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KCTD7-Related Progressive Myoclonic Epilepsy

Synonym: Epilepsy, Progressive Myoclonic 3, With or Without Intracellular Inclusions (EPM3)

, MD, DM, , MD, DM, , MD, PhD, FRCPC, and , MD, FRCPC, CSCN (EEG).

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Estimated reading time: 29 minutes

Summary

Clinical characteristics.

KCTD7-related progressive myoclonic epilepsy (KCTD7-PME) is characterized by early-onset myoclonic seizures that are frequently pharmacoresistant and progressive neurologic deterioration. In addition to myoclonic seizures, individuals may experience other generalized seizure types such as generalized tonic-clonic, atonic, tonic, atypical absence, myoclonic-atonic, generalized with eyelid myoclonia, clonic, focal, and spasms. Febrile seizures have also been reported in some individuals. Other neurologic manifestations include movement disorders (i.e., ataxia, tremor, dystonia, choreoathetosis), tone abnormalities (i.e., spasticity and/or hypotonia), microcephaly, vision impairment, and neurobehavioral problems. Other systemic comorbidities include frequent infections, feeding difficulties, and scoliosis.

Diagnosis/testing.

The diagnosis of KCTD7-PME is established in a proband with myoclonic seizures and other neurologic manifestations and biallelic pathogenic variants in KCTD7 identified by molecular genetic testing.

Management.

Treatment of manifestations: KCTD7-PME is often refractory to standard anti-seizure medications (ASMs). Various combinations of ASMs have been used in individuals with KCTD7-PME; the effectiveness of each ASM cannot be determined at this time. Clonazepam, valproate, levetiracetam, and lamotrigine have been found to be effective as monotherapy or polytherapy in some individuals. ASMs may be beneficial in reducing seizure burden and improving the quality of life of affected individuals. The ketogenic diet led to seizure reduction in a few cases.

Surveillance: Monitoring for new-onset seizures, regression of developmental milestones, evaluation of tone abnormalities, movement disorders, and neurobehavioral problems as well as growth is important. An ophthalmologic assessment should be completed when there is clinical suspicion for vision impairment. An electroencephalogram should be considered based on the frequency of seizures, their progression, and response to ASMs.

Agents/circumstances to avoid: Avoid agents that may worsen myoclonic seizures such as phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine, tiagabine, vigabatrin, pregabalin, gabapentin, and lacosamide.

Genetic counseling.

KCTD7-PME is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a KCTD7 pathogenic variant, each sib of an affected individual has at conception 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 KCTD7 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Diagnosis

No consensus clinical diagnostic criteria for KCTD7-related progressive myoclonic epilepsy (KCTD7-PME) have been published to date.

Suggestive Findings

KCTD7-PME should be suspected/considered in probands with the following clinical, electroencephalographic, and neuroimaging findings and family history.

Clinical findings

  • Epilepsy
    • Myoclonic seizures including multifocal fragmentary myoclonus, action myoclonus, or posture-induced myoclonus are common.
    • Other generalized seizure types may be seen including generalized tonic-clonic, atypical absence, atonic, tonic, myoclonic-atonic, generalized with eyelid myoclonia, clonic, and spasms.
    • Focal seizures or febrile seizures may occur.
    • Myoclonic status epilepticus, epilepsia partialis continua, and generalized convulsive and nonconvulsive status epilepticus may also occur.
  • Early normal development or developmental delay followed by developmental regression
  • Speech and language disorders including language delay, nonverbal status, expressive speech difficulties, dysarthria, and onomatopoeia (mimetic elements representing sound)
  • Movement disorders including tremor, dystonia, choreoathetosis, myoclonus-dystonia, dyskinesias, tics, head titubation, and truncal ataxia
  • Gait abnormalities including ataxia
  • Tone abnormalities including hypotonia and/or spasticity
  • Ophthalmologic involvement including vision impairment, diminished pupillary reflexes to light, optic atrophy, strabismus, nystagmus, and opsoclonus
  • Neurobehavioral issues including autism spectrum disorder, irritability, oppositional behavior, hyperactivity, impulsivity, attention-deficit/hyperactivity disorder, hallucinations, psychosis, depression, anxiety, and sleep disturbances
  • Drooling, dysphagia, or feeding problems
  • Microcephaly

Electroencephalographic findings

  • Disorganized and/or slow background and poor sleep architecture are reported in a majority of individuals.
  • Epileptiform discharges are frequently generalized spike and wave and polyspike and wave abnormalities or multifocal sharp and spike-wave discharges.
  • Epileptiform discharges from the occipital or posterior head region are predominant.
  • Sleep activation of epileptiform discharges has been observed.
  • Hypsarrhythmia has been reported in a few individuals with myoclonic seizures, even in the absence of epileptic spasms.
  • Photoparoxysmal responses have been detected in less than one fifth of individuals.

