuron migration. These developmental changes provide a
    human-cell-derived route from CSTB deficiency toward reduced cortical
    inhibitory-neuron recruitment.
  role: developmental_effector
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  - preferred_term: GABAergic neuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  biological_processes:
  - preferred_term: neural precursor cell proliferation
    term:
      id: GO:0061351
      label: neural precursor cell proliferation
    modifier: DECREASED
  - preferred_term: neuron migration
    term:
      id: GO:0001764
      label: neuron migration
    modifier: DECREASED
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:32378798
    reference_title: "Cystatin B is essential for proliferation and interneuron migration in individuals with EPM1 epilepsy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our results indicate that physiological levels of CSTB are essential for
      correct cell proliferation and interneurons migration both in vivo and in
      vitro. On the contrary, lower levels of functional CSTB in patient-derived
      hCOs result in a reduction of progenitor cell proliferation, premature
      differentiation, and reduced recruitment of interneurons.
    explanation: >-
      Human patient-derived cerebral organoids directly demonstrate the
      proliferation and interneuron-recruitment abnormalities represented here.
  downstream:
  - target: Cortical GABAergic Input Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32378798
      reference_title: "Cystatin B is essential for proliferation and interneuron migration in individuals with EPM1 epilepsy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        lower levels of functional CSTB in patient-derived hCOs result in a
        reduction of progenitor cell proliferation, premature differentiation,
        and reduced recruitment of interneurons.
      explanation: >-
        Impaired interneuron recruitment provides a human-cell-derived upstream
        route toward deficient cortical GABAergic input, but mature terminal loss
        was not directly measured in the organoids; support is PARTIAL.
- name: Cathepsin B-Dependent Oxidative Stress Vulnerability
  biological_scale: CELLULAR
  description: >-
    Cystatin B deficiency impairs neuronal redox homeostasis and sensitizes
    cerebellar granule neurons to oxidative-stress-induced death. Knockdown
    experiments identify lysosomal cathepsin B as a mediator of this
    vulnerability; the node does not claim that every cysteine cathepsin is
    globally overactive in patients.
  role: amplifier
  cell_types:
  - preferred_term: cerebellar granule cell
    term:
      id: CL:0001031
      label: cerebellar granule cell
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: ABNORMAL
  molecular_functions:
  - preferred_term: cysteine-type peptidase activity
    term:
      id: GO:0008234
      label: cysteine-type peptidase activity
    modifier: INCREASED
  evidence:
  - reference: PMID:19420257
    reference_title: "Cystatin B deficiency sensitizes neurons to oxidative stress in progressive myoclonus epilepsy, EPM1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The Cystatin B deficiency-induced predisposition to oxidative stress in
      neurons is mediated by the lysosomal protease Cathepsin B.
    explanation: >-
      Links loss of cystatin B to oxidative vulnerability through dysregulated
      cathepsin B activity, the coupled cathepsin/redox amplifier step.
  - reference: PMID:19420257
    reference_title: "Cystatin B deficiency sensitizes neurons to oxidative stress in progressive myoclonus epilepsy, EPM1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      increased lipid peroxidation, in the cerebellum of Cystatin B knock-out mice
      in vivo.
    explanation: >-
      Demonstrates in vivo oxidative damage in the cystatin B-deficient
      cerebellum.
  downstream:
  - target: Cerebellar Granule Neuron Death and Degeneration
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19420257
      reference_title: "Cystatin B deficiency sensitizes neurons to oxidative stress in progressive myoclonus epilepsy, EPM1."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Collectively, our findings define a pathophysiological mechanism in EPM1,
        whereby Cystatin B deficiency couples oxidative stress to neuronal death
        and degeneration
      explanation: >-
        The experimental study explicitly connects cystatin-B-deficient oxidative
        vulnerability to neuronal death and degeneration.
- name: Cerebellar Granule Neuron Death and Degeneration
  biological_scale: CELLULAR
  description: >-
    Cystatin-B-deficient cerebellar granule neurons undergo oxidative-stress-linked
    death and degeneration. In the knockout mouse, loss of cerebellar granule
    cells with fragmented DNA and condensed nuclei is the principal
    cytopathology. This node is kept separate from cortical GABAergic terminal
    loss because the sources establish different cell populations and do not show
    that one causes the other.
  role: central_effector
  cell_types:
  - preferred_term: cerebellar granule cell
    term:
      id: CL:0001031
      label: cerebellar granule cell
  biological_processes:
  - preferred_term: neuron apoptotic process
    term:
      id: GO:0051402
      label: neuron apoptotic process
    modifier: INCREASED
  locations:
  - preferred_term: cerebellar cortex
    term:
      id: UBERON:0002129
      label: cerebellar cortex
  evidence:
  - reference: PMID:9806543
    reference_title: "Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The principal cytopathology appears to be a loss of cerebellar granule
      cells, which frequently display condensed nuclei, fragmented DNA and other
      cellular changes characteristic of apoptosis.
    explanation: >-
      Establishes apoptotic cerebellar granule cell loss as the principal
      cytopathology in the cystatin B-null model.
  - reference: PMID:9806543
    reference_title: "Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      cystatin B, a non-caspase cysteine protease inhibitor, has a role in
      preventing cerebellar apoptosis.
    explanation: >-
      Attributes the cerebellar apoptosis directly to loss of cystatin B's
      protease-inhibitory function.
  downstream:
  - target: Progressive Cerebellar Ataxia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9806543
      reference_title: "Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        mice lacking cystatin B develop myoclonic seizures and ataxia, similar to
        symptoms seen in the human disease.
      explanation: >-
        The knockout model links cerebellar cytopathology with ataxia, but it does
        not isolate granule-cell death as the sole clinical cause; support is
        therefore PARTIAL.
  - target: Dysarthria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: &cerebellar_syndrome_manifestation_evidence
    - reference: PMID:18325013
      reference_title: "Clinical picture of EPM1-Unverricht-Lundborg disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Some years after the onset ataxia, incoordination, intentional tremor,
        and dysarthria develop.
      explanation: >-
        The clinical review groups dysarthria and intention tremor with the
        delayed ataxic syndrome. Coupled with the model's cerebellar pathology,
        this supports an indirect route while leaving its intermediates unknown.
