Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy

Clinical characteristics.

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). They vary from simple arousals from sleep to dramatic, often hyperkinetic events with tonic or dystonic features. Affected individuals may experience an aura. Retained awareness during seizures is common. A minority of individuals experience daytime seizures. 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. Clinical neurologic examination is normal and intellect is usually preserved, but reduced intellect, psychiatric comorbidities, or cognitive deficits may occur. Within a family, the manifestations of the disorder may vary considerably. ADSHE is lifelong but not progressive. As an individual reaches middle age, seizures may become milder and less frequent.

Diagnosis/testing.

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.

Management.

Treatment of manifestations: Many anti-seizure medications (ASM) may be effective. Carbamazepine is associated with remission in about 70% of individuals, often in relatively low doses. 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. Resistance to ASM is present in about 30% of affected individuals and typically requires a trial of all appropriate ASM. Adjunctive fenofibrate therapy or vagal nerve stimulation may be considered in individuals resistant to standard ASM.

Surveillance: Reevaluation of EEGs at regular intervals to monitor disease progression, as well as assessment for changes in seizure semiology, changes in tone, and movement disorders; monitoring of developmental progress and educational needs.

Evaluation of relatives at risk: A medical history from relatives at risk can identify those with ADSHE so that treatment can be initiated promptly.

Pregnancy management: Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible.

Genetic counseling.

ADSHE, by definition, is inherited in an autosomal dominant manner. Most individuals diagnosed with ADSHE have an affected parent. 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%. If the ADSHE-related pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

Autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) should be suspected in individuals with the following clinical and neuroimaging findings, EEG findings, and family history.

Clinical findings

• Clusters of brief (<2 minutes) motor seizures during sleep that are often stereotyped with abrupt onset and offset. Seizures may include the following:
  • Nightmares
  • Verbalizations
  • Sudden limb movements
• Preserved intellect, although reduced intellect, cognitive deficits, or psychiatric comorbidities may occur
• Normal clinical neurologic examination

Note: The clinical features of ADSHE are indistinguishable from those of nonfamilial SHE (i.e., SHE diagnosed in an individual with a negative family history), the causes of which are unknown but may include de novo variants of relevant genes [Hayman et al 1997, Tenchini et al 1999, Steinlein et al 2000, Tinuper et al 2016].

EEG findings

• Interictal EEG may be normal or show infrequent epileptiform discharges.
• Ictal scalp EEG may be normal or obscured by movement artifact.
• Intracranial recordings demonstrate that ictal discharge may arise from various frontal as well as extrafrontal areas.

Neuroimaging findings

• Usually normal in individuals with ADSHE
• Focal cortical dysplasia may be present in some individuals with drug-resistant SHE, especially in individuals with pathogenic variants in GATOR complex genes (e.g., DEPDC5, NPRL2, NRPL3).

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

A clinical diagnosis of ADSHE is established in a proband based on the presence of clinical features, EEG findings and family history detailed in Suggestive Findings. A molecular diagnosis of ADSHE is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in in one of the genes listed in Table 1. A pathogenic variant is identified in 19% of individuals with a family history of SHE and 7% of individuals with a negative family history [Licchetta et al 2020].

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous variant of uncertain significance in any of the genes in Table 1 does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the clinical findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other epilepsy phenotypes are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) is characterized by clusters of nocturnal motor seizures with a range of manifestations.

Sleep-related seizures. History may be obtained from the affected individual and witnesses, supplemented if necessary by video EEG monitoring.

Seizures may occur during any stage of sleep, although typically they cluster in non-REM (NREM) sleep, most commonly in stage 2 sleep [Picard & Scheffer 2012]. The affected individual often goes back to sleep rapidly after a seizure, only to be awakened by another event.

Seizures in ADSHE are often stereotyped and brief (<2 minutes); they vary from simple arousals from sleep to dramatic hyperkinetic events with tonic or dystonic features. Subtle and stereotypic motor seizures are accompanied by abrupt recurrent arousals from NREM sleep ("paroxysmal arousals"). The hyperkinetic manifestations may appear bizarre, sometimes with ambulation, bicycling, and a wide range of movements including flinging, throwing the arms, jumping, and pelvic thrusting. Seizures may have greater complexities ("epileptic wandering"). Reported seizure frequency ranges from one to 20 attacks each night, with a mean of 20 seizures per month; about 60% of affected individuals reported more than 15 seizures per month.

