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Epilepsy, progressive myoclonic, 12(EPM12)

MedGen UID:
1778162
Concept ID:
C5543069
Disease or Syndrome
Synonyms: EPILEPSY, PROGRESSIVE MYOCLONIC, 12; EPM12
 
Gene (location): SLC7A6OS (16q22.1)
 
Monarch Initiative: MONDO:0030936
OMIM®: 619191

Definition

Progressive myoclonic epilepsy-12 (EPM12) is an autosomal recessive neurologic disorder characterized by onset of tonic-clonic seizures and/or myoclonus in the second decade of life. Affected individuals develop cerebellar ataxia associated with progressive cerebral and cerebellar atrophy on brain imaging. Most patients lose ambulation and become wheelchair-bound. Additional more variable features include mild cognitive dysfunction or psychiatric manifestations, such as depression or anxiety (summary by Mazzola et al., 2021). For a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (254800). [from OMIM]

Clinical features

From HPO
Anxiety
MedGen UID:
1613
Concept ID:
C0003467
Finding
Intense feelings of nervousness, tension, or panic often arise in response to interpersonal stresses. There is worry about the negative effects of past unpleasant experiences and future negative possibilities. Individuals may feel fearful, apprehensive, or threatened by uncertainty, and they may also have fears of falling apart or losing control.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Depression
MedGen UID:
4229
Concept ID:
C0011581
Mental or Behavioral Dysfunction
Frequently experiencing feelings of being down, miserable, and/or hopeless; struggling to recover from these moods; having a pessimistic outlook on the future; feeling a pervasive sense of shame; having a low self-worth; experiencing thoughts of suicide and engaging in suicidal behavior.
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.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
Dysmetria
MedGen UID:
68583
Concept ID:
C0234162
Finding
A type of ataxia characterized by the inability to carry out movements with the correct range and motion across the plane of more than one joint related to incorrect estimation of the distances required for targeted movements.
Mental deterioration
MedGen UID:
66713
Concept ID:
C0234985
Mental or Behavioral Dysfunction
Loss of previously present mental abilities, generally in adults.
Bilateral tonic-clonic seizure
MedGen UID:
141670
Concept ID:
C0494475
Sign or Symptom
A bilateral tonic-clonic seizure is a seizure defined by a tonic (bilateral increased tone, lasting seconds to minutes) and then a clonic (bilateral sustained rhythmic jerking) phase.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
The term gait disturbance can refer to any disruption of the ability to walk.
Attention deficit hyperactivity disorder
MedGen UID:
220387
Concept ID:
C1263846
Mental or Behavioral Dysfunction
Attention-deficit/hyperactivity disorder (ADHD) is a behavioral disorder that typically begins in childhood and is characterized by a short attention span (inattention), an inability to be calm and stay still (hyperactivity), and poor impulse control (impulsivity). Some people with ADHD have problems with only inattention or with hyperactivity and impulsivity, but most have problems related to all three features.\n\nIn people with ADHD, the characteristic behaviors are frequent and severe enough to interfere with the activities of daily living such as school, work, and relationships with others. Because of an inability to stay focused on tasks, people with inattention may be easily distracted, forgetful, avoid tasks that require sustained attention, have difficulty organizing tasks, or frequently lose items.\n\nHyperactivity is usually shown by frequent movement. Individuals with this feature often fidget or tap their foot when seated, leave their seat when it is inappropriate to do so (such as in the classroom), or talk a lot and interrupt others.\n\nImpulsivity can result in hasty actions without thought for the consequences. Individuals with poor impulse control may have difficulty waiting for their turn, deferring to others, or considering their actions before acting.\n\nMore than two-thirds of all individuals with ADHD have additional conditions, including insomnia, mood or anxiety disorders, learning disorders, or substance use disorders. Affected individuals may also have autism spectrum disorder, which is characterized by impaired communication and social interaction, or Tourette syndrome, which is a disorder characterized by repetitive and involuntary movements or noises called tics.\n\nIn most affected individuals, ADHD continues throughout life, but in about one-third of individuals, signs and symptoms of ADHD go away by adulthood.

