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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.
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\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\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\nIn most affected individuals, ADHD continues throughout life, but in about one-third of individuals, signs and symptoms of ADHD go away by adulthood.\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.
Difficulty walking
MedGen UID:
86319
Concept ID:
C0311394
Finding
Reduced ability to walk (ambulate).

Professional guidelines

PubMed

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

Recent clinical studies

Etiology

Gardella E, Marini C, Trivisano M, Fitzgerald MP, Alber M, Howell KB, Darra F, Siliquini S, Bölsterli BK, Masnada S, Pichiecchio A, Johannesen KM, Jepsen B, Fontana E, Anibaldi G, Russo S, Cogliati F, Montomoli M, Specchio N, Rubboli G, Veggiotti P, Beniczky S, Wolff M, Helbig I, Vigevano F, Scheffer IE, Guerrini R, Møller RS
Neurology 2018 Sep 18;91(12):e1112-e1124. Epub 2018 Aug 31 doi: 10.1212/WNL.0000000000006199. PMID: 30171078
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
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
Schulze-Bonhage A
Expert Opin Pharmacother 2011 Aug;12(12):1959-66. Epub 2011 Jun 20 doi: 10.1517/14656566.2011.591380. PMID: 21682662
DiMauro S
Biochim Biophys Acta 2004 Jul 23;1658(1-2):80-8. doi: 10.1016/j.bbabio.2004.03.014. PMID: 15282178

Diagnosis

Gardella E, Marini C, Trivisano M, Fitzgerald MP, Alber M, Howell KB, Darra F, Siliquini S, Bölsterli BK, Masnada S, Pichiecchio A, Johannesen KM, Jepsen B, Fontana E, Anibaldi G, Russo S, Cogliati F, Montomoli M, Specchio N, Rubboli G, Veggiotti P, Beniczky S, Wolff M, Helbig I, Vigevano F, Scheffer IE, Guerrini R, Møller RS
Neurology 2018 Sep 18;91(12):e1112-e1124. Epub 2018 Aug 31 doi: 10.1212/WNL.0000000000006199. PMID: 30171078
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
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
Sinha S, Satishchandra P, Gayathri N, Yasha TC, Shankar SK
J Neurol Sci 2007 Jan 15;252(1):16-23. Epub 2006 Dec 12 doi: 10.1016/j.jns.2006.09.021. PMID: 17166519
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

de Valles-Ibáñez G, Hildebrand MS, Bahlo M, King C, Coleman M, Green TE, Goldsmith J, Davis S, Gill D, Mandelstam S, Scheffer IE, Sadleir LG
Epilepsia Open 2022 Mar;7(1):170-180. Epub 2021 Nov 18 doi: 10.1002/epi4.12553. PMID: 34717047Free 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
Boissé Lomax L, Bayly MA, Hjalgrim H, Møller RS, Vlaar AM, Aaberg KM, Marquardt I, Gandolfo LC, Willemsen M, Kamsteeg EJ, O'Sullivan JD, Korenke GC, Bloem BR, de Coo IF, Verhagen JM, Said I, Prescott T, Stray-Pedersen A, Rasmussen M, Vears DF, Lehesjoki AE, Corbett MA, Bahlo M, Gecz J, Dibbens LM, Berkovic SF
Brain 2013 Apr;136(Pt 4):1146-54. Epub 2013 Feb 28 doi: 10.1093/brain/awt021. PMID: 23449775
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

Lee MM, McDowell GSV, De Vivo DC, Friedman D, Berkovic SF, Spanou M, Dinopoulos A, Grand K, Sanchez-Lara PA, Allen-Sharpley M, Warman-Chardon J, Solyom A, Levade T, Schuchman EH, Bennett SAL, Dyment DA, Pearson TS
Ann Clin Transl Neurol 2022 Dec;9(12):1941-1952. Epub 2022 Nov 3 doi: 10.1002/acn3.51687. PMID: 36325744Free PMC Article
Poudel P, Kafle SP, Pokharel R
Epilepsia Open 2021 Mar;6(1):206-215. Epub 2021 Feb 8 doi: 10.1002/epi4.12470. PMID: 33681663Free PMC Article
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
Sinha S, Satishchandra P, Gayathri N, Yasha TC, Shankar SK
J Neurol Sci 2007 Jan 15;252(1):16-23. Epub 2006 Dec 12 doi: 10.1016/j.jns.2006.09.021. PMID: 17166519

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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