Progressive Myoclonus Epilepsy, Lafora Type

Clinical characteristics.

Progressive myoclonus epilepsy, Lafora type (also known as Lafora disease) is characterized by focal occipital seizures presenting as transient blindness or visual hallucinations and fragmentary, symmetric, or generalized myoclonus occurring in previously healthy individuals. Typical age of onset is eight to 19 years (peak: age14-16 years). Generalized tonic-clonic seizures, atypical absence seizures, atonic seizures, and focal seizures with impaired awareness may also occur. The course of the disease is characterized by increasing frequency and intractability of seizures. Status epilepticus with any of the seizure types is common. Cognitive decline becomes apparent at or soon after the onset of seizures. Dysarthria and ataxia appear early, while spasticity appears late. Emotional disturbances and confusion are common in the early stages of the disease and are followed by dementia. Most affected individuals die within ten years of onset, usually from status epilepticus or from complications related to neurologic degeneration.

Diagnosis/testing.

The diagnosis of Lafora disease is established in a proband with characteristic neurologic findings and/or biallelic pathogenic variants in one of the two known causative genes, EPM2A or NHLRC1, identified by molecular genetic testing. On rare occasion, a skin biopsy to detect Lafora bodies is necessary to confirm the diagnosis.

Management.

Treatment of manifestations: Medical treatment in combination with physical therapy and psychosocial support. Regular evaluation and readjustment are required as the disease progresses. Anti-seizure medications are effective against generalized seizures but do not alter the progression of cognitive and behavioral manifestations. Overmedication in treating drug-resistant myoclonus is a risk. Gastrostomy feedings can decrease the risk of aspiration pneumonia when the disease is advanced.

Surveillance: Clinical and psychosocial evaluations throughout the teenage years. Monitoring of developmental progress and educational needs, in conjunction with behavioral assessments. Continuous assessment of feeding, nutritional status, and airway protection (including aspiration risk).

Agents/circumstances to avoid: Phenytoin as maintenance therapy; possibly lamotrigine, carbamazepine, and oxcarbazepine.

Genetic counseling.

Lafora disease is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an EPM2A or NHLRC1 pathogenic variant, each sib of an affected individual has at conception 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, prenatal testing for at-risk pregnancies, and preimplantation genetic testing are possible if the pathogenic variants in the family are known.

Suggestive Findings

Lafora disease should be suspected in a previously healthy older child or adolescent (usually in the early teens) with the following clinical manifestations and family history:

Clinical manifestations

• Focal occipital seizures presenting as transient blindness or visual hallucinations
• Fragmentary, symmetric, or generalized myoclonus
• Generalized seizures including tonic-clonic seizures, absence seizures, or drop attacks
• Progressive neurologic degeneration including cognitive and/or behavioral deterioration, dysarthria, ataxia, and, at later stages, spasticity and dementia
• Slowing of EEG background activity, loss of alpha rhythm and sleep features, posteriorly dominant irregular spike-wave discharges, and photosensitivity on early EEGs
• Periodic acid Schiff-positive intracellular inclusion bodies (Lafora bodies) on skin biopsy (See Clinical Description.)
• Normal brain MRI at disease onset; progressive cortical atrophy possible later in the course of the disease

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of Lafora disease is established in a proband with characteristic neurologic findings and/or biallelic pathogenic (or likely pathogenic) variants in one of the genes listed in Table 1.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic variants of uncertain significance (or of one known pathogenic variant and one variant of uncertain significance) in the genes listed in Table 1 does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 2

When the diagnosis of Lafora disease has not been considered because an individual has atypical phenotypic features, comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. To date, the majority of EPM2A and NHLRC1 pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Progressive Myoclonus Epilepsy, Lafora Type

Skin biopsy. Although molecular genetic analysis of EPM2A and NHLRC1 represents the gold standard for confirming the diagnosis of Lafora disease, a skin biopsy remains a useful diagnostic tool in individuals with a clinical diagnosis of Lafora disease in whom no pathogenic variants can be identified. In affected individuals, a 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].

Clinical Description

Progressive myoclonus epilepsy, Lafora type, also known as Lafora disease, is a rare teenage-onset progressive myoclonus epilepsy. The term "myoclonus" is emphasized because this is a relatively infrequent neurologic symptom in teenagers. When seen in an otherwise healthy adolescent, it strongly suggests a common benign form of epilepsy, juvenile myoclonic epilepsy (JME). For this reason, most individuals with Lafora disease are briefly misdiagnosed with JME. However, while the EEG background in JME is normal, it is already abnormal (slow) when myoclonus appears in individuals with Lafora disease.

