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Lafora disease(LBD; EPM2A)

MedGen UID:
155631
Concept ID:
C0751783
Disease or Syndrome
Synonyms: Epilepsy progressive myoclonic 2; Lafora body disorder; Myoclonic epilepsy of Lafora; Progressive Myoclonus Epilepsy, Lafora Type
SNOMED CT: Lafora disease (230425004); Lafora body disease (230425004)
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).
 
Related genes: NHLRC1, EPM2A
 
Monarch Initiative: MONDO:0009697
OMIM®: 254780; 607566
OMIM® Phenotypic series: PS254780
Orphanet: ORPHA501

Disease characteristics

Excerpted from the GeneReview: Progressive Myoclonus Epilepsy, Lafora Type
Progressive myoclonus epilepsy, Lafora type (also known as Lafora disease [LD]) is characterized by focal occipital seizures presenting as transient blindness or visual hallucinations and fragmentary, symmetric, or generalized myoclonus beginning in previously healthy individuals at age eight to 19 years (peak 14-16 years). Generalized tonic-clonic seizures, atypical absence seizures, atonic seizures, and focal seizures with impaired awareness may occur. The course of the disease is characterized by increasing frequency and intractability of seizures. Status epilepticus with any of the seizure types is common. Cognitive decline becomes apparent at or soon after the onset of seizures. Dysarthria and ataxia appear early while spasticity appears late. Emotional disturbance and confusion are common in the early stages of the disease and are followed by dementia. Most affected individuals die within ten years of onset, usually from status epilepticus or from complications related to nervous system degeneration. [from GeneReviews]
Authors:
Anna C Jansen  |  Eva Andermann   view full author information

Additional descriptions

From OMIM
The Lafora type of progressive myoclonic epilepsy is an autosomal recessive disorder characterized by insidious onset of progressive neurodegeneration between 8 and 18 years of age. Initial features can include headache, difficulties in school work, myoclonic jerks, generalized seizures, and often visual hallucination. The myoclonus, seizures, and hallucinations gradually worsen and become intractable. This is accompanied by progressive cognitive decline, resulting in dementia. About 10 years after onset, affected individuals are in near-continuous myoclonus with absence seizures, frequent generalized seizures, and profound dementia or a vegetative state. Histologic studies of multiple tissues, including brain, muscle, liver, and heart show intracellular Lafora bodies, which are dense accumulations of malformed and insoluble glycogen molecules, termed polyglucosans (review by Ramachandran et al., 2009). Patients with Lafora disease-2 (620681) have a slightly slower progression of disease and later age at death (see Genotype/Phenotype Correlations). Genetic Heterogeneity of Lafora Disease Myoclonic epilepsy of Lafora-2 (MELF2, EPM2B; 620681) is caused by mutation in the NHLRC1 gene (608072), which encodes malin, on chromosome 6p22. For a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (254800).  http://www.omim.org/entry/254780
From MedlinePlus Genetics
Lafora progressive myoclonus epilepsy is a brain disorder characterized by recurrent seizures (epilepsy) and a decline in intellectual function. The signs and symptoms of the disorder usually appear in late childhood or adolescence and worsen with time.

Myoclonus is a term used to describe episodes of sudden, involuntary muscle jerking or twitching that can affect part of the body or the entire body. Myoclonus can occur when an affected person is at rest, and it is made worse by motion, excitement, or flashing light (photic stimulation). In the later stages of Lafora progressive myoclonus epilepsy, myoclonus often occurs continuously and affects the entire body.

Several types of seizures commonly occur in people with Lafora progressive myoclonus epilepsy. Generalized tonic-clonic seizures (also known as grand mal seizures) affect the entire body, causing muscle rigidity, convulsions, and loss of consciousness. Affected individuals may also experience occipital seizures, which can cause temporary blindness and visual hallucinations. Over time, the seizures worsen and become more difficult to treat. A life-threatening seizure condition called status epilepticus may also develop. Status epilepticus is a continuous state of seizure activity lasting longer than several minutes.

