Abstract
The Wide Spectrum of Tubulinopathies: What Are the Key Features for the Diagnosis?
Bahi-Buisson N, Poirier K, Fourniol F, Saillour Y, Valence S, Lebrun N, Hully M, Bianco CF, Boddaert N, Elie C, Lascelles K, Souville I, LIS-Tubulinopathies Consortium, Beldjord C, Chelly J. Brain 2014;137:1676–1700.
Complex cortical malformations associated with mutations in tubulin genes: TUBA1A, TUBA8, TUBB2B, TUBB3, TUBB5 and TUBG1 commonly referred to as tubulinopathies, are a heterogeneous group of conditions with a wide spectrum of clinical severity. Among the 106 patients selected as having complex cortical malformations, 45 were found to carry mutations in TUBA1A (42.5%), 18 in TUBB2B (16.9%), 11 in TUBB3 (10.4%), three in TUBB5 (2.8%), and three in TUBG1 (2.8%). No mutations were identified in TUBA8. Systematic review of patients’ neuroimaging and neuropathological data allowed us to distinguish at least five cortical malformation syndromes: (i) microlissencephaly (n = 12); (ii) lissencephaly (n = 19); (iii) central pachygyria and polymicrogyria-like cortical dysplasia (n = 24); (iv) generalized polymicrogyria-like cortical dysplasia (n = 6); and (v) a ‘simplified’ gyral pattern with area of focal polymicrogyria (n = 19). Dysmorphic basal ganglia are the hallmark of tubulinopathies (found in 75% of cases) and are present in 100% of central pachygyria and polymicrogyria-like cortical dysplasia and simplified gyral malformation syndromes. Tubulinopathies are also characterized by a high prevalence of corpus callosum agenesis (32/80; 40%), and mild to severe cerebellar hypoplasia and dysplasia (63/80; 78.7%). Foetal cases (n = 25) represent the severe end of the spectrum and show specific abnormalities that provide insights into the underlying pathophysiology. The overall complexity of tubulinopathies reflects the pleiotropic effects of tubulins and their specific spatio-temporal profiles of expression. In line with previous reports, this large cohort further clarifies overlapping phenotypes between tubulinopathies and although current structural data do not allow prediction of mutation-related phenotypes, within each mutated gene there is an associated predominant pattern of cortical dysgenesis allowing some phenotype–genotype correlation. The core phenotype of TUBA1A and TUBG1 tubulinopathies are lissencephalies and microlissencephalies, whereas TUBB2B tubulinopathies show in the majority, centrally predominant polymicrogyria-like cortical dysplasia. By contrast, TUBB3 and TUBB5 mutations cause milder malformations with focal or multifocal polymicrogyria-like cortical dysplasia with abnormal and simplified gyral pattern.
Commentary
Malformations of cortical development (MCDs) used to be much simpler. These disorders, which result from disruptions in the usual process by which the cerebral cortex develops during embryonic and fetal life, have long been known to be fairly prevalent causes of medically refractory epilepsy, particularly in children but also in adults (1). In the old days (the 1990s), it was reasonable and quite instructive to think of MCDs as being classified into categories based on the putative stage of development that was disrupted in each malformation: neuronal proliferation, neuronal migration, or postmigrational organization (2).
The cardinal cortical malformations mostly featured one major type of anatomic abnormality, which could be appreciated in an increasingly easy fashion as neuroimaging technology improved, and when causative gene mutations were first identified for some of these disorders, they implicated proteins whose functions made plausible biological sense in explaining the developmental defect (3). Thus ASPM mutations, affecting a cell-cycle protein important in mitosis of proliferating neuronal progenitors, lead to primary microcephaly, a disorder of brain size in the absence of other major dysplastic features (4). Similarly, mutations in DCX, a gene on the X chromosome encoding a microtubule-associated protein, lead to disorders of neuronal migration such as subcortical band heterotopia and classic lissencephaly, with the sex-specific nature of these conditions satisfactorily explained by X-inactivation in females (5).
