Alternative titles; symbols
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p22.3 | Myoclonic epilepsy of Lafora 2 | 620681 | Autosomal recessive | 3 | NHLRC1 | 608072 |
A number sign (#) is used with this entry because myoclonic epilepsy of Lafora-2 (MELF2), also known as progressive myoclonic epilepsy-2B (EPM2B), is caused by homozygous or compound heterozygous mutation in the NHLRC1 gene (608072), which encodes malin, on chromosome 6p22.
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). There is a slower progression of disease and later age at death in Lafora disease-2 than in Lafora disease-1 (MELF1, EPM2A; 254780); see Genotype/Phenotype Correlations.
Myoclonic epilepsy of Lafora-1 is caused by mutation in the EPM2A gene (608072), which encodes laforin, on chromosome 6q24.
For a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (254800).
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.
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, one 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 (254800). Andrade et al. (2003) noted the difficulty in diagnosing Lafora disease by axillary biopsy, and favored biopsy of skin outside the axilla.
Chan et al. (2003) performed genomewide linkage analysis on 4 consanguineous French Canadian families with classic Lafora disease. A 2-point maximum lod score of 5.2 was obtained for a 2.2-Mb region on chromosome 6p22. All families shared the same 9 marker disease haplotype. The authors termed the locus EPM2B.
The transmission pattern of Lafora disease-2 in the families reported by Chan et al. (2003) was consistent with autosomal recessive inheritance.
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.
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 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.
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.
More than 5% of purebred miniature wirehaired dachshunds (MWHDs) in the United Kingdom suffer an autosomal recessive progressive myoclonic epilepsy (PME), which Lohi et al. (2005) showed to be Lafora disease. Using homozygosity and linkage analysis, they mapped the MWHD disease locus to canine chromosome 35, which is syntenic in its entirety to human 6p25-p21. They then cloned canine Epm2b (NHLRC1; 608072). PCR identified a repeat region in affected dogs and revealed biallelic expansion of the dodecamer repeat with 19 to 26 copies of the D sequence. Comparing the amount of Epm2b mRNA in skeletal muscle from 3 affected dogs and 2 controls with quantitative RT-PCR showed that affected mRNA levels were more than 900 times reduced. To determine whether the extra D sequence is specific to MWHDs, Lohi et al. (2005) sequenced Epm2b from 2 normal unrelated dogs from each of 128 breeds. Sixty percent of their chromosomes had 3 repeats (2 Ds and 1 T) and 40%, 2 repeats (1 D and 1 T). Almost all breeds had examples of both variants in homozygous or heterozygous state. They tested the next non-MWHD PME case to present to the clinic, a basset hound, and found a homozygous 14-copy expansion of the repeat. Lohi et al. (2005) described a canine epilepsy mutation that represents a tandem repeat expansion outside humans and devised a test to detect and counteract it through controlled breeding.
Valles-Ortega et al. (2011) found that malin-knockout mice developed Lafora disease at around 11 months of age. Mutant animals showed neurodegeneration and seizures associated with Lafora bodies in several brain regions, including the hippocampus and cerebellum. Lafora bodies contained poorly branched glycogen and muscle glycogen synthase (GYS1; 138570), particularly in the insoluble fraction. Lafora bodies were present in neurons, astrocytes, and interneurons. Malin-null mice showed increased susceptibility to kainate-induced epilepsy.
Duran et al. (2014) generated a double-transgenic mouse model in which malin was deleted in all tissues and Gys1 was specifically deleted in the brain. Glycogen content in the brain was significantly decreased in Gys1 heterozygous mice and was absent in Gys1 homozygous-null malin-knockout mice. Double-knockout mice did not show the increase in markers of neurodegeneration, the impairments in electrophysiologic properties of hippocampal synapses, or the susceptibility to kainate-induced epilepsy seen in the malin-knockout model, consistent with rescue from neurodegeneration. These mice also did not show impaired autophagy, as observed in malin-knockout mice. Additional mouse models with overaccumulation of glycogen showed impaired autophagy, suggesting that the accumulation of glycogen itself can cause autophagy impairment. The findings indicated that glycogen accumulation accounts for the neurodegeneration and functional consequences seen in the malin-knockout model, as well as the impaired autophagy. Duran et al. (2014) suggested that regulation of glycogen synthesis may be a key target for the treatment of Lafora disease.