Neuroimaging findings

  • About 40% of individuals have abnormalities on brain magnetic resonance imaging. Findings include cortical atrophy (40% of individuals with neuroimaging abnormalities), white matter abnormalities (20%), combined cortical and cerebellar atrophy (20%), thinning of the corpus callosum (10%), and cerebellar atrophy (5%).
  • Additional abnormalities include a thick corpus callosum, delayed myelination, hypomyelination, focal cortical dysplasia, and dilated perivascular spaces.

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of KCTD7-PME is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in KCTD7 identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic KCTD7 variants of uncertain significance (or of one known KCTD7 pathogenic variant and one KCTD7 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Note: Single-gene testing (sequence analysis of KCTD7, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

Option 1

A multigene panel that includes KCTD7 and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance 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. (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.

Option 2

Comprehensive genomic testing does not require the clinician to determine which genes are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. To date, the majority of KCTD7 pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing.

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

Table 1.

KCTD7-Related Progressive Myoclonic Epilepsy: Molecular Genetic Testing

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method
KCTD7 Sequence analysis 3>99% 4
Gene-targeted deletion/duplication analysis 5<1% 4, 6
1.
2.

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

3.

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

4.

Data derived from Staropoli et al [2012], Mastrangelo et al [2019], Wang et al [2020], Yoganathan et al [2024], and the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.

6.

To date, only a few large intragenic deletions/duplications have been reported in individuals with KCTD7-PME [Blumkin et al 2012, Wang et al 2020].

Clinical Characteristics

Clinical Description

KCTD7-related progressive myoclonic epilepsy (KCTD7-PME) is a rare autosomal recessive disorder that manifests with early-onset multifocal fragmentary myoclonus often associated with seizures and progressive neurologic deterioration [Van Bogaert 2016]. Myoclonus may be spontaneous or induced by action or posture [Van Bogaert 2016, Yoganathan et al 2024]. Reported seizure types include generalized tonic-clonic, generalized atypical absence, generalized atonic, generalized tonic, generalized myoclonic-atonic, generalized with eyelid myoclonus, clonic, focal, febrile, and epileptic spasms [Yoganathan et al 2024]. Progressive neurologic deterioration includes regression of developmental milestones, ataxia, and other movement disorders. Though early development may be normal in about one third of individuals, regression of milestones occurs in all followed by stabilization or progressive deterioration [Van Bogaert 2016, Yoganathan et al 2024].

To date, at least 95 individuals have been reported with biallelic pathogenic variants in KCTD7 [Yoganathan et al 2024]. The following description of the phenotypic features associated with this condition is based on these reports.

Table 2.

KCTD7-Related Progressive Myoclonic Epilepsy: Frequency of Select Features

Feature% of Persons w/FeatureComment
Epilepsy 98%Myoclonic (95%-100%), generalized tonic-clonic (50%), atypical absence (20%), generalized atonic (18%), generalized tonic (15%), focal (15%), & recurrent febrile seizures (10%)
Developmental delay &/or intellectual disability 65%Can be a presenting feature or early development can be normal followed by progressive neurologic deterioration
Developmental regression 95%
Speech-language difficulties 100%
Movement disorders ~30%Dystonia (29%), choreoathetosis (29%), & tremor (37%)
Ataxia 59%
Tone abnormalities ~40%Spasticity (37%) & hypotonia (41%)
Neurobehavioral issues ~20%Autistic features (12%), behavioral issues (22%)
Ophthalmologic issues ~20%Vision impairment (22%), bilateral optic disc pallor (10%), nystagmus (12%)
Microcephaly 37%
Neuroimaging abnormalities 60%Cortical atrophy (40%), white matter abnormalities (20%), combined cortical & cerebellar atrophy (20%), thin corpus callosum (10%), cerebellar atrophy (5%)

Epilepsy. Progressive myoclonic epilepsies (PMEs) are a rare heterogeneous group of disorders characterized by the combination of myoclonus, seizures, and progressive neurologic deterioration [Kälviäinen 2015]. Myoclonus may be focal, segmental, or multifocal and fragmentary involving the face and distal extremities [Shahwan et al 2005, Kälviäinen 2015].

