SNOMEDCT: 1003444000; ORPHA: 171680; DO: 0112232;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.12 | Lissencephaly 3 | 611603 | Autosomal dominant | 3 | TUBA1A | 602529 |
A number sign (#) is used with this entry because of evidence that lissencephaly-3 (LIS3) is caused by heterozygous mutation in the TUBA1A gene (602529) on chromosome 12q13.
For a general description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (607432).
See also complex cortical dysplasia with other brain malformations (e.g., CDCBM1, 614039), which shows overlapping features.
Keays et al. (2007) and Poirier et al. (2007) reported 2 unrelated children with lissencephaly. One patient had microcephaly, pachygyria, an abnormally shaped corpus callosum, and hypoplasia of the cerebellar vermis and brainstem. Clinical features included severe mental retardation, mild motor delay, and absence of seizures. The second patient had a more severe phenotype, with microcephaly, agyria, thin corpus callosum, abnormal hippocampus, hypoplasia of the cerebellar vermis and brainstem, and severe ventricular dilatation. Clinical features included profound mental retardation, spastic tetraplegia, and intractable tonic-clonic seizures.
Poirier et al. (2007) reported 6 additional patients with a wide spectrum of brain dysgenesis, ranging from agyria to laminar heterotopia. Retrospective examination of brain MRI showed defects in the cerebellum, hippocampus, corpus callosum, and brainstem. Patients who survived showed mental retardation, seizures, motor delay, and microcephaly. The brain anomalies were consistent with a neuronal migration disorder.
Bahi-Buisson et al. (2008) reported 6 patients with LIS3 confirmed by genetic analysis. The phenotype ranged from the less severe perisylvian pachygyria to the more severe posteriorly predominant pachygyria, which was associated with dysgenesis of the anterior limb of the internal capsule and mild to severe cerebellar hypoplasia. Patients with TUBA1A mutations shared a common clinical phenotype consisting of congenital microcephaly, mental retardation, lack of language development, and diplegia/tetraplegia.
Jansen et al. (2011) reported a boy with genetically confirmed LIS3. He had microcephaly at birth, and presented with severe hypotonia and feeding difficulties. He developed refractory focal seizures soon after birth. At age 18 months, he had axial hypotonia with peripheral hypertonia and essentially no psychomotor development. Brain MRI showed grade 2 lissencephaly with an anterior-to-posterior gradient, enlarged ventricles, thin corpus callosum, and cerebellar hypoplasia. The TUBA1A mutation occurred de novo.
Poirier et al. (2013) reported 3 unrelated patients with polymicrogyria (PMG) associated with 3 different heterozygous de novo missense mutations in the TUBA1A gene. The first patient, a 7.5-year-old boy, had mildly delayed development with autistic features, refractory focal seizures, poor language, and right hemiparesis with hemianopsia. Brain MRI showed perisylvian PMG more prominent in the right perisylvian region and frontal region, dysmorphic basal ganglia, and hypoplasia of the corpus callosum. The second patient was an 11-year-old girl with microcephaly, hypotonia, refractory occipital seizures, left hemiparesis, lack of speech, and cortical blindness. Brain MRI showed PMG more localized in right perisylvian region, dysmorphic basal ganglia, dysplastic cerebellar vermis, hypoplastic pons, and hypoplasia of the corpus callosum. The third patient was a 12-month-old boy with microcephaly, hypotonia, convergent strabismus, and pyramidal signs. MRI showed asymmetrical perisylvian PMG that was localized on the left but extended to the parietal region on the right. There was also dysmorphic basal ganglia, dysplastic cerebellar vermis, severe brainstem hypoplasia, and hypoplasia of the corpus callosum. Protein structural data suggested that the mutations may specifically affect microtubule dynamics or stability, or local interactions with partner proteins. The patients were ascertained from a larger cohort of 95 patients with bilateral PMG and thus accounted for 3.1% of the total group. The report broadened the phenotypic spectrum associated with TUBA1A mutations to include PMG as well as additional brain abnormalities, including dysmorphic basal ganglia, hypoplastic pons, and cerebellar dysplasia.
