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Progressive Myoclonus Epilepsy, Lafora Type

Synonyms: Lafora Body Disease, Lafora Disease. Includes: EPM2A-Related Lafora Disease, NHLRC1-Related Lafora Disease

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

Author Information
, MD, PhD
Pediatric Neurology Unit
Department of Pediatrics
Universitair Ziekenhuis Brussel
Department of Public Health
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: November 3, 2011.

Summary

Disease 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 mutations in one of the two genes known to be associated with LD: EPM2A or NHLRC1 (EPM2B). On rare occasion skin biopsy to detect pathognomonic 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 disease-causing mutations 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 grey 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 the pathognomonic 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 includes 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 mutation can be identified.

Molecular Genetic Testing

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

Evidence for further locus heterogeneity. The proportion of families with LD in which a disease-causing mutation is identified varies: Gomez-Abad et al [2005] found mutations in 97% (75/77); Franceschetti et al [2006] in 95% (21/22); Lohi et al [2006] in 88% (75/85); Singh et al [2006] in 84% (23/28). Mutations in at least one other gene also cause LD. Chan et al [2004] described one family with three individuals with biopsy-verified LD and no identifiable mutation 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 an independent study [Singh et al 2005, Singh et al 2006].

Clinical testing

  • Sequence analysis of the entire coding region. Given the high allelic heterogeneity observed in LD, it is likely that the majority of the mutations arise as a single event and that only a very small proportion of mutant alleles can be predicted in certain populations (see Molecular Genetics). Studies of the combined mutation detection frequency of sequence analysis in EPM2A and NHLRC1 reveal that between 88% and 97% of mutations in these two genes can be detected using sequence analysis alone [Gomez-Abad et al 2005, Franceschetti et al 2006, Lohi et al 2006].
  • Deletion/duplication analysis. The proportion of mutations in EPM2A and NHLRC1 not detected by sequence analysis that are attributable to deletions is unknown. In the one study to date specifically looking for deletions in three individuals with a single heterozygous mutation who were suspected to have deletions, Lohi et al [2007] found three deletions in three families, one in EPM2A and two in NHLRC1.

Table 2. Summary of Molecular Genetic Testing Used in Progressive Myoclonus Epilepsy, Lafora Type

Gene SymbolProportion of LD Attributed to Mutations in This GeneTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
EPM2A 22%-70% 2, 3, 4, 5, 6 Sequence analysis Sequence variants 788%-97% 8
Deletion / duplication analysis 9Exonic or whole-gene deletionsUnknown
NHLRC1 (EPM2B)27%-73% 2, 3, 4, 5, 6Sequence analysis Sequence variants 788%-97% 8
Deletion / duplication analysis 9Exonic or whole-gene deletionsUnknown

1. The ability of the test method used to detect a mutation that is present in the indicated gene

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

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

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

5. Singh et al [2006] found mutations 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. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

8. Includes data for mutation detection frequency for both EPM2A and NHLRC1 [Chan et al 2003b, Gomez-Abad et al 2005, Franceschetti et al 2006, Lohi et al 2006, Singh et al 2006]

9. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.

Interpretation of test results

  • For issues to consider in interpretation of sequence analysis results, click here.
  • Deletions should be suspected in affected individuals who have a single heterozygous mutation in one of the genes, and in affected individuals who have an apparently homozygous mutation in one of the genes but the mutation is carried by only one parent.

Testing Strategy

To confirm/establish the diagnosis in a proband requires either of the following:

  • Identification of two mutations in either EPM2A or NHLRC1:
  • Detection of Lafora bodies on skin biopsy

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

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing LD.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

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 [Gomez-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, Gomez-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 mutation the phenotype can be highly variable [Gomez-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 mutations may influence the pathogenesis of LD [Gomez-Abad et al 2007, Lohi et al 2007].

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

Nomenclature

Lafora disease 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 outbred 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, mutations in NHLRC1 are more common than mutations in EPM2A. Conversely, EPM2A mutations are more common in the Spanish and French populations. Within the Indian and Arab populations the distribution of mutations 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 [Lehesjoki A and Kalviainen R, personal communication].

Differential Diagnosis

Juvenile myoclonic epilepsy. 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 EPM1 (Unverricht-Lundborg disease) 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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, 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 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

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

Overmedication is a risk in individuals with LD as a result of drug-resistant myoclonus.