Professional guidelines

PubMed

Cuccurullo C, Cerulli Irelli E, Ugga L, Riva A, D'Amico A, Cabet S, Lesca G, Bilo L, Zara F, Iliescu C, Barca D, Fung F, Helbig K, Ortiz-Gonzalez X, Schelhaas HJ, Willemsen MH, van der Linden I, Canafoglia L, Courage C, Gommaraschi S, Gonzalez-Alegre P, Bardakjian T, Syrbe S, Schuler E, Lemke JR, Vari S, Roende G, Bak M, Huq M, Powis Z, Johannesen KM, Hammer TB, Møller RS, Rabin R, Pappas J, Zupanc ML, Zadeh N, Cohen J, Naidu S, Krey I, Saneto R, Thies J, Licchetta L, Tinuper P, Bisulli F, Minardi R, Bayat A, Villeneuve N, Molinari F, Salimi Dafsari H, Moller B, Le Roux M, Houdayer C, Vecchi M, Mammi I, Fiorini E, Proietti J, Ferri S, Cantalupo G, Battaglia DI, Gambardella ML, Contaldo I, Brogna C, Trivisano M, De Dominicis A, Bova SM, Gardella E, Striano P, Coppola A
Epilepsia 2024 Sep;65(9):2728-2750. Epub 2024 Jul 2 doi: 10.1111/epi.18054. PMID: 38953796
Strzelczyk A, Willems LM, Willig S, Rosenow F, Bauer S
Expert Rev Clin Pharmacol 2015;8(6):733-40. Epub 2015 Oct 5 doi: 10.1586/17512433.2015.1091303. PMID: 26436331
Striano P, Belcastro V
Expert Rev Neurother 2012 Dec;12(12):1411-7; quiz 1418. doi: 10.1586/ern.12.90. PMID: 23237348

Recent clinical studies

Etiology

Cuccurullo C, Cerulli Irelli E, Ugga L, Riva A, D'Amico A, Cabet S, Lesca G, Bilo L, Zara F, Iliescu C, Barca D, Fung F, Helbig K, Ortiz-Gonzalez X, Schelhaas HJ, Willemsen MH, van der Linden I, Canafoglia L, Courage C, Gommaraschi S, Gonzalez-Alegre P, Bardakjian T, Syrbe S, Schuler E, Lemke JR, Vari S, Roende G, Bak M, Huq M, Powis Z, Johannesen KM, Hammer TB, Møller RS, Rabin R, Pappas J, Zupanc ML, Zadeh N, Cohen J, Naidu S, Krey I, Saneto R, Thies J, Licchetta L, Tinuper P, Bisulli F, Minardi R, Bayat A, Villeneuve N, Molinari F, Salimi Dafsari H, Moller B, Le Roux M, Houdayer C, Vecchi M, Mammi I, Fiorini E, Proietti J, Ferri S, Cantalupo G, Battaglia DI, Gambardella ML, Contaldo I, Brogna C, Trivisano M, De Dominicis A, Bova SM, Gardella E, Striano P, Coppola A
Epilepsia 2024 Sep;65(9):2728-2750. Epub 2024 Jul 2 doi: 10.1111/epi.18054. PMID: 38953796
Kızıltan ME, Gündüz A, Coşkun T, Delil Ş, Pazarcı N, Özkara Ç, Yeni N
Clin EEG Neurosci 2017 Mar;48(2):123-129. Epub 2016 Jul 10 doi: 10.1177/1550059416646292. PMID: 27170668
Fan HC, Ho LI, Chi CS, Chen SJ, Peng GS, Chan TM, Lin SZ, Harn HJ
Cell Transplant 2014;23(4-5):441-58. doi: 10.3727/096368914X678454. PMID: 24816443
Ramantani G, Maillard LG, Bast T, Husain RA, Niggemann P, Kohlhase J, Hertzberg C, Ungerath K, Innes MA, Walkenhorst H, Bevot A, von Stülpnagel C, Thomas K, Niemann F, Ergun MA, Tacke U, Häusler M, Ikonomidou C, Korinthenberg R, Lee-Kirsch MA
Eur J Paediatr Neurol 2014 Jan;18(1):30-7. Epub 2013 Sep 5 doi: 10.1016/j.ejpn.2013.07.005. PMID: 24011626
DiMauro S
Biochim Biophys Acta 2004 Jul 23;1658(1-2):80-8. doi: 10.1016/j.bbabio.2004.03.014. PMID: 15282178

