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SLC12A5-Related Epilepsy of Infancy with Migrating Focal Seizures

Synonyms: Early-Infantile Epileptic Encephalopathy 34 (EIEE34), SLC12A5-EIMFS

, MBChB and , PhD.

Author Information

Initial Posting: .

Estimated reading time: 19 minutes

Summary

Clinical characteristics.

SLC12A5-related epilepsy of infancy with migrating focal seizures (SLC12A5-EIMFS), reported to date in nine children, is characterized by onset of seizures before age six months and either developmental delay or developmental regression with seizure onset. Of these nine children, six had severe developmental delay with no progress of abilities and three made notable neurodevelopmental progress. Eight had postnatal microcephaly and hypotonia. In most children epilepsy begins as focal motor seizures (typically involving head and eye deviation) that become multifocal and intractable to conventional antiepileptic drugs (AEDs).

Diagnosis/testing.

The diagnosis of SLC12A5-EIMFS is established by identification of biallelic SLC12A5 pathogenic variants on molecular genetic testing.

Management.

Treatment of manifestations: There are no specific treatments for seizures in SLC12A5-EIMFS. In general, seizures in EIMFS are resistant to most AEDs. A ketogenic diet and potassium bromide showed attenuation of seizures in three patients each. A multidisciplinary approach to management of hypotonia, feeding difficulties, respiratory problems, and developmental delay is recommended.

Surveillance: Routine monitoring of: feeding, nutritional status, swallowing, gastroesophageal reflux, aspiration, and respiratory problems; back for scoliosis and hips for dislocation with spine and hip x-rays; effectiveness of seizure control; development including motor skills, speech/language, and general cognitive and vocational skills.

Genetic counseling.

SLC12A5-EIMFS is inherited in an autosomal recessive manner. The parents of a child with SLC12A5-EIMFS are typically heterozygotes (i.e., carriers of one SLC12A5 pathogenic variant). Heterozygous parents of a child with SLC12A5-EIMFS are not at risk of developing EIMFS. When both parents are heterozygotes (carriers) each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SLC12A5 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic diagnosis are possible.

Diagnosis

Since 2010 a description of the characteristic symptoms and findings of epilepsy of infancy with migrating focal seizures (EIMFS) has been included in the classification of epilepsy syndromes by the International League Against Epilepsy. The diagnosis of SLC12A5-EIMFS is established by molecular genetic testing.

Suggestive Findings

SLC12A5-related epilepsy of infancy with migrating focal seizures (SLC12A5-EIMFS) should be considered in children with the following epilepsy and electroencephalogram (EEG) findings and family history.

Epilepsy features

  • Seizure onset before age six months
  • Developmental delay or developmental regression with seizure onset

Seizure type

  • At onset in most children: focal motor seizures that also frequently involve head and eye deviation
  • Multifocal seizures proving intractable to conventional antiepileptic drugs

Epilepsy syndromes. Epilepsy of infancy with migrating focal seizures

EEG findings

  • Interictal multifocal spikes
  • In a single seizure, ictal-independent, unilateral, and migrating involvement of varying cortical areas with clinical-EEG correlation
  • Initial EEG may be normal shortly after seizure onset, but epileptiform abnormalities are usually present within one month after first presentation.
  • Migrating ictal foci may not be seen for several months after presentation.

Family history. Consistent with autosomal recessive inheritance, including parental consanguinity or more than one affected child

Establishing the Diagnosis

The diagnosis of SLC12A5-EIMFS is established in a proband with biallelic SLC12A5 pathogenic variants identified by molecular genetic testing (see Table 1).

Due to the genetic heterogeneity of early-onset epilepsy, use of either a multigene epilepsy panel or comprehensive genomic testing (exome or genome sequencing) is the preferred initial approach [McTague et al 2016]. Note: Single-gene testing (sequence analysis of SLC12A5, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

Testing Options to Consider

An epilepsy multigene panel that includes SLC12A5 and other genes of interest (see Differential Diagnosis) typically provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting identification of pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of SLC12A5-related epilepsy, some epilepsy panels may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another good option. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in SLC12A5-EIMFS

Gene 1Test MethodProportion of Pathogenic Variants 2 Detectable by This Method
SLC12A5Sequence analysis 39/9 (100%) 4
Gene-targeted deletion/duplication analysis 5Unknown (no data available)
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

SLC12A5-related epilepsy of infancy with migrating focal seizures (SLC12A5-EIMFS) is characterized by severe early-onset epileptic encephalopathy, with a distinct electroclinical phenotype that is common to all EIMFS regardless of cause. To date nine children have been reported with SLC12A5-EIMFS [Stödberg et al 2015, Saitsu et al 2016, Saito et al 2017].

