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 anti-seizure medication (ASM).

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 ASM. 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 testing are possible.

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 anti-seizure medication

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 (or likely pathogenic) variants identified by molecular genetic testing (see Table 1).

Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" 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.

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.

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].

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.

Treatment of Manifestations

Seizures. There are no specific treatments for seizures in SLC12A5-EIMFS. Seizures in EIMFS are generally resistant to most anti-seizure medication.

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:

• Levetiracetam, rufinamide, stiripentol, and clonazepam [Coppola et al 1995, Cilio et al 2009, Djuric et al 2011, Vendrame et al 2011, Merdariu et al 2013];
• Cannabinoids [Saade & Joshi 2015].

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 Foundation Toolbox.

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.

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.

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

• The parents of a child with SLC12A5-EIMFS are typically heterozygotes (i.e., carriers of one SLC12A5 pathogenic variant). In a one family reported to date, a compound heterozygous proband was found to have one maternally inherited SLC12A5 pathogenic variant and one de novo variant (the father was not a carrier of an SLC12A5 pathogenic variant) [Saito et al 2017].
• 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 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/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the SLC12A5 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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

SLC12A5 encodes KCC2, the neuronal-specific potassium chloride cotransporter which is a member of the family of cation chloride cotransporters [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 GABA_A 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.

Normal gene product. SLC12A5 encodes KCC2, the neuronal-specific potassium chloride cotransporter, a member of the family of cation chloride cotransporters [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].

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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