Diagnosis

Yan S, Fu F, Zhou H, Huang R, Wang Y, Liao C
Mol Genet Genomic Med 2024 Jan;12(1):e2317. Epub 2023 Nov 14 doi: 10.1002/mgg3.2317. PMID: 37962265Free PMC Article
Cameron JM, Ellis CA, Berkovic SF; ILAE Genetics Commission; ILAE Genetic Literacy Task Force
Epileptic Disord 2023 Oct;25(5):670-680. Epub 2023 Sep 6 doi: 10.1002/epd2.20152. PMID: 37616028Free 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
Kızıltan ME, Gündüz A, Coşkun T, Delil Ş, Pazarcı N, Özkara Ç, Yeni N
Clin EEG Neurosci 2017 Mar;48(2):123-129. Epub 2016 Jul 10 doi: 10.1177/1550059416646292. PMID: 27170668
Mehndiratta MM, Agarwal P, Tatke M, Krishnamurthy M
Neurol India 2002 Jun;50(2):162-7. PMID: 12134180

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
Strzelczyk A, Willems LM, Willig S, Rosenow F, Bauer S
Expert Rev Clin Pharmacol 2015;8(6):733-40. Epub 2015 Oct 5 doi: 10.1586/17512433.2015.1091303. PMID: 26436331
Striano P, Belcastro V
Expert Rev Neurother 2012 Dec;12(12):1411-7; quiz 1418. doi: 10.1586/ern.12.90. PMID: 23237348
Schulze-Bonhage A
Expert Opin Pharmacother 2011 Aug;12(12):1959-66. Epub 2011 Jun 20 doi: 10.1517/14656566.2011.591380. PMID: 21682662
Conry JA
Epilepsia 2004;45 Suppl 5:12-6. doi: 10.1111/j.0013-9580.2004.05004.x. PMID: 15283706

Prognosis

Sonoda Y, Fujita A, Torio M, Mukaino T, Sakata A, Matsukura M, Yonemoto K, Hatae K, Ichimiya Y, Chong PF, Ochiai M, Wada Y, Kadoya M, Okamoto N, Murakami Y, Suzuki T, Isobe N, Shigeto H, Matsumoto N, Sakai Y, Ohga S
Eur J Med Genet 2024 Feb;67:104895. Epub 2023 Dec 7 doi: 10.1016/j.ejmg.2023.104895. PMID: 38070824
Yan S, Fu F, Zhou H, Huang R, Wang Y, Liao C
Mol Genet Genomic Med 2024 Jan;12(1):e2317. Epub 2023 Nov 14 doi: 10.1002/mgg3.2317. PMID: 37962265Free PMC Article
Ebrahimi-Fakhari D, Wahlster L, Hoffmann GF, Kölker S
Pediatr Res 2014 Jan;75(1-2):217-26. Epub 2013 Oct 28 doi: 10.1038/pr.2013.185. PMID: 24165736
Ramantani G, Maillard LG, Bast T, Husain RA, Niggemann P, Kohlhase J, Hertzberg C, Ungerath K, Innes MA, Walkenhorst H, Bevot A, von Stülpnagel C, Thomas K, Niemann F, Ergun MA, Tacke U, Häusler M, Ikonomidou C, Korinthenberg R, Lee-Kirsch MA
Eur J Paediatr Neurol 2014 Jan;18(1):30-7. Epub 2013 Sep 5 doi: 10.1016/j.ejpn.2013.07.005. PMID: 24011626
Khiari HM, Franceschetti S, Jovic N, Mrabet A, Genton P
Neurol Sci 2009 Aug;30(4):315-8. Epub 2009 Jun 5 doi: 10.1007/s10072-009-0102-2. PMID: 19499178

