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Progressive Myoclonus Epilepsy, Lafora Type

Synonyms: Lafora Body Disease, Lafora Disease

, MD, PhD and , MD, PhD, FCCMG.

Author Information
, MD, PhD
Pediatric Neurology Unit
Department of Pediatrics
Universitair Ziekenhuis Brussel
Department of Health Sciences
Vrije Universiteit Brussel
Brussels, Belgium
, MD, PhD, FCCMG
Director, Neurogenetics Unit
Montreal Neurological Hospital & Institute
Professor, Departments of Neurology & Neurosurgery and Human Genetics
McGill University
Montreal, Quebec, Canada

Initial Posting: ; Last Update: January 22, 2015.

Summary

Clinical characteristics.

Lafora disease (LD) is characterized by fragmentary, symmetric, or generalized myoclonus and/or generalized tonic-clonic seizures, visual hallucinations (occipital seizures), and progressive neurologic degeneration including cognitive and/or behavioral deterioration, dysarthria, and ataxia beginning in previously healthy adolescents between ages 12 and 17 years. The frequency and intractability of seizures increase over time. Status epilepticus is common. Emotional disturbance and confusion are common at or soon after onset of seizures and are followed by dementia. Dysarthria and ataxia appear early, spasticity late. Most affected individuals die within ten years of onset, usually from status epilepticus or from complications related to nervous system degeneration.

Diagnosis/testing.

Diagnosis is usually based on clinical and EEG findings and detection of two pathogenic variants in one of the two genes known to be associated with LD: EPM2A or NHLRC1 (EPM2B). On rare occasion skin biopsy to detect Lafora bodies is necessary to confirm the diagnosis.

Management.

Treatment of manifestations: Antiepileptic drugs (AEDs) are effective against generalized seizures.

Prevention of secondary complications: Overmedication in treating drug-resistant myoclonus is a risk. Gastrostomy feedings can decrease the risk of aspiration pneumonia when disease is advanced.

Surveillance: Clinical and psychosocial evaluation at three- to six-month intervals throughout the teenage years.

Agents/circumstances to avoid: Phenytoin, and possibly carbamazepine, oxcarbazepine, and lamotrigine.

Genetic counseling.

Lafora disease is inherited in an autosomal recessive manner. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for at-risk pregnancies are possible if the pathogenic variants in the family are known.

Diagnosis

Clinical Diagnosis

The diagnosis of Lafora disease (LD) is suspected in a previously healthy older child or adolescent (usually in the early teens) who has the following:

  • Fragmentary, symmetric, or generalized myoclonus and/or generalized tonic-clonic seizures
  • Visual hallucinations (occipital seizures)
  • Progressive neurologic degeneration including cognitive and/or behavioral deterioration, dysarthria, ataxia, and, at later stages, spasticity and dementia
  • Slowing of background activity, loss of α-rhythm and sleep features, and photosensitivity on early EEGs
  • Periodic acid Schiff-positive intracellular inclusion bodies (Lafora bodies) on skin biopsy
  • Normal MRI of the brain at onset

See Table 1.

Table 1.

Clinical Evaluation of Lafora Disease

Evaluation TypeAt OnsetLater in Disease Course
General physical examination, including liver and spleen sizes NormalNormal
Neurologic examination, including fundi and reflexes NormalDysarthria, ataxia, spasticity; fundi remain normal
Mental state examination Visual hallucinations (epileptic), depressed mood, cognitive deficitsIncreased hallucinations, agitation, and dementia with predominantly frontal cognitive impairment affecting mainly performance ability and executive function
EEG Normal or slow background, loss of α-rhythm and sleep features; photosensitivity is commonSlow background, paroxysms of generalized irregular spike-wave discharges with occipital predominance, and focal, especially occipital, abnormalities
Visual, somatosensory, and auditory brain stem evoked potentials High-voltage visual and somatosensory evoked potentialsAmplitudes may return to normal size; prolongation of brain stem and central latencies
Nerve conduction studies NormalNormal
MRI of the brain NormalNormal or atrophy 1
Proton MR spectroscopy of the brain Data not availableReduced NAA/creatine ratio in frontal and occipital cortex, basal ganglia, and cerebellum; reduced NAA/myoinositol ratio in frontal gray and white matter; reduced NAA/choline ratio in cerebellum 2
Transcranial magnetic stimulation (TMS)Not applicableDefective short intracortical inhibition(SICI): inhibition at ISI 6 ms and ISI 10 ms;
Defective long interval cortical inhibition (LICI)

Minassian [2001], Minassian [2002], Villanueva et al [2006], Pichiecchio et al [2008], Altindag et al [2009], Canafoglia et al [2010]

1. 

No significant correlation observed with disease evolution

2. 

At least two years after onset of symptoms

Testing

Skin biopsy reveals Lafora bodies [Carpenter et al 1974, Carpenter & Karpati 1981] composed of starch-like polyglucosans, which are insufficiently branched and hence insoluble glycogen molecules. Lafora bodies are present in either eccrine duct cells or in apocrine myoepithelial cells.

Note: (1) Normal PAS-positive apical granules in secretory apocrine cells found in the axilla can be mistaken for Lafora bodies; thus, biopsy of skin outside the axilla and genital regions is favored, as eccrine duct cell Lafora bodies are unmistakable [Andrade et al 2003]. (2) Interpretation of findings on skin biopsy involves a risk of false negative results [Lesca et al 2010], especially in newly symptomatic individuals, and a risk of false positive results because of the difficulty in distinguishing Lafora bodies from normal PAS-positive polysaccharides in apocrine glands [Drury et al 1993, Andrade et al 2003]. (3) Although sequencing and deletion/duplication analysis of EPM2A and NHLRC1 represent the gold standard for confirming the diagnosis, skin biopsy remains a useful diagnostic tool in individuals with a clinical diagnosis of Lafora disease in whom no pathogenic variant can be identified.

Molecular Genetic Testing

Genes. The two genes in which pathogenic variants are known to cause LD are EPM2A [Minassian et al 1998] and NHLRC1 (also known as EPM2B) [Chan et al 2003b]. See Table 2.

Clinical testing

Table 2.

Summary of Molecular Genetic Testing Used in Progressive Myoclonus Epilepsy, Lafora Type

Gene 1 Proportion of Lafora Disease Attributed to Mutation of This GeneTest Method
EPM2A22%-70% 2, 3, 4, 5, 6Sequence analysis 7, 8
Deletion/duplication analysis 9, 10
NHLRC1 (EPM2B)27%-73% 2, 3, 4, 5, 6Sequence analysis 7, 8
Deletion/duplication analysis 9, 10
Unknown 11NANA
1.

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Gómez-Abad et al [2005] found pathogenic variants in 97% (75/77) of families with LD: EPM2A (70%) and NHLRC1 (27%).

3.

Franceschetti et al [2006] found pathogenic variants in 21/22 (95%) of families with LD: EPM2A (22%) and NHLRC1 (73%).

4.

Lohi et al [2006] found pathogenic variants in 88% (75/85) of families with LD: EPM2A (45%) and NHLRC1 (43%).

5.

Singh et al [2006] found pathogenic variants in 84% (23/28) of families with LD: EPM2A (54%) and NHLRC1 (34%).

6.

The marked variations may reflect ethnic differences or chance variation and small sample size.

7.

Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

8.

Studies of the combined pathogenic variant detection frequency of sequence analysis of EPM2A and NHLRC1 revealed that between 88% and 97% of pathogenic variants in these two genes can be detected using sequence analysis alone [Gómez-Abad et al 2005, Franceschetti et al 2006, Lohi et al 2006].

9.

Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

10.