  - target: Intention Tremor
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: *cerebellar_syndrome_manifestation_evidence
- name: Cortical GABAergic Input Loss
  biological_scale: TISSUE
  description: >-
    ULD cortex shows reduced vesicular GABA-transporter labeling, and the Cstb
    knockout model shows progressive loss of cortical GABA interneurons, reduced
    terminal GABA release, and reduced electrophysiologic inhibition. Human
    tissue evidence is limited to one reported case, which is stated explicitly
    rather than generalized into a population frequency.
  role: central_effector
  cell_types:
  - preferred_term: GABAergic neuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  biological_processes:
  - preferred_term: gamma-aminobutyric acid signaling pathway
    term:
      id: GO:0007214
      label: gamma-aminobutyric acid signaling pathway
    modifier: DECREASED
  locations:
  - preferred_term: neocortex
    term:
      id: UBERON:0001950
      label: neocortex
  evidence:
  - reference: PMID:22538221
    reference_title: "Loss of cortical GABA terminals in Unverricht-Lundborg disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In CSTB knockout mice, a progressive decrease in neocortex thickness was
      found, associated with a prevalent loss of GABA interneurons.
    explanation: >-
      The knockout model directly demonstrates progressive cortical
      GABA-interneuron loss.
  - reference: PMID:22538221
    reference_title: "Loss of cortical GABA terminals in Unverricht-Lundborg disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A marked reduction in VGAT labeling was found in the cortex of both CSTB
      knockout mice and an ULD patient.
    explanation: >-
      The human post-mortem case confirms reduced cortical GABA-terminal density,
      while the description preserves the single-case limitation.
  downstream:
  - target: Cortical Hyperexcitability
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22538221
      reference_title: "Loss of cortical GABA terminals in Unverricht-Lundborg disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        loss of cortical GABA input occurs in a relevant animal model and in a
        case of human ULD, leading to a condition of latent hyperexcitability that
        favors myoclonus and seizures.
      explanation: >-
        The source explicitly links reduced cortical GABA input to latent
        hyperexcitability.
- name: Cortical Hyperexcitability
  biological_scale: TISSUE
  conforms_to: "epilepsy_excitation_inhibition_imbalance#Neuronal Hyperexcitability and Hypersynchrony"
  description: >-
    Loss of cortical GABAergic inhibition shifts the cortical excitation-inhibition
    balance toward excitation, producing latent network hyperexcitability. This
    manifests as the hallmark stimulus-sensitive (action- and reflex-activated)
    myoclonus and as generalized, including photosensitive, seizures.
  role: effector
  cell_types:
  - preferred_term: GABAergic neuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  biological_processes:
  - preferred_term: gamma-aminobutyric acid signaling pathway
    term:
      id: GO:0007214
      label: gamma-aminobutyric acid signaling pathway
    modifier: DECREASED
  locations:
  - preferred_term: neocortex
    term:
      id: UBERON:0001950
      label: neocortex
  evidence:
  - reference: PMID:22538221
    reference_title: "Loss of cortical GABA terminals in Unverricht-Lundborg disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      loss of cortical GABA input occurs in a relevant animal model and in a case
      of human ULD, leading to a condition of latent hyperexcitability that favors
      myoclonus and seizures.
    explanation: >-
      Directly links loss of cortical GABAergic input to the hyperexcitable state
      that generates myoclonus and seizures.
  - reference: PMID:20301321
    reference_title: "Progressive Myoclonic Epilepsy Type 1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the myoclonic jerks are progressive, action activated, and treatment
      resistant, and can be severely disabling.
    explanation: >-
      Characterizes the action-activated, progressive, treatment-resistant
      myoclonus that is the clinical signature of this hyperexcitable arm.
  downstream:
  - target: Stimulus-Sensitive Action Myoclonus
    causal_link_type: DIRECT
    evidence: &hyperexcitability_manifestation_evidence
    - reference: PMID:22538221
      reference_title: "Loss of cortical GABA terminals in Unverricht-Lundborg disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        loss of cortical GABA input occurs in a relevant animal model and in a
        case of human ULD, leading to a condition of latent hyperexcitability that
        favors myoclonus and seizures.
      explanation: >-
        The mechanistic study explicitly states that latent cortical
        hyperexcitability favors myoclonus and seizures.
  - target: Generalized Tonic-Clonic Seizures
    causal_link_type: DIRECT
    evidence: *hyperexcitability_manifestation_evidence
  - target: Photosensitive Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22538221
      reference_title: "Loss of cortical GABA terminals in Unverricht-Lundborg disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        loss of cortical GABA input occurs in a relevant animal model and in a
        case of human ULD, leading to a condition of latent hyperexcitability that
        favors myoclonus and seizures.
      explanation: >-
        Establishes the hyperexcitability-to-seizure route but does not isolate
        photosensitivity; support for this phenotype-specific branch is PARTIAL.
    - reference: PMID:17158032
      reference_title: "Long-term evolution of EEG in Unverricht-Lundborg disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        PPR was present in 88% of patients at the disease onset and gradually
        disappeared with a significant difference (p<0.001) after the 10th year
        of disease.
      explanation: >-
        The high early photoparoxysmal-response frequency anchors the
        photosensitive manifestation, without claiming that it alone proves the
        intervening causal route.
phenotypes:
- name: Stimulus-Sensitive Action Myoclonus
  category: Clinical
  description: >-
    The clinical hallmark: stimulus-sensitive, action- and reflex-activated
    myoclonus that is progressive and treatment resistant, and can be severely
    disabling.
  diagnostic: true
  phenotype_term:
    preferred_term: Stimulus-sensitive action myoclonus
    term:
      id: HP:0001336
      label: Myoclonus
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:18325013
    reference_title: "Clinical picture of EPM1-Unverricht-Lundborg disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      characterized by age of onset from 6 to 16 years, stimulus-sensitive
      myoclonus, and tonic-clonic epileptic seizures.
    explanation: >-
      Establishes stimulus-sensitive myoclonus as a defining feature with typical
      6-16 year onset.