Clinical prediction guides

Cuccurullo C, Cerulli Irelli E, Ugga L, Riva A, D'Amico A, Cabet S, Lesca G, Bilo L, Zara F, Iliescu C, Barca D, Fung F, Helbig K, Ortiz-Gonzalez X, Schelhaas HJ, Willemsen MH, van der Linden I, Canafoglia L, Courage C, Gommaraschi S, Gonzalez-Alegre P, Bardakjian T, Syrbe S, Schuler E, Lemke JR, Vari S, Roende G, Bak M, Huq M, Powis Z, Johannesen KM, Hammer TB, Møller RS, Rabin R, Pappas J, Zupanc ML, Zadeh N, Cohen J, Naidu S, Krey I, Saneto R, Thies J, Licchetta L, Tinuper P, Bisulli F, Minardi R, Bayat A, Villeneuve N, Molinari F, Salimi Dafsari H, Moller B, Le Roux M, Houdayer C, Vecchi M, Mammi I, Fiorini E, Proietti J, Ferri S, Cantalupo G, Battaglia DI, Gambardella ML, Contaldo I, Brogna C, Trivisano M, De Dominicis A, Bova SM, Gardella E, Striano P, Coppola A
Epilepsia 2024 Sep;65(9):2728-2750. Epub 2024 Jul 2 doi: 10.1111/epi.18054. PMID: 38953796
Yan S, Fu F, Zhou H, Huang R, Wang Y, Liao C
Mol Genet Genomic Med 2024 Jan;12(1):e2317. Epub 2023 Nov 14 doi: 10.1002/mgg3.2317. PMID: 37962265Free 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
Van Bogaert P
Epileptic Disord 2016 Sep 1;18(S2):115-119. doi: 10.1684/epd.2016.0856. PMID: 27629772
Ramantani G, Maillard LG, Bast T, Husain RA, Niggemann P, Kohlhase J, Hertzberg C, Ungerath K, Innes MA, Walkenhorst H, Bevot A, von Stülpnagel C, Thomas K, Niemann F, Ergun MA, Tacke U, Häusler M, Ikonomidou C, Korinthenberg R, Lee-Kirsch MA
Eur J Paediatr Neurol 2014 Jan;18(1):30-7. Epub 2013 Sep 5 doi: 10.1016/j.ejpn.2013.07.005. PMID: 24011626

Recent systematic reviews

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
Trinka E, Lattanzi S, Carpenter K, Corradetti T, Nucera B, Rinaldi F, Shankar R, Brigo F
CNS Drugs 2021 Aug;35(8):821-837. Epub 2021 Jul 7 doi: 10.1007/s40263-021-00831-y. PMID: 34232492Free PMC Article
Muccioli L, Farolfi A, Pondrelli F, d'Orsi G, Michelucci R, Freri E, Canafoglia L, Licchetta L, Toni F, Bonfiglioli R, Civollani S, Pettinato C, Maietti E, Marotta G, Fanti S, Tinuper P, Bisulli F
Eur J Nucl Med Mol Imaging 2020 Jun;47(6):1576-1584. Epub 2019 Dec 19 doi: 10.1007/s00259-019-04647-3. PMID: 31858178
Verrotti A, Carelli A, Coppola G
J Child Neurol 2014 Dec;29(12):1757-64. Epub 2014 Jul 17 doi: 10.1177/0883073814541469. PMID: 25038123

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