The proportion of pathogenic variants in EPM2A and NHLRC1 not detected by sequence analysis that are attributable to deletions is unknown. In the one study that screened for suspected deletions in three individuals with a single heterozygous sequence-detectable pathogenic variant, Lohi et al [2007] found three deletions in three families, one in EPM2A and two in NHLRC1. See also Molecular Genetics. Kecmanović et al reported an affected individual with a homozygous deletion encompassing the entire NHLRC1 gene and with a clinical course more progressive than in most individuals with mutation of NHLRC1 [Kecmanović et al 2013].

11.

Pathogenic variants in at least one other gene also cause LD. Chan et al [2004] described one family with three individuals with biopsy-confirmed LD and no identifiable pathogenic variant in either EPM2A or NHLRC1. Linkage and haplotype analyses excluded both loci from causative involvement in this family, providing indirect evidence for a third locus for LD. The findings were supported by independent studies [Singh et al 2005, Singh et al 2006].

Interpretation of test results. Deletions should be suspected:

  • In affected individuals who have a single heterozygous pathogenic variant in one of the genes, and
  • In affected individuals who have an apparently homozygous pathogenic variant in one of the genes, but the pathogenic variant is carried by only one parent.

Testing Strategy

To Confirm/Establish the Diagnosis in a Proband

Molecular genetic testing

  • Single gene testing. One strategy for molecular diagnosis of a proband suspected of having LD is targeted analyses of NHLRC1 or EPM2A. Identification of biallelic pathogenic variants in either EPM2A or NHLRC1 is required:
  • Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having LD is use of a multi-gene panel which includes EPM2A, NHLRC1, and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.
  • Genomic testing. If single-gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of LD, genomic testing may be considered. Such testing may include whole-exome sequencing (WES), whole-genome sequencing (WGS), and whole-mitochondrial sequencing (WMitoSeq).

    Notes regarding WES and WGS. (1) False negative rates vary by genomic region; therefore, genomic testing may not be as accurate as targeted single-gene testing or multi-gene molecular genetic testing panels; (2) most laboratories confirm positive results using a second, well-established method; (3) nucleotide repeat expansions and epigenetic alterations cannot be detected; (4) deletions/duplications larger than 8-10 nucleotides are not detected effectively [Biesecker & Green 2014].

Note: Although some evidence suggests that persons with NHLRC1-associated LD tend to live longer than those with EPM2A-associated LD [Gómez-Abad et al 2005, Franceschetti et al 2006], the clinical manifestations of LD caused by pathogenic variants in either gene are so similar that it is not possible to predict which gene will be mutated in any given individual.

Skin biopsy. Detection of Lafora bodies on skin biopsy. Note: Lafora bodies may also be identified in individual with early-onset Lafora body disease; see Differential Diagnosis.

Clinical Characteristics

Clinical Description

Lafora disease (LD) typically starts between ages 12 and 17 years, after a period of apparently normal development. Many affected individuals experience isolated febrile or nonfebrile convulsions in infancy or early in childhood. Intractable seizures rarely begin as early as age six years. In families with more than one affected child, clinical signs such as subtle myoclonus, visual hallucinations, or headaches are noted earlier in subsequent affected children than in the proband [Minassian et al 2000b, Minassian 2002]. Intra- and interfamilial variability in age at onset is considerable [Gómez-Abad et al 2007, Lohi et al 2007].

The main seizure types in LD include myoclonic seizures and occipital seizures, although generalized tonic-clonic seizures, atypical absence seizures, and atonic and complex partial seizures may occur.

Myoclonus can be fragmentary, symmetric, or massive (generalized). It occurs at rest and is exaggerated by action, photic stimulation, or excitement. Both negative (loss of tone) and positive (jerking) myoclonus can occur. Myoclonus usually disappears with sleep. Trains of massive myoclonus with relative preservation of consciousness have been reported. Myoclonus is the primary reason for early wheelchair dependency. In the advanced stages of the disease, affected individuals often have continuous generalized myoclonus.

Occipital seizures present as transient blindness, simple or complex visual hallucinations, photomyoclonic or photoconvulsive seizures, or migraine with scintillating scotomata [Berkovic et al 1993, Minassian et al 2000b].

The course of the disease is characterized by increasing frequency and intractability of seizures. Status epilepticus with any of the previously mentioned seizure types is common. Cognitive decline becomes apparent at or soon after the onset of seizures. Dysarthria and ataxia appear early, spasticity late. Emotional disturbance and confusion are common in the early stages of the disease and are followed by dementia.

By their mid-twenties, most affected individuals are in a vegetative state with continuous myoclonus and require tube feeding. Some maintain minimal interactions with the family such as a reflex-like smiling upon cajoling. Affected individuals who are not tube-fed aspirate frequently as a result of seizures; death from aspiration pneumonia is common.

Most affected individuals die within ten years of onset, usually from status epilepticus or from complications related to nervous system degeneration [Minassian 2002].

Genotype-Phenotype Correlations

Genotype-phenotype correlations are difficult to establish in LD because compound heterozygotes in different combinations are common [Chan et al 2005, Gómez-Abad et al 2005]. Variation by country in the care available for individuals with LD may in part influence longevity and disease complications.

Within an ethnic group of individuals sharing the same pathogenic variant the phenotype can be highly variable [Gómez-Abad et al 2007] or very similar [Turnbull et al 2008].

Intra- and interfamilial variability in age at onset is considerable, suggesting that genetic factors other than the EPM2A or NHLRC1 pathogenic variants may influence the pathogenesis of LD [Gómez-Abad et al 2007, Lohi et al 2007]. The LD gene products laforin and malin are known to interact with a diverse set of proteins and variations in gene(s) that code for these interacting protein(s) could contribute to variations in phenotype [Singh & Ganesh 2012]. It has indeed been demonstrated that a sequence variant in PPP1R3C, which codes for the protein PTG (protein targeting to glycogen), contributes to a milder course of LD [Guerrero et al 2011].

To date, no correlations between phenotype and mutation type (missense or truncating) or location of the pathogenic variant in the gene have been demonstrated

Nomenclature

Lafora disease (LD) is also referred to as myoclonic epilepsy of Lafora or progressive myoclonic epilepsy type 2.

The term progressive myoclonus epilepsy (PME) covers a large and varied group of diseases characterized by myoclonus, generalized tonic-clonic seizures, and progressive neurologic deterioration [Berkovic et al 1986].

Prevalence

Exact prevalence figures for LD are not available.

LD occurs worldwide. Although relatively rare in the non-consanguineous populations of the United States, Canada, China, and Japan, LD is relatively common in the Mediterranean basin of Spain, France, and Italy, in restricted regions of central Asia, India, Pakistan, northern Africa, and the Middle East, in ethnic isolates from the southern United States and Quebec, and in other parts of the world with a high rate of consanguinity [Delgado-Escueta et al 2001].

Within the Italian and Japanese populations, pathogenic variants in NHLRC1 are more common than pathogenic variants in EPM2A. Conversely, EPM2A pathogenic variants are more common in the Spanish and French populations. Within the Indian and Arab populations the distribution of pathogenic variants in the two genes is more or less even [Singh & Ganesh 2009, Lesca et al 2010].

Note: LD has not been reported in Finland, where founder effects for a number of genetic disorders are common, and where EPM1 (Unverricht-Lundborg disease) has the highest prevalence [A Lehesjoki & R Kälviäinen, personal communication].

Differential Diagnosis

Early-onset Lafora body disease is a newly recognized condition characterized by progressive myoclonus epilepsy and Lafora bodies [Turnbull et al 2012]. In contrast to Lafora disease (LD), early-onset LD typically presents at around age five years. Symptoms include dysarthria, myoclonus, and ataxia, which can be confused with late infantile-variant neuronal ceroid lipofuscinosis. However, pathology reveals Lafora bodies instead of ceroid lipofuscinosis. The disease course of early-onset LD is much more protracted than either infantile neuronal ceroid lipofuscinosis or Lafora disease. Early-onset LD is caused by pathogenic variants in PRDM8.