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 teenage 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

Since the typical polyglucosan accumulations in LD result from alterations of proteins involved in the regulation of glycogen metabolism, the feasibility and tolerability of a long-term ketogenic diet in LD was studied in five individuals [Cardinali et al 2006]. Although the ketogenic diet was well tolerated and nutritional measures and laboratory findings remained stable, the ketogenic diet did not stop disease progression. However, given the considerable heterogeneity of the natural history of LD, the possibility that the ketogenic diet affects the natural history cannot be excluded. Larger studies are needed to further evaluate the utility of the ketogenic diet in treating 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 and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

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 is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

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. Sibs of the proband's parents are at a 50% risk of being carriers; first cousins of the proband are at a 25% risk of being carriers.

Carrier Detection

Carrier testing for at-risk family members is possible once the mutations have been identified in an affected family member.

Carrier testing is also possible for the reproductive partners of known carriers.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations 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)
    342 North Main Street
    West Hartford CT 06117-2507
    Phone: 860-586-7505
    Fax: 860-586-7550
    Email: info@aesnet.org
  • Epilepsy Foundation
    8301 Professional Place
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Fax: 301-577-2684
    Email: info@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 mutations in either EPM2A or NHLRC1 (EPM2B) result in Lafora disease (LD) 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. A significant breakthrough has recently been achieved by Turnbull and colleagues, who showed that depletion of protein targeting to glycogen (PTG) in a mouse model for LD resulted in a removal of Lafora bodies and a rescue of the epilepsy phenotype [Turnbull et al 2011].

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, mutations 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 [Niittyla 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].

There are two main hypotheses of polyglucosan formation. The first is based on evidence from cell models that laforin interacts with malin and with PTG, and that the laforin-malin complex downregulates GS through malin-mediated ubiquitination and degradation of PTG. In this hypothesis, absence of laforin or malin would increase PTG, which would over-activate GS, leading to excessive extension of glycogen chains and conversion of glycogen to polyglucosan [Fernandez-Sanchez et al 2003, Vilchez et al 2007, Solaz-Fuster et al 2008, Worby et al 2008].

The second hypothesis is based on the observation that laforin dephosphorylates glycogen and that in LD there is progressive hyperphosphorylation of glycogen, causing it to unfold and precipitate. GS remains bound to the precipitating glycogen, but glycogen branching enzyme, the enzyme responsible for branching, even under normal conditions does not associate tightly [Worby et al 2006, Tagliabracci et al 2007, Tagliabracci et al 2008, Turnbull et al 2010, Turnbull et al 2011]. In this hypothesis, elongation by GS of the chains of the precipitated glycogen, with no branching, would convert glycogen to polyglucosan.

Both hypotheses predict that inhibiting GS would prevent polyglucosan formation, and if Lafora bodies are causative of the progressive myoclonus epilepsy, this could ameliorate or cure the epilepsy.

To address this prediction, the following experiment was set up. Lafora-deficient mice (Epm2a/) replicate LD and are a standard, well-characterized model [Ganesh et al 2002a]. DePaoli-Roach generated PTG-deficient mice. By breeding LD mice with PTG-lacking mice, Turnbull and colleagues generated LD mice lacking the GS-activating effect of PTG. The double knockout mice had almost no polyglucosan, no neurodegeneration, and no seizures. This genetic depletion of PTG, one of the proteins that targets the PP1 phosphatase to glycogen and the glycogen metabolizing enzymes, corrects the pathology and eliminates the epilepsy in LD. The effect on glycogen is partial, returning the elevated glycogen levels of LD to normal wild type levels, correcting the cardinal features of the disease, and causing no apparent harm to the mice. The crystal structures of PP1, GS, GP, and GPK are known, as is the PTG interaction domain with GS, GP and GPK. Identification of inhibitors of this interaction through rational design or large-scale small molecule screens could result in a treatment for this fatal epilepsy. These treatments could also be applicable to other glycogen storage diseases [Turnbull et al 2011].

It has been reported that laforin enhances macroautophagy and that macroautophagy is dysfunctional in LD [Aguado et al 2010, Knecht et al 2010], indicating that laforin could potentially not only prevent polyglucosan formation but also clear polyglucosans when they do form. The experiment described by Turnbull and colleagues shows that preventing polyglucosan formation obviates other laforin functions and effectively prevents LD in mouse.

Studies in mice have shown that malin interacts with the glycogen debrancher enzyme amylo-1,6-glucosidase,4-alpha-glucanotransferase (AGL). Mutations in AGL cause Cori disease or glycogen storage disease III [Cheng et al 2007].