Seizures. In the nine children reported, three clinical stages were evident:

  • An early stage with emerging focal seizures. Median age of seizure onset was 1.5 months; mean age 1.8 months (range: 1 day - 4 months).
    • Seizures are characterized by apnea and focal clonic and tonic seizures with prominent head and eye deviation.
    • Subtle seizures with behavioral arrest, apnea, and cyanosis or generalized tonic or tonic-clonic seizures are also seen at onset. All children eventually develop focal motor seizures.
    • Clinically migrating seizures (which affect differing or alternating body parts) are seen in approximately 50% of children.
    • Autonomic features such as facial flushing, salivation, apnea, and cyanosis are common.
  • A second stage with up to 200 seizures per day at the peak of the seizures, usually at a median age of 16 weeks (range: 1-40 weeks). Either focal status epilepticus or frequent clusters of focal seizures are seen.
  • A late stage (age >1-2 years) with a reduction of seizure frequency. Of the four children who had seizure-free periods, two relapsed to frequent recurrent seizures.

Developmental delay was seen in all nine children. Five children experienced developmental regression (i.e., loss of previously acquired skills) at seizure onset.

Severe developmental delay with no progression of skills was seen in six of the nine. In contrast, three of the nine had notable neurodevelopmental progress, either regaining lost skills or acquiring new skills during periods of good seizure control. Two achieved independent ambulation (at ages 2.9 and 4 years) and one spoke single words at age six years.

Other

  • Postnatal (i.e., acquired) microcephaly and hypotonia was noted in eight of the nine children.
  • Of the four for whom feeding information was available, two had feeding difficulties; none had growth failure.
  • One had unilateral pyramidal signs.
  • Hyperkinetic movement disorders, seen in other causes of EIMFS including KCNT1 and SCN2A, have not been reported in SLC12A5-EIMFS [Howell et al 2015, McTague et al 2018].

Outcome. One child with frequent seizures died at age 2.5 years from respiratory infection and cardiac arrest [Stödberg et al 2015]; the others with SLC12A5-EIMFS (ages 3-22 years) are living as of this writing.

Electroencephalogram (EEG). Eight children had ictal EEGs consistent with a diagnosis of EIMFS. Early EEGs were not available for one child; thus, a formal diagnosis could not be made despite a clinical history consistent with EIMFS.

Interictal EEG features included background slowing and multifocal abnormalities.

MRI findings. The following nonspecific MRI features of EIMFS have been observed in SLC12A5-EIMFS:

  • Delayed myelination
  • Thin corpus callosum
  • Cerebral atrophy, either predominantly frontal or global
  • Increased signal in white matter on diffusion-weighted imaging

The following focal abnormalities have been reported in SLC12A5-EIMFS:

  • Unilateral hippocampal sclerosis noted at age four years (n=1) [Saito et al 2017]
  • Cerebellar atrophy and bilateral hippocampal atrophy with increased signal on FLAIR imaging at ages ten and 20 years in the oldest individual imaged to date [Saitsu et al 2016]. It is unclear if these findings represent the typical progression of imaging findings in SLC12A5-EIMFS as all other individuals imaged were age four years or younger.

Magnetic resonance spectroscopy (MRS) in a child age eight months demonstrated reduction in the relative N-acetyl aspartate peak, consistent with delayed maturation of myelin [Stödberg et al 2015].

Genotype-Phenotype Correlations

No clear correlation exists between biallelic SLC12A5 variants and phenotype, which may reflect the limited number of affected individuals reported to date.

Nomenclature

EIMFS is a type of early-infantile epileptic encephalopathy (EIEE); OMIM classifies SLC12A5-related epilepsy as EIEE34.

Terms previously used for EIMFS include the following:

  • Migrating partial seizures of infancy (MPSI)
  • Malignant migrating partial seizures of infancy (MMPSI)
  • Migrating focal seizures of infancy (MFSI)

SLC12A5-related epilepsy includes EIMFS and EIMFS-like severe early-onset epileptic encephalopathy (EIEE with some features of EIMFS but not fulfilling all criteria; e.g., when EEG is not available).

