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Generalized epilepsy with febrile seizures plus, type 2(GEFSP2)

MedGen UID:
Concept ID:
Disease or Syndrome
Synonyms: GEFS+, TYPE 2; GEFSP2; SCN1A- Related Generalized Epilepsy with Febrile Seizures Plus
Gene (location): SCN1A (2q24.3)
Monarch Initiative: MONDO:0011461
OMIM®: 604403

Disease characteristics

Excerpted from the GeneReview: SCN1A Seizure Disorders
SCN1A seizure disorders encompass a spectrum that ranges from simple febrile seizures and generalized epilepsy with febrile seizures plus (GEFS+) at the mild end to Dravet syndrome and intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) at the severe end. Phenotypes with intractable seizures including Dravet syndrome are often associated with cognitive decline. Less commonly observed phenotypes include myoclonic astatic epilepsy (MAE), Lennox-Gastaut syndrome, infantile spasms, epilepsy with focal seizures, and vaccine-related encephalopathy and seizures. The phenotype of SCN1A seizure disorders can vary even within the same family. [from GeneReviews]
Ian O Miller  |  Marcio A Sotero de Menezes   view full author information

Additional descriptions

Generalized epilepsy with febrile seizures plus, type 2 (GEFSP2) is an autosomal dominant neurologic disorder characterized by the onset of seizures associated with fever in the first months or years of life. Affected individuals continue to have various types of febrile and afebrile seizures later in life, including generalized tonic-clonic seizures (GTCS). Some patients may have offset of seizures in the first or second decades; rare patients may have mildly impaired intellectual development. In contrast, patients with isolated febrile seizures (FEB3A) have onset between ages 6 months and 4 years, show spontaneous remission by age 6 years, and have normal cognition. Mutations in the SCN1A gene thus cause a spectrum of seizure disorders, ranging from early-onset isolated febrile seizures to generalized epilepsy with febrile seizures plus, type 2, which represents a more severe phenotype (summary by Scheffer and Berkovic, 1997 and Mantegazza et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of GEFS+, see 604233. For a phenotypic description and a discussion of genetic heterogeneity of familial febrile seizures, see 121210.  http://www.omim.org/entry/604403
From MedlinePlus Genetics
Family members with GEFS+ may have different combinations of febrile seizures and epilepsy. For example, one affected family member may have only febrile seizures, while another also has myoclonic epilepsy. While GEFS+ is usually diagnosed in families, it can occur in individuals with no history of the condition in their family.

Some people with GEFS+ have seizure disorders of intermediate severity that may not fit into the classical diagnosis of simple febrile seizures, FS+, or Dravet syndrome.

A condition called Dravet syndrome (also known as severe myoclonic epilepsy of infancy or SMEI) is often considered part of the GEFS+ spectrum and is the most severe disorder in this group. Affected infants typically have prolonged seizures lasting several minutes (status epilepticus), which are triggered by fever. Other seizure types, including afebrile seizures, begin in early childhood. These types can include myoclonic or absence seizures. In Dravet syndrome, these seizures are difficult to control with medication, and they can worsen over time. A decline in brain function is also common in Dravet syndrome. Affected individuals usually develop normally in the first year of life, but then development stalls, and some affected children lose already-acquired skills (developmental regression). Many people with Dravet syndrome have difficulty coordinating movements (ataxia) and intellectual disability.

The most common and mildest feature of the GEFS+ spectrum is simple febrile seizures, which begin in infancy and usually stop by age 5. When the febrile seizures continue after age 5 or other types of seizure develop, the condition is called febrile seizures plus (FS+). Seizures in FS+ usually end in early adolescence.

Genetic epilepsy with febrile seizures plus (GEFS+) is a spectrum of seizure disorders of varying severity. GEFS+ is usually diagnosed in families whose members have a combination of febrile seizures, which are triggered by a high fever, and recurrent seizures (epilepsy) of other types, including seizures that are not related to fevers (afebrile seizures). The additional seizure types usually involve both sides of the brain (generalized seizures); however, seizures that involve only one side of the brain (partial seizures) occur in some affected individuals. The most common types of seizure in people with GEFS+ include myoclonic seizures, which cause involuntary muscle twitches; atonic seizures, which involve sudden episodes of weak muscle tone; and absence seizures, which cause loss of consciousness for short periods that appear as staring spells.  https://medlineplus.gov/genetics/condition/genetic-epilepsy-with-febrile-seizures-plus

Clinical features

From HPO
Febrile seizure (within the age range of 3 months to 6 years)
MedGen UID:
Concept ID:
Disease or Syndrome
A febrile seizure is any type of seizure (most often a generalized tonic-clonic seizure) occurring with fever (at least 38 degrees Celsius) but in the absence of central nervous system infection, severe metabolic disturbance or other alternative precipitant in children between the ages of 3 months and 6 years.
Atonic seizure
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Concept ID:
Disease or Syndrome
Atonic seizure is a type of motor seizure characterized by a sudden loss or diminution of muscle tone without apparent preceding myoclonic or tonic event lasting about 1 to 2 seconds, involving head, trunk, jaw, or limb musculature.
Bilateral tonic-clonic seizure
MedGen UID:
Concept ID:
Sign or Symptom
A bilateral tonic-clonic seizure is a seizure defined by a tonic (bilateral increased tone, lasting seconds to minutes) and then a clonic (bilateral sustained rhythmic jerking) phase.
Focal-onset seizure
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Concept ID:
Disease or Syndrome
A focal-onset seizure is a type of seizure originating within networks limited to one hemisphere. They may be discretely localized or more widely distributed, and may originate in subcortical structures.
Generalized tonic seizure
MedGen UID:
Concept ID:
Disease or Syndrome
A generalized tonic seizure is a type of generalized motor seizure characterized by bilateral limb stiffening or elevation, often with neck stiffening without a subsequent clonic phase. The tonic activity can be a sustained abnormal posture, either in extension or flexion, sometimes accompanied by tremor of the extremities.
Focal hemiclonic seizure
MedGen UID:
Concept ID:
Disease or Syndrome
A type of focal clonic seizure characterized by sustained rhythmic jerking rapidly involves one side of the body at seizure onset.
Generalized myoclonic seizure
MedGen UID:
Concept ID:
Disease or Syndrome
A generalized myoclonic seizure is a type of generalized motor seizure characterized by bilateral, sudden, brief (<100 ms) involuntary single or multiple contraction of muscles or muscle groups of variable topography (axial, proximal limb, distal). Myoclonus is less regularly repetitive and less sustained than is clonus.
Generalized non-motor (absence) seizure
MedGen UID:
Concept ID:
Disease or Syndrome
A generalized non-motor (absence) seizure is a type of a type of dialeptic seizure that is of electrographically generalized onset. It is a generalized seizure characterized by an interruption of activities, a blank stare, and usually the person will be unresponsive when spoken to. Any ictal motor phenomena are minor in comparison to these non-motor features.

Recent clinical studies


Sun L, Gilligan J, Staber C, Schutte RJ, Nguyen V, O'Dowd DK, Reenan R
J Neurosci 2012 Oct 10;32(41):14145-55. doi: 10.1523/JNEUROSCI.2932-12.2012. PMID: 23055484Free PMC Article

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