  - reference: PMID:20301321
    reference_title: "Progressive Myoclonic Epilepsy Type 1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the myoclonic jerks are progressive, action activated, and treatment
      resistant, and can be severely disabling.
    explanation: >-
      Documents the progressive, action-activated, treatment-resistant character
      of the myoclonus.
- name: Generalized Tonic-Clonic Seizures
  category: Clinical
  description: >-
    Generalized tonic-clonic epileptic seizures, present from onset; these are
    generally well controlled by antiseizure medication, in contrast to the
    treatment-resistant myoclonus.
  diagnostic: true
  phenotype_term:
    preferred_term: Generalized tonic-clonic seizures
    term:
      id: HP:0002069
      label: Bilateral tonic-clonic seizure
  evidence:
  - reference: PMID:18325013
    reference_title: "Clinical picture of EPM1-Unverricht-Lundborg disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      characterized by age of onset from 6 to 16 years, stimulus-sensitive
      myoclonus, and tonic-clonic epileptic seizures.
    explanation: >-
      Documents tonic-clonic epileptic seizures as a core feature.
- name: Photosensitive Seizures
  category: Clinical
  description: >-
    Photosensitivity is characteristic, with photic stimulation triggering
    myoclonus and seizures (photoparoxysmal response).
  phenotype_term:
    preferred_term: Photosensitive seizures
    term:
      id: HP:0001327
      label: Photosensitive myoclonic seizure
  evidence:
  - reference: PMID:38247861
    reference_title: "The Roles of Cystatin B in the Brain and Pathophysiological Mechanisms of Progressive Myoclonic Epilepsy Type 1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      EPM1 patients suffer from photo-sensitive seizures, stimulus-sensitive
      myoclonus, nocturnal myoclonic seizures, ataxia and dysarthria.
    explanation: >-
      Documents photosensitive seizures as part of the EPM1 phenotype. Evidence
      source is OTHER because this is a review article.
- name: Progressive Cerebellar Ataxia
  category: Clinical
  description: >-
    Cerebellar ataxia and incoordination develop some years after seizure onset
    and progress over time, reflecting cerebellar neurodegeneration.
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:18325013
    reference_title: "Clinical picture of EPM1-Unverricht-Lundborg disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Some years after the onset ataxia, incoordination, intentional tremor, and
      dysarthria develop.
    explanation: >-
      Documents progressive cerebellar ataxia developing after onset.
  - reference: PMID:9126745
    reference_title: "Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      onset between 6 and 13 years followed by variable progression to mental
      deterioration and cerebellar ataxia.
    explanation: >-
      Independent source documenting progression to cerebellar ataxia.
- name: Dysarthria
  category: Clinical
  description: >-
    Dysarthria develops as part of the delayed cerebellar syndrome.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:18325013
    reference_title: "Clinical picture of EPM1-Unverricht-Lundborg disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Some years after the onset ataxia, incoordination, intentional tremor, and
      dysarthria develop.
    explanation: >-
      Documents dysarthria as part of the delayed cerebellar arm.
- name: Intention Tremor
  category: Clinical
  description: >-
    Intention (intentional) tremor is a component of the cerebellar syndrome.
  phenotype_term:
    preferred_term: Intention tremor
    term:
      id: HP:0002080
      label: Intention tremor
  evidence:
  - reference: PMID:18325013
    reference_title: "Clinical picture of EPM1-Unverricht-Lundborg disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Some years after the onset ataxia, incoordination, intentional tremor, and
      dysarthria develop.
    explanation: >-
      Documents intention tremor within the cerebellar syndrome.
- name: Mild Cognitive Decline
  category: Clinical
  description: >-
    Patients remain largely mentally alert but show a mild decline in intellectual
    performance over time; formal neuropsychological assessment of large cohorts
    documents impaired cognitive performance relative to controls. This relative
    preservation of cognition distinguishes EPM1 from more severe progressive
    myoclonus epilepsies such as Lafora disease.
  phenotype_term:
    preferred_term: Mild cognitive decline
    term:
      id: HP:0001268
      label: Mental deterioration
    severity: MILD
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:18325013
    reference_title: "Clinical picture of EPM1-Unverricht-Lundborg disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals with EPM1 are mentally alert but show emotional lability,
      depression, and mild decline in intellectual performance over time.
    explanation: >-
      Documents the mild, slowly progressive cognitive decline with preserved
      alertness.
  - reference: PMID:34171687
    reference_title: "Cognitive functioning in progressive myoclonus epilepsy type 1 (Unverricht-Lundborg Disease, EPM1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cognitive performance of the EPM1 patient group was impaired.
    explanation: >-
      A large neuropsychological cohort study confirms measurable cognitive
      impairment.
- name: Depression
  category: Clinical
  description: >-
    Depression and emotional lability are common psychiatric features of EPM1.
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: PMID:18325013
    reference_title: "Clinical picture of EPM1-Unverricht-Lundborg disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals with EPM1 are mentally alert but show emotional lability,
      depression, and mild decline in intellectual performance over time.
    explanation: >-
      Documents depression as a recognized feature.
- name: Emotional Lability
  category: Clinical
  description: >-
    Emotional lability is a recognized behavioral feature.
  phenotype_term:
    preferred_term: Emotional lability
    term:
      id: HP:0000712
      label: Emotional lability
  evidence:
  - reference: PMID:18325013
    reference_title: "Clinical picture of EPM1-Unverricht-Lundborg disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals with EPM1 are mentally alert but show emotional lability,
      depression, and mild decline in intellectual performance over time.
    explanation: >-
      Documents emotional lability as a behavioral feature.
genetic:
- name: CSTB
  gene_term:
    preferred_term: CSTB
    term:
      id: hgnc:2482
      label: CSTB
  association: Loss-of-Function (dodecamer repeat expansion or point/indel variants)
  presence: Positive
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >-
    CSTB encodes cystatin B, an intracellular cysteine protease (cathepsin)
    inhibitor. The most common pathogenic allele is an unstable dodecamer (12-mer)
    repeat expansion in the promoter that reduces CSTB expression; minority
    alleles are loss-of-function point/indel variants, often compound heterozygous
    with the expansion. Premutation-length alleles are unstable on transmission.
  evidence:
  - reference: PMID:9126745
    reference_title: "Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two point mutations in the cysteine proteinase inhibitor gene cystatin B
      (CSTB), proved that this gene is responsible for EPM1
    explanation: >-
      Establishes CSTB (a cysteine proteinase inhibitor gene) as the EPM1 gene.
