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Infantile Epilepsy

 

Epilepsy is a medical condition that produces seizures affecting a variety of mental and physical functions. It’s also called a seizure disorder. When a person has two or more unprovoked seizures, they are considered to have epilepsy. A seizure happens when a brief, strong surge of electrical activity affects part or all of the brain. Because epilepsy is caused by abnormal activity in brain cells, seizures can affect any process your brain coordinates. A seizure can produce symptoms such as: convulsions, loss of consciousness, blank staring, lip smacking, or jerking movements of arms and legs.

Benign Familial Neonatal Seizures (BFNS) are rare, monogenic, autosomal-dominant, benign familial epilepsy syndrome. It is characterized by unprovoked and brief cluster of focal tonic-clonic convulsions occurring within the first days of life and frequently flowing into status epilepticus. There are no specific EEG traits as most results are normal. Seizures may disappear spontaneously within 2 months of life. However, 10-15% of children with BFNS develop seizures later in life but age of onset varies as well as duration. When these seizures occur they are mainly generalized tonic or tonic-clonic and the EEG may be characterized by centro-temporal spikes and sharp waves or benign epilepsy with centrotemporal spikes.

Early-infantile epileptic encephalopathy (EIEE) is characterized by tonic spasms occurring with or without clustering, seizure intractability. Most EEG results depict a characteristic interictal bursts suppression that is persistently observed in both waking and sleeping states. The causes of EIEE are heterogeneous. Brain malformations, neuronal migration disorders, and metabolic disorders have been found as causes of EIEE.

Epilepsy Idiopathic generalized (EIG) is a group of epileptic disorders that are believed to have a strong underlying genetic basis. Patients with an EIG subtype are typically otherwise normal and have no anatomical brain abnormalities. Patients often have a family history of epilepsy and seem to have a genetically predisposed risk of attack. EIG tends to manifest itself between early childhood and adolescence although it can be eventually diagnosed later.

Febrile convulsions (FEB) or seizures are the most common seizures of early childhood. The average age of onset is 18 to 22 months. Elevated temperature is the hallmark of febrile convulsions. The initial step in evaluation will be to identify the source of the fever. The most common febrile seizures are tonic-clonic or tonic, but any seizure type is possible. Symptoms that might occur as fever seizures: crying, loss of consciousness, muscle rigidity, staring, loss of muscle tone, rhythmic jerking movements involving both sides or one side. Three to 4 percent of all children experience at least one febrile seizure. Thirty to 40 percent of those who have these seizures will have a recurrence; however, the vast majority outgrows febrile convulsions by the age of 5 and develops normally. Relatively few will go on to develop epilepsy. Only 9 percent of children have three or more febrile convulsions. The risk of seizure recurrence is highest under the following conditions: first seizure occurs before the age of 18 months, seizure occurs within the first hours of an illness, fever is only moderate, history of febrile seizures in immediate family. Factors that increase the risk for later development of epilepsy are : febrile seizure lasting more than 15 minutes, partial or focal febrile seizure, two or more febrile seizures in 24 hours, Cerebral palsy, mental retardation or other neurological disorder, family history of epilepsy.

Genetic Epilepsy with Febrile seizure plus (GEFS+) is a familial autosomal-dominant epileptic syndrome. Patients may suffer from febrile seizures past the age of 6. Seizures can be afebrile myoclonic, absence, atonic, or partial seizures may appear. Febrile seizures are the milder form of GEFS+ whereas severe Myoclonic Epilepsy of Infancy (SMEI) is the most severe form.

Glucose transporter 1 (or GLUT1) is a protein that in humans is encoded by the SLC2A1 gene. GLUT1 facilitates the transport of glucose across the plasma membranes of human cells. Mutations in the SLC2A1 gene are responsible for GLUT1 deficiency or De Vivo disease, which is a rare autosomal dominant disorder. This disease is characterized by a low cerebrospinal fluid glucose concentration which results from impaired glucose transport across the blood–brain barrier. Symptoms may appear as infantile seizures, low glucose level in cerebrospinal fluid, ataxia, sudden confusion or lethargy, sleep disturbance, impaired speech and/or language development.

We provide testing for the mutations listed below that are believed to be related to many of the different types of epilepsy.

Type OMIM Gene Description

EIEE6

FEB3A

GEFS+

607208

604403

182389

SCN1A/ sodium channel, voltage-gated, type I, alpha subunit SCN1A is currently the most clinically relevant, with the largest number of epilepsy related mutations characterized to date. Mutations have been found in patients with generalized epilepsy with febrile seizures plus (GEFS+) and with Dravet syndrome (EIEE6).

