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Lafora disease(LBD; EPM2A)

MedGen UID:
155631
Concept ID:
C0751783
Disease or Syndrome
Synonyms: Epilepsy progressive myoclonic 2; EPILEPSY, PROGRESSIVE MYOCLONIC, 2A; EPM2A-Related Lafora Disease; Lafora body disorder; Myoclonic epilepsy of Lafora; NHLRC1-Related Lafora Disease; Progressive Myoclonus Epilepsy, Lafora Type
Modes of inheritance:
Heterogeneous
MedGen UID:
67020
Concept ID:
C0242960
Organism Attribute
Source: HPO
The presence of apparently similar characters for which the genetic evidence indicates that different genes or different genetic mechanisms are involved in different pedigrees. In clinical settings genetic heterogeneity refers to the presence of a variety of genetic defects which cause the same disease, often due to mutations at different loci on the same gene, a finding common to many human diseases including ALZHEIMER DISEASE; CYSTIC FIBROSIS; LIPOPROTEIN LIPASE DEFICIENCY, FAMILIAL; and POLYCYSTIC KIDNEY DISEASES. (Rieger, et al., Glossary of Genetics: Classical and Molecular, 5th ed; Segen, Dictionary of Modern Medicine, 1992)
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Lafora disease (230425004); Lafora body disease (230425004)
 
Genes (locations): EPM2A (6q24.3); NHLRC1 (6p22.3)
OMIM®: 254780
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). For a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (254800).  http://www.omim.org/entry/254780
From GHR
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://ghr.nlm.nih.gov/condition/lafora-progressive-myoclonus-epilepsy

Clinical features

From HPO
Hepatic 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 group of cognitive disorders characterized by the inability to perform previously learned skills that cannot be attributed to deficits of motor or sensory function. The two major subtypes of this condition are ideomotor (see APRAXIA, IDEOMOTOR) and ideational apraxia, which refers to loss of the ability to mentally formulate the processes involved with performing an action. For example, dressing apraxia may result from an inability to mentally formulate the act of placing clothes on the body. Apraxias are generally associated with lesions of the dominant PARIETAL LOBE and supramarginal gyrus. (From Adams et al., Principles of Neurology, 6th ed, pp56-7)
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Sign or Symptom
A rapid, involuntary jerk of a muscle or group of muscles.
Psychosis
MedGen UID:
19568
Concept ID:
C0033975
Mental or Behavioral Dysfunction
A mental disorder characterized by personality change, impaired functioning, and loss of touch with reality.
Visual hallucinations
MedGen UID:
66688
Concept ID:
C0233763
Sign or Symptom
Optical perception of an object, person or event in the absence of a corresponding stimulus.
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
A finding referring to walking difficulties.
Generalized tonic-clonic seizures with focal onset
MedGen UID:
164077
Concept ID:
C0877017
Disease or Syndrome
Bilateral convulsive seizures are focal seizure with secondary bilateral motor phenomena, not primary generalized seizures.
Visual auras
MedGen UID:
340622
Concept ID:
C1850765
Disease or Syndrome
Auras with sensation of flashing or flickering lights, spots, simple patterns, scotomata, or amaurosis.
Progressive neurologic deterioration
MedGen UID:
381506
Concept ID:
C1854838
Finding
Generalized myoclonic seizures
MedGen UID:
892704
Concept ID:
C4021759
Disease or Syndrome
Seizures with sudden, brief (< 100 msec) involuntary single or multiple contraction(s) of muscles(s) or muscle groups of variable topography (axial, proximal limb, distal).
Absence seizures
MedGen UID:
1385688
Concept ID:
C4316903
Disease or Syndrome
Generalized seizure that manifests in a form of a brief episode of impairment of consciousness with or without accompanying motor phenomena such as clonic-tonic components, automatisms, or autonomic components.
Simple partial occipital seizures
MedGen UID:
1373494
Concept ID:
C4317153
Disease or Syndrome
A type of focal seizure (i.e., affecting initially only one hemisphere of the brain) that is simple (not resulting in alteration of consciousness) that originates in the occipital lobe. Visual hallucinations are the hallmark of occipital seizures, but are not invariably present. Hallucinations typically commence in the visual field contralateral to the affected visual cortex and then spread to involve the entire visual field. Elementary visual seizures are characterized by fleeting visual manifestations which may be either positive (flashes, phosphenes) or, less commonly, negative (scotoma, hemianopia, amaurosis). Positive phenomena are usually flashes of colour or light, which are simple in shape and may be static or mobile.
Abnormality of metabolism/homeostasis
MedGen UID:
867398
Concept ID:
C4021768
Finding
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
Disturbance of eyesight.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Lafora disease in Orphanet.