  - reference: PMID:8596935
    reference_title: "Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      levels of messenger RNA encoded by this gene were found to be decreased in
      cells from affected individuals.
    explanation: >-
      Documents reduced CSTB expression in patient cells, the loss-of-function
      mechanism.
diagnosis:
- name: CSTB Molecular Diagnosis
  description: >-
    Diagnosis is established in a proband with suggestive clinical findings by
    identifying biallelic CSTB dodecamer repeat expansions, or compound
    heterozygosity for a repeat expansion and a CSTB sequence variant, by
    molecular genetic testing (repeat-primed PCR sizing for the expansion plus
    sequencing).
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: CSTB
        term:
          id: hgnc:2482
          label: CSTB
  results: >-
    Biallelic CSTB dodecamer repeat expansions (or a repeat expansion in compound
    heterozygosity with a CSTB sequence variant) confirm the diagnosis.
  evidence:
  - reference: PMID:20301321
    reference_title: "Progressive Myoclonic Epilepsy Type 1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      biallelic abnormal CCC-CGC-CCC-GCG dodecamer repeat expansions in CSTB or
      compound heterozygosity for a CSTB dodecamer repeat expansion and a CSTB
      sequence variant
    explanation: >-
      The GeneReviews chapter defines the molecular criteria for establishing the
      diagnosis.
- name: Electroencephalography
  description: >-
    EEG documents generalized epileptiform activity and a photoparoxysmal
    (photosensitive) response supporting the progressive myoclonus epilepsy
    phenotype.
  diagnosis_term:
    preferred_term: electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  results: >-
    Generalized spike- or polyspike-and-wave discharges and a photoparoxysmal
    response support the EPM1 phenotype. Both are common near onset but can
    diminish during long-term follow-up, so their absence later does not exclude
    EPM1.
  evidence:
  - reference: PMID:17158032
    reference_title: "Long-term evolution of EEG in Unverricht-Lundborg disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GSWD were present in 92% of patients at the onset of the disease and
      gradually disappeared during the follow-up with a significant difference
      (p<0.001) after the 15th year of disease. PPR was present in 88% of patients
      at the disease onset and gradually disappeared with a significant difference
      (p<0.001) after the 10th year of disease.
    explanation: >-
      Longitudinal EEG review in 25 patients supports generalized spike/polyspike
      discharges and photoparoxysmal responses near onset while documenting their
      later decline.
differential_diagnoses:
- name: Lafora Disease (EPM2)
  description: >-
    Lafora disease is the other classic autosomal recessive progressive myoclonus
    epilepsy of adolescent onset, caused by EPM2A (laforin) or NHLRC1/EPM2B
    (malin). Lafora bodies may be demonstrated on skin biopsy. It follows a more
    rapidly progressive course with early cognitive decline and dementia, unlike
    the relatively preserved cognition and slower course of EPM1.
  distinguishing_features:
  - Biallelic CSTB variants (dodecamer expansion) favor EPM1.
  - EPM2A/NHLRC1 variants with Lafora bodies and rapid dementia favor Lafora disease.
  evidence:
  - reference: PMID:20301563
    reference_title: "Progressive Myoclonus Epilepsy, Lafora Type."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cognitive decline becomes apparent at or soon after the onset of seizures.
      Dysarthria and ataxia appear early, while spasticity appears late. Emotional
      disturbances and confusion are common in the early stages of the disease
      and are followed by dementia.
    explanation: >-
      GeneReviews supports the early cognitive decline and dementia that help
      distinguish Lafora disease from the generally slower EPM1 course.
  - reference: PMID:20301563
    reference_title: "Progressive Myoclonus Epilepsy, Lafora Type."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of Lafora disease is established in a proband with
      characteristic neurologic findings and/or biallelic pathogenic variants in
      one of the two known causative genes, EPM2A or NHLRC1, identified by molecular
      genetic testing. On rare occasion, a skin biopsy to detect Lafora bodies is
      necessary to confirm the diagnosis.
    explanation: >-
      Supports the causal genes and the diagnostic occurrence of Lafora bodies.
- name: Other progressive myoclonus epilepsies
  description: >-
    Other PMEs (e.g., myoclonic epilepsy with ragged-red fibers/MERRF, the
    neuronal ceroid lipofuscinoses, and sialidosis) overlap through action
    myoclonus, seizures, and progressive neurologic deterioration. Their age of
    onset, associated features, clinical course, inheritance, and targeted
    biochemical, pathologic, or genetic testing help distinguish them.
  distinguishing_features:
  - A biallelic CSTB lesion favors EPM1.
  - A causal variant or storage material specific to another PME favors that diagnosis.
  evidence:
  - reference: PMID:26060909
    reference_title: "Progressive Myoclonus Epilepsies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The progressive myoclonus epilepsies (PMEs) comprise a group of rare and
      heterogeneous disorders defined by the combination of action myoclonus,
      epileptic seizures, and progressive neurologic deterioration.
    explanation: >-
      Defines the core overlapping clinical pattern of the PME differential.
  - reference: PMID:26060909
    reference_title: "Progressive Myoclonus Epilepsies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The specific diseases that cause PME are diagnosed by recognition of their
      age of onset, the associated clinical symptoms, the clinical course, the
      pattern of inheritance, and by special investigations such as enzyme
      measurement, skin/muscle biopsy, or gene testing.
    explanation: >-
      Supports the clinical, biochemical, pathologic, and genetic distinctions
      used to separate EPM1 from other PMEs.
progression:
- phase: Onset (childhood/adolescence)
  notes: >-
    Onset is typically between 6 and 16 years with stimulus-sensitive myoclonus
    and generalized tonic-clonic seizures.
  evidence:
  - reference: PMID:18325013
    reference_title: "Clinical picture of EPM1-Unverricht-Lundborg disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      characterized by age of onset from 6 to 16 years, stimulus-sensitive
      myoclonus, and tonic-clonic epileptic seizures.
    explanation: >-
      Documents the childhood-to-adolescent onset with myoclonus and tonic-clonic
      seizures.