EPM2A

Normal allelic variants. 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, Gomez-Garre et al 2000].

Several polymorphisms in EPM2A have been described [Gomez-Garre et al 2000, Minassian et al 2000b, Singh et al 2005]:

  • Among the polymorphisms, 136G>C (p.Ala46Pro) is specific to the Japanese and Chinese populations [Ganesh et al 2001].
  • 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, always 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].

Pathologic allelic variants. To date, at least 59 different mutations in EPM2A have been reported in more than 100 families [Minassian et al 1998, Serratosa et al 1999, Gomez-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 mutations can be found in the Lafora Progressive Myoclonus Epilepsy Mutation and Polymorphism Database [Ianzano et al 2005].

Of all the types of mutations 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 mutations are distributed evenly across EPM2A. Exceptions are the high prevalence of the following:

Normal gene product. EPM2A encodes laforin, a 331-amino acid protein phosphatase (reference sequence isoform A, NP_005661.1). 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]. Both isoforms of the laforin protein have alternate C termini [Ganesh et al 2002c]. The common segment consists of a carbohydrate-binding module and a dual-specificity protein phosphatase domain [Ganesh et al 2000]. Isoform A localizes at the rough endoplasmic reticulum. Isoform B localizes to the nucleus. Laforin is conserved in all vertebrates; it has been lost in the vast majority of lower organisms, and yet 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 [Fernandez-Sanchez et al 2003, Ganesh et al 2006]. Loss of phosphatase activity is not restricted to mutations located in the DSPD; it has also been observed for mutations affecting the CBD of EPM2A [Wang et al 2002, Fernandez-Sanchez 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, proteins that interact with laforin in vivo [Fernandez-Sanchez 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 mutations on the proteins function are yet to be developed [Singh & Ganesh 2009].

Two laforin isoforms have unique C termini, produced by differentially spliced transcripts of EPM2A [Ganesh et al 2002c, Ianzano et al 2004]. The unique carboxyl terminal of isoform 2 targets laforin to the nucleus, a feature that is not shared by laforin isoform 1. Ianzano et al [2004] demonstrated that disturbances in the physiologic functions of laforin isoform 1 underlie the pathogenesis of LD, and isoform 2 cannot functionally substitute for laforin isoform 1.

NHLRC1 (EPM2B)

Normal allelic variants. NHLRC1 (EPM2B) 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]. Six normal allelic variants have been reported [Chan et al 2003b, Singh et al 2005].

Pathologic allelic variants. To date, at least 59 mutations 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, Gomez-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. Reference sequences for pathologic variants discussed below are NM_198586.2 and NP_940988.2.

  • The c.468-469delAG c.468_469delAG (p.Gly158Argfs*17) mutation, involving the removal of two bases in the coding region, is the most common mutation 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].
  • The missense mutation c.205C>G (p.Pro69Ala), affecting the RING finger domain, is the most common missense mutation in NHLRC1 (20 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, Gomez-Abad et al 2005, Franceschetti et al 2006, Lesca et al 2010]. The high prevalence of this mutation is also explained both by founder effect and recurrent mutation events [Chan et al 2003a, Gomez-Abad et al 2005, Franceschetti et al 2006].

    Note: Whereas c.205C>G mutation is common in affected persons of Italian and Spanish heritage, both the c.205C>G and c.468_469delAG mutations have been identified in different ethnic groups, suggesting a recurrent mutational event; these two sites represent hot spots for NHLRC1 mutations [Ganesh et al 2006].
  • Missense mutation c.76T>A (p.Cys26Ser) 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 mutation. This individual was heterozygous for two other NHLRC1 mutations, but he was known to also have distant German and other European ancestry [Chan et al 2003a]. To date, this mutation has not been detected in non-French-Canadian families.

Normal gene product. NHLRC1 encodes 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].

Abnormal gene product. See Ganesh et al [2006]. Nearly all mutations in NHLRC1 are predicted to result in the loss of function of malin [Chan et al 2003b, Gomez-Abad et al 2005, Singh et al 2005]. 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, and missense mutations in NHLRC1 associated with LD disrupt this function [Gentry et al 2005].

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

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Suggested Reading

  1. Noebels JL. The inherited epilepsies. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 230. Available online. Accessed 10-26-11.

Chapter Notes

Author Notes

Web: mni.mcgill.ca

Revision History

  • 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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