Familial Sleep-Related Hypermotor Epilepsy

Mendelian MONDO:0000030 Pathograph 15 Epilepsy Sleep Disorder

Familial sleep-related hypermotor epilepsy is an autosomal dominant focal epilepsy syndrome in which recurrent, stereotyped nocturnal motor seizures arise from inherited variants in nicotinic acetylcholine receptor genes, KCNT1, DEPDC5/GATOR1-related genes, and rarer reported loci. The shared clinical expression is brief sleep-associated hypermotor, tonic, dystonic, or arousal-like events, while the molecular mechanisms are heterogeneous and include altered cholinergic receptor function, ion-channel excitability, and DEPDC5-related mTOR pathway dysregulation.

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1
Inheritance
6
Pathophys.
9
Phenotypes
15
Pathograph
6
Genes
4
Treatments
6
Subtypes
11
References
1
Deep Research
👪

Inheritance

1
Autosomal dominant HP:0000006
Familial SHE/ADSHE is defined by autosomal dominant transmission, although penetrance and severity vary within families.
Autosomal dominant inheritance
Show evidence (2 references)
ORPHA:98784 SUPPORT Other
"Autosomal dominant"
Orphanet records autosomal dominant inheritance for the structured SHE record.
PMID:20301348 SUPPORT Other
"ADSHE, by definition, is inherited in an autosomal dominant manner. Most individuals diagnosed with ADSHE have an affected parent."
GeneReviews supports autosomal dominant transmission and familial clustering.
◆

Subtypes

6
CHRNA4-related ADSHE (ENFL1) MONDO:0010899
CHRNA4 link
Gene-defined subtype caused by heterozygous CHRNA4 pathogenic variants that alter alpha-4 nicotinic acetylcholine receptor function.
Chromosome 15q24-linked ADSHE (ENFL2) MONDO:0011297
Historical chromosome 15q24-linked ADSHE subtype without a currently resolved single causal gene in MONDO.
CHRNB2-related ADSHE (ENFL3) MONDO:0011545
CHRNB2 link
Gene-defined subtype caused by heterozygous CHRNB2 pathogenic variants in the beta-2 nicotinic acetylcholine receptor subunit.
CHRNA2-related ADSHE (ENFL4) MONDO:0012474
CHRNA2 link
Gene-defined subtype caused by heterozygous CHRNA2 pathogenic variants in the alpha-2 nicotinic acetylcholine receptor subunit.
KCNT1-related ADSHE (ENFL5) MONDO:0014002
KCNT1 link
Gene-defined subtype caused by heterozygous KCNT1 variants affecting the Slack sodium-activated potassium channel.
DEPDC5/GATOR1-related sleep-related hypermotor epilepsy
DEPDC5 link
GATOR1-related form in which DEPDC5 loss-of-function variants are enriched, particularly among patients with genetic-structural etiology and focal cortical dysplasia.
⚙

Pathophysiology

6
Inherited ADSHE gene architecture
Familial SHE is initiated by heterozygous pathogenic variants in a genetically heterogeneous autosomal dominant set that includes nicotinic acetylcholine receptor genes, KCNT1, DEPDC5/GATOR1-related genes, and rarer reported loci.
CHRNA4 link CHRNA2 link CHRNB2 link DEPDC5 link KCNT1 link
Downstream
Nicotinic acetylcholine receptor dysfunction CHRNA4, CHRNA2, and CHRNB2 variants alter receptor function.
DEPDC5-GATOR1 mTOR signaling dysregulation DEPDC5 loss-of-function disrupts GATOR1 control of mTOR signaling.
KCNT1 Slack channel altered excitability KCNT1 variants alter sodium-activated potassium-channel effects on cortical excitability.
Show evidence (1 reference)
PMID:20301348 SUPPORT Other
"The diagnosis of ADSHE is established in a proband who has suggestive clinical findings and a family history consistent with autosomal dominant inheritance and/or a heterozygous pathogenic variant in CABP4, CHRNA4, CHRNA2, CHRNB2, CRH, DEPDC5, KCNT1, NPRL2, NPRL3, or STX1B identified by..."
GeneReviews summarizes the current genetically heterogeneous ADSHE architecture.
Nicotinic acetylcholine receptor dysfunction
CHRNA4, CHRNB2, and CHRNA2 pathogenic variants change alpha/beta nicotinic acetylcholine receptor function, altering cholinergic modulation of excitatory and inhibitory cortical transmission.
pyramidal neuron link GABAergic neuron link
CHRNA4 link CHRNA2 link CHRNB2 link
acetylcholine receptor signaling pathway link ↕ DYSREGULATED
Downstream
Cortical excitation-inhibition imbalance Altered nicotinic signaling perturbs cortical excitatory and inhibitory synaptic dynamics.
Show evidence (2 references)
PMID:30472464 SUPPORT In Vitro
"From this, we concluded that mutations that cause ADNFLE manifest themselves in a change in efficacy regardless of the stoichiometry of the receptor."
Oocyte expression experiments support altered nicotinic receptor efficacy for ADNFLE mutations.
PMID:30809122 SUPPORT In Vitro
"We conclude that mutations in CHRNA2 are more commonly linked to ADNFLE than previously thought, and may cause a loss-of-function phenotype."
HEK293 functional assays support CHRNA2-linked receptor loss of function in ADNFLE.
DEPDC5-GATOR1 mTOR signaling dysregulation
DEPDC5 loss-of-function reduces GATOR1 complex integrity, releasing downstream mTORC1 signaling and increasing risk of focal epilepsy and focal cortical dysplasia-associated SHE.
DEPDC5 link
TOR signaling link ↑ INCREASED
Downstream
Cortical excitation-inhibition imbalance mTOR-related focal epilepsy biology increases seizure-prone cortical network activity.
Show evidence (2 references)
PMID:24814846 SUPPORT Human Clinical
"In addition, 3 nonsense DEPDC5 mutations (p.Arg487*, p.Arg1087*, and p.Trp1369*) were detected in the probands of 2 French and one Belgian family."
Human family sequencing identifies truncating DEPDC5 variants in ADNFLE families.
PMID:31174205 SUPPORT Model Organism
"Loss of Depdc5 led to a decrease in the other GATOR1 protein levels (NPRL2 and NPRL3). Rapamycin failed to rescue GATOR1 protein levels but rather rescued downstream mTORC1 hyperactivity as measured by phosphorylation of S6."
Mouse data support DEPDC5 loss causing GATOR1 reduction and downstream mTORC1 hyperactivity.
KCNT1 Slack channel altered excitability
KCNT1 variants alter Slack sodium-activated potassium-channel behavior and can produce cortical network hyperexcitability through cell-type-specific effects on excitatory and inhibitory neurons.
neuron link
KCNT1 link
regulation of membrane potential link ↕ DYSREGULATED
Downstream
Cortical excitation-inhibition imbalance KCNT1 effects shift firing properties across cortical excitatory and inhibitory neurons.
Show evidence (1 reference)
PMID:38457342 SUPPORT Model Organism
"Gain-of-function mutations in humans cause cortical network hyperexcitability, seizures, and severe intellectual disability."
Mouse-model paper summarizes KCNT1 gain-of-function effects as cortical hyperexcitability and seizures.
Cortical excitation-inhibition imbalance
Convergent receptor, ion-channel, and mTOR mechanisms disturb the balance of excitatory and inhibitory cortical network activity, creating a seizure prone circuit state.
pyramidal neuron link GABAergic neuron link
regulation of neuronal synaptic plasticity link ↕ DYSREGULATED
Downstream
Sleep-related hypermotor seizure expression Seizure-prone cortical networks manifest as brief stereotyped hypermotor nocturnal events.
Show evidence (2 references)
PMID:25104926 SUPPORT In Vitro
"alters the local connectivity during synaptogenesis."
Neuronal culture data support altered local cortical network connectivity from an ADSHE-linked CHRNB2 variant.
PMID:25104926 SUPPORT In Vitro
"generally attributed to neocortical hyperexcitability in the frontal regions"
The study frames ADSHE variants as producing frontal neocortical hyperexcitability.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Familial Sleep-Related Hypermotor Epilepsy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