- phase: Progression (young adulthood)
  notes: >-
    Over subsequent years the action myoclonus worsens and becomes the dominant
    disabling feature, while cerebellar signs (ataxia, incoordination, intention
    tremor, dysarthria) develop and cognition declines mildly; tonic-clonic
    seizures are usually well controlled.
  evidence:
  - reference: PMID:18325013
    reference_title: "Clinical picture of EPM1-Unverricht-Lundborg disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Some years after the onset ataxia, incoordination, intentional tremor, and
      dysarthria develop.
    explanation: >-
      Documents the delayed progressive cerebellar arm.
- phase: Long-term disability and survival
  notes: >-
    Course is heterogeneous: approximately 10% of Finnish registry cases remained
    very mild with decades of independence, but disability commonly accumulated
    and survival diverged from matched controls after age 40. Lower respiratory
    tract infection was the immediate cause in 56% of recorded deaths.
  evidence:
  - reference: PMID:32943486
    reference_title: "Unverricht-Lundborg disease (EPM1) in Finland: A nationwide population-based study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The survival rates of the patients were comparable to matched controls up
      to 40 years of age, but poorer during long-term follow-up (cumulative
      survival 26.4% vs 78.0%), with a hazard ratio (HR) for death of 4.61.
    explanation: >-
      The nationwide registry provides matched-control long-term survival data.
  - reference: PMID:32943486
    reference_title: "Unverricht-Lundborg disease (EPM1) in Finland: A nationwide population-based study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The immediate cause of death was a lower respiratory tract infection in 56%
      of deaths.
    explanation: >-
      The registry directly quantifies the leading immediate cause of death.
  - reference: PMID:32943486
    reference_title: "Unverricht-Lundborg disease (EPM1) in Finland: A nationwide population-based study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In approximately 10% of all cases, the disease progression appeared very
      mild; some patients retained functional independence for decades.
    explanation: >-
      This preserves the important mild-course subgroup rather than presenting
      the Finnish prognosis as uniform.
treatments:
- name: Valproic Acid
  description: >-
    Valproic acid is the first drug of choice and diminishes myoclonus and the
    frequency of generalized seizures.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: valproic acid
      term:
        id: CHEBI:39867
        label: valproic acid
  evidence:
  - reference: PMID:18325013
    reference_title: "Clinical picture of EPM1-Unverricht-Lundborg disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Valproic acid, the first drug of choice, diminishes myoclonus and the
      frequency of generalized seizures.
    explanation: >-
      Documents valproic acid as first-line therapy reducing myoclonus and
      seizures.
- name: Myoclonus-Directed Add-On Therapy
  description: >-
    Clonazepam and high-dose piracetam are used to treat myoclonus, while
    levetiracetam is used for both myoclonus and generalized seizures. Topiramate
    and zonisamide may also be used as add-on therapy. An open-label series
    supports perampanel for refractory myoclonus and seizures, but psychological
    or behavioral adverse effects occurred in half of the small cohort and
    required withdrawal or dose reduction. Brivaracetam is excluded from this
    treatment block because two phase III trials did not show a statistically
    significant action-myoclonus benefit.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: clonazepam
      term:
        id: CHEBI:3756
        label: clonazepam
    - preferred_term: piracetam
      term:
        id: CHEBI:32010
        label: Piracetam
    - preferred_term: levetiracetam
      term:
        id: CHEBI:6437
        label: levetiracetam
    - preferred_term: topiramate
      term:
        id: CHEBI:63631
        label: topiramate
    - preferred_term: zonisamide
      term:
        id: CHEBI:10127
        label: zonisamide
    - preferred_term: perampanel
      term:
        id: CHEBI:71013
        label: perampanel
  evidence:
  - reference: PMID:18325013
    reference_title: "Clinical picture of EPM1-Unverricht-Lundborg disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clonazepam and high-dose piracetam are used to treat myoclonus, whereas
      levetiracetam seems to be effective for both myoclonus and generalized
      seizures.
    explanation: >-
      Documents clonazepam, high-dose piracetam, and levetiracetam in myoclonus
      management.
  - reference: PMID:20301321
    reference_title: "Progressive Myoclonic Epilepsy Type 1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Topiramate and zonisamide may also be used as add-on therapy.
    explanation: >-
      GeneReviews supplies the clinical-management basis for these two add-on
      agents not named in the older clinical review.
  - reference: PMID:28166365
    reference_title: "Perampanel in 12 patients with Unverricht-Lundborg disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ten patients had a clear clinical response of myoclonus, and five were able
      to reduce concomitant therapy. Improvement was noted sometimes as soon as
      with 2 mg/day. Epileptic seizures stopped on PER in the six patients who
      still had experienced generalized tonic-clonic or myoclonic seizures
      (100%).
    explanation: >-
      The small open-label series supports potential efficacy against myoclonus
      and ongoing seizures while not implying randomized-trial certainty.
  - reference: PMID:28166365
    reference_title: "Perampanel in 12 patients with Unverricht-Lundborg disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Psychological and behavioral side-effects were observed in six patients
      (50%) and led to withdrawal of PER in three cases and dose reduction in
      three, with abatement of the problems.
    explanation: >-
      Quantifies the important behavioral tolerability limitation and its clinical
      consequences in the same series.
- name: Avoidance of Aggravating Antiseizure Drugs
  description: >-
    Certain antiseizure drugs worsen EPM1 and are avoided. Phenytoin aggravates
    the neurologic symptoms or even accelerates cerebellar degeneration; sodium
    channel blockers (carbamazepine, oxcarbazepine), GABAergic drugs (tiagabine,
    vigabatrin), and gabapentin and pregabalin may aggravate the myoclonus and
    myoclonic seizures.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301321
    reference_title: "Progressive Myoclonic Epilepsy Type 1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Phenytoin aggravates neurologic symptoms or even accelerates cerebellar
      degeneration; sodium channel blockers (carbamazepine, oxcarbazepine),
      GABAergic drugs (tiagabine, vigabatrin), and gabapentin and pregabalin may
      aggravate myoclonus and myoclonic seizures.
    explanation: >-
      The GeneReviews agents-to-avoid guidance identifies phenytoin and
      sodium-channel-blocking/GABAergic drugs as harmful in EPM1.
