ORPHA: 83473;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q43-q44 | Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 | 615937 | Autosomal dominant | 3 | AKT3 | 611223 |
A number sign (#) is used with this entry because megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome-2 (MPPH2) is caused by heterozygous mutation in the AKT3 gene (611223) on chromosome 1q43-q44.
MPPH2 is an overgrowth syndrome comprising megalencephaly, hydrocephalus, and polymicrogyria; polydactyly may also be seen. There is considerable phenotypic similarity between this disorder and the megalencephaly-capillary malformation syndrome (MCAP; 602501) (summary by Gripp et al., 2009).
For a discussion of genetic heterogeneity of MPPH, see 603387.
Riviere et al. (2012) reported 2 unrelated patients with MPPH2. One patient (LR11-354) was a 2.5-year-old girl with macrocephaly, hydrocephalus, polymicrogyria, and connective tissue dysplasia. She did not have vascular malformations, syndactyly, or polydactyly. The other patient (LR08-018) was an 11-month-old boy with macrocephaly, hydrocephalus, polymicrogyria, cerebellar tonsillar ectopia, and connective tissue dysplasia. He also had vascular malformations that were not cutaneous or on the face or body. He did not have polydactyly or syndactyly. This patient had previously been reported by Mirzaa et al. (2012).
Nakamura et al. (2014) reported a 2-month-old boy with macrocephaly, cutis marmorata of the distal extremities, and hyperextensibility of the skin. Brain MRI at age 7 days showed right-dominant polymicrogyria, and at 2 months showed a thin corpus callosum and progressive hydrocephalus. Nakamura et al. (2014) stated that the phenotype was compatible with MCAP; however, the patient had only a skin capillary malformation. Genetic analysis identified a de novo heterozygous mutation in the AKT3 gene (N229S; 611223.0002). Nakamura et al. (2014) concluded that MPPH and MCAP show significant phenotypic overlap and have a common genetic basis.
Riviere et al. (2012) performed exome sequencing in an individual (LR08-018) with clinical features overlapping MPPH and MCAP and his parents and identified a de novo mutation in the AKT3 gene (R465W; 611223.0001). Sanger sequencing of the AKT3 gene in another 40 individuals with megalencephaly (many with asymmetric brain enlargement, and several diagnosed with hemimegalencephaly) identified a different de novo mutation in this gene in 1 patient (LR11-354) individual with MPPH (N229S; 611223.0002). Riviere et al. (2012) suggested that the AKT3 gene is a rare cause of megalencephaly (p = 0.002, calculated as the likelihood of observing a second de novo mutation in the AKT3 gene).
In 8 samples of brain tissue from individuals with hemimegalencephaly (HME), Poduri et al. (2012) identified somatic duplications of chromosome 1q encompassing the AKT3 gene in 2. Sequencing of the AKT3 gene in the other 6 samples identified 1 with a known activating mutation (E17K; 611223.0003); the mutation was not detectable in blood from this patient.
Lee et al. (2012) performed whole-exome sequencing on brain and peripheral blood DNA from 5 HME cases and identified 3 missense mutations: one in the PIK3CA gene (E545K; 171834.0003), one in the AKT3 gene (E17K; 611223.0003), and one in the MTOR gene (C1483Y). The individual with the MTOR gene mutation also carried a diagnosis of hypomelanosis of Ito (300337). Lee et al. (2012) then used a modified single base-extension protocol followed by mass spectrometry analysis to detect somatic mutations at a frequency as low as 3% in genetically heterogeneous samples. Reanalysis of the same DNA samples used for whole-exome sequencing again showed the absence of the mutant allele in blood but its presence in the brain, with similar mutation burden as that detected with Illumina sequencing. These somatic mutations were detected at a frequency of 36.6%, 40.4%, and 8.1% in each brain sample.
Gripp, K. W., Hopkins, E., Vinkler, C., Lev, D., Malinger, G., Lerman-Sagie, T., Dobyns, W. B. Significant overlap and possible identity of macrocephaly capillary malformation and megalencephaly polymicrogyria-polydactyly hydrocephalus syndromes. Am. J. Med. Genet. 149A: 868-876, 2009. [PubMed: 19353582] [Full Text: https://doi.org/10.1002/ajmg.a.32732]
Lee, J. H., Huynh, M., Silhavy, J. L., Kim, S., Dixon-Salazar, T., Heiberg, A., Scott, E., Bafna, V., Hill, K. J., Collazo, A., Funari, V., Russ, C., Gabriel, S. B., Mathern, G. W., Gleeson, J. G. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nature Genet. 44: 941-945, 2012. [PubMed: 22729223] [Full Text: https://doi.org/10.1038/ng.2329]
Mirzaa, G. M., Conway, R. L., Gripp, K. W., Lerman-Sagie, T., Siegel, D. H., deVries, L. S., Lev, D., Kramer, N., Hopkins, E., Graham, J. M., Jr., Dobyns, W. B. Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis. Am. J. Med. Genet. 158A: 269-291, 2012. [PubMed: 22228622] [Full Text: https://doi.org/10.1002/ajmg.a.34402]
Nakamura, K., Kato, M., Tohyama, J., Shiohama, T., Hayasaka, K., Nishiyama, K., Kodera, H., Nakashima, M., Tsurusaki, Y., Miyake, N., Matsumoto, N., Saitsu, H. AKT3 and PIK3R2 mutations in two patients with megalencephaly-related syndromes: MCAP and MPPH. (Letter) Clin. Genet. 85: 396-298, 2014. [PubMed: 23745724] [Full Text: https://doi.org/10.1111/cge.12188]
Poduri, A., Evrony, G. D., Cai, X., Elhosary, P. C., Beroukhim, R., Lehtinen, M. K., Hills, L. B., Heinzen, E. L., Hill, A., Hill, R. S., Barry, B. J., Bourgeois, B. F. D., Riviello, J. J., Barkovich, A. J., Black, P. M., Ligon, K. L., Walsh, C. A. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron 74: 41-48, 2012. [PubMed: 22500628] [Full Text: https://doi.org/10.1016/j.neuron.2012.03.010]
Riviere, J.-B., Mirzaa, G. M., O'Roak, B. J., Beddaoui, M., Alcantara, D., Conway, R. L., St-Onge, J., Schwartzentruber, J. A., Gripp, K. W., Nikkel, S. M., Worthylake, T., Sullivan, C. T., and 29 others. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nature Genet. 44: 934-940, 2012. [PubMed: 22729224] [Full Text: https://doi.org/10.1038/ng.2331]