Recent clinical studies

Etiology

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
Goldsmith D, Minassian BA
Epilepsy Behav 2016 Sep;62:132-5. Epub 2016 Jul 25 doi: 10.1016/j.yebeh.2016.06.041. PMID: 27459034Free PMC Article
Kecmanović M, Jović N, Keckarević-Marković M, Keckarević D, Stevanović G, Ignjatović P, Romac S
Clin Genet 2016 Jan;89(1):104-8. Epub 2015 Mar 19 doi: 10.1111/cge.12570. PMID: 25683376
Mittal S, Upadhyay M, Singh PK, Parihar R, Ganesh S
J Biosci 2015 Dec;40(5):863-71. doi: 10.1007/s12038-015-9570-0. PMID: 26648032
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

Diagnosis

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
Casciato S, Gambardella S, Mascia A, Quarato PP, D'Aniello A, Ackurina Y, Albano V, Fornai F, Scala S, Di Gennaro G
Int J Neurosci 2017 Dec;127(12):1150-1153. Epub 2017 Jun 12 doi: 10.1080/00207454.2017.1337012. PMID: 28556688
Ahmad A, Dad R, Ullah MI, Baig TA, Ahmad IN, Nasir A, Hübner CA, Hassan MJ
J Neurol Sci 2017 Feb 15;373:263-267. Epub 2017 Jan 4 doi: 10.1016/j.jns.2017.01.010. PMID: 28131202
DePaoli-Roach AA, Contreras CJ, Segvich DM, Heiss C, Ishihara M, Azadi P, Roach PJ
J Biol Chem 2015 Jan 9;290(2):841-50. Epub 2014 Nov 21 doi: 10.1074/jbc.M114.607796. PMID: 25416783Free PMC Article
Corcia L, Hohensee S, Olivero A, Wong J
Pediatr Neurol 2014 Nov;51(5):713-6. Epub 2014 Aug 7 doi: 10.1016/j.pediatrneurol.2014.07.034. PMID: 25217339

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
Goldsmith D, Minassian BA
Epilepsy Behav 2016 Sep;62:132-5. Epub 2016 Jul 25 doi: 10.1016/j.yebeh.2016.06.041. PMID: 27459034Free PMC Article
Monaghan TS, Delanty N
CNS Drugs 2010 Jul;24(7):549-61. doi: 10.2165/11319250-000000000-00000. PMID: 20527995
Madhavan D, Kuzniecky RI
Rev Neurol Dis 2006 Summer;3(3):131-5. PMID: 17047580
Kumada S, Kubota M, Hayashi M, Uchiyama A, Kurata K, Kagamihara Y
Neurology 2006 May 23;66(10):1574-6. doi: 10.1212/01.wnl.0000216147.12172.39. PMID: 16717223

Prognosis

Casciato S, Gambardella S, Mascia A, Quarato PP, D'Aniello A, Ackurina Y, Albano V, Fornai F, Scala S, Di Gennaro G
Int J Neurosci 2017 Dec;127(12):1150-1153. Epub 2017 Jun 12 doi: 10.1080/00207454.2017.1337012. PMID: 28556688
Ahmad A, Dad R, Ullah MI, Baig TA, Ahmad IN, Nasir A, Hübner CA, Hassan MJ
J Neurol Sci 2017 Feb 15;373:263-267. Epub 2017 Jan 4 doi: 10.1016/j.jns.2017.01.010. PMID: 28131202
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
Kecmanović M, Jović N, Keckarević-Marković M, Keckarević D, Stevanović G, Ignjatović P, Romac S
Clin Genet 2016 Jan;89(1):104-8. Epub 2015 Mar 19 doi: 10.1111/cge.12570. PMID: 25683376
Poyrazoğlu HG, Karaca E, Per H, Gümüs H, Onay H, Canpolat M, Canöz Ö, Ozkınay F, Kumandas S
J Child Neurol 2015 May;30(6):777-81. Epub 2014 Jul 10 doi: 10.1177/0883073814535489. PMID: 25015673

Clinical prediction guides

Chambers JK, Thongtharb A, Shiga T, Azakami D, Saito M, Sato M, Morozumi M, Nakayama H, Uchida K
Vet Pathol 2018 Jul;55(4):543-551. Epub 2018 Feb 14 doi: 10.1177/0300985818758471. PMID: 29444631
Ahmad A, Dad R, Ullah MI, Baig TA, Ahmad IN, Nasir A, Hübner CA, Hassan MJ
J Neurol Sci 2017 Feb 15;373:263-267. Epub 2017 Jan 4 doi: 10.1016/j.jns.2017.01.010. PMID: 28131202
Goldsmith D, Minassian BA
Epilepsy Behav 2016 Sep;62:132-5. Epub 2016 Jul 25 doi: 10.1016/j.yebeh.2016.06.041. PMID: 27459034Free PMC Article
Kecmanović M, Jović N, Keckarević-Marković M, Keckarević D, Stevanović G, Ignjatović P, Romac S
Clin Genet 2016 Jan;89(1):104-8. Epub 2015 Mar 19 doi: 10.1111/cge.12570. PMID: 25683376
Romá-Mateo C, Aguado C, García-Giménez JL, Ibáñez-Cabellos JS, Seco-Cervera M, Pallardó FV, Knecht E, Sanz P
Mol Neurobiol 2015;51(3):932-46. Epub 2014 May 17 doi: 10.1007/s12035-014-8747-0. PMID: 24838580

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