About the same time seizures begin, intellectual function starts to decline. Behavioral changes, depression, confusion, and speech difficulties (dysarthria) are among the early signs and symptoms of this disorder. As the condition worsens, a continued loss of intellectual function (dementia) impairs memory, judgment, and thought. Affected people lose the ability to perform the activities of daily living by their mid-twenties, and they ultimately require comprehensive care. People with Lafora progressive myoclonus epilepsy generally survive up to 10 years after symptoms first appear.  https://medlineplus.gov/genetics/condition/lafora-progressive-myoclonus-epilepsy

Clinical features

From HPO
Liver failure
MedGen UID:
88444
Concept ID:
C0085605
Disease or Syndrome
A disorder characterized by the inability of the liver to metabolize chemicals in the body. Causes include cirrhosis and drug-induced hepatotoxicity. Signs and symptoms include jaundice and encephalopathy. Laboratory test results reveal abnormal plasma levels of ammonia, bilirubin, lactic dehydrogenase, and alkaline phosphatase.
Apraxia
MedGen UID:
8166
Concept ID:
C0003635
Mental or Behavioral Dysfunction
A defect in the understanding of complex motor commands and in the execution of certain learned movements, i.e., deficits in the cognitive components of learned movements.
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.
Psychotic disorder
MedGen UID:
19568
Concept ID:
C0033975
Mental or Behavioral Dysfunction
A condition characterized by changes in personality and thought patterns, often accompanied by hallucinations and delusional beliefs, is known as psychosis.
Visual hallucination
MedGen UID:
66688
Concept ID:
C0233763
Sign or Symptom
Visual perception in the absence of a visual stimulus.
Focal sensory seizure with visual features
MedGen UID:
75815
Concept ID:
C0278188
Disease or Syndrome
A seizure characterized by elementary visual hallucinations such as flashing or flickering lights/colors, or other shapes, simple patterns, scotomata, or amaurosis as its first clinical manifestation.
Lafora bodies
MedGen UID:
569348
Concept ID:
C0333749
Cell Component
An intraneuronal inclusion body composed of acid mucopolysaccharides.
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.
Dementia
MedGen UID:
99229
Concept ID:
C0497327
Mental or Behavioral Dysfunction
A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
The term gait disturbance can refer to any disruption of the ability to walk. In general, this can refer to neurological diseases but also fractures or other sources of pain that is triggered upon walking. However, in the current context gait disturbance refers to difficulty walking on the basis of a neurological or muscular disease.
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.
Progressive neurologic deterioration
MedGen UID:
381506
Concept ID:
C1854838
Finding
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.
Generalized non-motor (absence) seizure
MedGen UID:
1385688
Concept ID:
C4316903
Disease or Syndrome
A generalized non-motor (absence) seizure is a type of a type of dialeptic seizure that is of electrographically generalized onset. It is a generalized seizure characterized by an interruption of activities, a blank stare, and usually the person will be unresponsive when spoken to. Any ictal motor phenomena are minor in comparison to these non-motor features.
Cutaneous photosensitivity
MedGen UID:
87601
Concept ID:
C0349506
Pathologic Function
An increased sensitivity of the skin to light. Photosensitivity may result in a rash upon exposure to the sun (which is known as photodermatosis). Photosensitivity can be diagnosed by phototests in which light is shone on small areas of skin.
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).