Prevalence

To date, nine probands with SLC12A5-related epilepsy have been reported.

The clinical syndrome epilepsy of infancy with migrating focal seizures (EIMFS) of all causes is itself rare. Prevalence of EIMFS was estimated at 0.11 per 100,000 children in the UK (using data that were not from a population-based epidemiologic study) [McTague et al 2013].

Differential Diagnosis

Since first described by Coppola et al [1995], epilepsy of infancy with migrating focal seizures (EIMFS) has been reported in over 170 individuals. EIMFS is genetically heterogeneous (Table 2). EIMFS can be isolated or have multisystem involvement; both autosomal dominant and recessive inheritance are observed.

Table 2.

Other Disorders to Consider in the Differential Diagnosis of SLC12A5-EIMFS

DisorderGene 1MOIComments
Isolated EIMFS
EIEE43
(OMIM 617113)
GABRB3 2AD1 set of monozygotic twins
EIEE14
(OMIM 614959)
KCNT1AD 3Causes 30%-50% of EIMFS 4, 5, 6
EIEE12
(OMIM 613722)
PLCB1 7AR 81 individual 7
Progressive microcephaly
w/seizures & cerebral
& cerebellar atrophy
(OMIM 615760)
QARSAR 82 individuals 9
SMC1A-related EIMFSSMC1A 10XL1 female infant
EIEE6SCN1A 11, 12, 13, 14AD 33 individuals 11, 12, 13, 14
EIEE11
(OMIM 613721)
SCN2A 15, 16AD 3Severe movement disorder 4; otherwise indistinguishable from other causes of EIMFS
EIEE13SCN8A 17AD 31 individual 17
EIEE3
(OMIM 609304)
SLC25A22 18AR 82 individuals 18
EIEE16TBC1D24 19, 20AR 83 families 19, 20
EIMFS with multisystem abnormalities
ALG3-CDG
(CDG-Id21
ALG 22AR
  • Abnormalities: gastrointestinal problems, coagulopathy, dysmorphic facial features, spastic quadriparesis
  • Transferrin isoelectric focusing testing consistent w/CDG type I
  • On brain MRI: cerebellar atrophy in all; brain stem atrophy in 3/4
  • Note: Extensive metabolic investigation in EIMFS is usually unrevealing.
ALG1-CDG
(CDG-Ik21
ALG1 22
RFT1-CDG
(CDG-In21
RFT1 22

Adapted from "Supplementary Table 1: Genes Reported in Migrating Partial Seizures of Infancy (MPSI)" [Stödberg et al 2015]

AD = autosomal dominant; AR = autosomal recessive; CDG = congenital disorder of glycosylation; EIEE = early-infantile epileptic encephalopathy; EIMFS = epilepsy of infancy with migrating focal seizures; MOI = mode of inheritance; XL = X-linked

1.

Genes are in alphabetic order.

2.
3.

Typically de novo

4.
5.
6.
7.
8.

Autosomal recessive inheritance of EIMFS is often described in consanguineous families or families with more than one affected individual.

9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.

Other early-infantile epileptic encephalopathies. A large number of genes have been implicated in the broader phenotype of early-onset epilepsy with developmental delay. See Early Infantile Epileptic Encephalopathy, OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SLC12A5-related epilepsy of infancy with migrating focal seizures (SLC12A5-EIMFS), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with SLC12A5-EIMFS

Organ/ConcernEvaluationComment
ConstitutionalAssess for evidence of failure to thrive.
EyesOphthalmologic evaluation incl assessment of vision
ENT/MouthAssess hearing.
Gastrointestinal/
Feeding
Assess swallowing, gastroesophageal reflux, feeding, & nutritional status.Incl assessment by a speech & language therapist
RespiratoryAssess respiratory status for evidence of ↑ risk of respiratory infections & aspiration.Preventive measures may be needed (e.g., flu vaccination & prophylactic antibiotics in winter).
NeurologicNeurologic evaluationIncl EEG & brain MRI
MusculoskeletalAssessment of tone by pediatric rehabilitation specialist &/or physical therapist
DevelopmentDevelopmental assessmentIncl evaluation of motor skills, speech/language, general cognitive, & vocational skills
Miscellaneous/
Other
Consultation w/clinical geneticist &/or genetic counselor

Treatment of Manifestations

Seizures. There are no specific treatments for seizures in SLC12A5-EIMFS. Seizures in EIMFS are generally resistant to most antiepileptic drugs.