Retained awareness during seizures is common and may cause affected individuals to fear falling asleep. Autonomic signs such as tachycardia, tachypnea, and irregular respiratory rhythm are also seen. Focal aware sensory or cognitive seizures, for example, or a sense of difficulty breathing and hyperventilation may precede the motor signs. Focal seizures evolving to bilateral tonic-clonic seizures can also occur.

Some individuals experience an aura preceding the seizure during sleep and are aware of the onset of a seizure. Auras may be nonspecific or may consist of numbness in one limb, fear, a shiver, vertigo, or a feeling of falling or being pushed.

Note: A minority of individuals experience daytime seizures, typically during a period of poor seizure control. Some of the reported seizures are paroxysmal dystonia similar to those during sleep, and others are generalized tonic-clonic seizures, generalized atonic seizures, and focal impaired awareness seizures.

EEG findings

• Ictal EEG recordings may not show definitive ictal patterns, or ictal patterns may be obscured by movement artifact. If present, ictal rhythms may show evolving sharp waves or a spike-and-wave pattern, rhythmic slow activity, or diffuse flattening [Riney et al 2022].
• Interictal waking EEG shows anterior quadrant epileptiform activity in very few affected individuals.
• Interictal sleep EEG shows epileptiform abnormalities over the frontal areas in approximately 50% of affected individuals [Provini et al 1999].

Cognitive findings. Clinical neurologic examination is typically normal and intellect is usually preserved [Oldani et al 1996, Nakken et al 1999]. Several studies have reported that some individuals with SHE have reduced intellect, cognitive deficits, or psychiatric comorbidities [Provini et al 1999, Picard et al 2000, Wood et al 2010, Licchetta et al 2018]. Picard et al [2009] found below-normal general intellect in five (45%) of 11 subjects, with special difficulty in executive tasks, and concluded that cognitive dysfunction is an integral part of ADSHE caused by heterozygous pathogenic variants in the nicotinic acetylcholine receptor (see Phenotype Correlations by Gene).

Licchetta et al [2018] reported 60 individuals with SHE. Of these, 15% had intellectual disability and 53.3% had neuropsychologic deficits. The profile of impairment showed worse verbal IQ, as well as deficits in extrafrontal and selective frontal functions. In addition, individuals with pathogenic variants in ADSHE genes had lower IQ than individuals without pathogenic variants, irrespective of the specific gene.

Familial variation. Within a family, the manifestations of the disorder may vary considerably; individuals with subtle manifestations may not present for medical attention.

A high incidence of true parasomnias has been reported in relatives of individuals with ADSHE [Provini et al 1999]. True parasomnias were distinguished from true seizures based on their age-dependent course, rarity, and nature of the episodes (episodes typically not violent and often not disturbing for the affected individual). They often ended well before the onset of clear-cut seizures.

Onset and prognosis. ADSHE is lifelong but not progressive. Onset ranges from infancy to adulthood. Most affected individuals develop ADSHE in the first two decades of life, typically in adolescence (age 11-14 years), but age of onset ranges from two months to 64 years [Scheffer et al 1995, Oldani et al 1996, Provini et al 1999, Licchetta et al 2017]. As an individual reaches middle age, attacks may become milder and less frequent. Seizures may vary over time. For example, tonic attacks appearing in early childhood may evolve into seizures with dystonic or hyperkinetic components in later childhood.

Phenotype Correlations by Gene

Genotype-Phenotype Correlations

Steinlein et al [2012] suggested that certain pathogenic variants in nicotinic acetylcholine receptor (nAChR) genes (CHRNA2, CHRNA4, CHRNB2) may be associated with an increased risk of unfavorable outcomes.

Individuals with the CHRNA4 pathogenic variant p.Ser284Leu tend to have early onset of epilepsy and less favorable cognitive function. They respond only partially to carbamazepine and are more responsive to zonisamide [Provini et al 1999, Ito et al 2000, Combi et al 2004].

