Epileptic encephalopathy with mutations in the KCNT1 gene: signs and symptoms, etiology, epidemiology, diagnosis and treatment

Early-onset epileptic encephalopathy (EOEE, OMIM 614959) is typically characterized by early seizures in newborns or infants, due to its frequent seizures, a large number of epileptic discharges and its genetic background, which is extremely harmful to brain development and maturation, and seriously affects the intellectual and motor development

First, the general overview

Pathogenic variants ("mutations") in the KCNT1 gene cause epilepsy

KCNT1 is not the name of the medical condition, but the name of the

2.

Infantile epilepsy accompanied by wandering focal seizures has the following characteristics: (1) onset within 6 months of birth; (2) Wandering focal seizures; (3) During the seizure period, the EEG shows multifocal discharge, which travels between one or both hemispheres and involves multiple parts, and the clinical episode is closely related to the EEG discharge in time and site; (4) Retrogression of progressive intellectual exercises; (5) Poor response to anti-epilepsy drug treatment and poor prognosis

Infantile epilepsy with migratory focal seizures caused by KCNT1 variants has an early onset and can occur immediately after birth, mainly concentrated in the 2 weeks to 2 months after birth, with an average age of onset of 46.

Autosomal dominant nocturnal frontal epilepsy is another important phenotype of KCNT1 gene variation, which is relatively serious than nocturnal frontal lobe epilepsy caused by CHRNA4, CHRNB2 and CHRNA2 variants, with early onset of illness, more frequent seizures, and often accompanied by mental problems

KCNT1-related epilepsy falls into two broad categories:

Seizures that begin in infancy, not related to fever, may be the first sign of

1.

2.

Children with frontal lobe epilepsy (ADNFLE) caused by KCNT1 have prepubertal seizures, but later than children

Many people with KCNT1-associated frontal lobe epilepsy have some degree of developmental delay or cognitive impairment, but usually they are able to walk and speak

Rarely, people with KCNT1-associated epilepsy have abnormal white matter in the brain, which can be detected

In addition, mutations in KCNT1 appear to cause widespread epilepsy, including ADNFLE, multifocal epilepsy, MMFSI, Ohtahara syndrome, and white matter encephalopathy

A large-scale study summarizing the phenotypic and genotype profiles of KCNT1 mutation-associated epilepsy in 248 individuals, possibly divided into four phenotypic groups: (i) EIMFS (152 individuals); (ii) Developmental and epileptic encephalopathy other than EIMFS (non-EIMFS developmental and epileptic encephalopathy) (37 people); (iii) Autosomal dominant or sporadic sleep-related hyperkinetic epilepsy (53 patients); (iv) Other phenotypes (six individuals

Table: Association between mutations in the KCNT1 gene and clinical presentation

3.

The KCNT1 gene is located at 9q34.
3 and encodes a sodium-activated potassium ion channel (Na+ activated K+ channel) consisting of 6 transmembrane fragments (S1-S6), S5 and S6 forming pores, terminated by regulators of K+ conductance (RCK) and NAD+ binding domains, the activity of which leads to slow supersing after repeated excitation
。 The gene is expressed in specific areas of the brain, liver, and spinal cord, especially in the frontal cortex of the brain, and lowest
in the skeletal muscles.
This genetic variant can lead to refractory epilepsy and severe intellectual motor developmental delay
.
24 KCNT1 gene mutation sites have been reported, of which c.
2800G>A, c.
862G>A, c.
1193G>A, c.
1283G>A, c.
1421G>A, c.
2782C>T are hot spot variants
.
KCNT1 gene variants are mainly concentrated in the RCK region, NAD+ binding domain and transmembrane protein S5 region, and the clinical manifestations are infantile epilepsy accompanied by wandering focal seizures, autosomal dominant nocturnal frontal epilepsy, Otahara syndrome, focal epilepsy and arrhythmias
.
Of the reported sites of variation, 16 sites of variation, including the hotspot variants described above, were associated
with wandering focal seizures associated with infantile epilepsy.
The most common causative gene for wandering focal seizures in infants with epilepsy is the KCNT1 gene
.

In a group of 11 children with KCNT1 gene variants reported by Ohba et al.
, 9 cases presented with infantile epilepsy accompanied by wandering focal seizures
.

Among the children in this group, 4 cases were reported variants, of which 3 cases belonged to the above hot spot variants, and the other 2 cases were first-time discoveries
.
Five children were diagnosed with infantile epilepsy accompanied by wandering focal seizures, and the other one did not see migratory seizures, but EEG showed multiple multifocal origin of partial seizures, which did not rule out the possibility
of wandering partial seizures.

