Tubulinopathies

Microtubules are cytoskeletal elements required for many cellular and developmental processes (Ex. mitosis, cell movement, intracellular movement). They coordinate proliferation and migration of neurons within the brain. They maintain neuronal polarity, support intracellular trafficking, and contribute to signal differentiation. Their dynamic remodeling contributes to neuronal differentiation, maturation, and establishment and maintenance of synaptic connections.

The structural unit of microtubules is the alpha/beta tubulin heterodimer. Different microtubules have different isoforms of alpha (TUBA) and beta tubulins (TUBB). The assembly of these heterodimers require 5 tubulin cofactors (TBCA, TBCB, TBCC, TBCD, TBCE) and the small GTPase, ARL2. Mutations in the genes encoding the 5 tubulin cofactors or microtubule-associated proteins cause a wide spectrum of neurodevelopmental and neurodegenerative disorders known as the tubulinopathies.

Tublinopathies are associated with malformations of cortical development. In addition to cortical abnormalities these patients commonly have abnormal basal ganglia (dysplasia in 75% of cases), corpus callosum (abnormalities in 40% of cases), and the cerebellum (hypoplasia or dysplasia in 79% of cases). Basal ganglia abnormalities, such as fusion of the caudate and putamen with absence of the anterior limb of the internal capsule, are so distinctive and should suggest the diagnosis of a tubulinopathy.

There are 5 distinct cortical malformation syndromes

1. Microlissencephaly (severe microcephaly and agyria, seen in fetuses), mostly associated with mutations in the TUBA1A gene;
2. 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;
3. Central pachygyria and polymicrogyria-like dysplasia (a bilateral, centrally located, cortical malformation, with clinical features of variable severity), with mutations in TUBA1A or TUBB2B;
4. Generalized polymicrogyria-like dysplasia (with a clinical phenotype similar to that seen with lissencephaly), with mutations in TUBB2B, TUBA1A, or TUBB3;
5. Simplified gyral pattern with focal polymicrogyria (the mildest of these clinical syndromes), mostly with mutations in TUBB3, TUBB2B, or TUBB5