EIG12

GLUT1

614847

138140

SLC2A1/ solute carrier family 2 (facilitated glucose transporter), member 1

SLC2A1 is the only gene in which mutations are known to cause glucose transporter type I deficiency syndrome (Glut1-DS). Mutations also linked to EIG12.

EIEE 2 300672 CDKL5/cyclin-dependent kinase-like 5

Mutations in the gene linked to EIEE2 also known as X-linked Infantile Spasm Syndrome (ISSX).

EIEE4

612164

STXBP1/syntaxin binding protein 1

Early Infantile Epileptic Encephalopathy-4 (EIEE4) is caused by a heterozygous mutation in the STXBP1 gene on chromosome 9q34.1. Mutation observed in less than 10% of patients with EIEE.

BFNS1

EIEE7

121200

613720

KCNQ2/ potassium channel, voltage-gated, subfamily Q, member 2

Mutations in this gene have been related to Benign Familial Neonatal Seizures and KCNQ2-Related Early Infantile Epileptic Encephalopathy (KCNQ2-EIEE7). Approximately  70% of people with BFNS have a mutation in either the KCNQ2 or KCNQ3 genes.

BFNS2

121201

KCNQ3/ potassium channel, voltage-gated, subfamily Q, member 3

Benign Familial Neonatal Seizures (BFNS). Approximately  70% of people with BFNS have a mutation in either the KCNQ2 or KCNQ3 genes.

BFNS3

EIEE11

607745

613721

SCN2A/ sodium channel, voltage-gated, type II, alpha subunit

Mutations in this gene have been connected to patients with EIEE11 and BFNS3.

Purpose: Confirmation of Clinical Diagnosis/Carrier Testing

Methodology: Next-Generation Sequencing

Test Requisition: Sequencing Requisition

Specimen Requirements: 2-5 mL Blood- Lavender Top Tube

Panel CPT Code: Cost: $3500.00 (Oklahoma Medicaid requires preauthorization for this test)

Provider can also select specific genes to be analyzed, this will affect pricing and CPT codes used for insurance filing.

Turn-around-time: 5-6 weeks

Shipping Information

References

1. Jr, N.; Douglas, R. (2005). "Idiopathic Generalized Epilepsies Recognized by the International League Against Epilepsy". Epilepsia 46: 48.

2. Nair, PP; Kalita, J, Misra, UK (2011). "Status epilepticus: why, what, and how". Journal of postgraduate medicine 57 (3): 242–52.

3. Parisi, P et al (2011). “Electro-clinical Syndromes” with onset in Paediatric Age: the highlights of the clinical-EEG, genetic and therapeutic advances". Italian Journal of Pediatrics 37:58.

4. Brockmann K, Wang D, Korenke CG, von Moers A, Ho YY, Pascual JM, Kuang K, Yang H, Ma L, Kranz-Eble P, Fischbarg J, Hanefeld F, De Vivo DC (2001). "Autosomal dominant glut-1 deficiency syndrome and familial epilepsy". Ann Neurol. 50(4):476-85.

5. De Vivo DC, Leary L, Wang D (2002). "Glucose transporter 1 deficiency syndrome and other glycolytic defects". J Child Neurol. 17 Suppl 3:3S15-23; discussion 3S24-5. Review.

6. Kato M (2006). "A new paradigm for West syndrome based on molecular and cell biology". Epilepsy Res. 70 Suppl 1: S87–95.

7. Bellini G, Miceli F, Soldovieri MV, et al (2010). "KCNQ2-Related Disorders". In: GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle.

8. Castaldo P, del Giudice EM, Coppola G, Pascotto A, Annunziato L, Taglialatela M (2002). "Benign familial neonatal convulsions caused by altered gating of KCNQ2/KCNQ3 potassium channels". J Neurosci. 22(2):RC199

9. John C. Mulley, Ingrid E. Scheffer, Steven Petrou, Leanne M. Dibbens, Samuel F. Berkovic, and Louise A. Harkin (2005). "SCN1A Mutations and Epilepsy". HUMAN MUTATION 25:535^542.

10. Mu, W, et al. "Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing". J Mol Diagn. 2016. 18(6):923-932.

 



 

 

 


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Genetics Laboratory
University of Oklahoma Health Sciences Center
1122 NE 13 Street, Suite 1400, Oklahoma City, OK 73104
Phone: (405) 271-3589 |Fax: (405) 271-7117 Email: Dr. Shibo Li

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