Juvenile myoclonic epilepsy. (OMIM 254770) Although the occurrence of myoclonus and generalized tonic-clonic seizures in adolescence may raise the possibility of juvenile myoclonic epilepsy, the persistence of EEG background slowing and cognitive deterioration should raise the suspicion of a more severe epilepsy syndrome, such as PME.

Earlier age at onset, slower rate of disease progression, and absence of Lafora bodies on skin biopsy differentiates Unverricht-Lundborg disease (EPM1) from Lafora disease (LD).

Careful ophthalmologic examination, including electroretinography, is useful in addressing the possibilities of neuronal ceroid-lipofuscinoses and sialidosis.

Cerebrospinal fluid concentration of lactate and titers of measles antibody can be helpful in dismissing the possibility of myoclonic epilepsy with ragged red fibers (MERRF) and subacute sclerosing panencephalitis (SSPE), respectively [Minassian 2001, Minassian 2002].

Visual hallucinations, withdrawal, and cognitive decline raise concerns of schizophrenia, which becomes less likely with the onset of convulsions and the appearance of an epileptiform EEG.

MRI excludes structural abnormalities, and posteriorly dominant irregular spike-wave discharges on EEG raise suspicion of LD.

See Epilepsy, progressive myoclonic: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to SimulConsult®, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Lafora disease (LD), the following are recommended:

  • Clinical evaluation
  • Evaluation of speech, walking, coordination, handwriting, school performance, and emotional status
  • Medical genetics consultation

Treatment of Manifestations

Antiepileptic drugs (AEDs) have a major effect against generalized seizures, sometimes controlling seizures for many months. Generalized seizures are rare in individuals who are treated, even years after disease onset.

Valproic acid is the traditional antiepileptic treatment for LD; because it is a broad-spectrum AED, it controls both the generalized tonic-clonic seizures and myoclonic jerks.

Clonazepam can be used as an adjunctive medication for control of myoclonus, as in other forms of PME, although the literature does not provide clear evidence for its effect on myoclonus in LD.

Zonisamide has had a significant effect on both seizures and myoclonus in a small number of individuals with Unverricht-Lundborg disease and Lafora disease.

Both piracetam and levetiracetam have been effective, sustained, and well tolerated as add-on treatment for myoclonus in progressive myoclonus epilepsy (PME) [Koskiniemi et al 1998, Genton et al 1999, Fedi et al 2001, Crest et al 2004]. Levetiracetam had a significant effect on myoclonus in two sisters with LD [Boccella et al 2003]. Lohi et al [2006] reported that levetiracetam exacerbated seizures while improving myoclonus in two persons with LD.

Prevention of Secondary Complications

Because the myoclonus associated with LD may be drug resistant, overmedication may be a risk in individuals with LD .

Placement by percutaneous endoscopy of a gastrostomy tube for feeding can be helpful in decreasing the risk of aspiration pneumonia in individuals with advanced disease.

Surveillance

Clinical and psychosocial evaluation should be performed at three- to six-month intervals throughout the teen years.

Agents/Circumstances to Avoid

As in other forms of progressive myoclonus epilepsies, the use of phenytoin should be avoided.

Anecdotal reports describe possible exacerbation of myoclonus with the following:

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to evaluation of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Work in animal models has shown that glycogen synthesis is requisite for glycogen accumulation and Lafora body formation; such glycogen accumulation is pathogenic [Turnbull et al 2011, Pederson et al 2013, Duran et al 2014, Turnbull et al 2014]. This suggests a therapeutic window for potential treatments using known and future small-molecule inhibitors of glycogen synthesis in individuals with LD.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Lafora disease (LD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one EPM2A or NHLRC1 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier of an EPM2A or NHLRC1 pathogenic variant is 2/3.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Because of the early onset and rapid deterioration, individuals with LD typically do not reproduce.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier of an EPM2A or NHLRC1 pathogenic variant; first cousins of the proband are at a 25% risk of being carriers.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the EPM2A or NHLRC1 pathogenic variants in the family.

Carrier testing is also possible for the reproductive partners of known carriers; however, absence of a detectable EPM2A or NHLRC1 pathogenic variant lowers the likelihood that the reproductive partner is a carrier but does not rule out this possibility.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the EPM2A or NHLRC1 pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the EPM2A or NHLRC1 pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Epilepsy Society (AES)
  • Epilepsy Foundation
    8301 Professional Place East
    Suite 200
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Email: ContactUs@efa.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Progressive Myoclonus Epilepsy, Lafora Type: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Progressive Myoclonus Epilepsy, Lafora Type (View All in OMIM)

254780MYOCLONIC EPILEPSY OF LAFORA
607566EPM2A GENE; EPM2A
608072NHL REPEAT-CONTAINING 1 GENE; NHLRC1

Molecular Genetic Pathogenesis

The mechanism by which pathogenic variants in either EPM2A or NHLRC1 result in Lafora disease and the exact role of the Lafora bodies in the pathogenesis of LD have been the subject of intensive research efforts over the past few years.

Pathology in LD consists of the progressive formation of polyglucosans (insoluble glucose polysaccharides that precipitate and aggregate into concretized masses called Lafora bodies) resulting in neurodegeneration. Lafora bodies form in neuronal perikarya and in neuronal short processes (mostly dendrites). Lafora bodies in the neuronal processes are much smaller but they massively outnumber Lafora bodies in the perikarya. Extraneurally, Lafora bodies also form in heart, liver, and skeletal muscle, but cause no symptoms in these organs [Turnbull et al 2011].

A normal glycogen molecule contains up to 55,000 glucose units, yet remains soluble because its glucose chains are short (13 units), each chain is a branch of another, and the whole molecule is a sphere, the surface of which is composed of the hydrophilic ends of chains [Graham et al 2010]. This unique organization allows mammalian cells to store large amounts of carbohydrate energy in a soluble, rapidly accessible form. Without branching, glucose polymers 13 units or longer are poorly soluble and tend to precipitate and crystallize [Hejazi et al 2008]. Polyglucosans are malformed glycogen molecules. They have very long chains, insufficient branches, and a resultant lack of spherical organization. They are more similar to plant amylopectin or starch than to glycogen, and like these plant carbohydrates they are insoluble, precipitate, and accumulate [Minassian 2001]. It has been demonstrated that in plants, variants in the starch excess 4 gene (SEX4) result in the accumulation of amylopectin, similar to the way loss of laforin leads to the accumulation of polyglucosans with formation of Lafora bodies in humans [Niittylä et al 2006, Gentry et al 2007, Gentry et al 2009]. In plants, human laforin can rescue the SEX4-mutated phenotype [Gentry et al 2007].

Glycogen is synthesized through coordinated actions of glycogen synthase (GS) and glycogen branching enzyme, the former responsible for chain elongation, the latter for chain branching. Glycogen is digested by glycogen phosphorylase (GP) and glycogen debranching enzyme. PTG (protein targeting to glycogen) is an indirect activator of GS and an indirect inhibitor of both GP and glycogen phosphorylase kinase (GPK), the enzyme that activates GP. PTG performs this reciprocal activation of synthesis and inhibition of breakdown by binding the pleiotropic phosphatase PP1 through its C-terminus, binding glycogen, and through a common region in its N-terminus binding GS, GP, or GPK, thus targeting PP1 to each of the three enzymes. PP1 dephosphorylates each of the three enzymes, activating GS and inhibiting GP and GPK [Turnbull et al 2011].