Fallet-Bianco et al. (2014) reported 19 fetuses with complex malformations of cortical development associated with mutations in the TUBA1A gene. Ten of the fetuses with the most severe phenotype were characterized as having microlissencephaly with microcephaly, poorly differentiated or absent cortical plate, heterotopic neurons, and agenesis of the olfactory bulbs (in some patients). Other features included enlarged germinal zones, hypoplastic basal ganglia, partial or complete absence of the corpus callosum, and pontocerebellar hypoplasia. Six fetuses were classified as having lissencephaly with pontocerebellar hypoplasia, and 3 were classified as having polymicrogyria with cortical dysplasia. Functional studies of the TUBA1A variants and studies of patient cells were not performed. The patients were part of a cohort of 26 fetuses with malformations of cortical development associated with mutations in tubulin genes; those with TUBA1A mutations tended to have the more severe phenotypes.
Most cases of LIS3 occur de novo. However, Jansen et al. (2011) reported 2 sisters with LIS3, born of consanguineous Moroccan parents, who each had the same heterozygous mutation in the TUBA1A gene (I5L; 602529.0009) inherited from their mother who was somatic mosaic for the mutation, which was found in 5.6% of her peripheral blood. The girls, aged 7 and 3 years, had global developmental delay, pyramidal signs, and limb ataxia. One had seizures. Brain MRI showed perisylvian polymicrogyria, gray matter heterotopia, enlarged lateral ventricle with a hooked aspect of the right frontal horn due to abnormally shaped basal ganglia, thin corpus callosum, and hypoplasia of the pons. One girl had optic nerve hypoplasia and mild vermian hypoplasia. Brain MRI of the clinically asymptomatic mother showed a thin corpus callosum, hypoplasia of the superior vermis, and a thin medulla. The report indicated that rare familial recurrence of LIS3 can occur.
In 2 unrelated patients with LIS3, Keays et al. (2007) and Poirier et al. (2007) identified 2 different de novo heterozygous mutations in the TUBA1A gene (602529.0001; 602529.0002).
Poirier et al. (2007) identified de novo heterozygous TUBA1A mutations (see, e.g., 602529.0003-602529.0005) in 6 additional patients with LIS3.
Bahi-Buisson et al. (2008) identified 6 de novo mutations in the TUBA1A gene (see, e.g., 602529.0006; 602529.0007) in 6 of 100 patients with lissencephaly who were negative for mutations in other known lissencephaly-associated genes.
Morris-Rosendahl et al. (2008) identified 4 different TUBA1A mutations (see, e.g., 602529.0008) in 5 of 46 patients with variable patterns of lissencephaly on brain MRI and no DCX (300121) or PAFAH1B1 (601545) mutation. Four of the 5 patients had congenital microcephaly, and all had dysgenesis of the corpus callosum, cerebellar hypoplasia, and variable cortical malformations, including subtle subcortical band heterotopia and absence or hypoplasia of the anterior limb of the internal capsule. Morris-Rosendahl et al. (2008) estimated that TUBA1A mutation is a rare cause of classic lissencephaly comprising a maximum of 4% of patients including those with DCX and PAFAH1B1 mutations.
Kumar et al. (2010) screened a cohort of 125 lissencephaly patients in whom mutations in DCX and PAFAH1B1 had been excluded and identified novel and recurrent TUBA1A mutations in 1% of children with classic lissencephaly and in 30% of children with lissencephaly with cerebellar hypoplasia. A TUBA1A mutation was also found in 1 child with agenesis of the corpus callosum and cerebellar hypoplasia without lissencephaly. The authors demonstrated a wider spectrum of phenotypes than had been reported and suggested that lissencephaly-associated mutations of TUBA1A may operate via diverse mechanisms that include disruption of binding sites for microtubule-associated proteins.