9
Nervous System 2
Involuntary movements FREQUENT Involuntary movements (HP:0004305)
Show evidence (1 reference)
ORPHA:98784 SUPPORT Other
"HP:0004305 | Involuntary movements | Frequent (79-30%)"
Orphanet lists involuntary movements as frequent in SHE.
Cognitive impairment OCCASIONAL Cognitive impairment (HP:0100543)
Show evidence (2 references)
PMID:20301348 SUPPORT Other
"intellect is usually preserved, but reduced intellect, psychiatric comorbidities, or cognitive deficits may occur"
GeneReviews confirms reduced intellect or cognitive deficits can occur in ADSHE.
ORPHA:98784 SUPPORT Other
"HP:0100543 | Cognitive impairment | Occasional (29-5%)"
Orphanet lists cognitive impairment as occasional in SHE.
Constitutional 1
Urinary incontinence OCCASIONAL Urinary incontinence (HP:0000020)
Show evidence (1 reference)
ORPHA:98784 SUPPORT Other
"HP:0000020 | Urinary incontinence | Occasional (29-5%)"
Orphanet lists urinary incontinence as occasional in SHE.
Other 6
Nocturnal seizures VERY_FREQUENT Nocturnal seizures (HP:0031951)
Show evidence (1 reference)
ORPHA:98784 SUPPORT Other
"HP:0031951 | Nocturnal seizures | Very frequent (99-80%)"
Orphanet lists nocturnal seizures as very frequent in SHE.
Paroxysmal dystonia FREQUENT Paroxysmal dystonia (HP:0002268)
Show evidence (1 reference)
ORPHA:98784 SUPPORT Other
"HP:0002268 | Paroxysmal dystonia | Frequent (79-30%)"
Orphanet lists paroxysmal dystonia as frequent in SHE.
Abnormal repetitive mannerisms FREQUENT Motor stereotypy (HP:0000733)
Show evidence (1 reference)
ORPHA:98784 SUPPORT Other
"HP:0000733 | Abnormal repetitive mannerisms | Frequent (79-30%)"
Orphanet lists abnormal repetitive mannerisms as frequent in SHE.
Hyperkinetic seizures OCCASIONAL Focal hyperkinetic seizure (HP:0011174)
Show evidence (1 reference)
ORPHA:98784 SUPPORT Other
"HP:0011174 | Hyperkinetic seizures | Occasional (29-5%)"
Orphanet lists hyperkinetic seizures as occasional in the structured phenotype table.
Interictal epileptiform activity OCCASIONAL Interictal epileptiform activity (HP:0011182)
Show evidence (1 reference)
ORPHA:98784 SUPPORT Other
"HP:0011182 | Interictal epileptiform activity | Occasional (29-5%)"
Orphanet lists interictal epileptiform activity as occasional in SHE.
Confusional arousal OCCASIONAL
Show evidence (1 reference)
ORPHA:98784 SUPPORT Other
"HP:0025237 | Confusional arousal | Occasional (29-5%)"
Orphanet lists confusional arousal as occasional in SHE.
🧬

Genetic Associations

6
CHRNA4 (Causal nicotinic receptor subunit variant)
Show evidence (2 references)
ORPHA:98784 SUPPORT Other
"CHRNA4 | cholinergic receptor nicotinic alpha 4 subunit | hgnc:1958 | Disease-causing germline mutation(s) in"
Orphanet lists CHRNA4 as a disease-causing germline gene for SHE.
PMID:7550350 SUPPORT Human Clinical
"The mutation is present in all 21 available affected family members and in four obligate carriers, but not in 333 healthy control subjects."
The original CHRNA4 family study shows segregation of the pathogenic variant with ADNFLE.
CHRNB2 (Causal nicotinic receptor subunit variant)
Show evidence (2 references)
ORPHA:98784 SUPPORT Other
"CHRNB2 | cholinergic receptor nicotinic beta 2 subunit | hgnc:1962 | Disease-causing germline mutation(s) in"
Orphanet lists CHRNB2 as a disease-causing germline gene for SHE.
PMID:11062464 SUPPORT Human Clinical
"The newly identified locus associated with ENFL3 harbours several candidate genes, including CHRNB2 (ref. 8), whose gene product, the beta 2 nicotinic acetylcholine receptor (nAChR) subunit, co-assembles with the alpha 4 nAChR subunit to form the active receptor."
The original ENFL3 study identifies CHRNB2 as the relevant nicotinic receptor candidate gene.
CHRNA2 (Causal nicotinic receptor subunit variant)
Show evidence (2 references)
ORPHA:98784 SUPPORT Other
"CHRNA2 | cholinergic receptor nicotinic alpha 2 subunit | hgnc:1956 | Disease-causing germline mutation(s) in"
Orphanet lists CHRNA2 as a disease-causing germline gene for SHE.
PMID:30809122 SUPPORT Human Clinical
"Here, we report the third mutation in the CHRNA2, found in a patient showing ADNFLE."
The case-functional study supports CHRNA2 involvement in familial SHE/ADNFLE.
DEPDC5 (Causal GATOR1 loss-of-function variant)
Show evidence (2 references)
ORPHA:98784 SUPPORT Other
"DEPDC5 | DEP domain containing 5, GATOR1 subcomplex subunit | hgnc:18423 | Disease-causing germline mutation(s) (loss of function) in"
Orphanet lists DEPDC5 loss-of-function variants for SHE.
PMID:24814846 SUPPORT Human Clinical
"DEPDC5 loss-of-function mutations were found in 13% of the families with a presentation of ADNFLE."
Human family sequencing supports DEPDC5 loss-of-function alleles in ADNFLE presentations.
KCNT1 (Causal potassium-channel variant)
Show evidence (1 reference)
ORPHA:98784 SUPPORT Other
"KCNT1 | potassium sodium-activated channel subfamily T member 1 | hgnc:18865 | Disease-causing germline mutation(s) in"
Orphanet lists KCNT1 as a disease-causing germline gene for SHE.
Additional reported SHE genes (Reported disease-causing germline genes)
Show evidence (2 references)
ORPHA:98784 SUPPORT Other
"CABP4 | calcium binding protein 4 | hgnc:1386 | Disease-causing germline mutation(s) in"
Orphanet lists CABP4 as a disease-causing germline gene for SHE.
ORPHA:98784 SUPPORT Other
"CRH | corticotropin releasing hormone | hgnc:2355 | Disease-causing germline mutation(s) in"
Orphanet lists CRH as a disease-causing germline gene for SHE.
💊