The Department of Pediatrics of Peking University First Hospital collected 175 children with early-onset epileptic encephalopathy, of which 6 cases were diagnosed with KCNT1 mutation-related epilepsy, all of which were missense variants, of which 4 were reported variants, c.
811G>T, p.
V271F; c.
1283G>A，p.
R428Q； c.
2800G>A，p.
A934T； c.
1421G> A, p.
R474H, the other 2 variants c.
2797C>G, p.
R933G and c.
1885A>G, p.
K629E have not been reported, are newly discovered variants
.
All variants were new and were not seen in the child's parents
.
Five cases in this group were located near the RCK region and the NAD+ binding domain, and one case was located in
the transmembrane protein S5.

In most children with KCNT1-associated developmental and epileptic encephalopathy, the pathogenic KCNT1 variant occurs spontaneously (from the beginning) and is not inherited
from either parent.
Only in rare cases, the pathogenic KCNT1 variant has been inherited
from asymptomatic parents due to parental chimerism.
However, parents may have a small subset of cells that do carry very low levels of pathogenic KCNT1 variants that may be difficult or impossible to detect
.
In these families where parents have a small subset of low-level, pathogenic KCNT1 variants, there may be a 50%
chance that future siblings may also have KCNT1-related epilepsy.

KCNT1-associated frontal lobe epilepsy, in some children with KCNT1-associated frontal lobe epilepsy, pathogenic variants are inherited from parents
who also have epilepsy.
A family history of epilepsy may indicate inherited KCNT1 variants in these families
.
However, in some cases, the pathogenic KCNT1 variant occurs spontaneously (from scratch) and is not inherited from either parent
.

4.
Epidemiology

Of the 175 cases of early-onset epileptic encephalopathy diagnosed and treated in the Pediatric Neurological Clinic and Ward of Peking University First Hospital, 6 cases of KCNT1 mutation-related epilepsy were confirmed, often showing infantile epilepsy accompanied by wandering focal seizures
.

From 31 patients with infantile epilepsy with transitional focal seizures (EIMFS), 12 patients were further genetically confirmed to have KCNT1 pathogenic mutations, of which 4 mutations were newly discovered mutations, and de novo mutations were the most common
.
Of the 12 patients with mutations, 10 were clinically diagnosed with EMFS, while the other 2 presented with early-onset severe nocturnal frontal lobe epilepsy
.
1 of the 3 patients receiving quinidine responded well clinically
.
The model showed that abnormal channel pore function (f346l) and tetramer formation abnormalities (f502v) were potential pathogenesis, while quinidine increased the amplitude of the KCNT1 mutation channel and altered the pore abnormality
.

5.
Differential diagnosis

1.
Lennox-Gastaut syndrome, see: Lennox-Gastaut syndrome, signs and symptoms, etiology, epidemiology, diagnosis and treatment

2.
Infant epilepsy accompanied by wandering focal seizures, some of which are caused by KCNT1 gene mutations, see: Infant epilepsy accompanied by wandering focal seizures: clinical characteristics, etiology, and treatment

6.
Diagnosis

Delays in developmental milestones in infancy and early childhood, as well as seizures, are not specific but consistent
with KCNT1-associated epilepsy.
However, no typical KCNT1-associated epilepsy symptoms can be diagnosed based on clinical features
alone.

Genetic testing is needed to diagnose KCNT1-related epilepsy
.

Other tests can also be performed, including:

Many children with KCNT1-related epilepsy are diagnosed with a specific epilepsy syndrome
based on the type of seizures they experience and the characteristics of the EEG.
Some of these epilepsy syndromes include:

Six cases of KCNT1 mutation-related epilepsy were treated in the Pediatric Neurological Clinic and Ward of Peking University First Hospital, with the following characteristics:

1.
EEG results:

All 6 children underwent at least one video EEG.

The EEG of 6 children between seizures all showed focal or multifocal discharge, and Example 2, Case 3, and Case 5 had a tendency to highly outrarapathic or atypically highly out of synchronic.

