Tubulinopathies Overview

Goal 1.

Describe the clinical characteristics of tubulinopathies.

Goal 2.

Review the genetic causes of tubulinopathies.

Goal 3.

Review the differential diagnosis of tubulinopathies.

Goal 4.

Provide an evaluation strategy to identify the genetic cause of a tubulinopathy in a proband (when possible).

Goal 5.

Review general medical management of tubulinopathies.

Goal 6.

Inform genetic counseling of family members of an individual with a tubulinopathy.

Brain Malformations

Lissencephaly ranges from a thickened cortex and complete absence of sulci (agyria) to a thickened cortex and a few shallow sulci (pachygyria) [Di Donato et al 2017].

• Classic lissencephaly is characterized by marked thickening of the cortex with a posterior-to-anterior gradient of severity (i.e., more severe involvement posteriorly [parietal and occipital lobes] than anteriorly [orbitofrontal and anterior temporal regions]). Most often, cerebellar structure is normal and the basal ganglia appear normal except that the anterior limb of the internal capsule is usually not visible.
• Lissencephaly with cerebellar hypoplasia. Some rare forms of lissencephaly are associated with a disproportionately small cerebellum.
• Lissencephaly with agenesis of the corpus callosum. The corpus callosum in living individuals is commonly dysmorphic (missing rostrum plus flat genu and anterior body), hypoplastic, or partially absent. In contrast, all prenatally diagnosed cases show complete agenesis (Figure 1 A-C and Figure 1 D-F).
• Centrally predominant pachygyria is characterized by pachygyria involving the insula and the frontal, temporal, and parietal opercula [Bahi-Buisson et al 2008]. All have abnormalities of the basal ganglia that appear as large round structures in which the caudate, putamen, and globus pallidus are indistinguishable. Hypoplasia of the anterior limbs of the internal capsule is a major feature. Common findings are vermian hypoplasia and brain stem hypoplasia. The corpus callosum is commonly dysmorphic or hypoplastic; less frequently, it is partially or completely absent (Figure 1 G-I).

Microlissencephaly refers to the most severe of the cortical dysplasias that combines extreme microcephaly and lissencephaly with hemispheres lacking primary fissures and olfactory sulci. Mainly diagnosed by prenatal MRI, findings at a median age of 25 weeks' gestation include microcephaly, absent-to-poorly operculized cortex, virtually no visible gyration, severe cerebellar hypoplasia, absent or severely hypoplastic basal ganglia, and usually complete agenesis of the corpus callosum. Associated malformations include pontocerebellar hypoplasia [Fallet-Bianco et al 2008, Lecourtois et al 2010, Fallet-Bianco et al 2014].

Dysgyria describes a cortex of normal thickness but with an abnormal gyral pattern characterized by abnormalities of sulcal depth or orientation: obliquely oriented sulci directed radially toward the center of the cerebrum and narrow gyri separated by abnormally deep or shallow sulci without imaging evidence of lissencephaly, pachygyria, cobblestone cortex, polymicrogyria, or other cortical abnormalities [Mutch et al 2016, Blumkin et al 2020]. This pattern tends to predominate in the perisylvian areas.

MRI reveals a "coarse" appearance with a thick cortex and irregular surfaces on both the pial and grey-white junction sides (Figure 1 J-L, Figure 2 A-F, Figure 3 D-I). Dysgyria can range in severity and distribution.

Note: Dysgyria was previously referred to as "simplified gyral pattern" or "polymicrogyria-like cortical dysplasia"; these terms are potentially confusing.

Basal ganglia, thalami, and corpus callosum. One of the key feature of tubulinopathies is dysmorphic basal ganglia. This pattern is usually asymmetric with bulbous appearance of the caudate and the thalami, with diffuse, branched or absent anterior limb of the internal capsule. The lateral ventricles have an irregular contour and abnormal rounding of the frontal horns likely related to the basal ganglia dysplasia.

The corpus callosum is variably affected, ranging from almost complete agenesis to normal.

Recognizable cerebellar and brain stem abnormalities. The most characteristic tubulinopathy-related cerebellar malformation is dysplasia of the superior cerebellum, especially the vermis (with "diagonal" folia – i.e., folia crossing the midline at an oblique angle). Less commonly, the vermis is hypoplastic with the anterior vermis more severely affected. The cerebellar hemispheres are either normal in size or mildly hypoplastic with mild asymmetry.

A large majority of affected individuals show brain stem hypoplasia that is usually asymmetric with a midline ventral indentation and asymmetric inferior and middle cerebellar peduncles [Oegema et al 2015].

Clinical Features of the Tubulinopathies

The clinical features of the tubulinopathies include motor and intellectual disabilities and epilepsy.