  - reference: PMID:18325013
    reference_title: "Clinical picture of EPM1-Unverricht-Lundborg disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      phenytoin aggravating the associated neurologic symptoms or even
      accelerating cerebellar degeneration.
    explanation: >-
      Independent clinical review confirming phenytoin aggravates EPM1 and can
      accelerate cerebellar degeneration.
- name: Rehabilitation and Supportive Care
  description: >-
    Symptomatic pharmacologic and rehabilitative management, including
    physiotherapy and psychosocial support, is the mainstay of care given the
    disabling myoclonus and progressive cerebellar disability.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:18325013
    reference_title: "Clinical picture of EPM1-Unverricht-Lundborg disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Symptomatic pharmacologic and rehabilitative management, including
      psychosocial support, are the mainstay of EPM1 patients' care.
    explanation: >-
      Documents rehabilitative and psychosocial supportive care as the mainstay of
      management.
- name: Genetic Counseling
  description: >-
    Genetic counseling addresses the autosomal recessive 25% sibling recurrence
    risk and, once both familial CSTB variants are known, carrier and prenatal
    testing options.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301321
    reference_title: "Progressive Myoclonic Epilepsy Type 1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      At conception, each sib of an affected individual has a 25% chance of being
      affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of
      being unaffected and not a carrier. Once both CSTB pathogenic variants in a
      family are known, carrier testing for at-risk relatives, prenatal testing
      for pregnancies at increased risk, and preimplantation genetic testing are
      possible.
    explanation: >-
      GeneReviews directly supports the recurrence-risk calculation and the
      reproductive-testing options stated in the treatment description.
animal_models:
- name: Cstb knockout mouse
  species: Mouse (Mus musculus)
  genotype: Cystatin B (Cstb) knockout
  description: >-
    Cystatin B-null mice develop myoclonic seizures and ataxia resembling the
    human disease, with apoptotic loss of cerebellar granule neurons, progressive
    loss of cortical GABAergic interneurons, and in vivo cerebellar oxidative
    damage, making them a validated EPM1 model.
  modeled_mechanisms:
  - target: Cerebellar Granule Neuron Death and Degeneration
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The knockout reproduces the principal apoptotic cerebellar granule-cell
      cytopathology used in the EPM1 causal graph.
    limitations: >-
      The null genotype models complete loss of Cstb rather than the residual
      expression typical of most human promoter-repeat alleles.
    evidence:
    - reference: PMID:9806543
      reference_title: "Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The principal cytopathology appears to be a loss of cerebellar granule
        cells, which frequently display condensed nuclei, fragmented DNA and
        other cellular changes characteristic of apoptosis.
      explanation: >-
        Directly establishes recapitulation of the graph's cerebellar
        granule-neuron-death mechanism.
  - target: Cortical GABAergic Input Loss
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      The knockout reproduces progressive cortical GABA-interneuron loss and
      reduced inhibitory input, a mechanism also observed in one human ULD cortex.
    limitations: >-
      Human tissue confirmation is limited to one post-mortem case, and the null
      mouse genotype is more severe than the common human promoter expansion.
    evidence:
    - reference: PMID:22538221
      reference_title: "Loss of cortical GABA terminals in Unverricht-Lundborg disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In CSTB knockout mice, a progressive decrease in neocortex thickness was
        found, associated with a prevalent loss of GABA interneurons.
      explanation: >-
        Directly supports partial recapitulation of cortical GABAergic input loss
        in the knockout model.
  evidence:
  - reference: PMID:9806543
    reference_title: "Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      mice lacking cystatin B develop myoclonic seizures and ataxia, similar to
      symptoms seen in the human disease.
    explanation: >-
      The cystatin B-null mouse recapitulates the core myoclonus/ataxia phenotype
      and cerebellar apoptosis of EPM1.
  - reference: PMID:19420257
    reference_title: "Cystatin B deficiency sensitizes neurons to oxidative stress in progressive myoclonus epilepsy, EPM1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cystatin B knockout in a mouse model of EPM1 triggers progressive
      degeneration of cerebellar granule neurons.
    explanation: >-
      Confirms progressive cerebellar granule neuron degeneration in the model.
clinical_trials:
- name: NCT00357669
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Randomized, double-blind, placebo-controlled 12-week study of adjunctive
    brivaracetam in genetically confirmed Unverricht-Lundborg disease in
    adolescents and adults aged 16 years or older. The pooled brivaracetam groups
    did not show a statistically significant reduction in action myoclonus versus
    placebo.
  evidence:
  - reference: clinicaltrials:NCT00357669
    reference_title: "A Multi-center, Randomized, Double-blind, Placebo-controlled, Parallel Study to Evaluate the Efficacy and Safety of Brivaracetam Used as Adjunctive Treatment for 12 Weeks in Adolescent and Adult Patients (≥16 Years) With Genetically Ascertained Unverricht-Lundborg Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The study will compare the efficacy and safety of brivaracetam with placebo
      in patients with Unverricht-Lundborg disease.
    explanation: >-
      The registry summary directly identifies the intervention, comparator, and
      disease population; the registry status was rechecked as COMPLETED on
      2026-08-11.
  - reference: PMID:26666500
    reference_title: "Brivaracetam in Unverricht-Lundborg disease (EPM1): Results from two randomized, double-blind, placebo-controlled studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Estimated differences versus placebo were not statistically significant.
    explanation: >-
      The joint publication of both phase III trials reports that the prespecified
      efficacy comparisons did not reach statistical significance.