Professional guidelines

PubMed

Nitschke F, Ahonen SJ, Nitschke S, Mitra S, Minassian BA
Nat Rev Neurol 2018 Oct;14(10):606-617. doi: 10.1038/s41582-018-0057-0. PMID: 30143794Free PMC Article
Parihar R, Rai A, Ganesh S
J Genet 2018 Jul;97(3):611-624. PMID: 30027899
Monaghan TS, Delanty N
CNS Drugs 2010 Jul;24(7):549-61. doi: 10.2165/11319250-000000000-00000. PMID: 20527995

Recent clinical studies

Etiology

Orsini A, Valetto A, Bertini V, Esposito M, Carli N, Minassian BA, Bonuccelli A, Peroni D, Michelucci R, Striano P
Seizure 2019 Oct;71:247-257. Epub 2019 Aug 23 doi: 10.1016/j.seizure.2019.08.012. PMID: 31476531Free PMC Article
Turnbull J, Tiberia E, Striano P, Genton P, Carpenter S, Ackerley CA, Minassian BA
Epileptic Disord 2016 Sep 1;18(S2):38-62. doi: 10.1684/epd.2016.0842. PMID: 27702709Free PMC Article
Kälviäinen R
Semin Neurol 2015 Jun;35(3):293-9. Epub 2015 Jun 10 doi: 10.1055/s-0035-1552620. PMID: 26060909
Girard JM, Turnbull J, Ramachandran N, Minassian BA
Handb Clin Neurol 2013;113:1731-6. doi: 10.1016/B978-0-444-59565-2.00043-5. PMID: 23622396
Zupanc ML, Legros B
Cerebellum 2004;3(3):156-71. doi: 10.1080/14734220410035356. PMID: 15543806

Diagnosis

Orsini A, Valetto A, Bertini V, Esposito M, Carli N, Minassian BA, Bonuccelli A, Peroni D, Michelucci R, Striano P
Seizure 2019 Oct;71:247-257. Epub 2019 Aug 23 doi: 10.1016/j.seizure.2019.08.012. PMID: 31476531Free PMC Article
Turnbull J, Tiberia E, Striano P, Genton P, Carpenter S, Ackerley CA, Minassian BA
Epileptic Disord 2016 Sep 1;18(S2):38-62. doi: 10.1684/epd.2016.0842. PMID: 27702709Free PMC Article
Kälviäinen R
Semin Neurol 2015 Jun;35(3):293-9. Epub 2015 Jun 10 doi: 10.1055/s-0035-1552620. PMID: 26060909
Girard JM, Turnbull J, Ramachandran N, Minassian BA
Handb Clin Neurol 2013;113:1731-6. doi: 10.1016/B978-0-444-59565-2.00043-5. PMID: 23622396
Zupanc ML, Legros B
Cerebellum 2004;3(3):156-71. doi: 10.1080/14734220410035356. PMID: 15543806

Therapy

Donohue KJ, Fitzsimmons B, Bruntz RC, Markussen KH, Young LEA, Clarke HA, Coburn PT, Griffith LE, Sanders W, Klier J, Burke SN, Maurer AP, Minassian BA, Sun RC, Kordasiewisz HB, Gentry MS
Neurotherapeutics 2023 Oct;20(6):1808-1819. Epub 2023 Sep 12 doi: 10.1007/s13311-023-01434-9. PMID: 37700152Free PMC Article
Mollá B, Heredia M, Campos Á, Sanz P
Mol Neurobiol 2022 Oct;59(10):6018-6032. Epub 2022 Jul 14 doi: 10.1007/s12035-022-02956-7. PMID: 35835895Free PMC Article
Brewer MK, Uittenbogaard A, Austin GL, Segvich DM, DePaoli-Roach A, Roach PJ, McCarthy JJ, Simmons ZR, Brandon JA, Zhou Z, Zeller J, Young LEA, Sun RC, Pauly JR, Aziz NM, Hodges BL, McKnight TR, Armstrong DD, Gentry MS
Cell Metab 2019 Oct 1;30(4):689-705.e6. Epub 2019 Jul 25 doi: 10.1016/j.cmet.2019.07.002. PMID: 31353261Free PMC Article
Nitschke F, Ahonen SJ, Nitschke S, Mitra S, Minassian BA
Nat Rev Neurol 2018 Oct;14(10):606-617. doi: 10.1038/s41582-018-0057-0. PMID: 30143794Free PMC Article
Monaghan TS, Delanty N
CNS Drugs 2010 Jul;24(7):549-61. doi: 10.2165/11319250-000000000-00000. PMID: 20527995