Treatments

4
Carbamazepine-centered antiseizure medication therapy
Action: anticonvulsant agent therapy MAXO:0000167
Agent: carbamazepine ↗
Carbamazepine is the best-established first-line antiseizure medication for ADSHE and is associated with remission in many affected individuals.
Target Phenotypes: Nocturnal seizures ↗
Show evidence (1 reference)
PMID:20301348 SUPPORT Other
"Carbamazepine is associated with remission in about 70% of individuals, often in relatively low doses."
GeneReviews supports carbamazepine as a common effective ADSHE treatment.
Genotype-informed adjunctive pharmacotherapy
Action: Pharmacotherapy NCIT:C15986
Agent: zonisamide ↗ quinidine ↗ fenofibrate ↗
Selected genotypes may require alternatives or adjuncts, including zonisamide for some CHRNA4 variants, quinidine for KCNT1-related ADSHE, and fenofibrate as an adjunct for standard-ASM-resistant disease.
Target Phenotypes: Nocturnal seizures ↗
Show evidence (2 references)
PMID:20301348 SUPPORT Other
"Individuals with ADSHE associated with the CHRNA4 pathogenic variant p.Ser284Leu are more responsive to zonisamide than carbamazepine. KCNT1-related ADSHE is difficult to treat but may be treatable using quinidine based on limited data."
GeneReviews supports genotype-specific consideration of zonisamide and quinidine.
PMID:20301348 SUPPORT Other
"Adjunctive fenofibrate therapy or vagal nerve stimulation may be considered in individuals resistant to standard ASM."
GeneReviews supports adjunctive fenofibrate or VNS for standard-ASM-resistant ADSHE.
Vagus nerve stimulation for refractory ADSHE
Action: vagus nerve stimulation MAXO:0000942
Vagus nerve stimulation is a nonpharmacologic adjunctive option for individuals with ADSHE that remains resistant to standard antiseizure medications.
Target Phenotypes: Nocturnal seizures ↗
Show evidence (1 reference)
PMID:20301348 SUPPORT Other
"Adjunctive fenofibrate therapy or vagal nerve stimulation may be considered in individuals resistant to standard ASM."
GeneReviews supports VNS as an adjunctive refractory-disease option.
Genetic counseling
Action: genetic counseling MAXO:0000079
Genetic counseling supports recurrence-risk assessment, evaluation of relatives, and reproductive counseling in autosomal dominant families.
Show evidence (1 reference)
PMID:20301348 SUPPORT Other
"Each child of an individual with ADSHE has a 50% chance of inheriting the ADSHE-related pathogenic variant; the chance that the offspring will manifest ADSHE is (50% x 70% =) 35%, assuming penetrance of 70%."
GeneReviews supports genetic counseling with recurrence-risk and penetrance estimates.
{ }

