Two different prenatal imaging cerebral patterns of tubulinopathy

Abstract

To illustrate the prenatal cerebral imaging features associated with tubulinopathy, we report on five affected fetuses from unrelated families, with a de‐novo heterozygous variant in a tubulin gene (TUBA1A, TUBB2B or TUBB3). We identified two distinct prenatal imaging patterns related to tubulinopathy: a severe form, characterized by enlarged germinal matrices, microlissencephaly and a kinked brainstem; and a mild form which has not been reported previously in the prenatal literature. The latter form is associated with non‐specific features, including an asymmetric brainstem, corpus callosal dysgenesis, a lack of Sylvian fissure operculization and distortion of the anterior part of the interhemispheric fissure with subsequent impacted medial borders of the frontal lobes, the combination of which, in the absence of additional extracerebral anomalies, is highly suggestive of tubulinopathy. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Cross-sectional quantitative analysis of the natural history of TUBA1A and TUBB2B tubulinopathies

“…4,16 Comparatively, less severe MCDs such as PMG and PMG-like CD, which are also seen in connatal infections, appear more specific for TUBB2B tubulinopathy, therefore not prompting early genetic testing. 35,36 Epilepsy is a cardinal feature at disease onset of TUBA1A and TUBB2B tubulinopathy: 65.9% and 54.8% of patients, respectively, developed seizures during the observation period. In the majority of cases, epilepsy manifests in the first year of life with infantile spasms as the most common epilepsy syndrome.…”

A novel family illustrating the mild phenotypic spectrum of TUBB2B variants

“…This suggests the influence of modifying factors on the phenotypic expression, although some cases are explained by the occurrence of somatic mosaicism in an apparently unaffected parent (Suppl Table 1) (15,19). The MRI phenotype of the terminated pregnancy is also compatible with subtle tubulinopathy (3,14,20,25). Literature review shows for TUBB2B, among tubulinopathies, very few familial cases and fetal diagnoses (3,8,14,15,19,23,25).…”

“…The MRI phenotype of the terminated pregnancy is also compatible with subtle tubulinopathy (3,14,20,25). Literature review shows for TUBB2B, among tubulinopathies, very few familial cases and fetal diagnoses (3,8,14,15,19,23,25). Besides cases with fetal akinesia and microlissencephaly, the most common fetal abnormalities, such as agenesis of corpus callosum and vermis hypoplasia, are rather non-specific and do not correlate to the severity of postnatal phenotype, making prenatal counseling difficult (3,14,25).…”

“…Literature review shows for TUBB2B, among tubulinopathies, very few familial cases and fetal diagnoses (3,8,14,15,19,23,25). Besides cases with fetal akinesia and microlissencephaly, the most common fetal abnormalities, such as agenesis of corpus callosum and vermis hypoplasia, are rather non-specific and do not correlate to the severity of postnatal phenotype, making prenatal counseling difficult (3,14,25). A possible explanation of the non-penetrant phenotype in the mother would be that she is a somatic mosaic, but she did not consent to further investigation.…”

“…Revision of the cortical malformation in multiple cases lead to the reclassification of the malformation as tubulinrelated dysgyria (7). Later, extension of the spectrum reported variable pachygyria, lissencephaly, dysmorphic basal ganglia, cerebellar vermis dysplasia, dysgenesis or agenesis of corpus callosum and brainstem hypoplasia (3,6,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Affected individuals can present with a variable combination of epilepsy, mild to severe intellectual disability, behavioral issues and delayed/abnormal motor skills, including eye movements in congenital fibrosis of extraocular muscles, myoclonus-dystonia and Uner Tan syndrome (Suppl Table 1) (3,6,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”