Pathogenetic variants of TUBAIA, as observed by Fallet-Bianco et al. (15), affect several cerebral cortical and subcortical structures with various and severe clinical manifestations. Clinical features related to subcortical and cerebral TUBAIA-tubulinopathy are reported.
<italic>TUBA1A</italic>-tubulinopathy and related cerebral malformations
Keays et al. (1) first reported two patients with TUBA3 mutations (the human homolog of TUBA1A) both presenting with lissencephaly, pachygyria, and hippocampus anomalies. Among 95 sporadic patients with non-syndromic bilateral PMG, including 54 patients with perisylvian PMG and 30 with PMG and additional brain abnormalities, Poirier et al. (9) identified three unrelated patients with mutations in TUBA1A representing 3.1% of the PMG group and 10% of PMGs with complex cerebral malformations. The last group included patients with bilateral perisylvian asymmetrical shapes, PMG with dysmorphic basal ganglia, cerebellar vermian dysplasia, and pontine hypoplasia. The authors (9) suggested that in addition to PMG, additional brain abnormalities such as dysmorphic basal ganglia, hypoplastic pons, and cerebellar dysplasia are relevant features for PMG TUBA1A-related diagnosis. The authors (9) concluded that patients with TUBA1A mutations share not only cortical dysgenesis but also cerebellar, hippocampal, corpus callosum, and brainstem abnormalities. Four fetuses with TUBA1A mutations and a prenatal diagnosis of major cerebral malformations with termination of pregnancy were reported by Fallet-Bianco et al. (15). The pathologic studies of the fetuses at 23, 25, 26, and 35 gestational weeks showed a spectrum of abnormalities, which encompassed five brain structures: the neocortex, hippocampus, corpus callosum, cerebellum, and brainstem. Other abnormalities involved the basal ganglia, olfactory bulbs, and germinal zones. Abnormal cortical and hippocampal lamination and heterotopic neurons in the cortex, cerebellum, and brainstem were found during the microscopic examination (15). Six patients with TUBA1A mutations were reported by Bahi-Buisson et al. (4). The authors showed that the TUBA1A-related lissencephaly spectrum ranges from perisylvian pachygyria in the less severe form to posteriorly predominant pachygyria in the most severe, associated with dysgenesis of the anterior limb of the internal capsule and mild to severe cerebellar hypoplasia. Mutation analysis in the TUBA1A gene was performed by Morris-Rosendahl et al. (20) in 46 patients with classical lissencephaly. They identified three novel pathogenic variants and one recurrent mutation in five patients with variable patterns of lissencephaly on the brain MRI. Congenital microcephaly was found in four of the five patients, and all showed dysgenesis of the corpus callosum, cerebellar hypoplasia, and variable cortical malformations, including subtle cortical band heterotopia and absence or hypoplasia of the anterior limb of the internal capsule. The authors maintained that the frequency of mutation in TUBA1A affects approximately 4% of the patients with lissencephaly. Kumar et al. (8) conducted a study of TUBA1A mutations in 125 patients with cortical dysgenesis including 72 patients with classical LIS, 22 with subcortical band heterotopia (SBH), 29 with LIS and cerebellar hypoplasia (LCH), and two with LIS and agenesis of corpus callosum (ACC). The results obtained consisted of missense mutations in five out of 72 patients with classic LIS (7%) and 10 missense mutations in 29 patients with LCH (32%). TUBA1A mutation was also found in one child with ACC and CBLH without LIS. The authors (8) summarized the brain MRI features of 17 patients with TUBA1A mutation in five distinct groups according to the observed variants. Three patients with TUBA1A mutations were reported by Jansen et al. (21) with classic LIS in a boy and polymicrogyria in two sisters whose mother showed somatic mosaicism, thus showing familial recurrence of the mutation. A single case in a 14-month-old girl with