Periods free of seizures or with reduced seizure frequency have been achieved with a ketogenic diet or potassium bromides [Fasulo et al 2012, Ünver et al 2013, Caraballo et al 2014, Caraballo et al 2015] including in children with SLC12A5-EIMFS [Stödberg et al 2015, Saitsu et al 2016, Saito et al 2017].

Seizure reduction has also been reported with:

Epileptic apneas are reported to respond to acetazolamide [Irahara et al 2011].

Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

Hypotonia. Manage postural problems with appropriate seating support.

Feeding. Consider gastrostomy insertion and feeding if swallowing is impaired.

Respiratory. Children may be susceptible to respiratory infections and aspiration pneumonia if swallowing is impaired. Consider influenza vaccine, prophylactic antibiotics, and chest physiotherapy as appropriate.

Developmental Disability / Intellectual Disability Educational Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.

Ages 5-21 years

  • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
  • Discussion of transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life. Some issues to consider:

  • Private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
  • In the US:
    • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
    • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility.
  • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy, typically from an occupational or speech therapist is recommended for affected individuals who have difficulty feeding due to poor oral motor control.

Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.

Social/Behavioral Difficulties

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is individualized therapy targeted to each child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavioral management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.

Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Surveillance

Routine monitoring of:

  • Feeding, nutritional status, swallowing abilities, gastroesophageal reflux, risk of aspiration pneumonia / respiratory infection
  • Postural problems (resulting from such complications as scoliosis and hip abnormalities) with regular spine and hip x-rays
  • Effectiveness of seizure control
  • Development including motor skills, speech/language, and general cognitive and vocational skills

Evaluation of Relatives at Risk

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

Therapies Under Investigation

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

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

SLC12A5-related epilepsy of infancy with migrating focal seizures (SLC12A5-EIMFS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • Heterozygous parents of a child with SLC12A5-EIMFS are not at risk of developing EIMFS. (SLC12A5 pathogenic variants associated with EIMFS have not been associated with epilepsy in the heterozygous state; see Genetically Related Disorders).

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) of an EIMFS-related SLC12A5 pathogenic variant are not at risk of developing EIMFS.

Offspring of a proband

  • Each child of an individual with SLC12A5-EIMFS has a 50% chance of inheriting the SLC12A5 pathogenic variant.
  • To date, individuals with biallelic SLC12A5-EIMFS are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an SLC12A5 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the SLC12A5 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals and young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the SLC12A5 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Epilepsy Society (AES)
  • Canadian Epilepsy Alliance
    Canada
    Phone: 1-866-EPILEPSY (1-866-374-5377)
  • Contact a Family
    209-211 City Road
    London EC1V 1JN
    United Kingdom
    Phone: 0808 808 3555 (toll free); 020 7608 8700
    Email: helpline@cafamily.org.uk
  • Epilepsy Action
    New Anstey House
    Gate Way Drive
    Yeadon Leeds LS19 7XY
    United Kingdom
    Phone: 0808 800 5050
    Email: epilepsy@epilepsy.org.uk
  • Epilepsy Canada
    Canada
    Phone: 877-734-0873
    Email: epilepsy@epilepsy.ca
  • Epilepsy Foundation
    8301 Professional Place East
    Suite 200
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Email: ContactUs@efa.org
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

SLC12A5-Related Epilepsy of Infancy with Migrating Focal Seizures: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for SLC12A5-Related Epilepsy of Infancy with Migrating Focal Seizures (View All in OMIM)

606726SOLUTE CARRIER FAMILY 12 (POTASSIUM/CHLORIDE TRANSPORTER), MEMBER 5; SLC12A5
616645EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 34; EIEE34

Molecular Pathogenesis

SLC12A5 encodes KCC2, the neuronal-specific potassium chloride co-transporter which is a member of the family of cation chloride co-transporters [Payne et al 1996]. KCC2 is mainly expressed in the central nervous system [Chamma et al 2012].

KCC2 is the major extruder of chloride in neurons and is responsible for generating neuronal chloride gradients, which determine the magnitude and polarity of GABA-mediated currents. Thus, when GABA, which has an important role in neuronal inhibition, binds to the GABA-A receptor, the low intraneuronal chloride allows influx of chloride and subsequent hyperpolarization, contributing to neuronal inhibition. KCC2 has been implicated as the major factor in the developmental GABAA shift from excitation to inhibition seen in early postnatal life in animal models and is vital to normal brain development [Chamma et al 2012].

