Progressive Myoclonus Epilepsy, Lafora Type
Summary
Clinical characteristics.
Progressive myoclonus epilepsy, Lafora type (also known as Lafora disease [LD]) is characterized by focal occipital seizures presenting as transient blindness or visual hallucinations and fragmentary, symmetric, or generalized myoclonus beginning in previously healthy individuals at age eight to 19 years (peak 14-16 years). Generalized tonic-clonic seizures, atypical absence seizures, atonic seizures, and focal seizures with impaired awareness may occur. The course of the disease is characterized by increasing frequency and intractability of seizures. Status epilepticus with any of the seizure types is common. Cognitive decline becomes apparent at or soon after the onset of seizures. Dysarthria and ataxia appear early while spasticity appears late. Emotional disturbance and confusion are common in the early stages of the disease and are followed by dementia. Most affected individuals die within ten years of onset, usually from status epilepticus or from complications related to nervous system degeneration.
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 on molecular genetic testing. On rare occasion 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. Antiepileptic drugs are effective against generalized seizures, but do not influence the progression of cognitive and behavioral symptoms. 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; possibly lamotrigine, carbamazepine, and oxcarbazepine.
Genetic counseling.
Lafora disease is inherited in an autosomal recessive manner. Heterozygotes (carriers) are asymptomatic and not at risk of developing the disorder. 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, prenatal diagnosis for at-risk pregnancies, and preimplantation genetic diagnosis are possible if the pathogenic variants in the family are known.
Diagnosis
Suggestive Findings
Progressive myoclonus epilepsy, Lafora type, also known as Lafora disease (LD), should be suspected in a previously healthy older child or adolescent (usually in the early teens) who has the following:
- 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 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 (see Clinical Description)
- Normal brain MRI at onset
Establishing the Diagnosis
The diagnosis of Lafora disease is established in a proband with characteristic neurologic findings and/or biallelic pathogenic variants in one of the genes listed in Table 1.
Skin biopsy can be performed in individuals with a clinical diagnosis of Lafora disease in whom no pathogenic variant can be identified on molecular genetic testing.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Lafora disease is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Lafora disease has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of Lafora disease, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.
Serial single-gene testing. Sequence analysis detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Sequence analysis of EPM2A and NHLRC1 may be performed in any order, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found. Because the clinical manifestations of LD caused by pathogenic variants in either gene are so similar, it is not possible to predict which gene will be involved in any given individual. Therefore, serial single-gene testing, while possible, is not the recommended approach.
A multigene panel that includes EPM2A and NHLRC1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of Lafora disease is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which genes are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
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
| Gene 1, 2 | Proportion of Lafora Disease Attributed to Pathogenic Variants in This Gene | Proportion of Pathogenic Variants 3 Detectable by Test Method | |
|---|---|---|---|
| Sequence analysis 4 | Gene-targeted deletion/duplication analysis 5 | ||
| EPM2A | 42% 6 | 85%-90% 6 | 10%-15% 6 |
| NHLRC1 | 58% 6 | >90% 6 | <10% 6 |
- 1.
Genes are listed alphabetically.
- 2.
See Table A. Genes and Databases for chromosome locus and protein.
- 3.
See Molecular Genetics for information on allelic variants detected in this gene.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Turnbull et al [2016]
Skin Biopsy
Although molecular genetic analysis of EPM2A and NHLRC1 represents 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.
In affected individuals, 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 Characteristics
Clinical Description
Age of onset. Lafora disease (LD) typically starts during childhood or adolescence (range: 8-19 years, peak 14-16 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].
Seizure types. The main seizure types in LD include myoclonic seizures and occipital seizures, although generalized tonic-clonic seizures, atypical absence seizures, atonic seizures, and focal seizures with impaired awareness 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]. Not all visual hallucinations in individuals with LD are epileptic in origin, as some respond initially to antipsychotic, rather than antiepileptic, 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 the onset of seizures. Dysarthria and ataxia appear early while spasticity appears late. Emotional disturbance and confusion are common in the early stages of the disease and are followed by dementia. 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 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 [Turnbull et al 2016]. Variation by country in the care available for individuals with LD may influence longevity and disease complications.
Table 2.
