Alternative titles; symbols
SNOMEDCT: 230425004; ICD10CM: G40.C, G40.C09; ORPHA: 501; DO: 3534;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6q24.3 | Myoclonic epilepsy of Lafora 1 | 254780 | Autosomal recessive | 3 | EPM2A | 607566 |
A number sign (#) is used with this entry because myoclonic epilepsy of Lafora-1 (MELF1), also known as progressive myoclonic epilepsy-2A (EPM2A), is caused by homozygous or compound heterozygous mutation in the laforin gene (EPM2A; 607566) on chromosome 6q24.
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). Patients with Lafora disease-2 (620681) have a slightly slower progression of disease and later age at death (see Genotype/Phenotype Correlations).
Genetic Heterogeneity of Lafora Disease
Myoclonic epilepsy of Lafora-2 (MELF2, EPM2B; 620681) is caused by mutation in the NHLRC1 gene (608072), which encodes malin, on chromosome 6p22.
For a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (254800).
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. 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 (EPM1A; 254800), 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 (age range, 25 to 62 years). In general, the EPM1A 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 EPM1A 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 EPM1A 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.
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, 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. Andrade et al. (2003) noted the difficulty in diagnosing Lafora disease by axillary biopsy, and favored biopsy of skin outside the axilla.
Harriman and Millar (1955) noted that the Lafora material has the properties of an acid mucopolysaccharide, and suggested that the Lafora bodies in the brain may be amyloid. Yokoi et al. (1968) arrived at a preliminary conclusion that the Lafora body is polyglucosan in nature. They pictured the existence of an enzyme defect which leads to deposition of polyglucosans near their site of synthesis in the agranular endoplasmic reticulum. In cultured fibroblasts, Fluharty et al. (1970) described bodies which may be the equivalent of the Lafora body observed histologically.
Lafora bodies are dense aggregates of abnormally branched glycogen molecules called polyglucosans (Andrade et al., 2003).
Gentry et al. (2005) found that malin directly bound and interacted with the laforin protein in HEK293T cells in vivo. Laforin is polyubiquitinated in a malin-dependent manner, which leads to laforin degradation. Mutations in the NHLRC1 gene abolished both laforin polyubiquitination and degradation. Gentry et al. (2005) concluded that malin regulates laforin protein concentrations and that mutations in the NHLRC1 gene resulting in loss of the E3 ligase activity of malin underlie the onset of Lafora disease in patients with these mutations.
By linkage studies in 3 Italian families with Lafora disease, Lehesjoki et al. (1992) demonstrated that the gene is located at a locus other than that for the Unverricht-Lundborg type on chromosome 21q22.3. Serratosa et al. (1995) studied linkage in 9 families in which Lafora disease had been proven by biopsy in at least 1 member. Using microsatellite markers spaced an average of 13 cM apart, they used linkage analysis in all 9 families and homozygosity mapping in 4 consanguineous families to assign the gene for Lafora disease to 6q23-q25. An extended pedigree with 5 affected members independently proved linkage. The multipoint 1-lod unit support interval covered a 2.5-cM region surrounding D6S403. Homozygosity mapping defined a 17-cM region in 6q23-q25 flanked by D6S292 and D6S420. The 9 families with a total of 19 patients affected with Lafora disease originated from the United States, Spain, Palestine, and Iran. Maddox et al. (1997) studied a 2-generation family in which a recombination event reduced the Lafora critical region to a 4-cM interval flanked by markers D6S308 and D6S311. Sainz et al. (1997) narrowed the assignment of the MELF locus within 6q24 by study of recombinants and homozygosities.
Genetic Heterogeneity
Serratosa et al. (1999) commented that in spite of the homogeneity of the Lafora disease phenotype, with the presence of Lafora bodies in all affected individuals, there are approximately 20% of families with Lafora disease in which the phenotype does not segregate with the 6q23-q25 critical region. The simplest explanation for this genetic heterogeneity is that another gene or genes in the same metabolic pathway are altered in the Lafora disease families not linked to 6q23-q25.
The transmission pattern of myoclonic epilepsy in the families reported by Minassian et al. (1998) was consistent with autosomal recessive inheritance.
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.
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.
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.
This disorder was first described by Lafora and Glueck (1911).
Ortiz-Hidalgo (1986) gave an account of the man for whom myoclonic epilepsy and the intraneuronal bodies observed microscopically are named. Gonzalo Rodriguez-Lafora (1886-1971) was born and died in Madrid and worked there under Ramon y Cajal except for a few years of study in Germany and France and 3 years in Washington, D.C., where he was neuropathologist for the National Psychiatric Institute. The Lafora sign, i.e., picking of the nose in the early stages of cerebrospinal meningitis, is hardly pathognomonic of that disease.
Ganesh et al. (2002) disrupted the Epm2a gene in mice. At 2 months of age, homozygous null mutants developed widespread degeneration of neurons, most of which occurred in the absence of Lafora bodies. Dying neurons characteristically exhibited swelling in the endoplasmic reticulum, Golgi networks, and mitochondria in the absence of apoptotic bodies or fragmentation of DNA. As Lafora bodies became more prominent at 4 to 12 months, organelles and nuclei were disrupted. The Lafora bodies, present both in neuronal and nonneural tissues, were positive for ubiquitin and advanced glycation end products only in neurons, suggesting a different pathologic consequence for Lafora inclusions in neuronal tissues. Neuronal degeneration and Lafora inclusion bodies predated the onset of impaired behavioral responses, ataxia, spontaneous myoclonic seizures, and EEG epileptiform activity. The authors hypothesized that Lafora disease is a primary neurodegenerative disorder that may utilize a nonapoptotic mechanism of cell death.
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