TUBA1A mutation and classical lissencephaly was reported by Sohal et al. (14). Marked ventricular dilatation with thin cortex, poorly differentiated basal ganglia, agenesis of corpus callosum, and cerebellar hypoplasia with preserved vermis were described by Okumura et al. (22) in a child with TUBA1A mutation and cerebellar hypoplasia. An extensive neuropathologic analysis showed a lacking lamination in the cerebral cortex, absent corpus callosum without Probst bundle, blurred demarcation among the striatum internal capsule and globus pallidus, irregular running of myelinated fibers, cerebellar hypoplasia with irregular undulation in the dentate nucleus and inferior olivary nucleus, absent olfactory bulbs and tracts, and pyramidal tract hypoplasia. Among 106 patients selected as having complex cortical malformations, Bahi-Buisson et al. (23) identified 45 (42.5%) patients presenting with mutations in TUBA1A, 18 in TUBB2B, (16.9%), 11 in TUBB3 (10.4%), three in TUBB5 (2.8%), and three in TUBG1 (2.8%). Five cortical malformation syndromes were distinguished by the authors (23) in a systemic revision of the data collected by neuroimaging and neuropathologic analysis in patients affected by TUBA1A and other tubulinopathies: microlissencephaly (n = 12), lissencephaly (n = 19), central pachygyria and polymicrogyria-like cortical dysplasia (n = 24), generalized polymicrogyria-like cortical dysplasia (n = 6), and simplified gyral pattern with area of focal polymicrogyria (n = 19).
Dysmorphic basal ganglia were reported in 75% of cases and central pachygyria, polymicrogyria-like cortical dysplasia, and simplified gyral malformations syndrome in 100% of the cases. Moreover, the authors (23) highlight a high prevalence of corpus callosum agenesis (32/80; 40%) and mild to severe cerebellar hypoplasia and dysplasia (63/80; 78.7%). Fallet-Bianco et al. (24) selected 19 cases of TUBA1A mutations in a cohort of 60 fetal cases. The authors refer that all the cases of lissencephaly with cerebellar hypoplasia showed distinct TUBA1A mutations, while those with classical lissencephaly harbored recurrent mutations in TUBA1A (three cases) or TUBB2B (one case). The authors (24) concluded that fetal TUBA1A-tubulinopathies most often present with microlissencephaly or classical lissencephaly with corpus callosum agenesis, but polymicrogyria may also occur in contrast to TUBB2B mutations in which either polymicrogyria or microlissencephaly may be found. TUBA1A mutations affect almost exclusively the central nervous system (CNS), but congenital malformations may involve other body organs as reported by Hikita et al. (25) in a 6-year-old girl who presented with lissencephaly, microcephaly, and early-onset epileptic seizures in addition to Hirschsprung disease and inappropriate antidiuretic hormone secretion (SIADH). In a cohort of 156 patients with malformations of cortical development of unknown origin, 79 patients were selected and submitted to a genetic analysis of the TUBA1A, TUBB2B, and TUBB3 (26). Two novel heterozygous mutations were found: a TUBA1A mutation in a 5-year-old female with microcephaly, severe intellectual disability, and absence of language and a TUBB2B in a 31-year-old female with microcephaly, spastic tetraparesis, severe intellectual disability, and scoliosis. The patient with TUBA1A mutations in the brain MRI showed pachygyria associated with a diffuse subcortical band heterotopia that spared the fronto-basal regions only; the heads of caudate nuclei and the putamen were fused; corpus callosum was thin with anterior commissure absent; the hippocampi showed a simplified pattern. Abnormal transition between the medulla and a-flattened pons, thickened mesencephalon, and a thinned pontomesencephalic junction were also present. The cerebellar vermis was mildly hypoplastic. Based on the results of the genetic analysis obtained in the patients, the authors (26) concluded that the frequent observation of hypoplastic and disorganized white matter tracts led to suggest that