SNOMEDCT: 702326000; ORPHA: 308; DO: 0111448;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q12 | Epilepsy, progressive myoclonic 1B | 612437 | Autosomal recessive | 3 | PRICKLE1 | 608500 |
A number sign (#) is used with this entry because of evidence that progressive myoclonic epilepsy-1B (EPM1B) is caused by homozygous mutation in the PRICKLE1 gene (608500) on chromosome 12q12.
For a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (254800).
Berkovic et al. (2005) reported a consanguineous Israeli Arab family in which 8 members had an early-onset form of progressive myoclonic epilepsy. Age at seizure onset was 7.3 years (range, 5 to 10 years). Five patients presented with myoclonic seizures, 1 with tonic-clonic seizures, and 2 with both. In 4 cases, the parents reported delayed walking in infancy with difficulty walking or running in childhood, consistent with ataxia, before the onset of seizures. Myoclonic seizures were aggravated by sunlight. The disorder was progressive, and 3 patients became wheelchair-bound. There was no significant progressive dementia; brain MRI of 1 patient was normal. The clinical phenotype of this family was similar to that of classic Unverricht-Lundborg disease, but differed by early age of onset and a slightly more severe course.
Straussberg et al. (2005) described a consanguineous Israeli Arab family in which 3 sibs had early-onset ataxia, dysarthria, upward gaze palsy, extensor plantar reflexes, axonal sensory neuropathy, and normal cognition. Onset of progressive ataxia was noted around age 4 years. The 2 older sibs, ages 11 and 9 years, developed myoclonic and generalized tonic-clonic seizures that were photosensitive. The youngest had not developed seizures at age 4. Specific features of all patients included tremor, dysmetria, impaired vibration and position sense, and extensor plantar responses. Genetic analysis excluded known loci for autosomal recessive ataxia.
El-Shanti et al. (2006) reported a consanguineous Jordanian family in which 4 sibs had onset of gait ataxia at age 15 months, followed by fine tremor progressing to coarse action tremor at age 4 years, and atonic seizures at about age 8 to 10 years. Brain MRI showed no evidence of cerebellar hypoplasia, and cognitive function was spared. The seizures and tremor were responsive to medication. El-Shanti et al. (2006) noted that none of the patients had frank myoclonic seizures, and concluded that the action tremor was related to appendicular ataxia rather than to action myoclonus. The tremor started with fine movement early in the disease process, worsened as the hand approached the target, and continued for a few seconds after the target was reached. However, the authors thought it was possible that the tremor was composed of 2 components consisting of ataxic tremor and action myoclonus. Bassuk et al. (2008) noted that affected members of the family reported by El-Shanti et al. (2006) had developed progressive myoclonic seizures, and that some patients had also developed upward gaze palsy.
The transmission pattern of EPM1B in the families reported by Bassuk et al. (2008) was consistent with autosomal recessive inheritance.
By homozygosity mapping of a consanguineous family with autosomal recessive myoclonic epilepsy and ataxia, Berkovic et al. (2005) identified linkage to chromosome 12 (maximum lod score of 6.32 at marker D12S1663). Haplotype analysis narrowed the disease locus, termed EPM1B, to a 15-Mb pericentromeric region on chromosome 12 defined by markers D12S345 and D12S1661.
By linkage analysis of a Jordanian family with autosomal recessive ataxia and tremor, El-Shanti et al. (2006) found linkage to chromosome 12 (multipoint maximum lod score of 3.3). Haplotype analysis delineated a minimal 18.67-cM (23-Mb) pericentromeric region on chromosome 12.
In affected members of the families with myoclonic epilepsy reported by Berkovic et al. (2005), Straussberg et al. (2005), and El-Shanti et al. (2006), Bassuk et al. (2008) identified the same homozygous mutation in the PRICKLE1 gene (R104Q; 608500.0001). The findings were consistent with a founder effect.
Tao et al. (2011) identified 2 different heterozygous mutations in the PRICKLE1 gene (R144H; 608500.0002 and Y472H; 608500.0003, respectively) in 2 unrelated patients with myoclonic epilepsy. One patient had mild mental retardation, and no additional clinical information was provided for the other patient. No information on family members of either patient was provided. The authors noted that both homozygous (Bassuk et al., 2008) and heterozygous mutations can result in seizures, suggesting a dosage effect. Tao et al. (2011) concluded that PRICKLE signaling is important in seizure prevention, and presented 2 hypotheses: (1) that PRICKLE affects cell polarity and contributes to the development of a functional neural network and (2) that PRICKLE affects calcium signaling, which may play a role in seizure genesis if disrupted.
Tao et al. (2011) demonstrated that disruption of the Prickle genes in zebrafish, Drosophila, and mice resulted in aberrant protein function and clinical features consistent with seizures.
Bassuk, A. G., Wallace, R. H., Buhr, A., Buller, A. R., Afawi, Z., Shimojo, M., Miyata, S., Chen, S., Gonzalez-Alegre, P., Griesbach, H. L., Wu, S., Nashelsky, M., and 18 others. A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome. Am. J. Hum. Genet. 83: 572-581, 2008. [PubMed: 18976727] [Full Text: https://doi.org/10.1016/j.ajhg.2008.10.003]
Berkovic, S. F., Mazarib, A., Walid, S., Neufeld, M. Y., Manelis, J., Nevo, Y., Korczyn, A. D., Yin, J., Xiong, L., Pandolfo, M., Mulley, J. C., Wallace, R. H. A new clinical and molecular form of Unverricht-Lundborg disease localized by homozygosity mapping. Brain 128: 652-658, 2005. [PubMed: 15634728] [Full Text: https://doi.org/10.1093/brain/awh377]
El-Shanti, H., Daoud, A., Sadoon, A. A., Leal, S. M., Chen, S., Lee, K., Spiegel, R. A distinct autosomal recessive ataxia maps to chromosome 12 in an inbred family from Jordan. Brain Dev. 28: 353-357, 2006. [PubMed: 16376507] [Full Text: https://doi.org/10.1016/j.braindev.2005.11.003]
Straussberg, R., Basel-Vanagaite, L., Kivity, S., Dabby, R., Cirak, S., Nurnberg, P., Voit, T., Mahajnah, M., Inbar, D., Saifi, G. M., Lupski, J. R., Delague, V., Megarbane, A., Richter, A., Leshinsky, E., Berkovic, S. F. An autosomal recessive cerebellar ataxia syndrome with upward gaze palsy, neuropathy, and seizures. Neurology 64: 142-144, 2005. [PubMed: 15642921] [Full Text: https://doi.org/10.1212/01.WNL.0000148600.60470.E6]
Tao, H., Manak, J. R., Sowers, L., Mei, X., Kiyonari, H., Abe, T., Dahdaleh, N. S., Yang, T., Wu, S., Chen, S., Fox, M. H., Gurnett, C., and 24 others. Mutations in prickle orthologs cause seizures in flies, mice, and humans. Am. J. Hum. Genet. 88: 138-149, 2011. [PubMed: 21276947] [Full Text: https://doi.org/10.1016/j.ajhg.2010.12.012]