Absence of laforin results in glycogen hyperphosphorylation, which disturbs the construction of glycogen, preventing its elaborate spherical architecture essential to solubility [Worby et al 2006, Tagliabracci et al 2008, Nitschke et al 2013]. The malformed glycogen (polyglucosan) precipitates, aggregates, and accumulates into Lafora bodies (LB). Glycogen synthase (GS) is essential to glycogen synthesis, whether the final structure is normal or polyglucosan [Tagliabracci et al 2008]. Glycogen accumulation has been shown to account for the neurodegeneration and functional consequences in LD mice, identifying the regulation of glycogen synthesis as a key target for the treatment of LD [Duran et al 2014]. Treating LD through downregulation of GS has been shown effective in different mouse models. Genetically removing brain GS from laforin-lacking LD mice resulted in correction of the LD phenotype, including elimination of LB, neurodegeneration, and seizure predisposition [Pederson et al 2013]. The same result was obtained through partial reduction of glycogen synthesis by genetically removing PTG, a protein that activates GS. This was shown effective in laforin-deficient LD mice [Turnbull et al 2011] as well as in malin-deficient LD mice [Worby et al 2008, Turnbull et al 2014].

Malin has been suggested to regulate autophagy [Criado et al 2012], the misfolded protein response [Mittal et al 2007], microRNA silencing [Singh et al 2012], Wnt signal transduction [Sharma et al 2012], and neuronatin-mediated endoplasmic reticulum stress [Sharma et al 2013], implying a possible complex causality in the EPM2B form of LD. Nevertheless, LD caused by mutation of EPM2B is as responsive to glycogen synthesis downregulation as is LD caused by mutation of EPM2A [Turnbull et al 2014].

EPM2A

Gene structure. EPM2A has four exons spanning 130 kb; they are alternatively spliced to form two major EPM2A transcripts [Minassian et al 1998, Serratosa et al 1999, Ganesh et al 2000, Gómez-Garre et al 2000]. NM_005670.3 represents the longer transcript and encodes the longer laforin isoform (a) of 331 amino acids. For a detailed summary of gene, transcript, and protein isoform information, see Table A, Gene Symbol and Normal gene product.

Benign allelic variants. Several benign variants in EPM2A have been described [Gómez-Garre et al 2000, Minassian et al 2000b, Singh et al 2005]. Among these, 136G>C (p.Ala46Pro) is specific to the Japanese and Chinese populations [Ganesh et al 2001].

Variants of uncertain significance. The p.Gln55Lys substitution in EPM2A was found in two affected persons who were also heterozygous for a large deletion in NHLRC1 as well as in seven of 500 individuals without LD and in a person with adult-onset disease, also in the heterozygous state. To date, it remains unclear whether this change constitutes a rare benign SNP of no consequence, whether it may cause LD when homozygous, or whether it could predispose to NHLRC1 deletion in certain situations [Lohi et al 2007].

Pathogenic allelic variants. To date, more than 60 different pathogenic variants in EPM2A have been reported in more than 100 families [Minassian et al 1998, Serratosa et al 1999, Gómez-Garre et al 2000, Minassian et al 2000a, Minassian et al 2000b, Ganesh et al 2002a, Ki et al 2003, Annesi et al 2004, Ianzano et al 2004, Singh et al 2005, Lohi et al 2006, Singh & Ganesh 2009, Lesca et al 2010, Harirchian et al 2011, Khiari et al 2011]. Nonsense and missense point mutations accounted for 61%, frameshift mutations for 29%, and large deletions for 10% of the total. One splice site mutation has been reported for EPM2A [Lesca et al 2010]. An overview of the different pathogenic variants can be found in the Lafora Progressive Myoclonus Epilepsy Mutation and Polymorphism Database [Ianzano et al 2005].

Of all the types of pathogenic variants in EPM2A described to date, 45% represent missense mutations; all the known missense mutations target either the carbohydrate-binding domain (CBD) or the dual-specificity phosphatase domain (DSPD) of laforin [Ganesh et al 2006, Singh & Ganesh 2009, Khiari et al 2011].

Except for the larger deletions, all the pathogenic variants are distributed evenly across EPM2A. The only exception is the high prevalence of the nonsense c.721C>T variant, the so-called ‘Spanish’ pathogenic variant, in over 20 families. Its high prevalence is the result of both a founder effect and recurrent events [Minassian et al 1998, Serratosa et al 1999, Gómez-Garre et al 2000, Ganesh et al 2002b].

Table 3.

EPM2A Variants Discussed in This GeneReview

Variant ClassificationDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
Benign136G>Cp.Ala46ProNM_005670​.3
NP_005661​.1
Of uncertain significancec.163C>Ap.Gln55Lys
Pathogenicc.721C>Tp.Arg241Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. EPM2A is known to encode two distinct proteins by differential splicing; a phosphatase active cytoplasmic isoform (a) (laforin, NP_005661.1) and a phosphatase inactive nuclear isoform (b) (NP_001018051.1). Both isoforms of the laforin protein have unique C termini [Ganesh et al 2002c, Ianzano et al 2004]. The carboxyl terminal of isoform (b) targets laforin to the nucleus, a feature that is not shared by longer laforin isoform (a). Ianzano et al [2004] demonstrated that disturbances in the physiologic functions of laforin isoform (a) underlie the pathogenesis of LD, and isoform (b) cannot functionally substitute for laforin isoform (a). The common segment of the laforin isoforms consists of a carbohydrate-binding module and a dual-specificity protein phosphatase domain [Ganesh et al 2000].

Dubey et al identified three additional EPM2A splice variants with potential to code for five distinct proteins in alternate reading frames. The novel isoforms, when ectopically expressed in cell lines, show distinct subcellular localization, interact with and serve as substrates of malin (protein product of NHLRC1). Alternative splicing could possibly be one of the mechanisms by which EPM2A regulates the cellular functions of the proteins it codes for [Dubey et al 2012].

Laforin contains an N-terminal carbohydrate-binding domain (CBD), encoded mainly by exon 1, and a dual-specificity phosphatase domain (DSPD) spanning exons 3 and 4 [Minassian et al 2000b, Ganesh et al 2002b].

Laforin is conserved in all vertebrates; while it has been lost in the vast majority of lower organisms, it is an ancient protein that is conserved in a subset of protists and invertebrates that have undergone slower rates of molecular evolution and/or metabolize a carbohydrate similar to Lafora bodies. The laforin protein holds a unique place in evolutionary biology and has yielded insights into glucan metabolism and the molecular etiology of Lafora disease [Gentry & Pace 2009].

Abnormal gene product. Nonsense mutations, insertions, and deletions in EPM2A are predicted to be functionally 'null' and to have lost phosphatase activity. Missense mutations in EPM2A also result in a lack of phosphatase activity in vitro, resulting in a 'null' effect [Fernández-Sánchez et al 2003, Ganesh et al 2006]. Loss of phosphatase activity is not restricted to pathogenic variants located in the DSPD; it has also been observed for pathogenic variants affecting the CBD of EPM2A [Wang et al 2002, Fernández-Sánchez et al 2003]. It is likely that the missense mutations affect proper folding of the laforin protein, as illustrated by transfection experiments overexpressing missense mutants, which resulted in ubiquitin-positive cytoplasmic aggregates, suggesting that they were folding mutants destined for degradation [Ganesh et al 2000, Ganesh et al 2002a]. Missense mutations also affect the subcellular localization of laforin [Ganesh et al 2002a, Mittal et al 2007] and disrupt the interaction of laforin with R5 and malin (protein product of NHLRC1) proteins that interact with laforin in vivo [Fernández-Sánchez et al 2003, Gentry et al 2005]. It is evident that not all aspects of the protein function have been tested for each missense mutation, and that sensitive assays for checking the effect of pathogenic variants on the proteins function are yet to be developed [Singh & Ganesh 2009].

NHLRC1 (EPM2B)

Gene structure. NHLRC1 is a single-exon gene spanning 1,188 base pairs that has all of the proposed features of the consensus sequence of a eukaryotic translational initiation site at its 5' end and two putative polyadenylation signals at its 3' end. Northern blot analysis indicates the presence of NHLRC1 as two transcripts of 1.5 kb and 2.4 kb in all tissues examined, including specific subregions of the brain [Chan et al 2003b]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Six benign variants have been reported [Chan et al 2003b, Singh et al 2005].