  • Age of onset. The neurologic manifestations in KCTD7-PME typically start between age 5 months and age 39 months [Van Bogaert 2016, Yoganathan et al 2024]. Seizures are the initial presenting manifestation in about 60%-70% of individuals [Yoganathan et al 2024]. In about one third of affected individuals, initial presenting features include developmental delay or regression, movement disorders, or ataxia without seizures. Seizures occur either in isolation or combined with other features [Yoganathan et al 2024].
  • Seizure types. Nearly all children (98%-100%) with KCTD7-PME develop seizures either at onset or during the disease course. The most common seizure type at disease onset is myoclonus followed by generalized tonic-clonic seizures, clonic seizures, generalized atonic seizures, focal seizures with impaired awareness, generalized tonic seizures, epileptic spasms, generalized myoclonic-atonic seizures, and generalized seizures with eyelid myoclonia. Myoclonic status epilepticus, epilepsia partialis continua, and generalized convulsive and nonconvulsive status epilepticus have also been reported [Yoganathan et al 2024].

Myoclonus in KCTD7-PME is usually multifocal, fragmentary, and may be precipitated by action or posture. More than 95% of affected individuals had myoclonic seizures at some stage of the disease, and daily myoclonus was observed in most of these individuals [Yoganathan et al 2024]. Myoclonus is most often cortical, though subcortical myoclonus has been reported in one individual to date [Metz et al 2018]. Response to treatment has been variable and most affected individuals' myoclonus is pharmacoresistant to standard anti-seizure medications (ASMs) [Yoganathan et al 2024].

Progressive neurologic decline. Regression of developmental milestones occurs in all individuals with KCTD7-PME. It is preceded by early normal or delayed development. Progressive regression has been observed in more than 50% of cases, while regression followed by stabilization has been noted in the remainder [Yoganathan et al 2024]. Ataxia may occur in 25%-60%, tremor in 15%-35%, dystonia in 15%-30%, and chorea in 15%-30% of affected individuals. Opsoclonus-myoclonus-ataxia syndrome has been reported in two individuals to date [Blumkin et al 2012, Burke et al 2021]. Myoclonus-dystonia has been reported in a family with two affected sibs [Dai et al 2019]. Tone abnormalities (hypotonia and/or hypertonia) have been reported in 90% of affected individuals.

About three quarters of individuals become nonambulatory or need assistance with ambulation. All affected individuals are partially or fully dependent in their activities of daily living [Yoganathan et al 2024]. Language delays, nonverbal status, expressive speech difficulty, dysarthria, and onomatopoeia may occur in affected individuals [Van Bogaert et al 2007, Blumkin et al 2012, Metz et al 2018, Dai et al 2019, Narayanan et al 2022, Yoganathan et al 2024].

A mortality rate of about 15% has been reported due to progressive neurologic deterioration, respiratory illness, respiratory failure, sepsis, sudden unexpected death in epilepsy (SUDEP), status epilepticus, accidents, and unknown causes [Yoganathan et al 2024]. The age at death varied from 18 months to 21 years, and the longest survivor reported in the literature to date is age 25 years [Van Bogaert 2016].

Ophthalmologic manifestations. Ophthalmologic manifestations have been reported in about one fifth of affected individuals. The spectrum of ophthalmologic manifestations includes vision impairment, refractive error, diminished pupillary reflexes to light, optic atrophy, strabismus, opsoclonus, and nystagmus [Staropoli et al 2012, Blumkin et al 2012, Moen et al 2016, Metz et al 2018, Burke et al 2021, Niu et al 2022, Yoganathan et al 2024]. Retinitis pigmentosa has been reported in one individual to date [Kozina et al 2020].