Lafora disease is associated with inexorable worsening of the epilepsy. Myoclonus gradually becomes near constant. Generalized tonic-clonic seizures gradually become intractable; atypical absences with or without myoclonus eventually take over. The affected individual's interactions become such that every thought, speech, feeding, etc., are interrupted, and each of these and other functions become slow and protracted. Walking ability is lost usually in most affected individuals before age 21 years. Within ten years of disease onset, most individuals are in a vegetative state and usually die in status epilepticus or complications of poor airway control.

To date, at least 300 individuals have been identified with Lafora disease [Orooj et al 2021, Zaganas et al 2021, d'Orsi et al 2022, Katz et al 2022, Krakhmal et al 2022, Liang et al 2022, Nordli et al 2022, Orsini et al 2022, Tang et al 2022, Zeka et al 2022, d'Orsi et al 2023, Ferrari Aggradi et al 2023, Pondrelli et al 2023, Duan et al 2024, Zhu et al 2024]. The following description of the phenotypic features associated with this condition is based on these reports.

Table 2.

Clinical Findings of Progressive Myoclonus Epilepsy, Lafora Type

Age of onset. Lafora disease typically starts during childhood or adolescence (range: age 8-19 years, peak: age 14-16 years), after a period of apparently normal development. Many affected individuals experience isolated febrile or nonfebrile seizures during infancy or early childhood. Intractable seizures rarely begin as early as age six years. In families with more than one affected individual, clinical manifestations such as subtle myoclonus, visual hallucinations, or headaches are noted earlier in subsequently 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].

Seizure types. The main seizure types in Lafora disease include myoclonic seizures and occipital seizures, although generalized tonic-clonic seizures, atypical absence seizures, atonic seizures, and focal seizures with impaired awareness may occur. Generalized seizures are rare in individuals who are treated, even years after disease onset.

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 migraines with scintillating scotomata [Berkovic et al 1993, Minassian et al 2000b]. Not all visual hallucinations in individuals with Lafora disease are epileptic in origin, as some respond initially to anti-psychotic, rather than anti-seizure, medications [Andrade et al 2005].

Progression. 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 seizure onset. Dysarthria and ataxia appear early, while spasticity appears late. Emotional disturbance and confusion are common in the early stages of the disease and are followed by dementia. See Table 2 for a comparison of the findings at onset and later in the disease course.

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 because 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 neurologic deterioration [Turnbull et al 2016].

Genotype-Phenotype Correlations

Most pathogenic variants in NHLRC1 (EPM2B) and EPM2A (EPM2A) result in complete loss of function. Phenotypes associated with these variants are indistinguishable and represent classic Lafora disease. To date, pathogenic variants in EPM2A affecting splicing result in the same severe classic Lafora disease [Duan et al 2024].

There are reports of mild Lafora disease with slow disease progression in association with missense variants. For example, the NHLRC1 pathogenic variant p.Asp146Asn has been reported in association with an atypical milder form of Lafora disease consisting of later onset of symptoms, longer disease course, and extended preservation of daily activities [Ferlazzo et al 2014, Lanoiselée et al 2014].

Nomenclature

Progressive myoclonus epilepsy, Lafora type, also known as Lafora disease, is also referred to as myoclonic epilepsy of Lafora.

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 [Genton et al 2016].

Prevalence

Exact prevalence figures for Lafora disease are lacking. Based on all published reports of Lafora disease-causing pathogenic variants to date, the overall global frequency is estimated at 4:1,000,000 [Turnbull et al 2016].

Lafora disease occurs worldwide. While relatively rare in the nonconsanguineous populations of the United States, Canada, China, and Japan, Lafora disease 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 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: Lafora disease has not been reported in Finland, where founder effects for a number of genetic disorders are common, and where progressive myoclonic epilepsy type 1 (EPM1; Unverricht-Lundborg disease) has the highest prevalence [A Lehesjoki & R Kälviäinen, personal communication].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Lafora disease, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Lafora Disease: Recommended Evaluations Following Initial Diagnosis

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Table 5.

