The Lafora type of progressive myoclonic epilepsy is an autosomal recessive disorder characterized by insidious onset of progressive neurodegeneration between 8 and 18 years of age. Initial features can include headache, difficulties in school work, myoclonic jerks, generalized ... The Lafora type of progressive myoclonic epilepsy is an autosomal recessive disorder characterized by insidious onset of progressive neurodegeneration between 8 and 18 years of age. Initial features can include headache, difficulties in school work, myoclonic jerks, generalized seizures, and often visual hallucination. The myoclonus, seizures, and hallucinations gradually worsen and become intractable. This is accompanied by progressive cognitive decline, resulting in dementia. About 10 years after onset, affected individuals are in near-continuous myoclonus with absence seizures, frequent generalized seizures, and profound dementia or a vegetative state. Histologic studies of multiple tissues, including brain, muscle, liver, and heart show intracellular Lafora bodies, which are dense accumulations of malformed and insoluble glycogen molecules, termed polyglucosans (review by Ramachandran et al., 2009). For a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (254800).
Sarlin et al. (1960) claimed that electroencephalographic abnormalities distinguished heterozygotes from homozygous normals. Schwarz and Yanoff (1965) proposed diagnosis by liver or muscle biopsy.
Busard et al. (1986, 1987) demonstrated that the diagnosis can be made ... Sarlin et al. (1960) claimed that electroencephalographic abnormalities distinguished heterozygotes from homozygous normals. Schwarz and Yanoff (1965) proposed diagnosis by liver or muscle biopsy. Busard et al. (1986, 1987) demonstrated that the diagnosis can be made reliably on axillary skin biopsy; all patients show typical periodic acid-Schiff (PAS)-positive inclusions in the myoepithelial cells of the secretory acini of the apocrine glands and/or in the cells of the eccrine duct. However, the method had no value for carrier detection. In patients with Lafora disease, Lafora bodies are found in myoepithelial cells surrounding axillary apocrine (odoriferous) glands, whereas outside the axilla, Lafora bodies are found in the cells composing the ducts of the eccrine (perspiration) glands. In 2 unrelated patients with Lafora disease, 1 with mutation in the EPM2A gene and the other with mutation in the NHLRC1 gene, Andrade et al. (2003) reported that the diagnosis had been made by Lafora bodies present in the myoepithelial cells of the axillary apocrine glands. In 2 other unrelated patients, each with mutations in the 2 different genes, the diagnosis of Lafora disease was made by Lafora bodies in the eccrine duct cells of forearm biopsies. The authors noted that patients with either genetic form of the disease have Lafora bodies in both apocrine myoepithelial cells and eccrine duct cells. Andrade et al. (2003) reported a patient who had originally been diagnosed with an atypical form of Lafora disease (de Quadros et al., 2000) based on an axillary biopsy showing PAS-positive material in the cells lining the gland lumen, but not in myoepithelial cells or in eccrine glands. Mutation analysis showed that the patient actually had Unverricht-Lundborg disease. Andrade et al. (2003) noted the difficulty in diagnosing Lafora disease by axillary biopsy, and favored biopsy of skin outside the axilla.
