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Progressive myoclonic epilepsy type 3(EPM3; CLN14)

MedGen UID:
388595
Concept ID:
C2673257
Disease or Syndrome
Synonyms: CEROID LIPOFUSCINOSIS, NEURONAL, 14; EPILEPSY, PROGRESSIVE MYOCLONIC, 3, WITH OR WITHOUT INTRACELLULAR INCLUSIONS; EPILEPSY, PROGRESSIVE MYOCLONIC, 3, WITHOUT INTRACELLULAR INCLUSIONS
SNOMED CT: Progressive myoclonic epilepsy due to KCTD7 deficiency (783064000); Progressive myoclonus epilepsy type 3 (783064000); Progressive myoclonic epilepsy type 3 (783064000); PME (progressive myoclonic epilepsy) type 3 (783064000)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): KCTD7 (7q11.21)
 
Monarch Initiative: MONDO:0012721
OMIM®: 611726
Orphanet: ORPHA263516

Definition

Mutations in the KCTD7 gene cause a severe neurodegenerative phenotype characterized by onset of intractable myoclonic seizures before age 2 years and accompanied by developmental regression. The initial description was consistent with a form of progressive myoclonic epilepsy (designated here as EPM3), whereas a later report identified intracellular accumulation of autofluorescent lipopigment storage material, consistent with neuronal ceroid lipofuscinosis (designated CLN14). Ultrastructural findings on skin biopsies thus appear to be variable. However, clinical features are generally consistent between reports (summary by Staropoli et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (254800). For a general phenotypic description and a discussion of genetic heterogeneity of neuronal ceroid lipofuscinosis, see CLN1 (256730). [from OMIM]

Clinical features

From HPO
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
Truncal ataxia
MedGen UID:
96535
Concept ID:
C0427190
Sign or Symptom
Truncal ataxia is a sign of ataxia characterized by instability of the trunk. It usually occurs during sitting.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Bilateral tonic-clonic seizure with focal onset
MedGen UID:
164077
Concept ID:
C0877017
Disease or Syndrome
A bilateral tonic-clonic seizure with focal onset is a focal-onset seizure which progresses into a bilateral tonic-clonic phase.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Generalized myoclonic seizure
MedGen UID:
892704
Concept ID:
C4021759
Disease or Syndrome
A generalized myoclonic seizure is a type of generalized motor seizure characterized by bilateral, sudden, brief (<100 ms) involuntary single or multiple contraction of muscles or muscle groups of variable topography (axial, proximal limb, distal). Myoclonus is less regularly repetitive and less sustained than is clonus.
Myoclonic seizure
MedGen UID:
1385980
Concept ID:
C4317123
Sign or Symptom
A myoclonic seizure is a type of motor seizure characterized by sudden, brief (<100 ms) involuntary single or multiple contraction of muscles or muscle groups of variable topography (axial, proximal limb, distal). Myoclonus is less regularly repetitive and less sustained than is clonus.
Myoclonic status epilepticus
MedGen UID:
1712171
Concept ID:
C5397681
Finding
A type of motor status epilepticus with repeating bilateral sudden brief (less than 100 ms) involuntary single or multiple contraction of muscles or muscle groups of variable topography.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Visual loss
MedGen UID:
784038
Concept ID:
C3665386
Finding
Loss of visual acuity (implying that vision was better at a certain time point in life). Otherwise the term reduced visual acuity should be used (or a subclass of that).
Fingerprint intracellular accumulation of autofluorescent lipopigment storage material
MedGen UID:
324619
Concept ID:
C1836851
Finding
An intracellular accumulation of autofluorescent lipopigment storage material in a trabecular or fingerprint-like pattern.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVProgressive myoclonic epilepsy type 3
Follow this link to review classifications for Progressive myoclonic epilepsy type 3 in Orphanet.