Lafora Disease: Treatment of Manifestations

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Table 6.

Lafora Disease: Recommended Surveillance

Agents/Circumstances to Avoid

As in other forms of progressive myoclonic epilepsies, the use of phenytoin as maintenance therapy should be avoided.

Anecdotal reports describe possible exacerbation of myoclonus with the following:

• Lamotrigine [Cerminara et al 2004, Crespel et al 2005]
• Carbamazepine [Nanba & Maegaki 1999]
• Oxcarbazepine [Kaddurah & Holmes 2006]

Evaluation of Relatives at Risk

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

Pregnancy Management

Due to the severity of the disorder, individuals with Lafora disease typically do not have children. However, in cases of mild Lafora disease with slow disease progression (as reported with the p.Asp146Asn variant in NHLRC1), pregnancies could occur [Ferlazzo et al 2014]. The universal use of anti-seizure medications in individuals with Lafora disease, even when mild, warrant counseling regarding the potential consequences of fetal exposure to maternal anti-convulsant therapy.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

An open-label trial with add-on perampanel in ten individuals with Lafora disease showed significant reduction in seizures greater than 74% from baseline in four individuals. Seven had major improvement in myoclonus. Three withdrew due to inefficacy or side effects. There was no improvement in disability or cognition [Goldsmith & Minassian 2016].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Progressive myoclonus epilepsy, Lafora type (also known as Lafora disease), is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an EPM2A or NHLRC1 pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an EPM2A or NHLRC1 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an EPM2A or NHLRC1 pathogenic variant, each sib of an affected individual has at conception 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.
• Variability in age at onset among affected family members is considerable (see Genotype-Phenotype Correlations).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

• The offspring of an individual with Lafora disease would be obligate heterozygotes (carriers) for a pathogenic variant in EPM2A or NHLRC1.
• Because of the early onset and rapid deterioration, individuals with Lafora disease typically do not reproduce.

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

Carrier Detection

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

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.
• It is appropriate to offer EPM2A and NHLRC1 molecular genetic testing for reproductive partners of individuals known to be heterozygous for a Lafora disease-related pathogenic variant, particularly if consanguinity is likely.

Prenatal Testing and Preimplantation Genetic Testing

Once the EPM2A or NHLRC1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

EPM2A. This gene encodes a dual-specificity phosphatase called laforin and may be involved in the regulation of glycogen metabolism. The protein acts on complex carbohydrates to prevent glycogen hyperphosphorylation, thus avoiding the formation of insoluble aggregates. There are two isoforms of the laforin protein that have unique C termini [Ganesh et al 2002b, Ianzano et al 2004]. The carboxyl terminal of isoform B targets laforin to the nucleus, a feature that is not shared by the longer laforin isoform A. Ianzano et al [2004] demonstrated that disturbances in the physiologic functions of laforin isoform A underlie the pathogenesis of Lafora disease, and isoform B cannot functionally substitute for laforin isoform A. Remarkably, more recent data indicates that laforin's phosphatase function is dispensable insofar as Lafora bodies, the neurotoxic accumulations that characterize the disease, are concerned. Several experiments showed that inactivating laforin's phosphatase domain while keeping the rest of the protein intact does not lead to Lafora body formation [Nitschke et al 2017, Skurat et al 2024]. All indications at present are that malin, encoded by NHLRC1, the second gene associated with Lafora disease, is key [Sullivan et al 2019].

NHLRC1. NHLRC1 encodes E3 ubiquitin-protein ligase NHLRC1 (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 pathology underlying Lafora disease consists of 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]. The current view on Lafora disease pathogenesis suggests that Lafora disease is predominantly caused by an impairment in chain-length regulation affecting only a small proportion of the cellular glycogen. The principal function of laforin (the gene product of EPM2A) relevant to Lafora disease is mediated through malin (the gene product of NHLRC1) and directed to preventing glycogen molecules with hyperextended chains. In the absence of either protein, some glycogen molecules precipitate and gradually over time aggregate and amass into Lafora bodies, which, reaching a certain threshold profusion (at age ~14 years in humans), initiate and then drive the progressive myoclonus epilepsy [Nitschke et al 2017, Sullivan et al 2017]. Laforin's key function appears to be the targeting of malin to glycogen for malin's E3 ubiquitin ligase to regulate certain yet unconfirmed proteins [Mitra et al 2023]. Suspected malin substrates are glycogen metabolism proteins [Skurat et al 2024].