Pathogenic allelic variants. To date, more than 60 pathogenic variants have been reported in more than 125 families. The majority are missense mutations, although insertions, deletions, and nonsense mutations have also been found [Chan et al 2003b, Gómez-Abad et al 2005, Singh et al 2005, Franceschetti et al 2006, Singh et al 2006, Lohi et al 2007, Singh & Ganesh 2009, Traoré et al 2009, Lesca et al 2010, Couarch et al 2011]. A heterozygous deletion of the entire NHLRC1 gene has been reported in an Italian and a Serbian family [Lohi et al 2007]. An overview of pathologic alleles in NHLRC1 is available in the Lafora Progressive Myoclonus Epilepsy Mutation and Polymorphism Database.

  • The missense mutation c.205C>G, affecting the RING finger domain, is the most common missense mutation in NHLRC1 (>30 families). It is present in all affected individuals of Portuguese origin and has been reported repeatedly in affected persons of Italian, French, and Spanish heritage [Chan et al 2003a, Gómez-Abad et al 2005, Franceschetti et al 2006, Lesca et al 2010]. The high prevalence of this pathogenic variant is also explained both by founder effect and recurrent mutation events [Chan et al 2003a, Gómez-Abad et al 2005, Franceschetti et al 2006].
  • The c.468_469delAG pathogenic variant, involving the removal of two bases in the coding region, is the second most common pathogenic variant in NHLRC1 and is by far the most common deletion mutation (25 families). It has been identified in 14 individuals belonging to the same genetic isolate of tribal Oman. All shared a common haplotype, suggesting a founder effect [Turnbull et al 2008].
  • Note: Whereas c.205C>G pathogenic variant is common in affected persons of Italian and Spanish heritage, both the c.205C>G and c.468_469delAG pathogenic variants have been identified in different ethnic groups, suggesting a recurrent mutational event; these two sites represent hot spots for NHLRC1 pathogenic variants [Ganesh et al 2006].
  • Missense pathogenic variant c.76T>A is prevalent in French-Canadian ethnic isolates [Chan et al 2003a, Singh et al 2006] and the shared chromosome 6p22 haplotype of these pedigrees suggested a founder effect [Chan et al 2003a]. To date, all but one French-Canadian individual were homozygous for the c.76T>A pathogenic variant. This individual was heterozygous for two other NHLRC1 pathogenic variants, but he was known to also have distant German and other European ancestry [Chan et al 2003a]. To date, this pathogenic variant has not been detected in non-French-Canadian families.

Table 4.

NHLRC1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.76T>A 1p.Cys26SerNM_198586​.2
NP_940988​.2
c.205C>G 1p.Pro69Ala
c.436G>Ap.Asp146Asn
c.593T>Ap.Ile198Asn
c.468_469delAG 1p.Gly158ArgfsTer17

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Details in Pathogenic allelic variants

Normal gene product. NHLRC1 encodes NHL repeat-containing protein 1, also known as malin, a 395-amino acid protein. Malin contains a zinc finger of the RING type and six NHL-repeat protein-protein interaction domains [Chan et al 2003b]. The presence of a RING finger predicts an E3 ubiquitin ligase function [Freemont 2000]. Malin colocalizes with laforin in the endoplasmic reticulum [Mittal et al 2007]. Laforin and malin interact with misfolded proteins and promote their degradation through the ubiquitin-proteasome system [Garyali et al 2009]. Malin is a single subunit E3 ubiquitin ligase involved in the ubiquitin-mediated proteolysis cascade [Gentry et al 2005, Lohi et al 2005]. Malin also interacts with and ubiquitinates laforin, leading to its degradation [Gentry et al 2005]. Thus, one of the critical functions of malin is to regulate the cellular concentration of laforin by ubiquitin-mediated degradation [Gentry et al 2005].

Abnormal gene product. See Ganesh et al [2006]. Nearly all pathogenic variants in NHLRC1 are predicted to result in the loss of function of malin [Chan et al 2003b, Gómez-Abad et al 2005, Singh et al 2005]. Missense mutations in NHLRC1 associated with LD disrupt a critical function of malin in regulating the cellular concentration of laforin by ubiquitin-mediated degradation [Gentry et al 2005].

Click here for more information on animal models of Lafora disease.

