The wide spectrum of tubulinopathies: what are the key features for the diagnosis?

Abstract

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.

Genetics and mechanisms leading to human cortical malformations

“…MTs have multiple functions, they are essential components of the mitotic spindle in dividing cells and during neurogenesis, they are constantly remodeled during neuronal migration, and once neurons reach their final position, helping to generate and stabilize axonal processes to mediate cell communication via synaptogenesis [139]. Tubulin-related cortical dysgeneses, (see Table 2), refer to MCDs involving mutations in tubulin genes: α-tubulin (principally TUBA1A), β-tubulin (TUBB2B, TUBB2A, TUBB3, TUBB(TUBB5)) and -tubulin (TUBG1) [47,49,152,153,174,175].…”

“…As well as the cLIS spectrum, brain malformations include lissencephaly with cerebellar hypoplasia, or with corpus callosum agenesis, and centrally predominant pachygyria, PMG-like cortical dysplasia, generalized PMG-like cortical dysplasia, simplified gyral pattern with areas of focal PMG, and microlissencephaly often in combination with dysplastic basal ganglia, corpus callosum abnormalities, and hypoplasia or dysplasia of the brainstem and cerebellum [47,175,177,178]. Clinical features include motor and intellectual disabilities, epilepsy and ocular impairments.…”

Genetic Basis of Brain Malformations

“…Nine genes (KIF2A , KIF5C , TUBA1A , TUBA8 , TUBB , TUBB2B , TUBB3 , TUBG1 , and DYNC1H1 ; table 1 ) associated with tubulinopathies have been identified so far [Bahi-Buisson et al, 2014]. Findings from functional studies suggest that abnormal brain development in tubulinopathies results from a dominant negative effect of heterozygous missense mutations (in the absence of lossof-function mutations) on the regulation of microtubuledependent mitotic processes in progenitor cells, and on the trafficking activities of the microtubule-dependent molecular motors KIF2A, KIF5C, and DYNC1H1 in postmitotic neuronal cells [Poirier et al, 2013].…”

Epilepsy in Multigene Tubulin Family Mutations

“…Consequently, in tubulin-genes disorders, epilepsy should not be considered a predominant symptom. When present, it is described with a wide range of severity (from a mild clinical presentation and spontaneous regression to intractable seizures, such as infantile spasms), without a specific pattern and it is often associated with MCDs [27].…”