Bahi-Buisson, N., Poirier, K., Boddaert, N., Saillour, Y., Castelnau, L., Philip, N., Buyse, G., Villard, L., Joriot, S., Marret, S., Bourgeois, M., Van Esch, H., Lagae, L., Amiel, J., Hertz-Pannier, L., Roubertie, A., Rivier, F., Pinard, J. M., Beldjord, C., Chelly, J. Refinement of cortical dysgeneses spectrum associated with TUBA1A mutations. J. Med. Genet. 45: 647-653, 2008. [PubMed: 18728072] [Full Text: https://doi.org/10.1136/jmg.2008.058073]
Fallet-Bianco, C., Laquerriere, A., Poirier, K., Razavi, F., Guimot, F., Dias, P., Loeuillet, L., Lascelles, K., Beldjord, C., Carion, N., Toussaint, A., Revencu, N., and 11 others. Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly. Acta Neuropath. Commun. 2: 69, 2014. Note: Electronic Article. [PubMed: 25059107] [Full Text: https://doi.org/10.1186/2051-5960-2-69]
Jansen, A. C., Oostra, A., Desprechins, B., De Vlaeminck, Y., Verhelst, H., Regal, L., Verloo, P., Bockaert, N., Keymolen, K., Seneca, S., De Meirleir, L., Lissens, W. TUBA1A mutations: from isolated lissencephaly to familial polymicrogyria. Neurology 76: 988-992, 2011. [PubMed: 21403111] [Full Text: https://doi.org/10.1212/WNL.0b013e31821043f5]
Keays, D. A., Tian, G., Poirier, K., Huang, G.-J., Siebold, C., Cleak, J., Oliver, P. L., Fray, M., Harvey, R. J., Molnar, Z., Pinon, M. C., Dear, N., Valdar, W., Brown, S. D. M., Davies, K. E., Rawlins, J. N. P., Cowan, N. J., Nolan, P., Chelly, J., Flint, J. Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans. Cell 128: 45-57, 2007. [PubMed: 17218254] [Full Text: https://doi.org/10.1016/j.cell.2006.12.017]
Kumar, R. A., Pilz, D. T., Babatz, T. D., Cushion, T. D., Harvey, K., Topf, M., Yates, L., Robb, S., Uyanik, G., Mancini, G. M. S., Rees, M. I., Harvey, R. J., Dobyns, W. B. TUBA1A mutations cause wide spectrum lissencephaly (smooth brain) and suggest that multiple neuronal migration pathways converge on alpha tubulins. Hum. Molec. Genet. 19: 2817-2827, 2010. [PubMed: 20466733] [Full Text: https://doi.org/10.1093/hmg/ddq182]
Morris-Rosendahl, D. J., Najm, J., Lachmeijer, A. M. A., Sztriha, L., Martins, M., Kuechler, A., Haug, V., Zeschnigk, C., Martin, P., Santos, M., Vasconcelos, C., Omran, H., Kraus, U., Van der Knaap, M. S., Schuierer, G., Kutsche, K., Uyanik, G. Refining the phenotype of alpha-1a tubulin (TUBA1A) mutation in patients with classical lissencephaly. Clin. Genet. 74: 425-433, 2008. [PubMed: 18954413] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.01093.x]
Poirier, K., Keays, D. A., Francis, F., Saillour, Y., Bahi, N., Manouvrier, S., Fallet-Bianco, C., Pasquier, L., Toutain, A., Tuy, F. P. D., Bienvenu, T., Joriot, S., and 12 others. Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A). Hum. Mutat. 28: 1055-1064, 2007. [PubMed: 17584854] [Full Text: https://doi.org/10.1002/humu.20572]
Poirier, K., Saillour, Y., Fourniol, F., Francis, F., Souville, I., Valence, S., Desguerre, I., Lepage, J. M., Boddaert, N., Jacquemont, M. L., Beldjord, C., Chelly, J., Bahi-Buisson, N. Expanding the spectrum of TUBA1A-related cortical dysgenesis to polymicrogyria. Europ. J. Hum. Genet. 21: 381-385, 2013. [PubMed: 22948023] [Full Text: https://doi.org/10.1038/ejhg.2012.195]