Mechanism of disease causation

• EPM2A-related Lafora disease: loss of function
• NHLRC1-related Lafora disease: loss of function

EPM2A- and NHLRC1-specific laboratory technical considerations. NHLRC1 is a single-exon gene spanning 1,188 base pairs that has all of the proposed features of the consensus sequence of an eukaryotic translational initiation site at its 5' end and two putative polyadenylation signals at its 3' end.

Table 7.

EPM2A and NHLRC1 Pathogenic Variants Referenced in This GeneReview

Author Notes

Berge A Minassian, MD, directs the Child Neurology program at University of Texas Southwestern and co-directs the university's Gene Therapy Program. The two are intimately linked because most of Child Neurology is neurogenetic diseases. In addition to his work on developing gene therapies for childhood neurologic diseases, he has had an abiding interest in understanding the pathogenesis of Lafora disease, to which he has been committed for more than 30 years.

Author History

Eva Andermann, MD, PhD, FCCMG; McGill University (2007-2025)
Anna C Jansen, MD, PhD; Vrije Universiteit Brussel (2007-2025)
Berge Minassian, MD (2025-present)

Revision History

• 23 January 2025 (gm) Comprehensive update posted live
• 21 February 2019 (ha) Comprehensive update posted live
• 22 January 2015 (me) Comprehensive update posted live
• 3 November 2011 (me) Comprehensive update posted live
• 28 December 2007 (me) Review posted live
• 2 January 2007 (ea) Original submission

Literature Cited

• 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]

• 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]

• Andrade DM, del Campo JM, Moro E, Minassian BA, Wennberg RA. Nonepileptic visual hallucinations in Lafora disease. Neurology. 2005;64:1311–2. [PubMed: 15824378]

• Berkovic SF, Cochius J, Andermann E, Andermann F. Progressive myoclonus epilepsies: clinical and genetic aspects. Epilepsia. 1993;34:S19–30. [PubMed: 8500430]

• 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]

• Carpenter S, Karpati G. Sweat gland duct cells in Lafora disease: diagnosis by skin biopsy. Neurology. 1981;31:1564–8. [PubMed: 6796905]

• 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]

• 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]

• 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]

• 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]

• 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]

• d'Orsi G, Di Claudio MT, Palumbo O, Carella M. Electro-clinical features and management of the late stage of Lafora disease. Front Neurol. 2022;13:969297. [PMC free article: PMC9580008] [PubMed: 36277909]

• d'Orsi G, Farolfi A, Muccioli L, Palumbo O, Palumbo P, Modoni S, Allegri V, Garibotto V, Di Claudio MT, Di Muro E, Benvenuto M, Bisulli F, Carella M. Association of CSF and PET markers of neurodegeneration with electroclinical progression in Lafora disease. Front Neurol. 2023;14:1202971. [PMC free article: PMC10337130] [PubMed: 37448753]

• Davarzani A, Shahrokhi A, Hashemi SS, Ghasemi A, Habibi Kavashkohei MR, Farboodi N, Lang AE, Ghiasi M, Rohani M, Alavi A. The second family affected with a PRDM8-related disease. Neurol Sci. 2022;43:3847-55. [PubMed: 35034233]

• 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]

• 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]

• Duan RN, Liu JD, Zhao XH, Song CY. Identification of biallelic intronic EPM2A mutations in a Lafora disease kindred. J Hum Genet. 2024. Epub ahead of print. [PubMed: 39558147]

• Ferlazzo E, Canafoglia L, Michelucci R, Gambardella A, Gennaro E, Pasini E, Riguzzi P, Plasmati R, Volpi L, Labate A, Gasparini S, Villani F, Casazza M, Viri M, Zara F, Minassian BA, Turnbull J, Serratosa JM, Guerrero-López R, Franceschetti S, Aguglia U. Mild Lafora disease: clinical, neurophysiologic, and genetic findings. Epilepsia. 2014;55:e129–33. [PubMed: 25270369]

• Ferlazzo E, Trenite DK, de Haan GJ, Felix Nitschke F, Ahonen S, Gasparini S, Minassian BA. Update on pharmacological treatment of progressive myoclonus epilepsies. Curr Pharm Des. 2017;23:5662-6. [PMC free article: PMC5954238] [PubMed: 28799509]