The CHRNB2 pathogenic variant p.Ile312Met was associated with clinically relevant deficits in cognitive function. Affected members from two unrelated families with the variant show normal or low-average intellect with moderate-to-significant verbal memory deficits [Bertrand et al 2005, Cho et al 2008].

Marked intrafamilial variation in severity is seen in ADSHE; the reasons for this are not well understood.

Penetrance

The penetrance of ADSHE is estimated to be 70%. KCNT1-related ADSHE demonstrates complete penetrance compared to 60%-80% in nAChR-related ADSHE.

Nomenclature

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is now referred to as autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) [Tinuper et al 2016, Riney et al 2022].

The term "nocturnal" implies a chronobiological pattern of seizure occurrence, whereas occurrence in sleep (rather than at night) is the most important characteristic of the epilepsy in ADSHE. The characteristic seizures that consist of hypermotor manifestations can arise from other cerebral regions in addition to the frontal lobe [Tinuper et al 2016]. The ILAE task force notes that "hyperkinetic" rather than "hypermotor" is the currently accepted term for the focal motor seizures with vigorous movements that can be seen in this syndrome [Riney et al 2022].

Prevalence

The number of families with ADSHE reported to date exceeds 100 [Picard & Brodtkorb 2007]. The estimated prevalence of SHE in the adult population is estimated to be 1.8-1.9 in 100,000 [Vignatelli et al 2017].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ADSHE, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 6).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Evaluation of Relatives at Risk

It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment. Evaluations can include one of the following:

• If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
• If the pathogenic variant in the family is not known, a medical history to seek evidence of affected status should be elicited from relatives at risk.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASM may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy during which the medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASM to treat a maternal seizure disorder during pregnancy is typically recommended.

Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

By definition, autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) is inherited in an autosomal dominant manner.

PRIMA1-related SHE, which is inherited in an autosomal recessive manner, was reported in only one family [Hildebrand et al 2015].

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with ADSHE have an affected parent.
• A proband may have the disorder as the result of a de novo ADSHE-related pathogenic variant.
• Recommendations for the evaluation of parents of a child with SHE and no known family history of SHE include:
  • A detailed clinical and family history;
  • Molecular genetic testing (if a molecular diagnosis has been established in the proband).
• If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with ADSHE may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluations of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the ADSHE-related pathogenic variant identified in the proband).

Sibs of a proband. The risk to sibs of a proband depends on the clinical and genetic status of the parents:

• If one parent has phenotypic features of ADSHE and/or is known to have an ADSHE-related pathogenic variant, the risk to each sib of inheriting the pathogenic variant is 50%. The chance that the sib will manifest ADSHE is (50% x 70% =) 35%, assuming an estimated penetrance of 70%. (Note: KCNT1-related ADSHE demonstrates complete penetrance.)
  Within a family, the manifestations of ADSHE in affected individuals may vary considerably.
• If the proband has a known ADSHE-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband

• 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%.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected with ADSHE or has an ADSHE-related pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Other genetic counseling issues. Individuals may not be aware of the significance of their attacks; in some families, individuals may be reluctant to reveal their symptoms [Picard & Scheffer 2012].

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Discussion of the risks and benefits of using a given anti-seizure medication during pregnancy should ideally take place before pregnancy (see Pregnancy Management).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

If the ADSHE-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Note: Because ADSHE is associated with intrafamilial clinical variability and reduced penetrance, the prenatal identification of an ADSHE-related pathogenic variant cannot be used to reliably predict future clinical manifestations.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Pathogenic variants in (1) genes encoding subunits of the neuronal nicotinic acetylcholine receptor (nAChR) (CHRNA4, CHRNB2, CHRNA2); (2) genes encoding components of GATOR1 (DEPDC5, NPRL2, NPRL3); and (3) KCNT1, CRH, CABP4, and STX1B are known to cause autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE).