References

Literature Cited

  1. Altindag E, Kara B, Baykan B, Terzibasioglu E, Sencer S, Onat L, Sirvanci M. MR spectroscopy findings in Lafora disease. J Neuroimaging. 2009;19:359–65. [PubMed: 19040628]
  2. Andrade DM, Ackerley CA, Minett TS, Teive HA, Bohlega S, Scherer SW, Minassian BA. Skin biopsy in Lafora disease: genotype-phenotype correlations and diagnostic pitfalls. Neurology. 2003;61:1611–4. [PubMed: 14663053]
  3. Annesi G, Sofia V, Gambardella A, Candiano IC, Spadafora P, Annesi F, Cutuli N, De Marco EV, Civitelli D, Carrideo S, Tarantino P, Barone R, Zappia M, Quattrone A. A novel exon 1 mutation in a patient with atypical lafora progressive myoclonus epilepsy seen as childhood-onset cognitive deficit. Epilepsia. 2004;45:294–5. [PubMed: 15009235]
  4. Baykan B, Striano P, Gianotti S, Bebek N, Gennaro E, Gurses C, Zara F. Late-onset and slow-progressing Lafora disease in four siblings with EPM2B mutation. Epilepsia. 2005;46:1695–7. [PubMed: 16190947]
  5. Berkovic SF, Andermann F, Carpenter S, Wolfe LS. Progressive myoclonus epilepsies: specific causes and diagnosis. N Engl J Med. 1986;315:296–305. [PubMed: 3088452]
  6. Berkovic SF, Cochius J, Andermann E, Andermann F. Progressive myoclonus epilepsies: clinical and genetic aspects. Epilepsia. 1993;34 Suppl 3:S19–30. [PubMed: 8500430]
  7. Biesecker LG, Green RC. Diagnostic clinical genome and exome sequencing. N Engl J Med. 2014;371:1170. [PubMed: 25229935]
  8. Boccella P, Striano P, Zara F, Barbieri F, Sarappa C, Vacca G, de Falco FA, Striano S. Bioptically demonstrated Lafora disease without EPM2A mutation: a clinical and neurophysiological study of two sisters. Clin Neurol Neurosurg. 2003;106:55–9. [PubMed: 14643920]
  9. Brackmann FA, Kiefer A, Agaimy A, Gencik M, Trollmann R. Rapidly Progressive Phenotype of Lafora Disease Associated With a Novel NHLRC1 Mutation. Pediatr Neurol. 2011;44:475–7. [PubMed: 21555062]
  10. Canafoglia L, Ciano C, Visani E, Anversa P, Panzica F, Viri M, Gennaro E, Zara F, Madia F, Franceschetti S. Short and long interval cortical inhibition in patients with Unverricht-Lundborg and Lafora body disease. Epilepsy Res. 2010;89:232–7. [PubMed: 20117916]
  11. Carpenter S, Karpati G. Sweat gland duct cells in Lafora disease: diagnosis by skin biopsy. Neurology. 1981;31:1564–8. [PubMed: 6796905]
  12. Carpenter S, Karpati G, Andermann F, Jacob JC, Andermann E. Lafora's disease: peroxisomal storage in skeletal muscle. Neurology. 1974;24:531–8. [PubMed: 4220225]
  13. Cerminara C, Montanaro ML, Curatolo P, Seri S. Lamotrigine-induced seizure aggravation and negative myoclonus in idiopathic rolandic epilepsy. Neurology. 2004;63:373–5. [PubMed: 15277643]
  14. Chan EM, Andrade DM, Franceschetti S, Minassian B. Progressive myoclonus epilepsies: EPM1, EPM2A, EPM2B. Adv Neurol. 2005;95:47–57. [PubMed: 15508913]
  15. Chan EM, Bulman DE, Paterson AD, Turnbull J, Andermann E, Andermann F, Rouleau GA, Delgado-Escueta AV, Scherer SW, Minassian BA. Genetic mapping of a new Lafora progressive myoclonus epilepsy locus (EPM2B) on 6p22. J Med Genet. 2003a;40:671–5. [PMC free article: PMC1735578] [PubMed: 12960212]
  16. Chan EM, Omer S, Ahmed M, Bridges LR, Bennett C, Scherer SW, Minassian BA. Progressive myoclonus epilepsy with polyglucosans (Lafora disease): evidence for a third locus. Neurology. 2004;63:565–7. [PubMed: 15304597]
  17. Chan EM, Young EJ, Ianzano L, Munteanu I, Zhao X, Christopoulos CC, Avanzini G, Elia M, Ackerley CA, Jovic NJ, Bohlega S, Andermann E, Rouleau GA, Delgado-Escueta AV, Minassian BA, Scherer SW. Mutations in NHLRC1 cause progressive myoclonus epilepsy. Nat Genet. 2003b;35:125–7. [PubMed: 12958597]
  18. Couarch P, Vernia S, Gourfinkel-An I, Lesca G, Gataullina S, Fedirko E, Trouillard O, Depienne C, Dulac O, Steschenko D, Leguern E, Sanz P, Baulac S. Lafora progressive myoclonus epilepsy: NHLRC1 mutations affect glycogen metabolism. J Mol Med (Berl) 2011 Sep;89(9):915–25. [PMC free article: PMC3154284] [PubMed: 21505799]
  19. Crespel A, Genton P, Berramdane M, Coubes P, Monicard C, Baldy-Moulinier M, Gelisse P. Lamotrigine associated with exacerbation or de novo myoclonus in idiopathic generalized epilepsies. Neurology. 2005;65:762–4. [PubMed: 16157917]
  20. Crest C, Dupont S, Leguern E, Adam C, Baulac M. Levetiracetam in progressive myoclonic epilepsy: an exploratory study in 9 patients. Neurology. 2004;62:640–3. [PubMed: 14981187]
  21. Criado O, Aguado C, Gayarre J, Duran-Trio L, Garcia-Cabrero AM, Vernia S, San Millán B, Heredia M, Romá-Mateo C, Mouron S, Juana-López L, Domínguez M, Navarro C, Serratosa JM, Sanchez M, Sanz P, Bovolenta P, Knecht E, Rodriguez de Cordoba S. Lafora bodies and neurological defects in malin-deficient mice correlate with impaired autophagy. Hum Mol Genet. 2012;21:1521–33. [PubMed: 22186026]
  22. Delgado-Escueta AV, Ganesh S, Yamakawa K. Advances in the genetics of progressive myoclonus epilepsy. Am J Med Genet. 2001;106:129–38. [PubMed: 11579433]
  23. Drury I, Blaivas M, Abou-Khalil BW, Beydoun A. Biopsy results in a kindred with Lafora disease. Arch Neurol. 1993;50:102–5. [PubMed: 8418793]
  24. Dubey D, Parihar R, Ganesh S. Identification and characterization of novel splice variants of the human EPM2A gene mutated in Lafora progressive myoclonus epilepsy. Genomics. 2012;99:36–43. [PubMed: 22036712]
  25. Duran J, Gruart A, García-Rocha M, Delgado-García JM, Guinovart JJ. Glycogen accumulation underlies neurodegeneration and autophagy impairment in Lafora disease. Hum Mol Genet. 2014;23:3147–56. [PubMed: 24452334]
  26. Fedi M, Reutens D, Dubeau F, Andermann E, D'Agostino D, Andermann F. Long-term efficacy and safety of piracetam in the treatment of progressive myoclonus epilepsy. Arch Neurol. 2001;58:781–6. [PubMed: 11346373]
  27. Fernández-Sánchez ME, Criado-Garcia O, Heath KE, Garcia-Fojeda B, Medrano-Fernandez I, Gomez-Garre P, Sanz P, Serratosa JM, Rodriguez de Cordoba S. Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation. Hum Mol Genet. 2003;12:3161–71. [PubMed: 14532330]
  28. Franceschetti S, Gambardella A, Canafoglia L, Striano P, Lohi H, Gennaro E, Ianzano L, Veggiotti P, Sofia V, Biondi R, Striano S, Gellera C, Annesi G, Madia F, Civitelli D, Rocca FE, Quattrone A, Avanzini G, Minassian B, Zara F. Clinical and genetic findings in 26 Italian patients with Lafora disease. Epilepsia. 2006;47:640–3. [PubMed: 16529633]
  29. Freemont PS. RING for destruction? Curr Biol. 2000;10:R84–7. [PubMed: 10662664]
  30. Ganesh S, Agarwala KL, Ueda K, Akagi T, Shoda K, Usui T, Hashikawa T, Osada H, Delgado-Escueta AV, Yamakawa K. Laforin, defective in the progressive myoclonus epilepsy of Lafora type, is a dual-specificity phosphatase associated with polyribosomes. Hum Mol Genet. 2000;9:2251–61. [PubMed: 11001928]
  31. Ganesh S, Delgado-Escueta AV, Sakamoto T, Avila MR, Machado-Salas J, Hoshii Y, Akagi T, Gomi H, Suzuki T, Amano K, Agarwala KL, Hasegawa Y, Bai DS, Ishihara T, Hashikawa T, Itohara S, Cornford EM, Niki H, Yamakawa K. Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice. Hum Mol Genet. 2002a;11:1251–62. [PubMed: 12019206]