Source YAML

click to show 
name: Familial Sleep-Related Hypermotor Epilepsy
creation_date: "2026-05-09T08:04:26Z"
updated_date: "2026-05-10T00:49:09Z"
category: Mendelian
description: >-
  Familial sleep-related hypermotor epilepsy is an autosomal dominant focal
  epilepsy syndrome in which recurrent, stereotyped nocturnal motor seizures
  arise from inherited variants in nicotinic acetylcholine receptor genes,
  KCNT1, DEPDC5/GATOR1-related genes, and rarer reported loci. The shared
  clinical expression is brief sleep-associated hypermotor, tonic, dystonic, or
  arousal-like events, while the molecular mechanisms are heterogeneous and
  include altered cholinergic receptor function, ion-channel excitability, and
  DEPDC5-related mTOR pathway dysregulation.
disease_term:
  preferred_term: familial sleep-related hypermotor epilepsy
  term:
    id: MONDO:0000030
    label: familial sleep-related hypermotor epilepsy
synonyms:
- autosomal dominant nocturnal frontal lobe epilepsy
- autosomal dominant sleep-related hypermotor epilepsy
- sleep-related hypermotor epilepsy
- ADNFLE
- ADSHE
- SHE
parents:
- Epilepsy
- Sleep Disorder
notes: >-
  The historical label ADNFLE is retained as a synonym, but the preferred scope
  follows the modern SHE/ADSHE terminology because attacks are sleep-related,
  can arise from extrafrontal networks, and are not limited to the frontal lobe.
  The Orphanet record uses the broader title Sleep-related hypermotor epilepsy
  and cross-references an obsolete MONDO identifier; this entry uses the active
  MONDO familial term and records the Orphanet data as structured evidence.
has_subtypes:
- name: Type 1
  display_name: CHRNA4-related ADSHE (ENFL1)
  subtype_term:
    preferred_term: autosomal dominant nocturnal frontal lobe epilepsy 1
    term:
      id: MONDO:0010899
      label: autosomal dominant nocturnal frontal lobe epilepsy 1
  genes:
  - preferred_term: CHRNA4
    term:
      id: hgnc:1958
      label: CHRNA4
  description: >-
    Gene-defined subtype caused by heterozygous CHRNA4 pathogenic variants that
    alter alpha-4 nicotinic acetylcholine receptor function.
- name: Type 2
  display_name: Chromosome 15q24-linked ADSHE (ENFL2)
  subtype_term:
    preferred_term: autosomal dominant nocturnal frontal lobe epilepsy 2
    term:
      id: MONDO:0011297
      label: autosomal dominant nocturnal frontal lobe epilepsy 2
  description: >-
    Historical chromosome 15q24-linked ADSHE subtype without a currently
    resolved single causal gene in MONDO.
- name: Type 3
  display_name: CHRNB2-related ADSHE (ENFL3)
  subtype_term:
    preferred_term: autosomal dominant nocturnal frontal lobe epilepsy 3
    term:
      id: MONDO:0011545
      label: autosomal dominant nocturnal frontal lobe epilepsy 3
  genes:
  - preferred_term: CHRNB2
    term:
      id: hgnc:1962
      label: CHRNB2
  description: >-
    Gene-defined subtype caused by heterozygous CHRNB2 pathogenic variants in
    the beta-2 nicotinic acetylcholine receptor subunit.
- name: Type 4
  display_name: CHRNA2-related ADSHE (ENFL4)
  subtype_term:
    preferred_term: autosomal dominant nocturnal frontal lobe epilepsy 4
    term:
      id: MONDO:0012474
      label: autosomal dominant nocturnal frontal lobe epilepsy 4
  genes:
  - preferred_term: CHRNA2
    term:
      id: hgnc:1956
      label: CHRNA2
  description: >-
    Gene-defined subtype caused by heterozygous CHRNA2 pathogenic variants in
    the alpha-2 nicotinic acetylcholine receptor subunit.
- name: Type 5
  display_name: KCNT1-related ADSHE (ENFL5)
  subtype_term:
    preferred_term: autosomal dominant nocturnal frontal lobe epilepsy 5
    term:
      id: MONDO:0014002
      label: autosomal dominant nocturnal frontal lobe epilepsy 5
  genes:
  - preferred_term: KCNT1
    term:
      id: hgnc:18865
      label: KCNT1
  description: >-
    Gene-defined subtype caused by heterozygous KCNT1 variants affecting the
    Slack sodium-activated potassium channel.
- name: DEPDC5-related SHE
  display_name: DEPDC5/GATOR1-related sleep-related hypermotor epilepsy
  genes:
  - preferred_term: DEPDC5
    term:
      id: hgnc:18423
      label: DEPDC5
  description: >-
    GATOR1-related form in which DEPDC5 loss-of-function variants are enriched,
    particularly among patients with genetic-structural etiology and focal
    cortical dysplasia.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Familial SHE/ADSHE is defined by autosomal dominant transmission, although
    penetrance and severity vary within families.
  evidence:
  - reference: ORPHA:98784
    reference_title: Sleep-related hypermotor epilepsy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal dominant"
    explanation: Orphanet records autosomal dominant inheritance for the structured SHE record.
  - reference: PMID:20301348
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ADSHE, by definition, is inherited in an autosomal dominant manner. Most
      individuals diagnosed with ADSHE have an affected parent.
    explanation: GeneReviews supports autosomal dominant transmission and familial clustering.
progression:
- phase: Childhood-to-young-adult onset of nocturnal motor seizures
  age_range: infancy to adulthood, usually first two decades
  notes: >-
    Most affected individuals develop brief stereotyped sleep-related motor
    seizures in childhood or adolescence, but age at onset can range from
    infancy through adulthood.
  evidence:
  - reference: PMID:20301348
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Age of onset ranges from infancy to adulthood. About 80% of individuals
      develop ADSHE in the first two decades of life; mean age of onset is ten
      years.
    explanation: GeneReviews summarizes the onset distribution for ADSHE.
- phase: Lifelong non-progressive epilepsy with variable later attenuation
  notes: >-
    The epilepsy is usually lifelong but not neurodegenerative; seizures may
    become milder or less frequent in middle age.
  evidence:
  - reference: PMID:20301348
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ADSHE is lifelong but not progressive. As an individual reaches middle
      age, seizures may become milder and less frequent.
    explanation: GeneReviews directly supports the typical long-term course.
genetic:
- name: CHRNA4
  association: Causal nicotinic receptor subunit variant
  gene_term:
    preferred_term: CHRNA4
    term:
      id: hgnc:1958
      label: CHRNA4
  notes: >-
    CHRNA4 was the first established ADSHE gene and encodes the alpha-4
    nicotinic acetylcholine receptor subunit.
  evidence:
  - reference: ORPHA:98784
    reference_title: Sleep-related hypermotor epilepsy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CHRNA4 | cholinergic receptor nicotinic alpha 4 subunit | hgnc:1958 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists CHRNA4 as a disease-causing germline gene for SHE.
  - reference: PMID:7550350
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation is present in all 21 available affected family members and
      in four obligate carriers, but not in 333 healthy control subjects.
    explanation: The original CHRNA4 family study shows segregation of the pathogenic variant with ADNFLE.
- name: CHRNB2
  association: Causal nicotinic receptor subunit variant
  gene_term:
    preferred_term: CHRNB2
    term:
      id: hgnc:1962
      label: CHRNB2
  notes: >-
    CHRNB2 encodes the beta-2 nicotinic receptor subunit that co-assembles with
    alpha-4-containing receptors implicated in ADSHE.
  evidence:
  - reference: ORPHA:98784
    reference_title: Sleep-related hypermotor epilepsy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CHRNB2 | cholinergic receptor nicotinic beta 2 subunit | hgnc:1962 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists CHRNB2 as a disease-causing germline gene for SHE.
  - reference: PMID:11062464
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The newly identified locus associated with ENFL3 harbours several
      candidate genes, including CHRNB2 (ref. 8), whose gene product, the beta
      2 nicotinic acetylcholine receptor (nAChR) subunit, co-assembles with the
      alpha 4 nAChR subunit to form the active receptor.
    explanation: The original ENFL3 study identifies CHRNB2 as the relevant nicotinic receptor candidate gene.
- name: CHRNA2
  association: Causal nicotinic receptor subunit variant
  gene_term:
    preferred_term: CHRNA2
    term:
      id: hgnc:1956
      label: CHRNA2
  notes: >-
    CHRNA2 variants provide another nicotinic-receptor mechanism and can alter
    alpha-2-containing receptor currents.
  evidence:
  - reference: ORPHA:98784
