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Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly.

Fallet-Bianco C, Laquerrière A, Poirier K, Razavi F, Guimiot F, Dias P, Loeuillet L, Lascelles K, Beldjord C, Carion N, Toussaint A, Revencu N, Addor MC, Lhermitte B, Gonzales M, Martinovich J, Bessieres B, Marcy-Bonnière M, Jossic F, Marcorelles P, Loget P, Chelly J, Bahi-Buisson N - Acta Neuropathol Commun (2014)

Bottom Line: The cortical plate was either absent (6/13), with a 2-3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13).The second subtype was lissencephaly (n = 7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7).Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6).

View Article: PubMed Central - PubMed

Affiliation: Institut Imagine, Université Paris Descartes - Sorbonne Paris Cités, Paris, France. nadia.bahi-buisson@nck.aphp.fr.

ABSTRACT
Complex cortical malformations associated with mutations in tubulin genes are commonly referred to as "Tubulinopathies". To further characterize the mutation frequency and phenotypes associated with tubulin mutations, we studied a cohort of 60 foetal cases. Twenty-six tubulin mutations were identified, of which TUBA1A mutations were the most prevalent (19 cases), followed by TUBB2B (6 cases) and TUBB3 (one case). Three subtypes clearly emerged. The most frequent (n = 13) was microlissencephaly with corpus callosum agenesis, severely hypoplastic brainstem and cerebellum. The cortical plate was either absent (6/13), with a 2-3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13). All cases had voluminous germinal zones and ganglionic eminences. The second subtype was lissencephaly (n = 7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7). All foetuses with lissencephaly and cerebellar hypoplasia carried distinct TUBA1A mutations, while those with classical lissencephaly harbored recurrent mutations in TUBA1A (3 cases) or TUBB2B (1 case). The third group was polymicrogyria-like cortical dysplasia (n = 6), consisting of asymmetric multifocal or generalized polymicrogyria with inconstant corpus callosum agenesis (4/6) and hypoplastic brainstem and cerebellum (3/6). Polymicrogyria was either unlayered or 4-layered with neuronal heterotopias (5/6) and occasional focal neuroglial overmigration (2/6). Three had TUBA1A mutations and 3 TUBB2B mutations. Foetal TUBA1A tubulinopathies most often consist in microlissencephaly or classical lissencephaly with corpus callosum agenesis, but polymicrogyria may also occur. Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6).

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Hallmarks of microlissencephaly in a 25 WG foetus (LIS_TUB_005_foetus01) withTUBA1Amutation Macroscopical data with abnormally short agyric hemispheres, severe hypoplastic brain stem and cerebellum (white arrow) (a), Smooth brain surface with no sylvian fissure (b), Smooth brain surface with agenesis of the corpus callosum without Probst bundles (arrow), and voluminous germinal zones (c), No individualized cortical plate but a thin layer made up of immature cells is present at the surface of the hemispheres (d), numerous heterotopias either radial (thin arrow) or columnar (thick arrow) in the white matter (e), with focal neuroglial cell overmigration within the meningeal spaces (f), (Scale bars: a, b: 1 mm, c: 50 μm, d, f: 20 μm, e: 100 μm).
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Fig2: Hallmarks of microlissencephaly in a 25 WG foetus (LIS_TUB_005_foetus01) withTUBA1Amutation Macroscopical data with abnormally short agyric hemispheres, severe hypoplastic brain stem and cerebellum (white arrow) (a), Smooth brain surface with no sylvian fissure (b), Smooth brain surface with agenesis of the corpus callosum without Probst bundles (arrow), and voluminous germinal zones (c), No individualized cortical plate but a thin layer made up of immature cells is present at the surface of the hemispheres (d), numerous heterotopias either radial (thin arrow) or columnar (thick arrow) in the white matter (e), with focal neuroglial cell overmigration within the meningeal spaces (f), (Scale bars: a, b: 1 mm, c: 50 μm, d, f: 20 μm, e: 100 μm).

Mentions: In all cases, macroscopical examination confirmed consistent features of extreme microcephaly (<3rd percentile) but with no intrauterine growth retardation. The brain surface was completely smooth, lacking primary fissures, olfactory sulci and bulbs (Figures 2a and 3a) and optic nerves in 2 cases. The brainstem and cerebellum were severely hypoplastic, with a widely opened fourth ventricle (Figures 2b and 3b). On sagittal sections, the corpus callosum was absent.Figure 2


Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly.