Other comorbidities. Systemic comorbidities are sparsely reported in the literature. Spine abnormalities, including scoliosis, have been reported in 14 individuals to date [Kousi et al 2012, Metz et al 2018, Burke et al 2021, Binaafar et al 2021, Yoganathan et al 2024]. Feeding difficulties [Van Bogaert et al 2007, Farhan et al 2014, Metz et al 2018] and recurrent infection have also been reported in a few individuals [Metz et al 2018, Binaafar et al 2021]. These systemic comorbidities are likely related to the progression of neurologic manifestations [Yoganathan et al 2024].

Neuroimaging findings. Brain magnetic resonance imaging (MRI) has been reported to be normal in about 60% of individuals with KCTD7-PME [Yoganathan et al 2024]. Among individuals with neuroimaging abnormalities, the spectrum of findings includes cortical atrophy in 40%, white matter abnormalities in 20%, combined cortical and cerebellar atrophy in 20%, thinning of corpus callosum in 10%, and cerebellar atrophy in 5% [Yoganathan et al 2024]. Other reported findings include a thick corpus callosum detected in one individual [Narayanan et al 2022], focal cortical dysplasia in one individual [Metz et al 2018] and dilated perivascular spaces in one individual [Metz et al 2018].

Electroencephalographic (EEG) findings. EEG features described in individuals with KCTD7-PME include background abnormalities and epileptiform changes. A disorganized or slow background and poor sleep architecture are reported in 78% [Yoganathan et al 2024]. Epileptiform discharges are frequently generalized spike and wave and polyspike and wave abnormalities or multifocal sharp and spike-wave discharges [Van Bogaert et al 2007, Kousi et al 2012, Farhan et al 2014, Moen et al 2016, Metz et al 2018, Dai et al 2019, Mastrangelo et al 2019, Burke et al 2021, Binaafar et al 2021, Dudipala et al 2021, Narayanan et al 2022, Niu et al 2022, Yoganathan et al 2024]. Predominance of epileptiform discharges from the occipital or posterior head region has been identified. Sleep activation of epileptiform discharges has been observed. Hypsarrhythmia has been reported in a few individuals with myoclonic seizures in the presence or absence of epileptic spasms [Krabichler et al 2012, Yoganathan et al 2024]. Photoparoxysmal responses were detected in less than one fifth of affected individuals [Yoganathan et al 2024].

Genotype-Phenotype Correlations

No consistent genotype-phenotype correlations have been identified to date [Van Bogaert 2016, Yoganathan et al 2024]. However, developmental delay followed by progressive regression is more likely to be observed in individuals with variants within the BTB/POZ domain of KCTD7 [Yoganathan et al 2024].

Penetrance

KCTD7-PME is expected to be completely penetrant to date.

Nomenclature

Neuronal ceroid lipofuscinosis 14. Several individuals with biallelic KCTD7 pathogenic variants and inclusions suggestive of neuronal ceroid lipofuscinosis (such as fingerprint profiles and granular osmiophilic deposits) on analysis of skin fibroblasts have been described in the literature [Staropoli et al 2012, Dai et al 2019, Mastrangelo et al 2019, Zeineddin et al 2024] leading to the designation of this phenotype as neuronal ceroid lipofuscinosis 14 (CLN14 disease). However, all four individuals in a recent KCTD7-PME cohort who underwent skin biopsy had no inclusions present [Yoganathan et al 2024].

Prevalence

The exact prevalence of KCTD7-PME is unknown. Approximately 95 individuals have been reported to date [Yoganathan et al 2024].

Differential Diagnosis

The differential diagnosis of KCTD7-related progressive myoclonic epilepsy (KCTD7-PME) includes genetic disorders (see Table 4) and acquired conditions.

Table 4.