in addition to defects in neuronal migration, disruption of axon growth and guidance represent a peculiar feature of the disorders linked to tubulinopathy. Shimojima et al. (27) reported a single case of a Japanese baby girl with microcephaly, lissencephaly with cerebellar hypoplasia, and corpus callosum hypoplasia. Genetic analysis disclosed a region anomaly that encodes the N-terminal domain of TUBA1, a region uncommonly involved. The brain MRI showed the presence of colpocephaly, lateral ventricle dilatation, and simplified gyral pattern. There was also hypoplasia of the corpus callosum and the cerebellar vermis. A TUBA1A variant was reported by Bosemani et al. (28) in a 22-month-old girl with developmental delay. Brain MRI showed vermian hypoplasia with abnormally increased rostrocaudal length of the medulla and midbrain involving the pons, and loss of the normal flat dorsal surface of the brainstem. In a study on patients with hindbrain imaging abnormalities, Oegema et al. (29) identified 10 patients. In seven of 10 patients (78%), targeted sequencing revealed mutations in three different tubulin genes (TUBA1A, TUBB2B, and TUBB3) occurring de novo or inherited from a mosaic parent. Brain MRI revealed cerebellar dysplasia combined with basal ganglia dysplasia in all of the cases (100%) and brainstem dysplasia in almost all (80%), and only irregular patterns of cortical gyri and sulci. With regard to the two patients with TUBA1A mutations, they showed microcephaly, severe developmental delay, and epilepsy. The MRI features in both cases showed diffuse irregular gyration and sulcation of cortex, vermis hypoplasia, asymmetry of pons, medulla dysplasia (in one case), partial agenesis of corpus callosum, basal ganglia hypoplasia, enlarged ventricle, and cranial nerve hypoplasia. A 9-year-old girl affected by epileptic seizures, developmental delay, hypotonia, and microcephaly was reported by Mencarelli et al. (30). The girl showed mild facial dysmorphism including bulbous nasal tip, large mouth, edema of the hands and feet with camptodactyly, bilateral thelarche, hypoplasia of the labia minora, and poor visual and social interaction. The girl had a de novo heterozygous mutation in TUBA1A gene. Brain MRI showed complex cerebral malformations with mild asymmetry and dilatation of lateral ventricles and reduced white matter. Cortical dysgenesis with dysmorphic frontal lobes, simplified gyral pattern, and poor development of the Sylvian fissure were also present. The corpus callosum was thin and basal ganglia were hypoplastic. Right caudate nucleus and right lenticular nucleus were dysmorphic. Cerebellar vermis and pons hypoplasia were also reported. A study was conducted by Romaniello et al. (31) on 28 patients harboring 23 heterozygous pathogenic variants in tubulin genes TUBA1A (n = 10), TUBB2B (n = 8), and TUBB3 (n = 5). Neuroimaging patterns of patients showed cerebellar dysplasia and other posterior fossa morphological anomalies. Cerebellar anomalies were found in 24/28 patients (86%): cerebellar dysplasia in 19/28 (68%) including cortical cerebellar dysplasia (18/28), either involving only the cerebellar hemispheres (12/28) or associated with vermis dysplasia (6/28). Cortical cerebellar dysplasia was found only in the right hemisphere in 13/18 including four TUNN2B, four TUBB3, and five TUBA1A mutations. In contrast to the remaining five TUBA1A patients, cortical cerebellar dysplasia was located only in the left hemispheres or in both. The authors refer that the cerebellar involvement in tubulinopathies shows peculiar aspects that may be labeled as “tubulin-related cerebellar dysplasia” (31). Epilepsy is common in patients with TUBA1A. In a cohort of 15 patients and 75 from published studies, Romaniello et al. (32) reported epileptic disorders in 60% of the patients affected by TUBA1A mutations, 74% by TUBB2B, and 25% by TUBB3. In these patients, brain MRIs were consistent with the extensive brain malformations involving subcortical and midline structures (32).