Genes encoding subunits of the neuronal nicotinic acetylcholine receptor (nAChR)

• CHRNA4, encoding the alpha-4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR)
• CHRNB2, encoding the beta-2 subunit of the nAChR
• CHRNA2, encoding the alpha-2 subunit of the nAChR

The nAChR is a heterologous pentamer comprising various combinations of alpha and beta subunits, encoded by CHRNA2-CHRNA7 and CHRNB2-CHRNB4, respectively. The most common configuration in the thalamus and the cortex is (α-4)₂(β-2)₃ subunits (i.e., 2 α-4 and 3 β-2 subunits). The nicotinic acetylcholine receptor is widely distributed in the brain, including the frontal lobes. It is thought that the receptor is a presynaptic modulator of other neurotransmitter systems, including gamma-amino butyric acid (GABA), glutamate, and dopamine, and therefore may have variable effects on excitatory and inhibitory pathways [Kuryatov et al 1997, Bertrand 1999, Buisson et al 1999, Picard et al 1999].

Each nAChR subunit has a conserved N-terminal extracellular domain followed by three conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region [Elliott et al 1996]. The α subunits are characterized by the presence of a pair of cysteine residues (Cys161 and Cys175, NP_000735.1) presumed to function as part of the acetylcholine binding site when the α-4 subunits are complexed as a heterologous pentamer with the β subunits [Figl et al 1998]. CHRNB2 is similar to CHRNA4, but the β subunits encoded by the genes are defined by the lack of paired cysteine residues [Elliott et al 1996]. The second transmembrane domain of the receptor forms the ion channel pore and is the site of most of the pathogenic variants implicated in ADSHE.

Pathogenic variants in CHRNA4, CHRNA2, and CHRNB2 associated with ADSHE occur in highly conserved amino acids and alter the function of the resulting receptors. Functional studies of different pathogenic variants provide conflicting results, although an increase in in vitro acetylcholine sensitivity is typical for known ADSHE-associated pathogenic variants [Kuryatov et al 1997, Steinlein et al 1997, Bertrand et al 1998, Bertrand 1999, De Fusco et al 2000, Phillips et al 2001, di Corcia et al 2005]; thus, the mechanism whereby pathogenic variants cause ADSHE is poorly understood, though increased receptor sensitivity to acetylcholine and gain of function of nAChR may be a contributing mechanism [Aridon et al 2006, Hoda et al 2009]. Carbamazepine and oxcarbazepine produce a noncompetitive channel inhibition in heteromeric neuronal nicotinic receptors including mutated α-2 subunits as well as wild type α-2 subunits, but the different heteromeric nicotinic receptors exhibit distinct pharmacologic properties [Di Resta et al 2010].

Genes encoding components of GATOR1

• DEPDC5, encoding dishevelled, egl-10, and pleckstrin (DEP) domain-containing protein 5
• NPRL2, nitrogen permease regulator-like 2
• NPRL3, nitrogen permease regulator-like 3

DEPDC5 is a component of GATOR1 (GTPase-activating protein [GAP] activity toward Rags complex 1), which negatively regulates mTORC1 (mammalian target of rapamycin complex 1) [Bar-Peled et al 2013] and is expressed ubiquitously in human tissues. The mTOR pathway plays a role in many activities including cell growth, cell proliferation, and metabolism. Most pathogenic variants in DEPDC5 are truncating variants that can be expected to result in nonsense-mediated mRNA degradation. Pathogenic variants in DEPDC5 appear to have a less dramatic effect on mTORC1 signaling but disturb it sufficiently to cause focal epilepsy. Indeed, the phenotype of individuals with DEPDC5 pathogenic variants has expanded with the identification of variants associated with Rolandic epilepsy, unclassified focal epilepsy [Lal et al 2014], and focal epilepsy with brain malformations [Scheffer et al 2014]. NPRL2 and NPLR3 are also components of GATOR1, and pathogenic variants in these genes have been reported in ADSHE and sporadic SHE, as well as other focal epilepsies [Ricos et al 2016].