Motor and cognitive and impairments, present in almost all individuals with a tubulinopathy, correlate with the severity of brain malformations.

• Lissencephaly, microlissencephaly, and generalized severe dysgyria: spastic tetraplegia and virtually no voluntary motor control and absent eye contact
• Mild-to-moderate dysgyria: mild motor disability and intellectual disabilities

While most affected individuals have severe-to-profound intellectual disability, a minority have less extensive cortical malformations that result in only moderate intellectual disability, and a few have limited malformations that allow near-normal cognitive abilities. In the latter instance, the cortical malformation is typically less severe and less extensive on MRI.

Epilepsy varies significantly among affected individuals and is not necessarily determined by the severity of the cortical malformation, the gene involved, or the causative pathogenic variant [Romaniello et al 2019]. However:

• Early epileptic encephalopathy (with or without infantile spasms) is common in lissencephaly and generalized severe dysgyria.
• Seizures are usually present in fewer than 30% of individuals with a simplified gyral pattern with the exception of the two individuals with TUBB2A-related tubulinopathy who had infantile spasms with hypsarrhythmia (i.e., West syndrome) [Cushion et al 2014].

Additional findings. Facial diplegia and strabismus suggestive of pseudobulbar palsy are often observed in central pachygyria and various forms of dysgyria [Bahi-Buisson et al 2008].

Prognosis. Individuals with the milder forms of tubulinopathies survive into adulthood, while those with the most severe forms may die at a young age as a result of complications such as seizures or pneumonia.

Mode of Inheritance

Tubulinopathies caused by pathogenic variants in TUBA1A, TUBB2A, TUBB2B, TUBB3, TUBB (TUBB5), or TUBG1 are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• More than 95% of individuals diagnosed with a tubulinopathy have a de novo pathogenic variant in TUBA1A, TUBB2A, TUBB2B, TUBB3, TUBB (TUBB5), or TUBG1.
• Rarely, an individual diagnosed with a tubulinopathy has an affected parent. These individuals generally have either a TUBB3 or (less frequently) TUBB2B pathogenic variant.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Maternal germline mosaicism has been reported in two families with multiple affected offspring [Zillhardt et al 2016]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
    * A parent with somatic and germline mosaicism for a pathogenic variant may be mildly/minimally affected. While this situation is unusual, several groups have reported somatic mosaic pathogenic variants in genes encoding tubulin [Jamuar & Walsh 2014, Zillhardt et al 2016].
• The family history of some individuals diagnosed with a tubulinopathy may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the proband has a known tubulinopathy-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Poirier et al 2013a, Zillhardt et al 2016].
• If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, the risk to the sibs of the proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for a tubulinopathy because of the possibility of the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with a tubulinopathy has a 50% chance of inheriting the pathogenic variant.

Other family members

• The risk to other family members depends on the status of the proband's parents: if a parent is affected, the parent's family members may be at risk.
• The risk to other family members appears to be low given that most probands with an autosomal dominant tubulinopathy have the disorder as a result of a de novo pathogenic variant.

Prenatal Testing and Preimplantation Genetic Testing

Once the tubulinopathy-related pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Author Notes

Nadia Bahi-Buisson is a pediatric neurologist specializing in cortical malformations and fetal neurology. Her research at Imagine Institute focuses on the genetic and pathophysiologic bases of cortical malformations. She follows more than 100 patients with diffuse cortical malformations, and has consulted on more than 500 such cases. Dr Bahi-Buisson is involved in the European consortium on cortical malformations. This work is performed in collaboration with Chérif Beldjord, MD, PhD (director of the Laboratory of Biochemical Genetics – Cochin-Port-Royal).

Acknowledgments

• Catherine Fallet Bianco and Annie Laquerriere, for sharing their fetal cases and for their helpful discussion of fetal brain tubulinopathies
• Chérif Beldjord, Aurelie Toussaint, and Nathalie Carion, for their help in the screening of tubulin genes for diagnosis – from Sanger sequencing to the recent development of NGS panel screening
• Jamel Chelly and Karine Poirier, who allowed the first author to collaborate on the identification of tubulin genes and to define/refine the associated phenotypes; and who have contributed through constructive discussion to the understanding of the pathophysiology of tubulinopathies
• Sophie Thomas and Stanislas Lyonnet (Imagine Institute), for welcoming the authors to the Laboratory of Embryology and Genetics of Congenital Malformations and supporting their continued work in the identification of genes associated with cortical malformations

Author History

Nadia Bahi-Buisson, MD, PhD (2016-present)
Mara Cavallin, MD; Paris Descartes University (2016-2021)
Camille Maillard, PhD (2021-present)

Revision History

• 16 September 2021 (bp) Comprehensive update posted live
• 24 March 2016 (bp) Review posted live
• 7 July 2015 (nbb) Original submission

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