Schwarz and Yanoff (1965) described a brother and sister, offspring of a one-and-one-half cousin marriage, with this disease. Seizures began at age 15 in the boy with slowly progressive motor and mental deterioration leading to death at age ... Schwarz and Yanoff (1965) described a brother and sister, offspring of a one-and-one-half cousin marriage, with this disease. Seizures began at age 15 in the boy with slowly progressive motor and mental deterioration leading to death at age 23.5 years. The sister's seizures began at age 14 years and progression to dementia and blindness occurred, with death at age 19. Intra- and extracellular Lafora bodies were found in the CNS, retina, axis cylinders of spinal nerves, heart muscle, liver cells, and striated muscle fibers. Norio and Koskiniemi (1979), as well as others, concluded that there are 3 types of what they termed progressive myoclonic epilepsy (PME). The Lafora type shows onset of grand mal seizures and/or myoclonus around the fifteenth year of life, rapid and severe mental deterioration, often with psychotic symptoms, short survival, histologic finding of Lafora bodies, and autosomal recessive inheritance. The Unverricht-Lundborg type, which is frequent in Finland, has onset around the tenth year, variable severity, progressive incapacitation from myoclonus associated with mild mental symptoms, variable survival, 'degenerative' histologic changes, and autosomal recessive inheritance. The Hartung type (159600) is a dominant form of myoclonic epilepsy without inclusion bodies. Canafoglia et al. (2004) found different electrophysiologic profiles representing sensorimotor cortex hyperexcitability in 8 patients with Lafora body disease (age range, 14 to 27 years) and 10 patients with Unverricht-Lundborg disease (ULD) (age range, 25 to 62 years). In general, the ULD patients had a quasistationary disease course, rare seizures, and little or no mental impairment, whereas the Lafora disease patients had recurrent seizures and worsening mental status. Patients with ULD had prominent action myoclonus clearly triggered by voluntary movements. Lafora disease patients experienced spontaneous myoclonic jerks associated with clear EEG paroxysms with only minor action myoclonus. Although both groups had enlarged or giant somatosensory evoked potentials, the pattern in the Lafora disease group was consistent with a distortion of cortical circuitry. Patients with ULD had enhanced long-loop reflexes with extremely brief cortical relay times. The findings were consistent with an aberrant subcortical or cortical loop, possibly short-cutting the somatosensory cortex, that may be involved in generating the prominent action myoclonus that characterizes EPM1. Patients with Lafora disease had varied cortical relay times and delayed and prolonged facilitation as evidenced by sustained hyperexcitability of the sensorimotor cortex in response to afferent stimuli. The findings were consistent with an impairment of inhibitory mechanisms in Lafora disease. Gomez-Abad et al. (2005) reported detailed clinical characteristics of 17 patients with Lafora disease caused by mutations in the NHLRC1 gene. Age at onset ranged from 12 to 15 years, with the exception of 7 and 22 years in 2 patients. Seizures were the most common presentation, including generalized tonic-clonic seizures (50%); simple partial occipital seizures (18.7%); partial seizures with secondary generalization (12.4%); absence seizures (6.3%); and myoclonic seizures (6.3%). One patient presented with hepatic failure and did not develop neurologic symptoms. Other variable features included cognitive decline, inability to attend school, gait disturbance, inability to walk alone, and complete deterioration of mental status.
Ganesh et al. (2002) related mutations in EPM2A with phenotypes of 22 patients (14 families) and identified 2 subsyndromes: (1) classic Lafora disease with adolescent-onset stimulus-sensitive grand mal, absence, and myoclonic seizures followed by dementia and neurologic deterioration, ... Ganesh et al. (2002) related mutations in EPM2A with phenotypes of 22 patients (14 families) and identified 2 subsyndromes: (1) classic Lafora disease with adolescent-onset stimulus-sensitive grand mal, absence, and myoclonic seizures followed by dementia and neurologic deterioration, and associated mainly with mutations in exon 4 (P = 0.0007); (2) atypical Lafora disease with childhood-onset dyslexia and learning disorder followed by epilepsy and neurologic deterioration, and associated mainly with mutations in exon 1 (P = 0.0015). The authors further investigated the effect of 5 missense mutations in the carbohydrate-binding domain (CBD4; coded by exon 1) and 3 missense mutations in the dual phosphatase domain (DSPD; coded by exons 3 and 4) on laforin's intracellular localization in transfected HeLa cells. Expression of 3 mutant proteins in DSPD formed ubiquitin-positive cytoplasmic aggregates, suggesting that they were folding mutants set for degradation. In contrast, none of the 3 CBD4 mutants showed cytoplasmic clumping. However, 2 of the CBD4 mutants targeted both cytoplasm and nucleus, suggesting that laforin had diminished its usual affinity for polysomes. In a clinical analysis of patients with Lafora disease, Gomez-Abad et al. (2005) found that 21 patients with NHLRC1 mutations had a slightly longer disease course and later age at death compared to 70 patients from 54 families with EPM2A mutations. Two patients with NHLRC1 mutations reached the fourth decade of life. Among a total of 77 families with Lafora disease, 70.1% of probands had EPM2A mutations and 27.3% of probands had NHLRC1 mutations. No mutations in either gene were identified in 2 (2.6%) unrelated probands. Singh et al. (2006) compared the clinical course of 13 patients with NHLRC1 mutations to 22 patients with EPM2A mutations. Although age at onset was similar in the 2 groups (approximately 12 years), patients with NHLRC1 mutations had a slower rate of disease progression and thus appeared to live longer. For example, respiratory assistance was required in patients with NHLRC1 and EPM2A mutations at a mean of 20 years and 6.5 years after disease onset, respectively. Cognitive decline, ataxia, and spasticity appeared 2 to 4 years after disease onset in both groups. Singh et al. (2006) postulated that malin, encoded by the NHLRC1 gene, may act upstream of laforin, encoded by the EPM2A gene, in a cellular cascade.