Gene structure. SLC12A5 has two major neuron-specific isoforms, KCC2a (corresponding to transcript variant 1, NM_001134771) and the shorter KCC2b (transcript variant 2, NM_020708) [Uvarov et al 2007, 2009], both containing 26 exons. KCC2a differs from KCC2b by 40 unique amino acids in the N terminus encoded by alternate exon 1a.

Pathogenic variants. Pathogenic variants identified to date are mostly missense variants; however, a few splice site and in-frame variants have been reported.

Table 4.

Selected SLC12A5 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.279+1G>Cp.Glu50_Gln93delNM_020708​.4
NP​_065759
c.572C>Tp.Arg191Val
c.863T>A
(c.932T>A) 1
p.Leu288His
(p.Leu311His) 1
c.953G>Cp.Trp318Ser
c.967T>Cp.Ser323Pro
c.1127C>T
(c.1196C>T) 1
p.Ser376Leu
(p.Ser399Leu) 1
c.1208T>C
(c.1277T>C) 1
p.Leu403Pro
(p.Leu426Pro) 1
c.1243A>Gp.Met415Val
c.1583G>A
(c.1652G>A) 1
p.Gly528Asp
(p.Gly551Asp) 1
c.2242_2244delp.Ser748del
c.2570G>T
(c.2639G>T) 1
p.Arg857Leu
(p.Arg880Leu) 1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation as published on reference sequence position NM_001134771​.1, NP_001128243​.1

Normal gene product. SLC12A5 encodes KCC2, the neuronal-specific potassium chloride co-transporter, a member of the family of cation chloride co-transporters [Payne et al 1996]. KCC2 is mainly expressed in the central nervous system [Chamma et al 2012]. The two major SLC12A5 transcripts KCC2a (corresponding to NM_001134771) and KCC2b (NM_020708) comprise 26 exons and are translated into 1,139 and 1,116 amino acids, respectively.

KCC2 also plays a role at excitatory synapses and in dendritic spine formation [Chamma et al 2012, Puskarjov et al 2014]. Further evidence for the role of KCC2 in epileptogenesis comes from animal models of acquired epilepsy in which reduced KCC2 expression is seen following status epilepticus, and from human studies in which tumor-associated epilepsy is associated with alterations in KCC2 expression [Pallud et al 2014, Moore et al 2017].

Abnormal gene product. SLC12A5 pathogenic variants have been shown in several studies to be associated with a loss of transporter function in cellular models [Stödberg et al 2015, Saitsu et al 2016].

The variants p.Arg952His and p.Arg1049Cys have also been studied for pathogenic effects. (See Genetically Related Disorders.)

The p.Arg952His variant was shown to have reduced cell surface expression and reduced chloride extrusion capacity compared to wild type KCC2 [Kahle et al 2014, Puskarjov et al 2014]. In addition, p.Arg952His led to reduced dendritic spine formation in vitro, which could be rescued by overexpression of wild type KCC2.

The p.Arg1049Cys variant was shown to have decreased chloride extrusion ability [Kahle et al 2014].

Both p.Arg952His and p.Arg1049Cys were also shown to have decreased phosphorylation at serine 940, a key site for the regulation of KCC2 function [Kahle et al 2014].

Complete knockout of SLC12A5 in animal models leads to neonatal death due to respiratory failure, and knockout of the KCC2b isoform only leads to spontaneous seizures and early postnatal mortality [Hübner et al 2001, Woo et al 2002, Tornberg et al 2005].

References

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Chapter Notes

Author Notes

Dr Amy McTague is a consultant pediatric neurologist and a NIHR Great Ormond Street BRC Catalyst Fellow who has recently completed a PhD investigating the molecular genetics of EIMFS in the Kurian group at the UCL Great Ormond Street Institute of Child Health.

Dr Manju Kurian is a NIHR Research Professor and group leader in the Developmental Neurosciences programme at the UCL Great Ormond Street Institute of Child Health and a consultant pediatric neurologist at Great Ormond Street Hospital.

Revision History

  • 14 February 2019 (bp) Review posted live
  • 13 November 2017 (am) Original submission
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