    reference_title: Sleep-related hypermotor epilepsy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CHRNA2 | cholinergic receptor nicotinic alpha 2 subunit | hgnc:1956 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists CHRNA2 as a disease-causing germline gene for SHE.
  - reference: PMID:30809122
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report the third mutation in the CHRNA2, found in a patient
      showing ADNFLE.
    explanation: The case-functional study supports CHRNA2 involvement in familial SHE/ADNFLE.
- name: DEPDC5
  association: Causal GATOR1 loss-of-function variant
  gene_term:
    preferred_term: DEPDC5
    term:
      id: hgnc:18423
      label: DEPDC5
  notes: >-
    DEPDC5 loss-of-function variants contribute to familial SHE and often
    overlap with focal cortical dysplasia or other genetic-structural focal
    epilepsy presentations.
  evidence:
  - reference: ORPHA:98784
    reference_title: Sleep-related hypermotor epilepsy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "DEPDC5 | DEP domain containing 5, GATOR1 subcomplex subunit | hgnc:18423 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet lists DEPDC5 loss-of-function variants for SHE.
  - reference: PMID:24814846
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DEPDC5 loss-of-function mutations were found in 13% of the families with
      a presentation of ADNFLE.
    explanation: Human family sequencing supports DEPDC5 loss-of-function alleles in ADNFLE presentations.
- name: KCNT1
  association: Causal potassium-channel variant
  gene_term:
    preferred_term: KCNT1
    term:
      id: hgnc:18865
      label: KCNT1
  notes: >-
    KCNT1 encodes the Slack sodium-activated potassium channel and is associated
    with severe or treatment-resistant ADSHE in some families.
  evidence:
  - reference: ORPHA:98784
    reference_title: Sleep-related hypermotor epilepsy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KCNT1 | potassium sodium-activated channel subfamily T member 1 | hgnc:18865 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists KCNT1 as a disease-causing germline gene for SHE.
- name: Additional reported SHE genes
  association: Reported disease-causing germline genes
  gene_term:
    preferred_term: CABP4
    term:
      id: hgnc:1386
      label: CABP4
  notes: >-
    Orphanet and GeneReviews list additional reported familial SHE genes,
    including CABP4 and CRH, while newer reviews also include NPRL2, NPRL3, and
    STX1B. These genes are recorded as genetic heterogeneity rather than as
    separate mechanistic branches here.
  evidence:
  - reference: ORPHA:98784
    reference_title: Sleep-related hypermotor epilepsy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CABP4 | calcium binding protein 4 | hgnc:1386 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists CABP4 as a disease-causing germline gene for SHE.
  - reference: ORPHA:98784
    reference_title: Sleep-related hypermotor epilepsy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CRH | corticotropin releasing hormone | hgnc:2355 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists CRH as a disease-causing germline gene for SHE.
pathophysiology:
- name: Inherited ADSHE gene architecture
  description: >-
    Familial SHE is initiated by heterozygous pathogenic variants in a
    genetically heterogeneous autosomal dominant set that includes nicotinic
    acetylcholine receptor genes, KCNT1, DEPDC5/GATOR1-related genes, and rarer
    reported loci.
  role: trigger
  genes:
  - preferred_term: CHRNA4
    term:
      id: hgnc:1958
      label: CHRNA4
  - preferred_term: CHRNA2
    term:
      id: hgnc:1956
      label: CHRNA2
  - preferred_term: CHRNB2
    term:
      id: hgnc:1962
      label: CHRNB2
  - preferred_term: DEPDC5
    term:
      id: hgnc:18423
      label: DEPDC5
  - preferred_term: KCNT1
    term:
      id: hgnc:18865
      label: KCNT1
  evidence:
  - reference: PMID:20301348
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of ADSHE is established in a proband who has suggestive
      clinical findings and a family history consistent with autosomal dominant
      inheritance and/or a heterozygous pathogenic variant in CABP4, CHRNA4,
      CHRNA2, CHRNB2, CRH, DEPDC5, KCNT1, NPRL2, NPRL3, or STX1B identified by
      molecular genetic testing.
    explanation: GeneReviews summarizes the current genetically heterogeneous ADSHE architecture.
  downstream:
  - target: Nicotinic acetylcholine receptor dysfunction
    causal_link_type: DIRECT
    description: CHRNA4, CHRNA2, and CHRNB2 variants alter receptor function.
  - target: DEPDC5-GATOR1 mTOR signaling dysregulation
    causal_link_type: DIRECT
    description: DEPDC5 loss-of-function disrupts GATOR1 control of mTOR signaling.
  - target: KCNT1 Slack channel altered excitability
    causal_link_type: DIRECT
    description: KCNT1 variants alter sodium-activated potassium-channel effects on cortical excitability.
- name: Nicotinic acetylcholine receptor dysfunction
  description: >-
    CHRNA4, CHRNB2, and CHRNA2 pathogenic variants change alpha/beta nicotinic
    acetylcholine receptor function, altering cholinergic modulation of
    excitatory and inhibitory cortical transmission.
  role: central_effector
  genes:
  - preferred_term: CHRNA4
    term:
      id: hgnc:1958
      label: CHRNA4
  - preferred_term: CHRNA2
    term:
      id: hgnc:1956
      label: CHRNA2
  - preferred_term: CHRNB2
    term:
      id: hgnc:1962
      label: CHRNB2
  cell_types:
  - preferred_term: pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  - preferred_term: GABAergic neuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  biological_processes:
  - preferred_term: acetylcholine receptor signaling pathway
    modifier: DYSREGULATED
    term:
      id: GO:0095500
      label: acetylcholine receptor signaling pathway
  evidence:
  - reference: PMID:30472464
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      From this, we concluded that mutations that cause ADNFLE manifest
      themselves in a change in efficacy regardless of the stoichiometry of the
      receptor.
    explanation: Oocyte expression experiments support altered nicotinic receptor efficacy for ADNFLE mutations.
  - reference: PMID:30809122
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We conclude that mutations in CHRNA2 are more commonly linked to ADNFLE
      than previously thought, and may cause a loss-of-function phenotype.
    explanation: HEK293 functional assays support CHRNA2-linked receptor loss of function in ADNFLE.
  downstream:
  - target: Cortical excitation-inhibition imbalance
    causal_link_type: DIRECT
    description: Altered nicotinic signaling perturbs cortical excitatory and inhibitory synaptic dynamics.
- name: DEPDC5-GATOR1 mTOR signaling dysregulation
  description: >-
    DEPDC5 loss-of-function reduces GATOR1 complex integrity, releasing
    downstream mTORC1 signaling and increasing risk of focal epilepsy and focal
    cortical dysplasia-associated SHE.
  role: central_effector
  genes:
  - preferred_term: DEPDC5
    term:
      id: hgnc:18423
      label: DEPDC5
  biological_processes:
  - preferred_term: TOR signaling
    modifier: INCREASED
    term:
      id: GO:0031929
      label: TOR signaling
  evidence:
  - reference: PMID:24814846
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, 3 nonsense DEPDC5 mutations (p.Arg487*, p.Arg1087*, and
      p.Trp1369*) were detected in the probands of 2 French and one Belgian
      family.
    explanation: Human family sequencing identifies truncating DEPDC5 variants in ADNFLE families.
  - reference: PMID:31174205
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Loss of Depdc5 led to a decrease in the other GATOR1 protein levels
      (NPRL2 and NPRL3). Rapamycin failed to rescue GATOR1 protein levels but
      rather rescued downstream mTORC1 hyperactivity as measured by
      phosphorylation of S6.
    explanation: Mouse data support DEPDC5 loss causing GATOR1 reduction and downstream mTORC1 hyperactivity.
  downstream:
  - target: Cortical excitation-inhibition imbalance
    causal_link_type: DIRECT
    description: mTOR-related focal epilepsy biology increases seizure-prone cortical network activity.
- name: KCNT1 Slack channel altered excitability
  description: >-
    KCNT1 variants alter Slack sodium-activated potassium-channel behavior and
    can produce cortical network hyperexcitability through cell-type-specific
    effects on excitatory and inhibitory neurons.
  role: central_effector
  genes:
  - preferred_term: KCNT1
    term:
      id: hgnc:18865
      label: KCNT1
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: regulation of membrane potential
    modifier: DYSREGULATED
    term:
      id: GO:0042391
      label: regulation of membrane potential
  evidence:
  - reference: PMID:38457342
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Gain-of-function mutations in humans cause cortical network
      hyperexcitability, seizures, and severe intellectual disability.
    explanation: Mouse-model paper summarizes KCNT1 gain-of-function effects as cortical hyperexcitability and seizures.
  downstream:
  - target: Cortical excitation-inhibition imbalance
    causal_link_type: DIRECT
    description: KCNT1 effects shift firing properties across cortical excitatory and inhibitory neurons.
- name: Cortical excitation-inhibition imbalance
  description: >-
    Convergent receptor, ion-channel, and mTOR mechanisms disturb the balance
    of excitatory and inhibitory cortical network activity, creating a seizure
    prone circuit state.
  role: central_effector
  cell_types:
  - preferred_term: pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  - preferred_term: GABAergic neuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  biological_processes:
  - preferred_term: regulation of neuronal synaptic plasticity
    modifier: DYSREGULATED
    term:
      id: GO:0048168
      label: regulation of neuronal synaptic plasticity
  evidence:
  - reference: PMID:25104926
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "alters the local connectivity during synaptogenesis."
    explanation: Neuronal culture data support altered local cortical network connectivity from an ADSHE-linked CHRNB2 variant.
  - reference: PMID:25104926
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "generally attributed to neocortical hyperexcitability in the frontal regions"
    explanation: The study frames ADSHE variants as producing frontal neocortical hyperexcitability.
  downstream:
  - target: Sleep-related hypermotor seizure expression
    causal_link_type: DIRECT
    description: Seizure-prone cortical networks manifest as brief stereotyped hypermotor nocturnal events.
- name: Sleep-related hypermotor seizure expression
  description: >-
    The final clinical expression is clusters of stereotyped, brief,
    sleep-associated motor seizures that can include hyperkinetic, tonic,
    dystonic, arousal-like, or wandering behaviors.
  role: outcome
  evidence:
  - reference: ORPHA:98784
    reference_title: Sleep-related hypermotor epilepsy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A rare seizure disorder characterized by intermittent dystonia and/or
      choreoathetoid movements that occur during sleep.
    explanation: Orphanet definition supports the sleep-associated dystonic/hypermotor seizure expression.
  - reference: PMID:20301348
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy
      (ADSHE) is a seizure disorder characterized by clusters of nocturnal motor
      seizures that are often stereotyped and brief (<2 minutes).
    explanation: GeneReviews supports the stereotyped, brief nocturnal motor seizure phenotype.
phenotypes:
- name: Nocturnal seizures
  category: Neurologic
  frequency: VERY_FREQUENT
  description: >-
    Sleep-associated seizures are the core phenotype and typically occur as
    recurrent nocturnal clusters.
  phenotype_term:
    preferred_term: Nocturnal seizures
    term:
      id: HP:0031951
      label: Nocturnal seizures
  evidence:
  - reference: ORPHA:98784
    reference_title: Sleep-related hypermotor epilepsy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0031951 | Nocturnal seizures | Very frequent (99-80%)"
    explanation: Orphanet lists nocturnal seizures as very frequent in SHE.
- name: Paroxysmal dystonia
  category: Neurologic
  frequency: FREQUENT
  description: >-
    Brief dystonic posturing can be part of the hypermotor seizure semiology.
  phenotype_term:
    preferred_term: Paroxysmal dystonia
    term:
      id: HP:0002268
      label: Paroxysmal dystonia
  evidence:
  - reference: ORPHA:98784
    reference_title: Sleep-related hypermotor epilepsy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002268 | Paroxysmal dystonia | Frequent (79-30%)"
    explanation: Orphanet lists paroxysmal dystonia as frequent in SHE.
- name: Involuntary movements
  category: Neurologic
  frequency: FREQUENT
  description: >-
    Hypermotor events can include involuntary limb and body movements during
    sleep-related seizures.
  phenotype_term:
    preferred_term: Involuntary movements
    term:
      id: HP:0004305
      label: Involuntary movements
  evidence:
  - reference: ORPHA:98784
    reference_title: Sleep-related hypermotor epilepsy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004305 | Involuntary movements | Frequent (79-30%)"
    explanation: Orphanet lists involuntary movements as frequent in SHE.
- name: Abnormal repetitive mannerisms
  category: Neurologic
  frequency: FREQUENT
  description: >-
    Stereotyped repetitive motor behaviors occur as part of the sleep-related
    hypermotor event pattern.
  phenotype_term:
    preferred_term: Abnormal repetitive mannerisms
    term:
      id: HP:0000733
      label: Motor stereotypy
  evidence:
  - reference: ORPHA:98784
    reference_title: Sleep-related hypermotor epilepsy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000733 | Abnormal repetitive mannerisms | Frequent (79-30%)"
    explanation: Orphanet lists abnormal repetitive mannerisms as frequent in SHE.
- name: Hyperkinetic seizures
  category: Neurologic
  frequency: OCCASIONAL
  description: >-
    Some patients have hyperkinetic seizure semiology with complex motor
    behavior, consistent with the modern SHE terminology.
  phenotype_term:
    preferred_term: Hyperkinetic seizures
    term:
      id: HP:0011174
      label: Focal hyperkinetic seizure
  evidence:
  - reference: ORPHA:98784
    reference_title: Sleep-related hypermotor epilepsy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011174 | Hyperkinetic seizures | Occasional (29-5%)"
    explanation: Orphanet lists hyperkinetic seizures as occasional in the structured phenotype table.
- name: Interictal epileptiform activity
  category: Neurologic
  frequency: OCCASIONAL
  description: >-
    Interictal epileptiform abnormalities may support diagnosis but can be
    absent, contributing to confusion with parasomnia.
  phenotype_term:
    preferred_term: Interictal epileptiform activity
    term:
      id: HP:0011182
      label: Interictal epileptiform activity
  evidence:
  - reference: ORPHA:98784
    reference_title: Sleep-related hypermotor epilepsy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011182 | Interictal epileptiform activity | Occasional (29-5%)"
    explanation: Orphanet lists interictal epileptiform activity as occasional in SHE.
- name: Confusional arousal
  category: Neurologic
  frequency: OCCASIONAL
  description: >-
    Confusional arousals from sleep can be part of the SHE semiology and overlap
    with NREM parasomnias, contributing to diagnostic uncertainty.
  phenotype_term:
    preferred_term: Confusional arousal
  review_notes: >-
    NTR: Orphanet lists HP:0025237 for confusional arousal, but the current
    local HPO release marks HP:0025237 as obsolete and provides no non-obsolete
    replacement term.
  evidence:
  - reference: ORPHA:98784
    reference_title: Sleep-related hypermotor epilepsy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025237 | Confusional arousal | Occasional (29-5%)"
    explanation: Orphanet lists confusional arousal as occasional in SHE.
- name: Cognitive impairment
  category: Neurologic
  frequency: OCCASIONAL
  description: >-
    Intellect is usually preserved, but reduced intellect or cognitive deficits
    may occur in a minority of affected individuals.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:20301348
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "intellect is usually preserved, but reduced intellect, psychiatric comorbidities, or cognitive deficits may occur"
    explanation: GeneReviews confirms reduced intellect or cognitive deficits can occur in ADSHE.
  - reference: ORPHA:98784
    reference_title: Sleep-related hypermotor epilepsy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100543 | Cognitive impairment | Occasional (29-5%)"
    explanation: Orphanet lists cognitive impairment as occasional in SHE.
- name: Urinary incontinence
  category: Neurologic
  frequency: OCCASIONAL
  description: >-
    Urinary incontinence can occur during nocturnal events in a minority of
    affected individuals.
  phenotype_term:
    preferred_term: Urinary incontinence
    term:
      id: HP:0000020
      label: Urinary incontinence
  evidence:
  - reference: ORPHA:98784
    reference_title: Sleep-related hypermotor epilepsy (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000020 | Urinary incontinence | Occasional (29-5%)"