Professional guidelines

PubMed

Silvennoinen K, Säisänen L, Hyppönen J, Rissanen SM, Karjalainen PA, D'Ambrosio S, Jimenez-Jimenez D, Zagaglia S, Rothwell JC, Balestrini S, Sisodiya SM, Julkunen P, Mervaala E, Kälviäinen R
Epilepsia 2023 Jan;64(1):208-217. Epub 2022 Dec 1 doi: 10.1111/epi.17466. PMID: 36398398Free PMC Article
Rus CM, Weissensteiner T, Pereira C, Susnea I, Danquah BD, Morales Torres G, Rocha ME, Cozma C, Saravanakumar D, Mannepalli S, Kandaswamy KK, Di Bucchianico S, Zimmermann R, Rolfs A, Bauer P, Beetz C
Orphanet J Rare Dis 2022 May 3;17(1):179. doi: 10.1186/s13023-022-02288-8. PMID: 35505348Free PMC Article
Guazzi GC, Federico A
Acta Neurol (Napoli) 1992 Aug-Dec;14(4-6):469-84. PMID: 1293989

Recent clinical studies

Etiology

Silvennoinen K, Säisänen L, Hyppönen J, Rissanen SM, Karjalainen PA, D'Ambrosio S, Jimenez-Jimenez D, Zagaglia S, Rothwell JC, Balestrini S, Sisodiya SM, Julkunen P, Mervaala E, Kälviäinen R
Epilepsia 2023 Jan;64(1):208-217. Epub 2022 Dec 1 doi: 10.1111/epi.17466. PMID: 36398398Free PMC Article
Mir A, Alghamdi A, Alotaibi W, Samreen D, Alotaibi M, Albaradie R, Bashir S
Epileptic Disord 2022 Aug 1;24(4):633-646. doi: 10.1684/epd.2022.1439. PMID: 35770766
Macdonald M, Crawford J, Datta AN
J Child Neurol 2021 Oct;36(11):1027-1033. Epub 2021 Jul 27 doi: 10.1177/08830738211026072. PMID: 34315269
Genton P, Striano P, Minassian BA
Epileptic Disord 2016 Sep 1;18(S2):3-10. doi: 10.1684/epd.2016.0834. PMID: 27621064Free PMC Article
Kälviäinen R
Semin Neurol 2015 Jun;35(3):293-9. Epub 2015 Jun 10 doi: 10.1055/s-0035-1552620. PMID: 26060909

Diagnosis

Yoganathan S, Whitney R, Thomas M, Danda S, Chettali AM, Prasad AN, Farhan SMK, AlSowat D, Abukhaled M, Aldhalaan H, Gowda VK, Kinhal UV, Bylappa AY, Konanki R, Lingappa L, Parchuri BM, Appendino JP, Scantlebury MH, Cunningham J, Hadjinicolaou A, El Achkar CM, Kamate M, Menon RN, Jose M, Riordan G, Kannan L, Jain V, Manokaran RK, Chau V, Donner EJ, Costain G, Minassian BA, Jain P
Epilepsia 2024 Mar;65(3):709-724. Epub 2024 Jan 17 doi: 10.1111/epi.17880. PMID: 38231304
Genton P, Striano P, Minassian BA
Epileptic Disord 2016 Sep 1;18(S2):3-10. doi: 10.1684/epd.2016.0834. PMID: 27621064Free PMC Article
Kälviäinen R
Semin Neurol 2015 Jun;35(3):293-9. Epub 2015 Jun 10 doi: 10.1055/s-0035-1552620. PMID: 26060909
Valero T
Curr Pharm Des 2014;20(35):5507-9. doi: 10.2174/138161282035140911142118. PMID: 24606795
Berkovic SF, So NK, Andermann F
J Clin Neurophysiol 1991 Jul;8(3):261-74. PMID: 1918332

Therapy

Mir A, Alghamdi A, Alotaibi W, Samreen D, Alotaibi M, Albaradie R, Bashir S
Epileptic Disord 2022 Aug 1;24(4):633-646. doi: 10.1684/epd.2022.1439. PMID: 35770766
Tahara M, Higurashi N, Narita A, Ida H
Brain Dev 2022 Apr;44(4):308-312. Epub 2022 Jan 3 doi: 10.1016/j.braindev.2021.12.002. PMID: 34991910
Valero T
Curr Pharm Des 2014;20(35):5507-9. doi: 10.2174/138161282035140911142118. PMID: 24606795
Kelemen A, Rásonyl G, Neuwirth M, Barcs G, Szucs A, Jakus R, Fabó D, Juhos V, Pálfy B, Halász P
Ideggyogy Sz 2011 Mar 30;64(5-6):187-92. PMID: 21688720
Delgado-Escueta AV, Bourgeois BF
Epilepsia 2008 Dec;49 Suppl 9:13-24. doi: 10.1111/j.1528-1167.2008.01922.x. PMID: 19087113