Ganesh et al. (2006) and Singh and Ganesh (2009) provided detailed reviews of the molecular basis of Lafora disease, with specific review of the mutational spectrum of EPM2A and NHLRC1 genes.
- EPM2A
In ... Ganesh et al. (2006) and Singh and Ganesh (2009) provided detailed reviews of the molecular basis of Lafora disease, with specific review of the mutational spectrum of EPM2A and NHLRC1 genes. - EPM2A In 10 families with myoclonic epilepsy of Lafora, Minassian et al. (1998) identified 6 distinct DNA sequence variations in the EPM2A gene and 1 homozygous microdeletion, each segregating with the disorder (see, e.g., 607566.0001-607566.0003). These mutations were predicted to cause deleterious effects in the laforin protein, resulting in the disorder. - EPM2B In 34 probands with Lafora disease, Chan et al. (2003) identified 17 different mutations in the NHLRC1 gene in 26 families, including 8 deletions, 1 insertion, 7 missense changes, and 1 nonsense change (see, e.g., C26S; 608072.0001). Eighteen families were homozygous and 8 were compound heterozygous for the mutations. Gomez-Abad et al. (2005) identified 18 mutations, including 12 novel mutations, in the malin gene (see, e.g., 608072.0005-608072.0007) in 23 of 25 patients with Lafora disease who did not have mutations in the laforin gene. P69A (608072.0002) was the predominant mutation, identified in 14 chromosomes from 9 unrelated patients; haplotype analysis suggested a founder effect for only 2 of these families. Singh et al. (2005) identified 6 different mutations in the NHLRC1 gene in 5 of 8 Japanese families with Lafora disease. Another Japanese family had a mutation in the EPM2A gene, and 2 Japanese families did not have mutations in either gene. Singh et al. (2005) concluded that mutations in the NHLRC1 gene are a common cause of Lafora disease in Japan. Singh et al. (2006) identified 7 different mutations, including 2 novel mutations, in the NHLRC1 gene in affected members of 8 families with Lafora disease. The authors stated that 39 different mutations had been identified in the NHLRC1 gene.
Chan et al. (2003) identified a homozygous C26S mutation in the NHLRC1 gene in affected members of 4 French Canadian families with Lafora disease. Haplotype analysis indicated a founder effect. Singh et al. (2006) identified an additional French ... Chan et al. (2003) identified a homozygous C26S mutation in the NHLRC1 gene in affected members of 4 French Canadian families with Lafora disease. Haplotype analysis indicated a founder effect. Singh et al. (2006) identified an additional French Canadian family with the C26S mutation, and they devised a DNA-based diagnostic test to screen for the C26S mutation for use in the French Canadian population.
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:...