- name: NCT00368251
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Second randomized, double-blind, placebo-controlled 12-week phase III study
    of adjunctive brivaracetam in genetically confirmed Unverricht-Lundborg
    disease in adolescents and adults aged 16 years or older. Brivaracetam did
    not show a statistically significant reduction in action myoclonus versus
    placebo.
  evidence:
  - reference: clinicaltrials:NCT00368251
    reference_title: "A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Study to Evaluate the Efficacy and Safety of Brivaracetam Used as Adjunctive Treatment for 12 Weeks in Adolescent and Adult Patients (≥ 16 Years) With Genetically Ascertained Unverricht-Lundborg Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The study will compare the efficacy and safety of Brivaracetam with placebo
      in patients with Unverricht- Lundborg Disease (ULD).
    explanation: >-
      The registry summary directly identifies the intervention, comparator, and
      disease population; the registry status was rechecked as COMPLETED on
      2026-08-11.
  - reference: PMID:26666500
    reference_title: "Brivaracetam in Unverricht-Lundborg disease (EPM1): Results from two randomized, double-blind, placebo-controlled studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Effect of BRV on action myoclonus was not statistically significant.
    explanation: >-
      The joint publication reports the negative primary efficacy result while
      noting good tolerability and high completion.
discussions:
- discussion_id: gap_epm1_cathepsin_vs_oxidative_primary_driver
  prompt: >-
    Is the primary neurodegenerative driver in EPM1 the dysregulation of lysosomal
    cysteine cathepsins released from cystatin B inhibition, or the loss of
    cystatin B's oxidative-stress/mitochondrial protective function, and how do
    these two arms interact to cause selective neuronal death?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#Cathepsin B-Dependent Oxidative Stress Vulnerability
  - pathophysiology#Cerebellar Granule Neuron Death and Degeneration
  rationale: >-
    Cystatin B is defined biochemically as a cathepsin inhibitor, yet cystatin
    B-deficient neurodegeneration is demonstrably coupled to oxidative stress and
    is mediated, at least in part, by cathepsin B. Whether the disease is driven
    primarily by unrestrained cathepsin proteolysis, by failed antioxidant/
    mitochondrial protection, or by an obligate interaction of the two is
    unresolved, and the answer determines whether cathepsin inhibition or
    antioxidant strategies are the more rational disease-modifying target.
  evidence:
  - reference: PMID:19420257
    reference_title: "Cystatin B deficiency sensitizes neurons to oxidative stress in progressive myoclonus epilepsy, EPM1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The Cystatin B deficiency-induced predisposition to oxidative stress in
      neurons is mediated by the lysosomal protease Cathepsin B.
    explanation: >-
      Shows the two candidate arms are mechanistically linked (cathepsin B
      mediates the oxidative-stress vulnerability), framing the primary-driver
      question.
  - reference: PMID:38247861
    reference_title: "The Roles of Cystatin B in the Brain and Pathophysiological Mechanisms of Progressive Myoclonic Epilepsy Type 1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      protection against oxidative stress, likely through regulation of
      mitochondrial function.
    explanation: >-
      Highlights the parallel oxidative/mitochondrial-protective role of cystatin
      B whose loss is the alternative primary driver. Evidence source is OTHER
      because this is a review article.
  proposed_experiments:
  - experiment_id: exp_epm1_cathepsin_vs_antioxidant_rescue
    name: Cathepsin-inhibition versus antioxidant rescue in cystatin B-deficient neurons
    description: >-
      In cystatin B-null cerebellar granule neurons and mice, compare selective
      cathepsin B inhibition, genetic cathepsin B reduction, and antioxidant/
      mitochondrial-protective treatment for their ability to prevent neuronal
      apoptosis, cerebellar degeneration, and myoclonus, to determine which arm is
      the dominant driver.
    experiment_type:
      preferred_term: pharmacologic and genetic rescue experiment
    perturbations:
    - name: Cathepsin B inhibition or knockdown versus antioxidant treatment
      target: pathophysiology#Cathepsin B-Dependent Oxidative Stress Vulnerability
      genes:
      - preferred_term: CSTB
        term:
          id: hgnc:2482
          label: CSTB
      description: >-
        Apply selective cathepsin B inhibition or genetic cathepsin B reduction,
        versus antioxidant/mitochondrial-protective treatment, on the cystatin
        B-deficient background.
    readouts:
    - name: Neuronal apoptosis and cerebellar degeneration
      target: pathophysiology#Cerebellar Granule Neuron Death and Degeneration
      biological_processes:
      - preferred_term: neuron apoptotic process
        term:
          id: GO:0051402
          label: neuron apoptotic process
        modifier: INCREASED
      assays:
      - preferred_term: TUNEL apoptosis assay
      - preferred_term: cerebellar histopathology
      direction: NEGATIVE
    controls:
    - name: Untreated cystatin B-deficient neurons
      description: Cystatin B-deficient neurons/mice receiving vehicle only.
    - name: Wild-type neurons
      description: Cystatin B-sufficient neurons/mice.
    decision_criterion: >-
      The arm whose targeted correction most fully prevents apoptosis, cerebellar
      degeneration, and myoclonus is the dominant driver; comparable partial
      rescue by both, with additivity, supports an obligate interaction.
    would_support:
    - pathophysiology#Cathepsin B-Dependent Oxidative Stress Vulnerability
    - pathophysiology#Cerebellar Granule Neuron Death and Degeneration
- discussion_id: gap_epm1_cstb_mouse_fidelity
  prompt: >-
    Does the cystatin B-null mouse, which shows early and prominent cerebellar
    granule cell apoptosis, faithfully capture the human EPM1 trajectory — in
    which action myoclonus and cortical GABAergic dysfunction dominate and
    cognition is relatively preserved — or does it over-represent cerebellar
    degeneration relative to the human cortical-hyperexcitability phenotype?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Cerebellar Granule Neuron Death and Degeneration
  - pathophysiology#Cortical Hyperexcitability
  rationale: >-
    Model evidence clearly exists: the Cstb-null mouse reproduces myoclonus,
    ataxia, cerebellar granule cell apoptosis, cortical GABAergic interneuron
    loss, and cerebellar oxidative damage. The open translational question is
    fidelity of emphasis — human EPM1 is dominated by disabling,
    treatment-resistant cortical action myoclonus with relatively preserved cognition,
    whereas the mouse phenotype foregrounds cerebellar granule cell death; whether
    the model's cell-type and regional emphasis matches the human disease gates
    its use for preclinical testing of cortically targeted therapies.
  evidence:
  - reference: PMID:9806543
    reference_title: "Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The principal cytopathology appears to be a loss of cerebellar granule
      cells, which frequently display condensed nuclei, fragmented DNA and other
      cellular changes characteristic of apoptosis.
    explanation: >-
      Establishes that the model's principal lesion is cerebellar granule cell
      apoptosis, confirming model evidence exists for the mismatch question.