KCTD7-Related Progressive Myoclonic Epilepsy: Differential Diagnosis

Gene(s)DisorderMOIFeatures of Disorder
Overlapping w/KCTD7-PMEDistinguishing from KCTD7-PME
ASAH1 Spinal muscular atrophy w/PME (See ASAH1-Related Disorders.)AR
  • Progressive myoclonic seizures & other seizure types incl generalized absence, generalized atonic, & generalized tonic-clonic
  • EEG shows slowing of background & generalized spike & wave discharges.
  • Early normal motor & cognitive milestones
  • Age at onset: 17 mos-10 yrs
  • Variable cognitive deterioration
  • Onset w/proximal muscle weakness followed by seizures
  • Sensorineural hearing loss
  • EMG shows chronic denervation.
CLN3
CLN5
CLN6
CLN8
CTSD
CTSF
DNAJC5
GRN
MFSD8
PPT1
TPP1 		Neuronal ceroid lipofuscinoses AR
(AD) 1
  • Myoclonus, other seizure types
  • Progressive cognitive & motor deterioration
  • Vision loss
Retinopathy
CSTB 2PME type 1 (Unverricht-Lundborg disease)AR
  • Asynchronous & multifocal myoclonic seizures are the predominant seizure type.
  • Spontaneous & action-induced myoclonus
  • Myoclonic seizures are frequently pharmacoresistant to ASMs.
  • Other seizure types incl generalized tonic-clonic, generalized absence, & focal seizures.
  • Ataxia, tremor, & dysarthria
  • Initial development is usually normal.
  • EEG shows generalized spike or polyspike & wave discharges or epileptiform discharges predominant over posterior head region & photosensitivity.
  • Age at onset: 6-15 yrs
  • Stimulus-sensitive myoclonus (provoked by light, noise, stress, & physical exertion)
  • Deterioration in gross motor & cognitive function is usually gradual & late in onset.
  • EEG background is usually normal or mildly slow w/disappearance of physiologic sleep patterns late in course of disease.
DHDDS DHDDS-related DD & seizures ± movement abnormalities (OMIM 617836)AD
  • Myoclonus
  • DD/ID
  • Other seizure types incl generalized myoclonic-atonic, generalized absence, generalized tonic-clonic, generalized atonic, generalized tonic, & focal seizures ± photosensitivity.
  • Ataxia & other movement disorders
  • Cognitive decline
  • Age at onset of seizures: 6 mos to 10 yrs
  • Epilepsy improves over disease course.
EPM2A
NHLRC1 		PME, Lafora type AR
  • Fragmentary myoclonus (spontaneous & stimulus sensitive)
  • Other seizure types incl generalized tonic-clonic, generalized absence, generalized atonic, & focal seizures.
  • Progressive cognitive decline, ataxia, & dysarthria
  • Psychomotor development is normal prior to disease onset.
  • EEG shows deterioration of background, loss of sleep architecture, generalized & multifocal epileptiform discharges w/occipital predominance, & photosensitivity.
  • Later age at onset: 10-17 yrs
  • Presence of occipital seizures w/visual hallucinations & transient blindness
  • Presence of Lafora bodies (periodic acid Schiff-positive intracellular inclusion bodies) on skin biopsy
GOSR2 PME type 6 (OMIM 614018)AR
  • Multifocal myoclonus (spontaneous & action induced) is predominant seizure type & often pharmacoresistant.
  • Other seizure types incl generalized tonic-clonic, generalized absence, generalized atonic, generalized tonic, & clonic seizures.
  • DD & progressive neurologic deterioration
  • Gait abnormalities
  • EEG can show slow background, occipital predominance of epileptiform discharges, generalized or multifocal epileptiform discharges, & photoparoxysmal responses.
  • Early onset (age: 1-4 yrs) w/ataxia & areflexia followed by seizures
  • Myoclonus occurs more at night & early morning; triggers for myoclonus incl fever, illness, heat, light, noise, stress, & emotions.
  • Relative preservation of cognitive function
  • Prominent scoliosis
  • ↑ serum CK
  • Nerve conduction studies show sensory neuronopathy & anterior horn cell involvement.
IRF2BPL IRF2BPL-related disorder AD
  • Early normal development followed by regression of milestones or DD
  • Erratic myoclonus, triggered by action
  • Seizure types incl generalized tonic-clonic, generalized absence, atonic, focal, & epileptic spasms
  • Cerebellar signs & movement disorders incl dystonia & choreoathetosis
  • Age at onset is variable, from early childhood to adulthood.
  • Oculomotor abnormalities, mood changes, neuropathy & endocrinological abnormalities may be observed.
KCNC1 PME type 7
(See KCNC1-Related Disorders.)		AD
  • Clinical phenotype resembles Unverricht-Lundborg disease at onset.
  • Incapacitating myoclonus limiting ambulation; other seizure types incl generalized tonic-clonic seizures.
  • Ataxia & tremor
  • Developmental milestones may be normal prior to disease onset.
  • EEG shows generalized epileptiform discharges & photoparoxysmal responses.
  • Usual age at onset: 6-14 yrs
  • Mild cognitive decline
MT-TF
MT-TH
MT-TI
MT-TK
MT-TL1
MT-TP
MT-TS1
MT-TS2 		MERRF MT
  • Myoclonus, generalized epilepsy, ataxia
  • Cognitive impairment
  • Multisystem involvement
  • Muscle wasting & weakness
  • Lactic acidosis in blood & CSF
  • Muscle biopsy shows ragged red fibers & cytochrome c oxidase negative-fibers.
NEU1 Sialidosis types I & II (OMIM 256550)AR
  • Sialidosis type I: myoclonus (postural & action), seizures, & ataxia
  • EEG shows generalized or focal epileptiform discharges & photosensitivity.
  • Sialidosis type I: mild & late-onset manifestations; preserved cognitive functions; visual field defects & cherry-red spots on macula
  • Sialidosis type II: dysostosis multiplex, neurodevelopmental delays, hepatosplenomegaly
NUS1 NUS1-related intellectual developmental disorder w/seizures (OMIM 617831)AD
  • Cortical myoclonus, epilepsy, ataxia
  • DD/ID
Multifocal myoclonus of face
PRICKLE1 PRICKLE1-related PME w/ataxia (See PRICKLE1-Related Disorders.)ARAtaxia & progressive myoclonus
  • Intellect is preserved or only a mild decline is observed.
  • Ataxia develops at onset (age 4-5 yrs) followed by myoclonus onset at age 5-10 yrs
  • Impaired upward gaze
SCARB2 SCARB2-related action myoclonus– renal failure syndrome AR
  • Progressive multifocal myoclonus, spontaneous or action induced; other reported seizure types incl generalized tonic-clonic seizures.
  • Cerebellar ataxia & speech disturbances
  • Early development is normal.
  • EEG shows background slowing, generalized epileptiform discharges, & photosensitivity.
  • Later age at onset: 2nd or 3rd decade of life
  • Cortical tremor is 1st finding.
  • Sensorimotor neuropathy & hearing loss
  • Cognitive decline is infrequent.
  • Proteinuria, focal segmental glomerulosclerosis, & kidney failure
  • Neurologic manifestations may occur before or after onset of kidney manifestations. Neurologic & kidney manifestations can rarely occur simultaneously.
TBC1D24 TBC1D24-related PME (See TBC1D24-Related Disorders.)ARPMESensorineural hearing loss may be observed.