Prognosis

Mitra S, Gumusgoz E, Minassian BA
Rev Neurol (Paris) 2022 Apr;178(4):315-325. Epub 2021 Jul 21 doi: 10.1016/j.neurol.2021.06.006. PMID: 34301405Free PMC Article
Orsini A, Valetto A, Bertini V, Esposito M, Carli N, Minassian BA, Bonuccelli A, Peroni D, Michelucci R, Striano P
Seizure 2019 Oct;71:247-257. Epub 2019 Aug 23 doi: 10.1016/j.seizure.2019.08.012. PMID: 31476531Free PMC Article
Turnbull J, Tiberia E, Striano P, Genton P, Carpenter S, Ackerley CA, Minassian BA
Epileptic Disord 2016 Sep 1;18(S2):38-62. doi: 10.1684/epd.2016.0842. PMID: 27702709Free PMC Article
Kälviäinen R
Semin Neurol 2015 Jun;35(3):293-9. Epub 2015 Jun 10 doi: 10.1055/s-0035-1552620. PMID: 26060909
Turnbull J, Girard JM, Lohi H, Chan EM, Wang P, Tiberia E, Omer S, Ahmed M, Bennett C, Chakrabarty A, Tyagi A, Liu Y, Pencea N, Zhao X, Scherer SW, Ackerley CA, Minassian BA
Brain 2012 Sep;135(Pt 9):2684-98. doi: 10.1093/brain/aws205. PMID: 22961547Free PMC Article

Clinical prediction guides

Acharya JN, Acharya VJ
J Clin Neurophysiol 2023 Feb 1;40(2):100-108. Epub 2022 Jun 30 doi: 10.1097/WNP.0000000000000913. PMID: 36735458
Riva A, Orsini A, Scala M, Taramasso V, Canafoglia L, d'Orsi G, Di Claudio MT, Avolio C, D'Aniello A, Elia M, Franceschetti S, Di Gennaro G, Bisulli F, Tinuper P, Tappatà M, Romeo A, Freri E, Marini C, Costa C, Sofia V, Ferlazzo E, Magaudda A, Veggiotti P, Gennaro E, Pistorio A, Minetti C, Bianchi A, Striano S, Michelucci R, Zara F, Minassian BA, Striano P; Italian League Against Epilepsy Genetic Commission
J Neurol Sci 2021 May 15;424:117409. Epub 2021 Mar 20 doi: 10.1016/j.jns.2021.117409. PMID: 33773408Free PMC Article
Duran J, Gruart A, López-Ramos JC, Delgado-García JM, Guinovart JJ
Adv Neurobiol 2019;23:311-329. doi: 10.1007/978-3-030-27480-1_10. PMID: 31667813Free PMC Article
Ellingwood SS, Cheng A
J Endocrinol 2018 Sep;238(3):R131-R141. Epub 2018 Jun 6 doi: 10.1530/JOE-18-0120. PMID: 29875163Free PMC Article
Ferlazzo E, Canafoglia L, Michelucci R, Gambardella A, Gennaro E, Pasini E, Riguzzi P, Plasmati R, Volpi L, Labate A, Gasparini S, Villani F, Casazza M, Viri M, Zara F, Minassian BA, Turnbull J, Serratosa JM, Guerrero-López R, Franceschetti S, Aguglia U
Epilepsia 2014 Dec;55(12):e129-33. Epub 2014 Sep 30 doi: 10.1111/epi.12806. PMID: 25270369

Recent systematic reviews

Pondrelli F, Minardi R, Muccioli L, Zenesini C, Vignatelli L, Licchetta L, Mostacci B, Tinuper P, Vander Kooi CW, Gentry MS, Bisulli F
Orphanet J Rare Dis 2023 Sep 2;18(1):263. doi: 10.1186/s13023-023-02880-6. PMID: 37658439Free PMC Article
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
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

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