  32. Ganesh S, Delgado-Escueta AV, Suzuki T, Francheschetti S, Riggio C, Avanzini G, Rabinowicz A, Bohlega S, Bailey J, Alonso ME, Rasmussen A, Thomson AE, Ochoa A, Prado AJ, Medina MT, Yamakawa K. Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: exon 1 mutations associate with an early-onset cognitive deficit subphenotype. Hum Mol Genet. 2002b;11:1263–71. [PubMed: 12019207]
  33. Ganesh S, Puri R, Singh S, Mittal S, Dubey D. Recent advances in the molecular basis of Lafora's progressive myoclonus epilepsy. J Hum Genet. 2006;51:1–8. [PubMed: 16311711]
  34. Ganesh S, Shoda K, Amano K, Uchiyama A, Kumada S, Moriyama N, Hirose S, Yamakawa K. Mutation screening for Japanese Lafora's disease patients: identification of novel sequence variants in the coding and upstream regulatory regions of EPM2A gene. Mol Cell Probes. 2001;15:281–9. [PubMed: 11735300]
  35. Ganesh S, Suzuki T, Yamakawa K. Alternative splicing modulates subcellular localization of laforin. Biochem Biophys Res Commun. 2002c;291:1134–7. [PubMed: 11883934]
  36. Garyali P, Siwach P, Singh PK, Puri R, Mittal S, Sengupta S, Parihar R, Ganesh S. The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system. Hum Mol Genet. 2009;18:688–700. [PubMed: 19036738]
  37. Genton P, Guerrini R, Remy C. Piracetam in the treatment of cortical myoclonus. Pharmacopsychiatry. 1999;32 Suppl 1:49–53. [PubMed: 10338109]
  38. Gentry MS, Dixon JE, Worby CA. Lafora disease: insights into neurodegeneration from plant metabolism. Trends Biochem Sci. 2009;34:628–39. [PMC free article: PMC2805077] [PubMed: 19818631]
  39. Gentry MS, Dowen RH 3rd, Worby CA, Mattoo S, Ecker JR, Dixon JE. The phosphatase laforin crosses evolutionary boundaries and links carbohydrate metabolism to neuronal disease. J Cell Biol. 2007;178:477–88. [PMC free article: PMC2064834] [PubMed: 17646401]
  40. Gentry MS, Pace RM. Conservation of the glucan phosphatase laforin is linked to rates of molecular evolution and the glucan metabolism of the organism. BMC Evol Biol. 2009;9:138. [PMC free article: PMC2714694] [PubMed: 19545434]
  41. Gentry MS, Worby CA, Dixon JE. Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin. Proc Natl Acad Sci U S A. 2005;102:8501–6. [PMC free article: PMC1150849] [PubMed: 15930137]
  42. Gómez-Abad C, Afawi Z, Korczyn AD, Misk A, Shalev SA, Spiegel R, Lerman-Sagie T, Lev D, Kron KL, Gomez-Garre P, Serratosa JM, Berkovic SF. Founder effect with variable age at onset in Arab families with Lafora disease and EPM2A mutation. Epilepsia. 2007;48:1011–4. [PubMed: 17509003]
  43. Gómez-Abad C, Gomez-Garre P, Gutierrez-Delicado E, Saygi S, Michelucci R, Tassinari CA, Rodriguez de Cordoba S, Serratosa JM. Lafora disease due to EPM2B mutations: a clinical and genetic study. Neurology. 2005;64:982–6. [PubMed: 15781812]
  44. Gómez-Garre P, Sanz Y, Rodriguez De Cordoba SR, Serratosa JM. Mutational spectrum of the EPM2A gene in progressive myoclonus epilepsy of Lafora: high degree of allelic heterogeneity and prevalence of deletions. Eur J Hum Genet. 2000;8:946–54. [PubMed: 11175283]
  45. Graham TE, Yuan Z, Hill AK, Wilson RJ. The regulation of muscle glycogen: the granule and its proteins. Acta Physiol (Oxf) 2010;199:489–98. [PubMed: 20353490]
  46. Guerrero R, Vernia S, Sanz R, Abreu-Rodríguez I, Almaraz C, García-Hoyos M, Michelucci R, Tassinari CA, Riguzzi P, Nobile C, Sanz P, Serratosa JM, Gómez-Garre P. A PTG variant contributes to a milder phenotype in Lafora disease. PLoS One. 2011;6:e21294. [PMC free article: PMC3127956] [PubMed: 21738631]
  47. Harirchian MH, Shandiz EE, Turnbull J, Minassian BA, Shahsiah R. Lafora disease: A case report, pathologic and genetic study. Indian J Pathol Microbiol. 2011;54:374–5. [PubMed: 21623095]
  48. Hejazi M, Fettke J, Haebel S, Edner C, Paris O, Frohberg C, Steup M, Ritte G. Glucan, water dikinase phosphorylates crystalline maltodextrins and thereby initiates solubilization. Plant J. 2008;55:323–334. [PubMed: 18419779]
  49. Ianzano L, Young EJ, Zhao XC, Chan EM, Rodriguez MT, Torrado MV, Scherer SW, Minassian BA. Loss of function of the cytoplasmic isoform of the protein laforin (EPM2A) causes Lafora progressive myoclonus epilepsy. Hum Mutat. 2004;23:170–6. [PubMed: 14722920]
  50. Ianzano L, Zhang J, Chan EM, Zhao XC, Lohi H, Scherer SW, Minassian BA. Lafora progressive Myoclonus Epilepsy mutation database-EPM2A and NHLRC1 (EPM2B) genes. Hum Mutat. 2005;26:397. [PubMed: 16134145]
  51. Kaddurah AK, Holmes GL. Possible precipitation of myoclonic seizures with oxcarbazepine. Epilepsy Behav. 2006;8:289–93. [PubMed: 16356781]
  52. Kecmanović M, Jović N, Cukić M, Keckarević-Marković M, Keckarević D, Stevanović G, Romac S. Lafora disease: severe phenotype associated with homozygous deletion of the NHLRC1 gene. J Neurol Sci. 2013;325:170–3. [PubMed: 23317923]
  53. Khiari HM, Lesca G, Malafosse A, Mrabet A. A novel exon 3 mutation in a Tunisian patient with Lafora's disease. J Neurol Sci. 2011;304:136–7. [PubMed: 21371719]
  54. Ki CS, Kong SY, Seo DW, Hong SB, Kim HJ, Kim JW. Two novel mutations in the EPM2A gene in a Korean patient with Lafora's progressive myoclonus epilepsy. J Hum Genet. 2003;48:51–4. [PubMed: 12560877]
  55. Koskiniemi M, Van Vleymen B, Hakamies L, Lamusuo S, Taalas J. Piracetam relieves symptoms in progressive myoclonus epilepsy: a multicentre, randomised, double blind, crossover study comparing the efficacy and safety of three dosages of oral piracetam with placebo. J Neurol Neurosurg Psychiatry. 1998;64:344–8. [PMC free article: PMC2169975] [PubMed: 9527146]
  56. Lesca G, Boutry-Kryza N, de Toffol B, Milh M, Steschenko D, Lemesle-Martin M, Maillard L, Foletti G, Rudolf G, Nielsen JE. á Rogvi-Hansen B, Erdal J, Mancini J, Thauvin-Robinet C, M'Rrabet A, Ville D, Szepetowski P, Raffo E, Hirsch E, Ryvlin P, Calender A, Genton P. Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease. Epilepsia. 2010;51:1691–8. [PubMed: 20738377]
  57. Lohi H, Chan EM, Scherer SW, Minassian BA. On the road to tractability: the current biochemical understanding of progressive myoclonus epilepsies. Adv Neurol. 2006;97:399–415. [PubMed: 16383151]
  58. Lohi H, Ianzano L, Zhao XC, Chan EM, Turnbull J, Scherer SW, Ackerley CA, Minassian BA. Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy. Hum Mol Genet. 2005;14:2727–36. [PubMed: 16115820]
  59. Lohi H, Turnbull J, Zhao XC, Pullenayegum S, Ianzano L, Yahyaoui M, Mikati MA, Quinn NP, Franceschetti S, Zara F, Minassian BA. Genetic diagnosis in Lafora disease: genotype-phenotype correlations and diagnostic pitfalls. Neurology. 2007;68:996–1001. [PubMed: 17389303]
  60. Minassian BA. Lafora's disease: towards a clinical, pathologic, and molecular synthesis. Pediatr Neurol. 2001;25:21–9. [PubMed: 11483392]
  61. Minassian BA. Progressive myoclonus epilepsy with polyglucosan bodies: Lafora disease. Adv Neurol. 2002;89:199–210. [PubMed: 11968446]