AD = autosomal dominant; AR = autosomal recessive; CK = creatine kinase; DD = developmental delay; EMG = electromyography; ID = intellectual disability; MT = mitochondrial; MERRF = myoclonic epilepsy with ragged red fibers; MOI = mode of inheritance; PME = progressive myoclonic epilepsy

1.

Except for DNAJC5-related neuronal ceroid lipofuscinosis (CLN4 disease), which is inherited in an autosomal dominant manner, neuronal ceroid lipofuscinoses are inherited in an autosomal recessive manner.

2.

PME type 1 is caused by either biallelic abnormal CCC-CGC-CCC-GCG dodecamer repeat expansions in CSTB or compound heterozygosity for a CSTB dodecamer repeat expansion and a CSTB sequence variant.

Acquired conditions of interest in the differential diagnosis of KCTD7-PME include:

  • Subacute sclerosing panencephalitis
  • Opsoclonus-myoclonus-ataxia syndrome (paraneoplastic or parainfectious)

Management

No clinical practice guidelines for KCTD7-related progressive myoclonic epilepsy (KCTD7-PME) have been published. In the absence of established guidelines, the following recommendations are based on the authors' personal experience in managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To assess the disease extent and needs of an individual with KCTD7-PME, perform the evaluations summarized in Table 5 (if not performed already as part of the evaluation that led to the diagnosis).

Table 5.