    explanation: Orphanet lists urinary incontinence as occasional in SHE.
diagnosis:
- name: Video-EEG documented SHE
  description: >-
    Video-EEG documentation provides the highest diagnostic certainty by
    capturing sleep-related hypermotor events with electroclinical correlation.
  diagnosis_term:
    preferred_term: electroencephalography
    term:
      id: MAXO:0000932
      label: electroencephalography
  results: Video-EEG-documented sleep-related hypermotor events support confirmed SHE.
  evidence:
  - reference: PMID:27164717
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Diagnostic criteria were developed with 3 levels of certainty: witnessed
      (possible) SHE, video-documented (clinical) SHE, and video-EEG-documented
      (confirmed) SHE.
    explanation: Consensus criteria define video-EEG documentation as the confirmed diagnostic level.
- name: Nocturnal video-polysomnography
  description: >-
    Polysomnography can capture NREM-stage events and distinguish SHE from
    parasomnias or psychogenic nonepileptic events.
  diagnosis_term:
    preferred_term: polysomnography
    term:
      id: MAXO:0000915
      label: polysomnography
  results: Recorded nocturnal motor events during sleep support the clinical diagnosis.
  evidence:
  - reference: PMID:30809122
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was examined by scalp EEG, contrast-enhanced brain magnetic
      resonance imaging (MRI), and nocturnal video-polysomnographic recording.
    explanation: A CHRNA2-linked ADNFLE case used nocturnal video-polysomnography as part of diagnostic workup.
- name: Molecular genetic testing
  description: >-
    Sequencing of familial SHE genes supports diagnosis, recurrence-risk
    counseling, and genotype-specific management considerations.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  results: Heterozygous pathogenic variant in a SHE-associated gene supports ADSHE.
  evidence:
  - reference: PMID:20301348
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of ADSHE is established in a proband who has suggestive
      clinical findings and a family history consistent with autosomal dominant
      inheritance and/or a heterozygous pathogenic variant in CABP4, CHRNA4,
      CHRNA2, CHRNB2, CRH, DEPDC5, KCNT1, NPRL2, NPRL3, or STX1B identified by
      molecular genetic testing.
    explanation: GeneReviews supports molecular testing as part of the diagnostic definition.
treatments:
- name: Carbamazepine-centered antiseizure medication therapy
  description: >-
    Carbamazepine is the best-established first-line antiseizure medication for
    ADSHE and is associated with remission in many affected individuals.
  treatment_term:
    preferred_term: anticonvulsant agent therapy
    term:
      id: MAXO:0000167
      label: anticonvulsant agent therapy
    therapeutic_agent:
    - preferred_term: carbamazepine
      term:
        id: CHEBI:3387
        label: carbamazepine
  target_phenotypes:
  - preferred_term: Nocturnal seizures
    term:
      id: HP:0031951
      label: Nocturnal seizures
  evidence:
  - reference: PMID:20301348
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Carbamazepine is associated with remission in about 70% of individuals,
      often in relatively low doses.
    explanation: GeneReviews supports carbamazepine as a common effective ADSHE treatment.
- name: Genotype-informed adjunctive pharmacotherapy
  description: >-
    Selected genotypes may require alternatives or adjuncts, including
    zonisamide for some CHRNA4 variants, quinidine for KCNT1-related ADSHE, and
    fenofibrate as an adjunct for standard-ASM-resistant disease.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: zonisamide
      term:
        id: CHEBI:10127
        label: zonisamide
    - preferred_term: quinidine
      term:
        id: CHEBI:28593
        label: quinidine
    - preferred_term: fenofibrate
      term:
        id: CHEBI:5001
        label: fenofibrate
  target_phenotypes:
  - preferred_term: Nocturnal seizures
    term:
      id: HP:0031951
      label: Nocturnal seizures
  evidence:
  - reference: PMID:20301348
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals with ADSHE associated with the CHRNA4 pathogenic variant
      p.Ser284Leu are more responsive to zonisamide than carbamazepine.
      KCNT1-related ADSHE is difficult to treat but may be treatable using
      quinidine based on limited data.
    explanation: GeneReviews supports genotype-specific consideration of zonisamide and quinidine.
  - reference: PMID:20301348
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Adjunctive fenofibrate therapy or vagal nerve stimulation may be
      considered in individuals resistant to standard ASM.
    explanation: GeneReviews supports adjunctive fenofibrate or VNS for standard-ASM-resistant ADSHE.
- name: Vagus nerve stimulation for refractory ADSHE
  description: >-
    Vagus nerve stimulation is a nonpharmacologic adjunctive option for
    individuals with ADSHE that remains resistant to standard antiseizure
    medications.
  treatment_term:
    preferred_term: vagus nerve stimulation
    term:
      id: MAXO:0000942
      label: vagus nerve stimulation
  target_phenotypes:
  - preferred_term: Nocturnal seizures
    term:
      id: HP:0031951
      label: Nocturnal seizures
  evidence:
  - reference: PMID:20301348
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Adjunctive fenofibrate therapy or vagal nerve stimulation may be
      considered in individuals resistant to standard ASM.
    explanation: GeneReviews supports VNS as an adjunctive refractory-disease option.
- name: Genetic counseling
  description: >-
    Genetic counseling supports recurrence-risk assessment, evaluation of
    relatives, and reproductive counseling in autosomal dominant families.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:20301348
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Each child of an individual with ADSHE has a 50% chance of inheriting the
      ADSHE-related pathogenic variant; the chance that the offspring will
      manifest ADSHE is (50% x 70% =) 35%, assuming penetrance of 70%.
    explanation: GeneReviews supports genetic counseling with recurrence-risk and penetrance estimates.
references:
- reference: ORPHA:98784
  title: Sleep-related hypermotor epilepsy.
  found_in:
  - Familial_Sleep_Related_Hypermotor_Epilepsy-deep-research-fallback.md
  findings: []
- reference: PMID:20301348
  title: Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy.
  found_in:
  - Familial_Sleep_Related_Hypermotor_Epilepsy-deep-research-fallback.md
  findings: []
- reference: PMID:27164717
  title: Definition and diagnostic criteria of sleep-related hypermotor epilepsy.
  found_in:
  - Familial_Sleep_Related_Hypermotor_Epilepsy-deep-research-fallback.md
  findings: []
- reference: PMID:7550350
  title: A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy.
  found_in:
  - Familial_Sleep_Related_Hypermotor_Epilepsy-deep-research-fallback.md
  findings: []
- reference: PMID:11062464
  title: The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy.
  found_in:
  - Familial_Sleep_Related_Hypermotor_Epilepsy-deep-research-fallback.md
  findings: []
- reference: PMID:30809122
  title: "CHRNA2 and Nocturnal Frontal Lobe Epilepsy: Identification and Characterization of a Novel Loss of Function Mutation."
  found_in:
  - Familial_Sleep_Related_Hypermotor_Epilepsy-deep-research-fallback.md
  findings: []
- reference: PMID:24814846
  title: DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy.
  found_in:
  - Familial_Sleep_Related_Hypermotor_Epilepsy-deep-research-fallback.md
  findings: []
- reference: PMID:31174205
  title: Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice.
  found_in:
  - Familial_Sleep_Related_Hypermotor_Epilepsy-deep-research-fallback.md
  findings: []
- reference: PMID:30472464
  title: Revisiting autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) mutations in the nicotinic acetylcholine receptor reveal an increase in efficacy regardless of stochiometry.
  found_in:
  - Familial_Sleep_Related_Hypermotor_Epilepsy-deep-research-fallback.md
  findings: []
- reference: PMID:25104926
  title: Multi-electrode array study of neuronal cultures expressing nicotinic β2-V287L subunits, linked to autosomal dominant nocturnal frontal lobe epilepsy. An in vitro model of spontaneous epilepsy.
  found_in:
  - Familial_Sleep_Related_Hypermotor_Epilepsy-deep-research-fallback.md
  findings: []
- reference: PMID:38457342
  title: Disease-causing Slack potassium channel mutations produce opposite effects on excitability of excitatory and inhibitory neurons.
  found_in:
  - Familial_Sleep_Related_Hypermotor_Epilepsy-deep-research-fallback.md
  findings: []
📚