Clinical Findings of Progressive Myoclonus Epilepsy, Lafora Type
| Evaluation Type | At Onset | Later in Disease Course |
|---|---|---|
| General physical examination, incl liver & spleen size | Normal | Normal |
| Neurologic examination, incl fundi & reflexes | Normal | Dysarthria, ataxia, spasticity; fundi remain normal |
| Mental state examination | Visual hallucinations, cognitive deficits, depressed mood, headaches | ↑ hallucinations, agitation, & dementia w/predominantly frontal cognitive impairment affecting mainly performance ability & executive function |
| EEG | Normal or slow background, occipital discharges | Slow background, paroxysms of generalized irregular spike-wave discharges w/occipital predominance, & focal (especially occipital) abnormalities, loss of sleep features, marked photosensitivity |
| Visual, somatosensory, & auditory brain stem evoked potentials | High-voltage visual & somatosensory evoked potentials | Amplitudes may return to normal size; prolongation of brain stem & central latencies |
| Nerve conduction studies | Normal | Normal |
| MRI of the brain | Normal | Normal or atrophy 1 |
| Proton MR spectroscopy of the brain | Data not available | ↓ NAA/creatine ratio in frontal & occipital cortex, basal ganglia, & cerebellum; ↓ NAA/myoinositol ratio in frontal gray & white matter; ↓ NAA/choline ratio in cerebellum 2 |
| Transcranial magnetic stimulation | Not applicable | Defective short intracortical inhibition: inhibition at ISI 6 ms & ISI 10 ms; defective long-interval cortical inhibition |
Altindag et al [2009], Canafoglia et al [2010], Turnbull et al [2016]
ISI = interstimulus intervals; NAA = N-acetylaspartate
- 1.
No significant correlation observed with disease evolution
- 2.
At least two years after onset of symptoms
Genotype-Phenotype Correlations
Genotype-phenotype correlations are difficult to establish in LD due to the large number of pathogenic variants in both EPM2A and NHLRC1, as well as the frequent occurrence of compound heterozygotes in different combinations [Chan et al 2005, Gómez-Abad et al 2005].
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-associated gene products laforin and malin are known to interact with a diverse set of proteins, and variations in genes that code for these interacting proteins 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 variant type (missense or truncating) or location of the pathogenic variant in the gene have been demonstrated.
- A potential sub-phenotype consisting of childhood-onset learning disorder followed by epilepsy and neurologic deterioration has been associated with either pathogenic variants in exon 1 of EPM2A [Ganesh et al 2002a, Annesi et al 2004] or the p.Ile198Asn pathogenic variant located in an NHL protein-protein interaction domain of NHLRC1 [Gómez-Abad et al 2005]. However, further study is needed to clarify whether this observation represents a true "sub-phenotype" or is the result of as-yet unknown genetic and/or environmental modifying factors [Lesca et al 2010].
- Some studies have indicated that individuals with pathogenic variants in NHLRC1 have a slightly milder course than those with pathogenic variants in EPM2A [Gómez-Abad et al 2005, Franceschetti et al 2006, Singh et al 2006], while others found no difference in disease severity between the two [Traoré et al 2009, Brackmann et al 2011]. This observation may, at least in part, be due to the relatively common occurrence of the pathogenic variant p.Asp146Asn in NHLRC1, which is associated with an atypical milder form of LD consisting of a later onset of symptoms, longer disease course, and extended preservation of daily activities in all individuals reported to date. This pathogenic variant has never been reported in individuals with typical LD [Ferlazzo et al 2014, Lanoiselée et al 2014].
Nomenclature
Lafora disease (LD) is also referred to as myoclonic epilepsy of Lafora or progressive myoclonic epilepsy-2 (EPM2).
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 LD are lacking; based on all published reports of LD-causing pathogenic variants, the overall global frequency is estimated at 4:1,000,000 individuals [Turnbull et al 2016].
LD occurs worldwide. While relatively rare in the nonconsanguineous 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 (OMIM 616640) is characterized by progressive myoclonus epilepsy and the presence of Lafora bodies in muscle but not in sweat glands. In contrast to typical Lafora disease (LD), early-onset LD 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 typical LD. Early-onset LD has been reported in one individual with homozygous pathogenic variants in PRDM8; inheritance is autosomal recessive [Turnbull et al 2012].