KCTD7-Related Progressive Myoclonic Epilepsy: Recommended Evaluations Following Initial Diagnosis

System/ConcernEvaluationComment
Constitutional Assess weight, height & head size.
Neurologic Neurologic eval
  • Brain MRI
  • Consider EEG.
Ataxia &/or musculoskeletal Orthopedics / physical medicine & rehab / PT & OT evalTo incl assessment of:
  • Gross motor & fine motor skills
  • Mobility, ADL, & need for adaptive devices
  • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Speech & language Assessment of speech & languageSpeech therapy as indicated
Development Developmental assessment
  • To include motor, adaptive, cognitive, & speech-language eval
  • Evaluate for early intervention / special education
Neurobehavioral/
Psychiatric 		Neuropsychiatric evalFor persons age >12 mos: screening for concerns incl sleep disturbances, ADHD, anxiety, &/or findings suggestive of ASD
Gastrointestinal/
Feeding 		Gastroenterology / nutrition / feeding team eval
  • To include eval of aspiration risk & nutritional status
  • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Eyes Ophthalmologic evalTo assess for ↓ vision, abnormal ocular movements, best corrected visual acuity, refractive errors, strabismus, & more complex findings (e.g., optic atrophy) that may require referral for subspecialty care &/or low vision services
Respiratory Pulmonary consultation
  • Assess respiratory status for risk of infection & aspiration.
  • Preventative measures such as influenza vaccination, & antibiotics as needed
  • Sleep study / polysomnography if indicated
Genetic counseling By genetics professionals 1To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of KCTD7-PME to facilitate medical & personal decision making
Family support
& resources 		By clinicians, wider care team, & family support organizationsAssessment of family & social structure to determine need for:

ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; KCTD7-PME = KCTD7-related progressive myoclonic epilepsy; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy

1.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

There is no known cure for KCTD7-PME to date. Supportive care to improve the quality of life, function, and minimize complications is recommended, ideally with multidisciplinary specialist involvement (see Table 6).

Table 6.

KCTD7-Related Progressive Myoclonic Epilepsy: Treatment of Manifestations

Manifestation/ConcernTreatmentConsiderations/Other
Developmental delay / Intellectual disability / Neurobehavioral issues See Developmental Delay / Intellectual Disability Management Issues.
Epilepsy Standardized treatment w/ASM by experienced neurologist
  • Clonazepam, valproate, levetiracetam, & lamotrigine have been effective as monotherapy or polytherapy in some persons. 1
  • 1 person benefitted from corpus callosotomy. 2
  • The role of vagal nerve stimulation & deep brain stimulation is unknown currently.
  • Sodium channel ASMs may worsen myoclonus.
  • Education of parents/caregivers 3
Tone abnormalities Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & fallsConsider need for positioning & mobility devices & disability parking placard.
Movement disorders Standardized treatment depending on type of abnormal movement (i.e., dystonia, chorea, myoclonus)Consider involvement of movement disorder specialist if movements are refractory to standard treatments.
Ataxia Orthopedics / physical medicine & rehab / PT & OT eval to assess gross & fine motor skills
  • Consider need for adaptive devices.
  • Consider PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
Poor weight gain /
Failure to thrive
  • Feeding therapy
  • Gastrostomy tube placement may be required for persistent feeding issues.
Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
Eyes OphthalmologistFor refractive errors, strabismus, nystagmus
Ophthalmic subspecialistFor more complex findings (i.e., optic disc pallor, optic atrophy)
Low vision services
  • Children: through early intervention programs &/or school district
  • Adults: low vision clinic &/or community vision services / OT / mobility services
Cerebral visual impairment No specific treatmentEarly intervention program to stimulate visual development
Respiratory
  • Assess airway control & protection.
  • Consider influenza vaccine, antibiotics when needed, & chest PT if needed.
  • Monitor respiratory status & risk of infection & aspiration.
  • Placement of percutaneous endoscopy or gastrostomy tube for feeding can be helpful in ↓ risk of aspiration pneumonia in persons w/advanced disease.
Bowel dysfunction Monitor for constipation.Stool softeners, prokinetics, osmotic agents, or laxatives as needed
Transition to adult care Develop realistic plans for adult life (see American Epilepsy Society Transitions from Pediatric Epilepsy to Adult Epilepsy Care).Starting by age ~10 yrs
Family/Community
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
  • Ongoing assessment of need for palliative care involvement &/or home nursing
  • Consider involvement in adaptive sports or Special Olympics.

ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy

1.
2.
3.

Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; 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 as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

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 for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

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

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • Vision consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, 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.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US 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 and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
  • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures.

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 should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.

Neurobehavioral/Psychiatric Concerns

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

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior 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

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Table 7.