Fallet-Bianco C, Laquerrière A, Poirier K, Razavi F, Guimiot F, Dias P, Loeuillet L, Lascelles K, Beldjord C, Carion N, Toussaint A, Revencu N, Addor MC, Lhermitte B, Gonzales M, Martinovich J, Bessieres B, Marcy-Bonnière M, Jossic F, Marcorelles P, Loget P, Chelly J, Bahi-Buisson N - Acta Neuropathol Commun (2014)

Hallmarks of microlissencephaly in a 25 WG foetus (LIS_TUB_005_foetus01) withTUBA1Amutation Macroscopical data with abnormally short agyric hemispheres, severe hypoplastic brain stem and cerebellum (white arrow) (a), Smooth brain surface with no sylvian fissure (b), Smooth brain surface with agenesis of the corpus callosum without Probst bundles (arrow), and voluminous germinal zones (c), No individualized cortical plate but a thin layer made up of immature cells is present at the surface of the hemispheres (d), numerous heterotopias either radial (thin arrow) or columnar (thick arrow) in the white matter (e), with focal neuroglial cell overmigration within the meningeal spaces (f), (Scale bars: a, b: 1 mm, c: 50 μm, d, f: 20 μm, e: 100 μm).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4222268&req=5

Fig2: Hallmarks of microlissencephaly in a 25 WG foetus (LIS_TUB_005_foetus01) withTUBA1Amutation Macroscopical data with abnormally short agyric hemispheres, severe hypoplastic brain stem and cerebellum (white arrow) (a), Smooth brain surface with no sylvian fissure (b), Smooth brain surface with agenesis of the corpus callosum without Probst bundles (arrow), and voluminous germinal zones (c), No individualized cortical plate but a thin layer made up of immature cells is present at the surface of the hemispheres (d), numerous heterotopias either radial (thin arrow) or columnar (thick arrow) in the white matter (e), with focal neuroglial cell overmigration within the meningeal spaces (f), (Scale bars: a, b: 1 mm, c: 50 μm, d, f: 20 μm, e: 100 μm).
Mentions: In all cases, macroscopical examination confirmed consistent features of extreme microcephaly (<3rd percentile) but with no intrauterine growth retardation. The brain surface was completely smooth, lacking primary fissures, olfactory sulci and bulbs (Figures 2a and 3a) and optic nerves in 2 cases. The brainstem and cerebellum were severely hypoplastic, with a widely opened fourth ventricle (Figures 2b and 3b). On sagittal sections, the corpus callosum was absent.Figure 2

Bottom Line: The cortical plate was either absent (6/13), with a 2-3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13).The second subtype was lissencephaly (n = 7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7).Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6).

View Article: PubMed Central - PubMed

Affiliation: Institut Imagine, Université Paris Descartes - Sorbonne Paris Cités, Paris, France. nadia.bahi-buisson@nck.aphp.fr.

ABSTRACT
Complex cortical malformations associated with mutations in tubulin genes are commonly referred to as "Tubulinopathies". To further characterize the mutation frequency and phenotypes associated with tubulin mutations, we studied a cohort of 60 foetal cases. Twenty-six tubulin mutations were identified, of which TUBA1A mutations were the most prevalent (19 cases), followed by TUBB2B (6 cases) and TUBB3 (one case). Three subtypes clearly emerged. The most frequent (n = 13) was microlissencephaly with corpus callosum agenesis, severely hypoplastic brainstem and cerebellum. The cortical plate was either absent (6/13), with a 2-3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13). All cases had voluminous germinal zones and ganglionic eminences. The second subtype was lissencephaly (n = 7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7). All foetuses with lissencephaly and cerebellar hypoplasia carried distinct TUBA1A mutations, while those with classical lissencephaly harbored recurrent mutations in TUBA1A (3 cases) or TUBB2B (1 case). The third group was polymicrogyria-like cortical dysplasia (n = 6), consisting of asymmetric multifocal or generalized polymicrogyria with inconstant corpus callosum agenesis (4/6) and hypoplastic brainstem and cerebellum (3/6). Polymicrogyria was either unlayered or 4-layered with neuronal heterotopias (5/6) and occasional focal neuroglial overmigration (2/6). Three had TUBA1A mutations and 3 TUBB2B mutations. Foetal TUBA1A tubulinopathies most often consist in microlissencephaly or classical lissencephaly with corpus callosum agenesis, but polymicrogyria may also occur. Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6).

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Related in: MedlinePlus