Andrade, D. M., Ackerley, C. A., Minett, T. S. C., Teive, H. A. G., Bohlega, S., Scherer, S. W., Minassian, B. A. Skin biopsy in Lafora disease: genotype-phenotype correlations and diagnostic pitfalls. Neurology 61: 1611-1614, 2003. [PubMed: 14663053] [Full Text: https://doi.org/10.1212/01.wnl.0000096017.19978.cb]
Chan, E. M., Bulman, D. E., Paterson, A. D., Turnbull, J., Andermann, E., Andermann, F., Rouleau, G. A., Delgado-Escueta, A. V., Scherer, S. W., Minassian, B. A. Genetic mapping of a new Lafora progressive myoclonus epilepsy locus (EPM2B) on 6p22. J. Med. Genet. 40: 671-675, 2003. [PubMed: 12960212] [Full Text: https://doi.org/10.1136/jmg.40.9.671]
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de Quadros, A., Sa, D. S., Kowacs, P. A., Teive, H. A. G., Werneck, L. C. Doenca de lafora E disturbios do movimento: relato de dois casos. Arq. Neuropsiquiatr. 58: 720-723, 2000. [PubMed: 10973115] [Full Text: https://doi.org/10.1590/s0004-282x2000000400019]
Duran, J., Gruart, A., Garcia-Rocha, M., Delgado-Garcia, J. M., Guinovart, J. J. Glycogen accumulation underlies neurodegeneration and autophagy impairment in Lafora disease. Hum. Molec. Genet. 23: 3147-3156, 2014. [PubMed: 24452334] [Full Text: https://doi.org/10.1093/hmg/ddu024]
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Gomez-Abad, C., Gomez-Garre, P., Gutierrez-Delicado, E., Saygi, S., Michelucci, R., Tassinari, C. A., Rodriguez de Cordoba, S., Serratosa, J. M. Lafora disease due to EPM2B mutations: a clinical and genetic study. Neurology 64: 982-986, 2005. [PubMed: 15781812] [Full Text: https://doi.org/10.1212/01.WNL.0000154519.10805.F7]
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Singh, S., Ganesh, S. Lafora progressive myoclonus epilepsy: a meta-analysis of reported mutations in the first decade following discovery of the EPM2A and NHLRC1 genes. Hum. Mutat. 30: 715-723, 2009. [PubMed: 19267391] [Full Text: https://doi.org/10.1002/humu.20954]
Singh, S., Sethi, I., Francheschetti, S., Riggio, C., Avanzini, G., Yamakawa, K., Delgado-Escueta, A. V., Ganesh, S. Novel NHLRC1 mutations and genotype-phenotype correlations in patients with Lafora's progressive myoclonic epilepsy. J. Med. Genet. 43: e48, 2006. Note: Electronic Article. [PubMed: 16950819] [Full Text: https://doi.org/10.1136/jmg.2005.039479]
Singh, S., Suzuki, T., Uchiyama, A., Kumada, S., Moriyama, N., Hirose, S., Takahashi, Y., Sugie, H., Mizoguchi, K., Inoue, Y., Kimura, K., Sawaishi, Y., Yamakawa, K., Ganesh, S. Mutations in the NHLRC1 gene are the common cause for Lafora disease in the Japanese population. J. Hum. Genet. 50: 347-352, 2005. [PubMed: 16021330] [Full Text: https://doi.org/10.1007/s10038-005-0263-7]
Valles-Ortega, J., Duran, J., Garcia-Rocha, M., Bosch, C., Saez, I., Pujadas, L., Serafin, A., Canas, X., Soriano, E., Delgado-Garcia, J. M., Gruart, A., Guinovart, J. J. Neurodegeneration and functional impairments associated with glycogen synthase accumulation in a mouse model of Lafora disease. EMBO Molec. Med. 3: 667-681, 2011. [PubMed: 21882344] [Full Text: https://doi.org/10.1002/emmm.201100174]