Prognosis

Macdonald M, Crawford J, Datta AN
J Child Neurol 2021 Oct;36(11):1027-1033. Epub 2021 Jul 27 doi: 10.1177/08830738211026072. PMID: 34315269
Opri R, Fabrizi GM, Cantalupo G, Ferrarini M, Simonati A, Dalla Bernardina B, Darra F
Seizure 2016 Nov;42:1-6. Epub 2016 Sep 5 doi: 10.1016/j.seizure.2016.08.008. PMID: 27632409
Kälviäinen R
Semin Neurol 2015 Jun;35(3):293-9. Epub 2015 Jun 10 doi: 10.1055/s-0035-1552620. PMID: 26060909
Valero T
Curr Pharm Des 2014;20(35):5507-9. doi: 10.2174/138161282035140911142118. PMID: 24606795
Berkovic SF, So NK, Andermann F
J Clin Neurophysiol 1991 Jul;8(3):261-74. PMID: 1918332

Clinical prediction guides

Mir A, Alghamdi A, Alotaibi W, Samreen D, Alotaibi M, Albaradie R, Bashir S
Epileptic Disord 2022 Aug 1;24(4):633-646. doi: 10.1684/epd.2022.1439. PMID: 35770766
Macdonald M, Crawford J, Datta AN
J Child Neurol 2021 Oct;36(11):1027-1033. Epub 2021 Jul 27 doi: 10.1177/08830738211026072. PMID: 34315269
Poffenberger CN, Inati S, Tayebi N, Stubblefield BK, Ryan E, Schiffmann R, Sidransky E, Lopez G
Mol Genet Metab 2020 Nov;131(3):358-363. Epub 2020 Oct 20 doi: 10.1016/j.ymgme.2020.10.010. PMID: 33183916Free PMC Article
Oliver KL, Franceschetti S, Milligan CJ, Muona M, Mandelstam SA, Canafoglia L, Boguszewska-Chachulska AM, Korczyn AD, Bisulli F, Di Bonaventura C, Ragona F, Michelucci R, Ben-Zeev B, Straussberg R, Panzica F, Massano J, Friedman D, Crespel A, Engelsen BA, Andermann F, Andermann E, Spodar K, Lasek-Bal A, Riguzzi P, Pasini E, Tinuper P, Licchetta L, Gardella E, Lindenau M, Wulf A, Møller RS, Benninger F, Afawi Z, Rubboli G, Reid CA, Maljevic S, Lerche H, Lehesjoki AE, Petrou S, Berkovic SF
Ann Neurol 2017 May;81(5):677-689. doi: 10.1002/ana.24929. PMID: 28380698
Valero T
Curr Pharm Des 2014;20(35):5507-9. doi: 10.2174/138161282035140911142118. PMID: 24606795

Recent systematic reviews

Yoganathan S, Whitney R, Thomas M, Danda S, Chettali AM, Prasad AN, Farhan SMK, AlSowat D, Abukhaled M, Aldhalaan H, Gowda VK, Kinhal UV, Bylappa AY, Konanki R, Lingappa L, Parchuri BM, Appendino JP, Scantlebury MH, Cunningham J, Hadjinicolaou A, El Achkar CM, Kamate M, Menon RN, Jose M, Riordan G, Kannan L, Jain V, Manokaran RK, Chau V, Donner EJ, Costain G, Minassian BA, Jain P
Epilepsia 2024 Mar;65(3):709-724. Epub 2024 Jan 17 doi: 10.1111/epi.17880. PMID: 38231304
Corniello C, Dono F, Evangelista G, Thomas A, Onofrj M, Sensi SL
Seizure 2024 Jan;114:90-95. Epub 2023 Nov 20 doi: 10.1016/j.seizure.2023.11.009. PMID: 38101201
Mir A, Alghamdi A, Alotaibi W, Samreen D, Alotaibi M, Albaradie R, Bashir S
Epileptic Disord 2022 Aug 1;24(4):633-646. doi: 10.1684/epd.2022.1439. PMID: 35770766
Pondrelli F, Muccioli L, Licchetta L, Mostacci B, Zenesini C, Tinuper P, Vignatelli L, Bisulli F
Orphanet J Rare Dis 2021 Aug 16;16(1):362. doi: 10.1186/s13023-021-01989-w. PMID: 34399803Free PMC Article

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