Diagnosis
Clinical DiagnosisThe 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 DiseaseView in own windowEvaluation TypeAt OnsetLater in Disease CourseGeneral physical examination, including liver and spleen sizes
NormalNormalNeurologic examination, including fundi and reflexes NormalDysarthria, ataxia, spasticity; fundi remain normalMental state examination Visual hallucinations (epileptic), depressed mood, cognitive deficitsIncreased hallucinations, agitation, and dementia with predominantly frontal cognitive impairment affecting mainly performance ability and executive functionEEG 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, abnormalitiesVisual, 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 latenciesNerve conduction studies NormalNormalMRI 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 evolution2. At least two years after onset of symptomsTestingSkin 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 TestingGenes. 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 TypeView in own windowGene SymbolProportion of LD Attributed to Mutations in This GeneTest MethodMutations DetectedMutation Detection Frequency by Test Method 1 Test AvailabilityEPM2A 22%-70% 2, 3, 4, 5, 6 Sequence analysis Sequence variants 788%-97% 8ClinicalDeletion / duplication analysis 9Exonic or whole-gene deletionsUnknownNHLRC1 (EPM2B)27%-73% 2, 3, 4, 5, 6Sequence analysis Sequence variants 788%-97% 8ClinicalDeletion / 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 StrategyTo confirm/establish the diagnosis in a proband requires either of the following: Identification of two mutations in either EPM2A or NHLRC1: Sequence analysis of NHLRC1If no mutations are identified in NHLRC1, sequence analysis of EPM2A If one mutation is identified in NHLRC1 or EPM2A, consider deletion/duplication analysis of that gene (see Interpretation of test results)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.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in EPM2A or NHLRC1.
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]....
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 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....
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. Although a sub-phenotype consisting of childhood-onset learning disorder followed by epilepsy and neurologic deterioration has been associated with either mutations in exon 1 of EPM2A [Ganesh et al 2002a, Annesi et al 2004] or the p.Ile198Asn mutation located in an NHL protein-protein interaction domain of NHLRC1 (EPM2B) [Gomez-Abad et al 2005], these findings need to be replicated, expanded, and studied further in order to understand their relationship to the underlying pathophysiologic processes. Individuals with mutations in NHLRC1 tend to live longer than those with mutations in EPM2A [Gomez-Abad et al 2005, Franceschetti et al 2006, Singh et al 2006]. This finding has been demonstrated repeatedly for persons with the NHLRC1 (EPM2B) mutation p.Asp146Asn [Baykan et al 2005, Gomez-Abad et al 2005, Franceschetti et al 2006]. However, this does not apply to all persons with mutations in NHLRC1, as some may have extremely severe phenotypes [Traoré et al 2009, Brackmann et al 2011].
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. ...
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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Lafora disease (LD), the following are recommended:...
Management
Evaluations Following Initial DiagnosisTo 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 ManifestationsAntiepileptic 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 ComplicationsOvermedication 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.SurveillanceClinical and psychosocial evaluation should be performed at three- to six-month intervals throughout the teenage years.Agents/Circumstances to AvoidAs in other forms of progressive myoclonus epilepsies, the use of phenytoin should be avoided.Anecdotal reports describe possible exacerbation of myoclonus with the following:Carbamazepine [Nanba & Maegaki 1999] Oxcarbazepine [Kaddurah & Holmes 2006] Lamotrigine [Cerminara et al 2004, Crespel et al 2005] Evaluation of Relatives at RiskSee Genetic Counseling for issues related to evaluation of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSince 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDEPM2A6q24.3
LaforinEPM2A homepage - Mendelian genesEPM2ANHLRC16p22.3NHL repeat-containing protein 1NHLRC1 homepage - Mendelian genesNHLRC1Data 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) View in own window 254780MYOCLONIC EPILEPSY OF LAFORA 607566EPM2A GENE; EPM2A 608072NHL REPEAT-CONTAINING 1 GENE; NHLRC1Molecular Genetic PathogenesisThe 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:Homozygous deletions of exon 2 in 14 familiesThe nonsense mutation NM_005670.3:c.721C>T (p.Arg241X), the ‘Spanish’ mutation, in 14 families. Its high prevalence is the result of both a founder effect and recurrent events [Gomez-Garre et al 2000, Ganesh et al 2002b]. The nonsense mutation NM_005670.3:c.835G>A (p.Gly279Ser) affecting the DSPD domain in six familiesNormal 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.