• Ferrari Aggradi CR, Rimoldi M, Romagnoli G, Velardo D, Meneri M, Iacobucci D, Ripolone M, Napoli L, Ciscato P, Moggio M, Comi GP, Ronchi D, Corti S, Abati E. Lafora disease: a case report and evolving treatment advancements. Brain Sci. 2023;13:1679. [PMC free article: PMC10742041] [PubMed: 38137127]

• 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]

• 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. 2002a;11:1263–71. [PubMed: 12019207]

• Ganesh S, Suzuki T, Yamakawa K. Alternative splicing modulates subcellular localization of laforin. Biochem Biophys Res Commun. 2002b;291:1134–7. [PubMed: 11883934]

• Genton P, Striano P, Minassian BA. The history of progressive myoclonus epilepsies. Epileptic Disord. 2016;18(S2):3–10. [PMC free article: PMC5777179] [PubMed: 27621064]

• Goldsmith D, Minassian BA. Efficacy and tolerability of perampanel in ten patients with Lafora disease. Epilepsy Behav. 2016;62:132–5. [PMC free article: PMC5691360] [PubMed: 27459034]

• 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]

• 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]

• 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]

• Hajnsek S, Petelin Gadze Z, Borovecki F, Nankovic S, Mrak G, Gotovac K, Sulentic V, Kovacevic I, Bujan Kovac A. Vagus nerve stimulation in Lafora body disease. Epilepsy Behav Case Rep. 2013;1:150–2. [PMC free article: PMC4150640] [PubMed: 25667850]

• 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]

• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519-22. [PubMed: 28959963]

• Kaddurah AK, Holmes GL. Possible precipitation of myoclonic seizures with oxcarbazepine. Epilepsy Behav. 2006;8:289–93. [PubMed: 16356781]

• Katz T, Chellamani H, Hauptman AJ. A new finding of catatonia as part of Lafora disease: a case report. J Acad Consult Liaison Psychiatry. 2022;63:404-5. [PubMed: 35868834]

• Krakhmal NV, Vasilchenko DV, Vtorushin SV. [Lafora disease with a fatal outcome]. Arkh Patol. 2022;84:61-6. [PubMed: 36469720]

• Lanoiselée HM, Genton P, Lesca G, Brault F, De Toffol B. Are c.436G>A mutations less severe forms of Lafora disease? A case report. Epilepsy Behav Case Rep. 2014;2:19–21. [PMC free article: PMC4307960] [PubMed: 25667860]

• 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]

• Liang T, Wu J, Chen H, Qian J, Xu Z. Novel mutation of EPM2A causes progressive myoclonic epilepsy: a case report. Neurol Sci. 2022;43:3467-71. [PubMed: 35257260]

• 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]

• Michelucci R, Pasini E, Riguzzi P, Andermann E, Kälviäinen R, Genton P. Myoclonus and seizures in progressive myoclonus epilepsies: pharmacology and therapeutic trials. Epileptic Disord. 2016;18(S2):145–153. [PubMed: 27629998]

• Mikati MA, Tabbara F. Managing Lafora body disease with vagal nerve stimulation. Epileptic Disord. 2017;19:82–86. [PubMed: 28238966]

• Minassian BA. Progressive myoclonus epilepsy with polyglucosan bodies: Lafora disease. Adv Neurol. 2002;89:199–210. [PubMed: 11968446]

• Minassian BA, Ianzano L, Meloche M, Andermann E, Rouleau GA, Delgado-Escueta AV, Scherer SW. Mutation spectrum and preicted function of laforin in Lafora's progressive myoclonus epilepsy. Neurology. 2000b;55:341–6. [PubMed: 10932264]

• Mitra S, Chen B, Wang P, Chown EE, Dear M, Guisso DR, Mariam U, Wu J, Gumusgoz E, Minassian BA. Laforin targets malin to glycogen in Lafora progressive myoclonus epilepsy. Dis Model Mech. 2023;16:dmm049802. [PMC free article: PMC9844227] [PubMed: 36511140]

• 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]

• Nitschke F, Sullivan MA, Wang P, Zhao X, Chown EE, Perri AM, Israelian L, Juana-López L, Bovolenta P, Rodríguez de Córdoba S, Steup M, Minassian BA. Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease. EMBO Mol Med. 2017;9:906–917. [PMC free article: PMC5494504] [PubMed: 28536304]

• Nordli DR, Rao CK, Delgado-Escueta AV, Galan F. A novel mutation in Lafora disease and update on pathophysiology and future treatments. Child Neurol Open. 2022;9:2329048X221126361.