KCNT1. KCNT1 (previously known as SLACK, SLO2.2, and KCa4.1) encodes a sodium-activated potassium channel [Joiner et al 1998]. The sodium-activated potassium channel encoded by KCNT1 is widely distributed in many regions of the mammalian brain, including the frontal cortex. Its activity contributes to the slow hyperpolarization that follows repetitive firing. The KCNT1 channel contains six putative membrane-spanning regions and an extended C-terminus. The C-terminal cytoplasmic domain contains several motifs believed to interact with a protein network. One of the proteins is fragile X mental retardation protein (FMRP), a potent stimulator of KCNT1 channel activity [Brown et al 2010]. All identified pathogenic variants to date are located within the intracellular region, and most alter amino acids within or immediately adjacent to a nicotinamide adenine dinucleotide (NAD+)-binding site. Mutated channels with pathogenic variants identified in ADSHE produce voltage-activated currents with higher magnitude compared to wild type, leading to gain of function. However, the mechanisms underlying increased neuronal excitability due to a gain of function of KCNT1 channels are not known.

CRH. CRH encodes corticotropin-releasing hormone (CRH), which is widely distributed throughout the central nervous system; it acts as a neurotransmitter or neuromodulator in extrahypothalamic circuits to integrate a multisystem response to stress that controls numerous behaviors including sleep and arousal. Variations in the promoter [Combi et al 2005] or in the pro-sequence region [Sansoni et al 2013] have been reported. The variant identified in one family with ADSHE decreases peptide secretion in vitro [Sansoni et al 2013].

CABP4. CABP4 encodes the calcium-binding protein 4 (CABP4), which belongs to the family of neuronal Ca²⁺-binding proteins and shares structural homology with calmodulin. It has been shown to modulate voltage-dependent Ca²⁺ channels. Pathogenic variants in CABP4 have been identified in individuals with retinal diseases. Missense variant c.464G>A (p.Gly155Asp) was identified in seven affected individuals from a four-generation ADSHE pedigree [Chen et al 2017]. The mechanisms by which pathogenic variants in this gene cause ADSHE are still unclear; the missense variant noted above was associated with reduced expression of CABP4 proteins in vitro [Guo et al 2022].

STX1B. STX1B, encoding syntaxin-1B, is involved in the release of glutamate and GABA and plays a role in the regulation of fast synaptic vesicle exocytosis [Mishima et al 2014]. STX1B pathogenic variants have been identified in individuals with fever-associated epilepsy syndromes [Schubert et al 2014]. In one study, multigene panel testing revealed a likely pathogenic variant c.106-2A>G in an individual with SHE [Peres et al 2018]. Seizures in this individual were accompanied by autonomic features evidenced by significant peri-ictal hypotension. This splice site variant is predicted to abolish the native splicer acceptor site, leading to aberrant splicing resulting in abnormal protein or nonsense-mediated mRNA decay.

Mechanism of disease causation

• CHRNA2, CHRNA4, CHRNB2, KCNT1. Likely gain of function
• DEPDC5, NPRL2, NPRL3, STX1B. Loss of function (haploinsufficiency)
• CRH. The direct role in the pathogenesis of SHE is still unclear, but alteration of hormone levels may be associated.
• CABP4. The direct role in the pathogenesis of SHE is still unclear, but reduction of the expression of CABP4 may be associated.
• STX1B. The direct role in the pathogenesis of SHE is still unclear; loss of function of STX1B leads to impairment of regulation of synaptic vesicle exocytosis, which may cause SHE.

Author History

Judith Adams, MBBS, FRACP; University of Melbourne (2002-2004)
Samuel F Berkovic, MD, FRACP; Epilepsy Research Institute (2002-2010)
Shinichi Hirose, MD, PhD (2010-present)
Hirokazu Kurahashi, MD, PhD (2010-present)
Ingrid E Scheffer, MBBS, FRACP, PhD; Austin and Repatriation Medical Centre (2002-2010)

Revision History

• 23 March 2023 (gm) Comprehensive update posted live
• 15 March 2018 (ma) Comprehensive update posted live
• 19 February 2015 (me) Comprehensive update posted live
• 20 September 2012 (me) Comprehensive update posted live
• 5 April 2010 (me) Comprehensive update posted live
• 24 June 2004 (me) Comprehensive update posted live
• 23 January 2004 (cd) Revision: mutation detection rate
• 16 May 2002 (me) Review posted live
• 22 January 2002 (ja) Original submission

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