  - reference: PMID:22538221
    reference_title: "Loss of cortical GABA terminals in Unverricht-Lundborg disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A marked reduction in VGAT labeling was found in the cortex of both CSTB
      knockout mice and an ULD patient.
    explanation: >-
      Documents the cortical GABAergic phenotype in human ULD tissue, the human
      arm whose murine emphasis is the open question.
  proposed_experiments:
  - experiment_id: exp_epm1_cortical_vs_cerebellar_mapping
    name: Cross-species cortical-versus-cerebellar contribution mapping in EPM1
    description: >-
      Quantitatively compare the temporal and regional sequence of cortical
      GABAergic interneuron loss versus cerebellar granule cell apoptosis in
      Cstb-null mice against human EPM1 natural-history imaging/neurophysiology and
      post-mortem tissue, and against EPM1 patient iPSC-derived cortical
      interneuron and cerebellar models, to test whether the mouse over-weights the
      cerebellar arm.
    experiment_type:
      preferred_term: cross-species regional phenotyping experiment
    perturbations:
    - name: Cystatin B loss of function
      target: pathophysiology#Cerebellar Granule Neuron Death and Degeneration
      genes:
      - preferred_term: CSTB
        term:
          id: hgnc:2482
          label: CSTB
      description: >-
        Cstb-null mice and CSTB-deficient human iPSC-derived cortical interneuron
        and cerebellar neuron models compared against controls.
    readouts:
    - name: Regional GABAergic versus cerebellar granule cell loss over time
      target: pathophysiology#Cortical Hyperexcitability
      biological_processes:
      - preferred_term: neuron apoptotic process
        term:
          id: GO:0051402
          label: neuron apoptotic process
        modifier: INCREASED
      assays:
      - preferred_term: quantitative immunohistochemistry
      - preferred_term: electrophysiological recording
      direction: POSITIVE
    controls:
    - name: Wild-type littermates
      description: Age-matched cystatin B-sufficient mice.
    - name: Isogenic-corrected human neurons
      description: Patient iPSC lines with the CSTB lesion corrected.
    decision_criterion: >-
      The mouse is a faithful EPM1 model if the relative timing and magnitude of
      cortical GABAergic versus cerebellar granule cell involvement matches human
      data; a mismatch is supported if the mouse disproportionately foregrounds
      cerebellar granule cell death relative to the human cortical phenotype.
    would_support:
    - pathophysiology#Cerebellar Granule Neuron Death and Degeneration
    - pathophysiology#Cortical Hyperexcitability
review_notes: >-
  The REVIEW separates the experimentally supported cerebellar oxidative-death
  arm from the cortical GABAergic-input arm, adds model-supported early
  microglial and human-organoid neurodevelopmental arms, and attaches
  claim-specific evidence to every retained causal edge. Photosensitive seizures,
  dysarthria, and intention tremor are connected with explicitly PARTIAL evidence;
  cognitive decline, depression, and emotional lability remain unwired because
  the retained sources establish their occurrence but not a specific causal route
  from a curated mechanism node. The two completed brivaracetam trials are
  recorded with their negative primary efficacy result, which takes precedence
  over older narrative guidance suggesting efficacy. PMID:18325013 and
  PMID:20301321 evidence items are classified as OTHER because both sources are
  narrative clinical reviews rather than primary human studies.
📚

References & Deep Research

References

17
PMID:20301321
Progressive Myoclonic Epilepsy Type 1.
No top-level findings curated for this source.
PMID:8596935
Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1).
No top-level findings curated for this source.
PMID:9126745
Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy.
No top-level findings curated for this source.
PMID:9806543
Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice.
No top-level findings curated for this source.
PMID:19420257
Cystatin B deficiency sensitizes neurons to oxidative stress in progressive myoclonus epilepsy, EPM1.
No top-level findings curated for this source.
PMID:22538221
Loss of cortical GABA terminals in Unverricht-Lundborg disease.
No top-level findings curated for this source.
PMID:18325013
Clinical picture of EPM1-Unverricht-Lundborg disease.
No top-level findings curated for this source.
PMID:34171687
Cognitive functioning in progressive myoclonus epilepsy type 1 (Unverricht-Lundborg Disease, EPM1).
No top-level findings curated for this source.
PMID:38247861
The Roles of Cystatin B in the Brain and Pathophysiological Mechanisms of Progressive Myoclonic Epilepsy Type 1.
No top-level findings curated for this source.
PMID:32943486
Unverricht-Lundborg disease (EPM1) in Finland: A nationwide population-based study.
No top-level findings curated for this source.
PMID:17158032
Long-term evolution of EEG in Unverricht-Lundborg disease.
No top-level findings curated for this source.
PMID:26666500
Brivaracetam in Unverricht-Lundborg disease (EPM1): Results from two randomized, double-blind, placebo-controlled studies.
No top-level findings curated for this source.
PMID:20301563
Progressive Myoclonus Epilepsy, Lafora Type.
No top-level findings curated for this source.
PMID:26060909
Progressive Myoclonus Epilepsies.
No top-level findings curated for this source.
PMID:28166365
Perampanel in 12 patients with Unverricht-Lundborg disease.
No top-level findings curated for this source.
PMID:22157618
Early microglial activation precedes neuronal loss in the brain of the Cstb-/- mouse model of progressive myoclonus epilepsy, EPM1.
No top-level findings curated for this source.
PMID:32378798
Cystatin B is essential for proliferation and interneuron migration in individuals with EPM1 epilepsy.
No top-level findings curated for this source.