  62. Minassian BA, Ianzano L, Delgado-Escueta AV, Scherer SW. Identification of new and common mutations in the EPM2A gene in Lafora disease. Neurology. 2000a;54:488–90. [PubMed: 10668720]
  63. Minassian BA, Ianzano L, Meloche M, Andermann E, Rouleau GA, Delgado-Escueta AV, Scherer SW. Mutation spectrum and predicted function of laforin in Lafora's progressive myoclonus epilepsy. Neurology. 2000b;55:341–6. [PubMed: 10932264]
  64. Minassian BA, Lee JR, Herbrick JA, Huizenga J, Soder S, Mungall AJ, Dunham I, Gardner R, Fong CY, Carpenter S, Jardim L, Satishchandra P, Andermann E, Snead OC 3rd, Lopes-Cendes I, Tsui LC, Delgado-Escueta AV, Rouleau GA, Scherer SW. Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy. Nat Genet. 1998;20:171–4. [PubMed: 9771710]
  65. Mittal S, Dubey D, Yamakawa K, Ganesh S. Lafora disease proteins malin and laforin are recruited to aggresomes in response to proteasomal impairment. Hum Mol Genet. 2007;16:753–62. [PubMed: 17337485]
  66. Nanba Y, Maegaki Y. Epileptic negative myoclonus induced by carbamazepine in a child with BECTS. Benign childhood epilepsy with centrotemporal spikes. Pediatr Neurol. 1999;21:664–7. [PubMed: 10513696]
  67. Niittylä T, Comparot-Moss S, Lue WL, Messerli G, Trevisan M, Seymour MD, Gatehouse JA, Villadsen D, Smith SM, Chen J, Zeeman SC, Smith AM. Similar protein phosphatases control starch metabolism in plants and glycogen metabolism in mammals. J Biol Chem. 2006;281:11815–8. [PubMed: 16513634]
  68. Nitschke F, Wang P, Schmieder P, Girard JM, Awrey DE, Wang T, Israelian J, Zhao X, Turnbull J, Heydenreich M, Kleinpeter E, Steup M, Minassian BA. Hyperphosphorylation of glucosyl C6 carbons and altered structure of glycogen in the neurodegenerative epilepsy Lafora disease. Cell Metab. 2013;17:756–67. [PubMed: 23663739]
  69. Pederson BA, Turnbull J, Epp JR, Weaver SA, Zhao X, Pencea N, Roach PJ, Frankland PW, Ackerley CA, Minassian BA. Inhibiting glycogen synthesis prevents lafora disease in a mouse model. Ann Neurol. 2013;74:297–300. [PMC free article: PMC3823666] [PubMed: 23913475]
  70. Pichiecchio A, Veggiotti P, Cardinali S, Longaretti F, Poloni GU, Uggetti C. Lafora disease: spectroscopy study correlated with neuropsychological findings. Eur J Paediatr Neurol. 2008;12:342–7. [PubMed: 18063398]
  71. Serratosa JM, Gomez-Garre P, Gallardo ME, Anta B, de Bernabe DB, Lindhout D, Augustijn PB, Tassinari CA, Malafosse RM, Topcu M, Grid D, Dravet C, Berkovic SF, de Cordoba SR. A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2). Hum Mol Genet. 1999;8:345–52. [PubMed: 9931343]
  72. Sharma J, Mukherjee D, Rao SN, Iyengar S, Shankar SK, Satishchandra P, Jana NR. Neuronatin-mediated aberrant calcium signaling and endoplasmic reticulum stress underlie neuropathology in Lafora disease. J Biol Chem. 2013;288:9482–90. [PMC free article: PMC3611017] [PubMed: 23408434]
  73. Sharma J, Mulherkar S, Mukherjee D, Jana NR. Malin regulates Wnt signaling pathway through degradation of dishevelled2. J Biol Chem. 2012;287:6830–9. [PMC free article: PMC3307269] [PubMed: 22223637]
  74. Singh S, Ganesh S. Lafora progressive myoclonus epilepsy: a meta-analysis of reported mutations in the first decade following the discovery of the EPM2A and NHLRC1 genes. Hum Mutat. 2009;30:715–23. [PubMed: 19267391]
  75. Singh S, Ganesh S. Phenotype variations in Lafora progressive myoclonus epilepsy: possible involvement of genetic modifiers? J Hum Genet. 2012;57:283–5. [PubMed: 22456482]
  76. Singh S, Sethi I, Francheschetti S, Riggio C, Avanzini G, Yamakawa K, Delgado-Escueta AV, Ganesh S. Novel NHLRC1 mutations and genotype-phenotype correlations in patients with Lafora's progressive myoclonic epilepsy. J Med Genet. 2006;43:e48. [PMC free article: PMC2564581] [PubMed: 16950819]
  77. Singh S, Singh PK, Bhadauriya P, Ganesh S. Lafora disease E3 ubiquitin ligase malin is recruited to the processing bodies and regulates the microRNA-mediated gene silencing process via the decapping enzyme Dcp1a. RNA Biol. 2012;9:1440–9. [PubMed: 23131811]
  78. Singh S, Suzuki T, Uchiyama A, Kumada S, Moriyama N, Hirose S, Takahashi Y, Sugie H, Mizoguchi K, Inoue Y, Kimura K, Sawaishi Y, Yamakawa K, Ganesh S. Mutations in the NHLRC1 gene are the common cause for Lafora disease in the Japanese population. J Hum Genet. 2005;50:347–52. [PubMed: 16021330]
  79. Tagliabracci VS, Girard JM, Segvich D, Meyer C, Turnbull J, Zhao X, Minassian BA, Depaoli-Roach AA, Roach PJ. Abnormal metabolism of glycogen phosphate as a cause for Lafora disease. J Biol Chem. 2008;283:33816–25. [PMC free article: PMC2590708] [PubMed: 18852261]
  80. Traoré M, Landouré G, Motley W, Sangaré M, Meilleur K, Coulibaly S, Traoré S, Niaré B, Mochel F, La Pean A, Vortmeyer A, Mani H, Fischbeck KH. Novel mutation in the NHLRC1 gene in a Malian family with a severe phenotype of Lafora disease. Neurogenetics. 2009;10:319–23. [PMC free article: PMC2758214] [PubMed: 19322595]
  81. Turnbull J, DePaoli-Roach AA, Zhao X, Cortez MA, Pencea N, Tiberia E, Piliguian M, Roach PJ, Wang P, Ackerley CA, Minassian BA. PTG depletion removes Lafora bodies and rescues the fatal epilepsy of Lafora disease. PLoS Genet. 2011;7:e1002037. [PMC free article: PMC3084203] [PubMed: 21552327]
  82. Turnbull J, Epp JR, Goldsmith D, Zhao X, Pencea N, Wang P, Frankland PW, Ackerley CA, Minassian BA. PTG protein depletion rescues malin-deficient Lafora disease in mouse. Ann Neurol. 2014;75:442–6. [PubMed: 24419970]
  83. 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. Early-onset Lafora body disease. Brain. 2012;135:2684–98. [PMC free article: PMC3437029] [PubMed: 22961547]
  84. Turnbull J, Kumar S, Ren ZP, Muralitharan S, Naranian T, Ackerley CA, Minassian BA. Lafora progressive myoclonus epilepsy: disease course homogeneity in a genetic isolate. J Child Neurol. 2008;23:240–2. [PubMed: 18263761]
  85. Villanueva V, Alvarez-Linera J, Gomez-Garre P, Gutierrez J, Serratosa JM. MRI volumetry and proton MR spectroscopy of the brain in Lafora disease. Epilepsia. 2006;47:788–92. [PubMed: 16650146]
  86. Wang J, Stuckey JA, Wishart MJ, Dixon JE. A unique carbohydrate binding domain targets the lafora disease phosphatase to glycogen. J Biol Chem. 2002;277:2377–80. [PubMed: 11739371]
  87. Worby CA, Gentry MS, Dixon JE. Laforin, a dual specificity phosphatase that dephosphorylates complex carbohydrates. J Biol Chem. 2006;281:30412–8. [PMC free article: PMC2774450] [PubMed: 16901901]
  88. Worby CA, Gentry MS, Dixon JE. Malin decreases glycogen accumulation by promoting the degradation of protein targeting to glycogen (PTG). J Biol Chem. 2008;283:4069–76. [PMC free article: PMC2251628] [PubMed: 18070875]

Suggested Reading

  1. Noebels JL. The inherited epilepsies. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). 2015. New York, NY: McGraw-Hill. Chap 230.

Chapter Notes

Revision History

  • 22 January 2015 (me) Comprehensive update posted live
  • 3 November 2011 (me) Comprehensive update posted live
  • 28 December 2007 (me) Review posted to live Web site
  • 2 January 2007 (ea) Original submission
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