In recent years, however, this more simplistic understanding of MCDs has been gradually chipped away by accumulating clinical, radiologic, pathological, genetic, and molecular evidence, such that the exceptions to the rules have now become the norm, and we must look at MCDs in a different way. For example, some syndromes of polymicrogyria, previously classified as a disorder of cortical organization, appear radiologically and histologically to share features in common with cobblestone lissencephalies, which are thought to be associated with neuronal overmigration through a defective pial basement membrane (6). The WDR62 gene, which encodes a centrosomal and nuclear protein important in neuronal proliferation, causes not only primary microcephaly but also, at times, lissencephaly, gray-matter heterotopia, polymicrogyria, and schizencephaly (7).
Perhaps the most important of the recent genetic advances in our understanding of MCDs is the identification of the so-called tubulinopathies—that is, disorders associated with mutations in tubulin genes (which encode proteins that in heterodimer form make up microtubules). The first such link between a tubulin-gene mutation and a brain malformation appeared in 2007 (8), with TUBA1A, and in the years since, a remarkable number of additional tubulin-related malformation syndromes have been described. Indeed, the field has advanced to a point at which a systematic analysis of a large cohort of patients with various tubulin-gene mutations can yield important genotype–phenotype correlations and highlight the key commonalities among all of these related disorders, which is precisely what Bahi-Buisson et al. have accomplished.
The authors report on their comprehensive review of clinical, genetic, neuroimaging, and neuropathological data from 80 patients with tubulinopathies and complex cortical malformations, representing 61 distinct tubulin-gene mutations. They identify five distinct malformation syndromes:
microlissencephaly (severe microcephaly and agyria, seen in several fetuses in this series), mostly associated with mutations in the TUBA1A gene; lissencephaly (along the classic agyria–pachygyria spectrum, usually with clinical features of refractory epilepsy and severe motor and cognitive delay), mostly associated with mutations in TUBA1A but with a few examples of TUBG1 mutations; central pachygyria and polymicrogyria-like dysplasia (a bilateral, centrally located, cortical malformation, with clinical features of variable severity), with mutations in TUBA1A or TUBB2B; generalized polymicrogyria-like dysplasia (with a clinical phenotype similar to that seen with lissencephaly), with mutations in TUBB2B, TUBA1A, or TUBB3; simplified gyral pattern with focal polymicrogyria (the mildest of these clinical syndromes), mostly with mutations in TUBB3, TUBB2B, or TUBB5.
Outside of the distinguishing dysplastic appearance of the cerebral cortex as described above, there are three additional brain regions commonly affected in these tubulin-related malformations; namely, the basal ganglia (with dysplasia seen in 75% of all cases), the corpus callosum (with abnormalities in 40%), and the cerebellum (with hypoplasia or dysplasia in 79%). The basal ganglia abnormalities, and in particular, an unusual dysplastic entity in which the caudate and putamen appear fused with an absence of the anterior limb of the internal capsule, are so distinctive within the phenotypic range of MCDs, in fact, that this specific finding, when seen in the setting of other cortical malformations, should strongly suggest the diagnosis of a tubulinopathy.
Although there are intriguing genotype–phenotype correlations discussed in this article, the authors acknowledge that none are specific enough to allow for confident identification of a particular causative tubulin gene or mutation based on clinical and radiologic presentations alone. Realistically, for most epileptologists not closely familiar with the latest literature on cortical malformations (and likely even for those who are), an encounter with a patient who has a complex cortical malformation that might be tubulin related will require a close review of the very helpful and extensive set of MR images provided in the figures in the article by Bahi-Buisson et al., or in the original reports of each mutation, so it becomes possible to identify how closely their patient's brain disorder matches the described syndromes.
At this time, as we have gained additional understanding of the spectrum of disorders that comprise the MCDs, the most widely used classification scheme has moved from a purely anatomic one to one that incorporates more genetic knowledge (9). We hope that in the future, there will be a comprehensive approach to cortical malformations that is fundamentally based on molecular mechanisms but remains of high practical utility to clinicians caring for patients with these conditions, and that the underlying pathways that are disrupted will be understood sufficiently to offer multiple opportunities for therapeutic targets.