• Orooj F, Umm EK, Zhao X, Ahmad A, Ahmed IN, Faheem M, Hassan MJ, Minasian BA. A novel deletion mutation in EPM2A underlies progressive myoclonic epilepsy (Lafora body disease) in a Pakistani family. Neurol Asia. 2021;26:427-33. [PMC free article: PMC8562703] [PubMed: 34733372]

• Orsini A, Ferrari D, Riva A, Santangelo A, Macri A, Freri E, Canafoglia L, D'Aniello A, Di Gennaro G, Massimetti G, Minetti C, Zara F, Michelucci R, Tumber A, Vincent A, Minassian BA, Striano P. Ocular phenotype and electroretinogram abnormalities in Lafora disease and correlation with disease stage. J Neurol. 2022;269:3597-604. [PMC free article: PMC9217906] [PubMed: 35184210]

• Pondrelli F, Minardi R, Muccioli L, Zenesini C, Vignatelli L, Licchetta L, Mostacci B, Tinuper P, Vander Kooi CW, Gentry MS, Bisulli F. Prognostic value of pathogenic variants in Lafora Disease: systematic review and meta-analysis of patient-level data. Orphanet J Rare Dis. 2023;18:263. [PMC free article: PMC10474773] [PubMed: 37658439]

• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]

• 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]

• 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]

• Skurat AV, Segvich DM, Contreras CJ, Hu YC, Hurley TD, DePaoli-Roach AA, Roach PJ. Impaired malin expression and interaction with partner proteins in Lafora disease. J Biol Chem. 2024;300:107271. [PMC free article: PMC11063907] [PubMed: 38588813]

• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]

• Sullivan MA, Nitschke S, Skwara EP, Wang P, Zhao X, Pan XS, Chown EE, Wang T, Perri AM, Lee JPY, Vilaplana F, Minassian BA, Nitschke F. Skeletal muscle glycogen chain length correlates with insolubility in mouse models of polyglucosan-associated neurodegenerative diseases. Cell Rep. 2019;27:1334-1344 e6. [PMC free article: PMC6530600] [PubMed: 31042462]

• Sullivan MA, Nitschke S, Steup M, Minassian BA, Nitschke F. Pathogenesis of Lafora disease: transition of soluble glycogen to insoluble polyglucosan. Int J Mol Sci. 2017;18:E1743. pii. [PMC free article: PMC5578133] [PubMed: 28800070]

• Tang X, Li X, Chen Y, Wu D. Compound heterozygosity for novel variations of the NHLRC1 gene in a family with Lafora disease. Clin Neurol Neurosurg. 2022;218:107255. [PubMed: 35569391]

• 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]

• 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]

• 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]

• Turnbull J, Tiberia E, Striano P, Genton P, Carpenter S, Ackerley CA, Minassian BA. Lafora disease. Epileptic Disord. 2016;18:38–62. [PMC free article: PMC5777303] [PubMed: 27702709]

• Zaganas I, Vorgia P, Spilioti M, Mathioudakis L, Raissaki M, Ilia S, Giorgi M, Skoula I, Chinitrakis G, Michaelidou K, Paraskevoulakos E, Grafakou O, Kariniotaki C, Psyllou T, Zafeiris S, Tzardi M, Briassoulis G, Dinopoulos A, Mitsias P, Evangeliou A. Genetic cause of epilepsy in a Greek cohort of children and young adults with heterogeneous epilepsy syndromes. Epilepsy Behav Rep. 2021;16:100477. [PMC free article: PMC8449081] [PubMed: 34568804]

• Zeka N, Zogaj L, Gerguri A, Bejiqi R, Ratkoceri R, Maloku A, Mustafa A, Shahini L, Maxharaj J. Lafora disease: a case report. J Med Case Rep. 2022;16:360. [PMC free article: PMC9528140] [PubMed: 36192771]

• Zhu Y, Guan C, Yin Z, Wang K, Ji C. A novel compound heterozygous EPM2A variant in a Chinese family with Lafora disease. Acta Neurol Belg. 2024;124:1713-5. [PubMed: 38407811]