Although the occurrence of myoclonus and generalized tonic-clonic seizures in adolescence may raise the possibility of juvenile myoclonic epilepsy (OMIM 254770), the persistence of EEG background slowing and cognitive deterioration should raise the suspicion of a more severe epilepsy syndrome, such as progressive myoclonus epilepsy. Juvenile myoclonic epilepsy is caused by pathogenic variants in EFHC1; inheritance is autosomal dominant.
Earlier age at onset, slower rate of disease progression, and absence of Lafora bodies on skin biopsy differentiates Unverricht-Lundborg disease (EPM1) from LD.
Careful ophthalmologic examination, including electroretinography, is useful in addressing the possibilities of neuronal ceroid-lipofuscinoses and sialidosis types I and II (OMIM 256550).
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.
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.
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 if they have not already been completed:
- Clinical evaluation
- Multidisciplinary evaluation of all aspects of development including concerns regarding behavior, intellectual ability, academic performance, neuropsychological skills, speech and language skills, motor skills, psychosocial skills, and impact on parents and sibs
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Management of LD consists of medical treatment in combination with physical therapy and psychosocial support. Regular evaluation and readjustment are required as the disease progresses.
Medical Treatment
In general, treatment recommendations for LD follow those of other PMEs [Michelucci et al 2016, Ferlazzo et al 2017]. Apart from an open-label trial with perampanel in ten individuals with LD, no specific clinical trials have been performed in LD.
Antiepileptic drugs (AEDs) have a clear effect against generalized seizures, sometimes controlling seizures for many months. Generalized seizures are rare in individuals who are treated, even years after disease onset. However, AEDs do not influence the progression of cognitive and behavioral symptoms.
- First-line AEDs include valproic acid and benzodiazepines.
- Valproic acid is the traditional antiepileptic treatment for LD; because it is a broad-spectrum AED, it suppresses, for some time, the generalized tonic-clonic seizures and myoclonic jerks.
- Benzodiazepines (clonazepam, clobazam, diazepam) 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. Some individuals may develop tolerance, requiring dose adjustment or switching to another benzodiazepine.
- Because the myoclonus associated with LD may be drug resistant, overmedication may be a risk in individuals with LD.
- Second-line AEDs include levetiracetam, zonisamide, topiramate, and perampanel, although evidence is limited.
- Common polytherapy combinations consist of valproic acid with perampanel, topiramate, zonisamide, or levetiracetam, and a benzodiazepine.
- An open-label trial with add-on perampanel in ten individuals with LD showed significant reduction in seizures greater than 74% from baseline in four. Seven had major improvement in myoclonus. Three withdrew due to inefficacy or side effects. There was no improvement in disability or cognition [Goldsmith and Minassian 2016].
- Third-line strategies include primidone, phenobarbital, piracetam, and ethosuximide.There are two anecdotal reports on the use of vagal nerve stimulation in LD [Hajnsek et al 2013, Mikati & Tabbara 2017].
- Emergency treatment for severe aggravation with serial seizures or status epilepticus consists of intravenous benzodiazepines or loading with phenytoin. Phenytoin should not be kept as maintenance therapy after arrest of the status.
Physical Therapy
Physical therapy is recommended in order to maintain ambulation as long as possible, and to prevent pulmonary and orthopedic complications.
Support in Later Stages
As the disease progresses, generalized seizures become more frequent and myoclonus more disabling, requiring more intensive support in the home environment or through institutionalization, depending on availability of care and family preferences.
- Serial seizures or status epilepticus may require admission to critical care.
- 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 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 LD typically do not have children. However, in cases of mild LD with slow disease progression as reported with the p.Asp146Asn variant in NHLRC1, pregnancies could occur [Ferlazzo et al 2014]. The universal use of AEDs in individuals with LD, even when mild, warrant counseling regarding the potential consequences of fetal exposure to maternal anticonvulsant therapy.
See MotherToBaby for further information on medication use during pregnancy.
Therapies Under Investigation
It is anticipated that with an improved understanding of the pathogenesis in LD, targeted treatments might become available in the future [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.