KCTD7-Related Progressive Myoclonic Epilepsy: Recommended Surveillance

System/ConcernEvaluationFrequency
Feeding
  • Measurement of growth parameters
  • Eval of nutritional status & safety of oral intake
At each visit
Gastrointestinal Monitor for constipation.
Respiratory Monitor for evidence of aspiration & respiratory insufficiency.
Neurologic
  • Monitor those w/seizures as clinically indicated.
  • Assess for new manifestations such as seizures, changes in tone, & movement disorders.
Development Monitor developmental progress & educational needs.
Neurobehavioral/
Psychiatric 		Assess for anxiety, ADHD, ASD, aggression, & self-injury.
Musculoskeletal Physical medicine & OT/PT assessment of mobility & self-help skills
Ophthalmologic involvement Monitor visual acuity, refractive errors, optic atrophy, strabismus, & other abnormal eye movements.Per treating ophthalmologist(s)
Low vision servicesPer treating clinicians
Family/Community Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).At each visit

ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy

Agents/Circumstances to Avoid

Avoid agents that may worsen myoclonic seizures such as phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine, tiagabine, vigabatrin, pregabalin, gabapentin, and lacosamide [Perucca et al 1998, Striano & Belcastro 2012, Rosati et al 2015, Orsini et al 2019].

Pregnancy Management

See MotherToBaby for further information on medication use during pregnancy.

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, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

KCTD7-related progressive myoclonic epilepsy (KCTD7-PME) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are presumed to be heterozygous for a KCTD7 pathogenic variant.
  • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a KCTD7 pathogenic variant and to allow reliable recurrence risk assessment.
  • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • If both parents are known to be heterozygous for a KCTD7 pathogenic variant, each sib of an affected individual has at conception 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) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

  • Unless an affected individual's reproductive partner also has KCTD7-PME or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in KCTD7.
  • To date, individuals with KCTD7-PME 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 a KCTD7 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the KCTD7 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk 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 young adults who are carriers or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the KCTD7 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 and preimplantation genetic testing. While most health care professionals would consider the use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

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.

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.

KCTD7-Related Progressive Myoclonic Epilepsy: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
KCTD77q11​.21BTB/POZ domain-containing protein KCTD7Neuronal Ceroid Lipofuscinoses; NCL Mutations (KCTD7)
KCTD7 database		KCTD7KCTD7

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 KCTD7-Related Progressive Myoclonic Epilepsy (View All in OMIM)

611725POTASSIUM CHANNEL TETRAMERIZATION DOMAIN-CONTAINING PROTEIN 7; KCTD7
611726EPILEPSY, PROGRESSIVE MYOCLONIC, 3, WITH OR WITHOUT INTRACELLULAR INCLUSIONS; EPM3

Molecular Pathogenesis

KCTD7 encodes BTB/POZ domain-containing protein KCTD7 (KCTD7), a member of the potassium channel tetramerization domain-containing protein family [Azizieh et al 2011]. KCTD7 is highly conserved and composed of 289 amino acids. KCDT7 does not conduct potassium, but it helps regulate the conduction of potassium through interactions with other Kv subunits [Van Bogaert et al 2007, Moen et al 2016]. In addition, KCDT7 regulates transcription and is an essential component for cytoskeletal organization [Van Bogaert et al 2007].

KCTD7 is expressed postnatally throughout the central nervous system and is found in the cerebellum, cortical spinal tracts, and hippocampus [Van Bogaert et al 2007]. Loss of function of KCTD7 results in a depolarized resting membrane potential as well as increased excitability and seizures. In contrast, overexpression of KCTD7 causes hyperpolarization and decreased excitation [Azizieh et al 2011].

Mechanism of disease causation. Loss of function

Chapter Notes

Author Notes

Sangeetha Yoganathan, Robyn Whitney, and Puneet Jain are actively involved in clinical research regarding individuals with KCTD7-related progressive myoclonic epilepsy (KCTD7-PME). They would be happy to communicate with persons who have any questions regarding the diagnosis of KCTD7-PME or other considerations.

Contact Gregory Costain to inquire about the review of KCTD7 variants of uncertain significance.

Gregory Costain is also interested in hearing from clinicians treating families affected by PMEs in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Revision History

  • 20 November 2025 (gm) Review posted live
  • 19 March 2025 (sy) Original submission

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