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Lafora disease

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® 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

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
Cenacchi G, Papa V, Costa R, Pegoraro V, Marozzo R, Fanin M, Angelini C
Virchows Arch 2019 Dec;475(6):671-686. Epub 2019 Jul 30 doi: 10.1007/s00428-019-02633-6. PMID: 31363843
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
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
Madhavan D, Kuzniecky RI
Rev Neurol Dis 2006 Summer;3(3):131-5. PMID: 17047580

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
Cenacchi G, Papa V, Costa R, Pegoraro V, Marozzo R, Fanin M, Angelini C
Virchows Arch 2019 Dec;475(6):671-686. Epub 2019 Jul 30 doi: 10.1007/s00428-019-02633-6. PMID: 31363843
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
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
DiMauro S, Lamperti C
Muscle Nerve 2001 Aug;24(8):984-99. doi: 10.1002/mus.1103. PMID: 11439374

Therapy

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
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
Michelucci R, Pasini E, Riguzzi P, Andermann E, Kälviäinen R, Genton P
Epileptic Disord 2016 Sep 1;18(S2):145-153. doi: 10.1684/epd.2016.0861. PMID: 27629998
Delgado-Escueta AV, Bourgeois BF
Epilepsia 2008 Dec;49 Suppl 9:13-24. doi: 10.1111/j.1528-1167.2008.01922.x. PMID: 19087113
Madhavan D, Kuzniecky RI
Rev Neurol Dis 2006 Summer;3(3):131-5. PMID: 17047580

Prognosis

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
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
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

Clinical prediction guides

Markussen KH, Corti M, Byrne BJ, Vander Kooi CW, Sun RC, Gentry MS
J Neurochem 2024 May;168(5):728-743. Epub 2023 Aug 9 doi: 10.1111/jnc.15926. PMID: 37554056Free PMC Article
Goebel HH, Müller HD
Ultrastruct Pathol 2013 Feb;37(1):19-22. doi: 10.3109/01913123.2012.670060. PMID: 23383614
DiMauro S, Spiegel R
Acta Myol 2011 Oct;30(2):96-102. PMID: 22106711Free PMC Article
Delgado-Escueta AV, Bourgeois BF
Epilepsia 2008 Dec;49 Suppl 9:13-24. doi: 10.1111/j.1528-1167.2008.01922.x. PMID: 19087113
Ganesh S, Puri R, Singh S, Mittal S, Dubey D
J Hum Genet 2006;51(1):1-8. Epub 2005 Nov 26 doi: 10.1007/s10038-005-0321-1. PMID: 16311711

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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