References & Deep Research

References

11
ORPHA:98784
Sleep-related hypermotor epilepsy.
No top-level findings curated for this source.
PMID:20301348
Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy.
No top-level findings curated for this source.
PMID:27164717
Definition and diagnostic criteria of sleep-related hypermotor epilepsy.
No top-level findings curated for this source.
PMID:7550350
A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy.
No top-level findings curated for this source.
PMID:11062464
The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy.
No top-level findings curated for this source.
PMID:30809122
CHRNA2 and Nocturnal Frontal Lobe Epilepsy: Identification and Characterization of a Novel Loss of Function Mutation.
No top-level findings curated for this source.
PMID:24814846
DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy.
No top-level findings curated for this source.
PMID:31174205
Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice.
No top-level findings curated for this source.
PMID:30472464
Revisiting autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) mutations in the nicotinic acetylcholine receptor reveal an increase in efficacy regardless of stochiometry.
No top-level findings curated for this source.
PMID:25104926
Multi-electrode array study of neuronal cultures expressing nicotinic β2-V287L subunits, linked to autosomal dominant nocturnal frontal lobe epilepsy. An in vitro model of spontaneous epilepsy.
No top-level findings curated for this source.
PMID:38457342
Disease-causing Slack potassium channel mutations produce opposite effects on excitability of excitatory and inhibitory neurons.
No top-level findings curated for this source.

Deep Research

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Familial Sleep-Related Hypermotor Epilepsy Deep Research Fallback ▸

Familial Sleep-Related Hypermotor Epilepsy Deep Research Fallback

Provider Attempts

  • falcon: timeout --foreground 120s just research-disorder falcon Familial_Sleep_Related_Hypermotor_Epilepsy produced no usable content and was terminated with signal 15.
  • openai: timeout --foreground 120s just research-disorder openai Familial_Sleep_Related_Hypermotor_Epilepsy produced no usable content and was terminated with signal 15.

Because the preferred deep-research providers did not return usable content in bounded attempts, this fallback records the literature scope used for curation. All YAML evidence was taken from generated Orphanet and PubMed reference caches, not from hand-created reference text.

Literature Scope

Familial sleep-related hypermotor epilepsy corresponds to MONDO:0000030 and Orphanet ORPHA:98784. The Orphanet record provides the structured definition, autosomal dominant inheritance, gene rows for CABP4, CHRNA2, CHRNA4, CHRNB2, CRH, DEPDC5, and KCNT1, and the HPO phenotype-frequency table used for frequency-backed phenotype entries.

The clinical scope was anchored with the GeneReviews ADSHE chapter and the Neurology consensus definition paper. Those sources support the modern sleep-related hypermotor epilepsy terminology, diagnostic certainty levels based on witnessed, video-documented, and video-EEG-documented events, genetic testing across the heterogeneous ADSHE gene set, non-progressive but lifelong course, carbamazepine-centered therapy, genotype-informed alternatives, VNS, and genetic counseling.

Mechanistic curation focused on three evidence-backed branches. CHRNA4, CHRNB2, and CHRNA2 studies support nicotinic acetylcholine receptor dysfunction with altered receptor efficacy or loss of function. DEPDC5 evidence supports loss-of-function variants in ADNFLE families and GATOR1/mTORC1 dysregulation in model systems. KCNT1 evidence supports altered Slack-channel effects on cortical neuronal excitability. These branches converge on cortical excitation-inhibition imbalance and sleep-related hypermotor seizure expression.

Curation Decisions

  • Used MONDO:0000030 as the disease term because the ORPHA record title is broader and its MONDO cross-reference points to an obsolete identifier.
  • Included all ORPHA very frequent and frequent HPO phenotypes: nocturnal seizures, paroxysmal dystonia, involuntary movements, and motor stereotypy.
  • Retained additional occasional ORPHA phenotypes when clinically coherent for SHE semiology or diagnosis: focal hyperkinetic seizure, interictal epileptiform activity, and urinary incontinence.
  • Modeled the five MONDO/OMIM ENFL subtypes as root subtypes, and added a DEPDC5-related SHE subtype because Orphanet and human family sequencing both support DEPDC5 loss-of-function in SHE/ADNFLE presentations.
  • Did not force individual mechanistic branches for CABP4 or CRH because the available curated evidence was sufficient to record them as genetic heterogeneity but not enough for a distinct mechanism node.