The clinical seizures of the children were monitored during the EEG examination, and the focal seizures were monitored in Case 1, and focal seizures with generalizations were monitored; Example 2 and Example 4 detect focal seizures and wandering focal seizures; Example 3, Example 6 monitored focal seizures, wandering focal seizures, spastic seizures, tonic attacks; Case 5 detected focal seizures, wandering focal seizures, and spastic seizures
.
Examples 2 to 6 detect children with wandering focal seizures, the EEG during the same period of seizures shows that the EEG travels in different leads of the ipsilateral hemisphere or from one hemisphere to the contralateral cerebral hemisphere
.
Example 5 is manifested by clenching a fist in the right hand, squinting to the right, blinking at the corner of the right eye, twitching at the corner of the mouth, and flexing and shaking
of the upper limbs on both sides.
The EEG shows the beginning of the low-amplitude fast wave at the top of the left side, and the final amplitude gradually increases, and the low-amplitude fast wave appears when it travels to the bilateral frontal pole and the forehead dominant joint, the amplitude gradually increases, the frequency gradually slows down, the high-amplitude spike rhythmic emission in 4 to 5 Hz, the left middle and posterior temporal lead amplitude gradually increases, the frequency gradually slows down, and the high-amplitude rhythmic electrical activity
in 5 to 7 Hz is gradually increased.

2.
Imaging examination results:

All children underwent cranial magnetic resonance imaging, and children in Case 1 and Case 6 showed cerebellar atrophy (data loss), and the remaining 4 cases had no obvious abnormalities
.

3.
Blood and urine metabolism screening results:

Example 3 The first urinary metabolism screening suggests a large amount of а-ketoglutaric acid, and no abnormalities were found after several re-examinations, and the first urinary metabolism screening in Case 4 showed no abnormalities after multiple re-examinations of glutaric aciduria type 2/ethylmalonic aciduria, which was considered to be transient increase, and the remaining 4 cases were normal
.

4.
Cardiovascular examination results:

All children underwent an electrocardiogram and no abnormalities
were found.
Example 2 echocardiography suggests pulmonary arteriovenous fistula
.

7.
Treatment

Treatment of KCNT1-related epilepsy will depend on the type and severity of the
seizures.

Combinations of seizure drugs are often used to control different seizure types
.
Quinidine is a drug that blocks potassium channels and helps control seizures in some patients, but it can cause significant side effects
.
Epilepsy Neurogenetics Initiative (ENGIN) providers have experience in epilepsy management in children with KCNT1-related epilepsy and can guide optimal drug options
.
One review showed that 33 patients with KCNT1 mutations recorded 20 patients who received ≥ 50% reduction
in seizures as a result of quinidine treatment.
However, quinidine therapy often has different effects
on patients with the same KCNT1 mutation.
Age, KCNT1 mutation genotype, seizure type, and brain MRI did not have a significant effect on
the therapeutic efficacy of quinidine.
QTc prolongation is the most common
of all quinidine adverse events.
It is important to note that the results of the in vitro quinidine test are inconsistent with the in vivo
test.

A different set of medications, called "rescue therapy," can be given to help prevent or shorten the onset of an episode
.

Chlorpalcan is treated with a 70% to 80% reduction in episodes and chlonitrazepam given during frequent episodes
.
Levetiracetam, also commonly used for the control
of epilepsy.

When medications are not effective in controlling seizures, implantable devices such as vagus nerve stimulation (VNS) or reactive nerve stimulation (RNS)
may be considered.

Dietary therapies, such as the ketogenic diet, may be helpful
in some cases.

Family training and support are key elements
of a successful epilepsy treatment plan.
Parents and caregivers must know how to observe and respond to seizures
.

Cognitive and developmental delay or autism spectrum disorders associated with epilepsy associated with KCNT1 are treated with support from physical, occupational, and speech therapy
and early intervention services.
Care
can be provided by a developmental paediatrician.

8.
Rare disease information registration

If you are willing to seek constantly updated information, it is recommended that you register the patient's information here, even if you are not fully diagnosed, you can register, click to enter:

Patient Information Registry System for Rare Diseases

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Bearden D, Strong A, Ehnot J, DiGiovine M, Dlugos D, Goldberg EM.
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Lim CX, Ricos MG, Dibbens LM, Heron SE.
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Fitzgerald MP, Fiannacca M, Smith DM, Gertler TS, Gunning B, Syrbe S, Verbeek N, Stamberger H, Weckhuysen S, Ceulemans B, Schoonjans AS, Rossi M, Demarquay G, Lesca G, Olofsson K, Koolen DA, Hornemann F, Baulac S, Rubboli G, Minks KQ, Lee B, Helbig I, Dlugos D, Møller RS, Bearden D.
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McTague et al.
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Chen Yan, Bao Xinhua, Zhang Qingping, Wang Jiaping, Wen Yongxin, Yu Shujie, Zhao Ying
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Genetics and clinical analysis of children with early-onset epileptic encephalopathy due to KCNT1 gene variations
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