Elsevier

Pediatric Neurology

Volume 53, Issue 5, November 2015, Pages 442-444
Pediatric Neurology

Clinical Observations
TUBA1A Mutation Associated With Eye Abnormalities in Addition to Brain Malformation

https://doi.org/10.1016/j.pediatrneurol.2015.07.004Get rights and content

Abstract

Objective

We describe the case of a boy with a TUBA1A mutation presenting with microphthalmia and congenital cataracts in addition to microcephaly and severe brain malformation.

Methods

A boy presented in early infancy with microphthalmia, congenital cataracts, and microcephaly. His neurological course included severe hypotonia and drug-resistant epilepsy. Magnetic resonance imaging of the brain revealed a complex malformation that included agenesis of the corpus callosum, severely hypoplastic cerebellar vermis, mildly hypoplastic and dysplastic cerebellar hemispheres, mildly hypoplastic brainstem, mild posterior simplified cerebral gyral pattern, dysplastic basal ganglia and thalami, hypoplastic optic nerves, and absent olfactory bulbs.

Results

TUBA1A genetic testing was conducted and revealed a previously unreported heterozygous 808G>T missense mutation. Parental genetic testing was negative, indicating that the child's mutation was de novo.

Conclusion

The TUBA1A gene encodes tubulin alpha-1A, a protein with an important role in microtubule function and stability. Human mutations can result in a wide spectrum of brain malformations including lissencephaly, microlissencephaly, cerebellar hypoplasia, agenesis of the corpus callosum, pachygyria and polymicrogyria. Although TUBA1A is expressed in both developing brain and retinal tissue, there are no reported cases of TUBA1A mutations in association with major developmental ophthalmologic abnormalities.

Introduction

TUBA1A (OMIM #605529) is a gene encoding tubulin alpha-1A, a protein with an important role in microtubule function and stability.1 Human mutations can result in a wide spectrum of malformations, most of which are thought secondary to defective neuronal migration and/or proliferation, including lissencephaly, microlissencephaly, cerebellar hypoplasia, agenesis of the corpus callosum, pachygyria, and polymicrogyria.2, 3 Although TUBA1A is expressed in both the fetal brain4 and the retina,5 reported cases of TUBA1A mutations have thus far been limited to descriptions of brain malformations without major ophthalmologic abnormalities. We present a patient with TUBA1A mutation and associated developmental ophthalmologic abnormalities, in addition to microcephaly and a typical pattern of brain malformation, further expanding the phenotypic spectrum for mutations in this gene.

Section snippets

Patient Description

This 19-month-old boy was born at term following a generally uncomplicated pregnancy. An ultrasound at 20 weeks' gestation queried abnormal brain structure; however, a follow-up study was reported as normal and the parents declined further imaging or other testing. He had significant microcephaly from birth (greater than 2 standard deviations below the third percentile) with weight and length following the 25th-50th percentiles. There was no known family history of congenital anomalies and no

Discussion

We present a boy with a previously unreported TUBA1A mutation presenting with ophthalmological abnormalities in addition to a pattern of brain malformation frequently seen with mutations in this gene. The TUBA1A mutation is thought to be pathogenic because the mutation is novel and de novo, and this genomic region is highly conserved. The known expression of TUBA1A in the retina as well as the developing brain lends further credence to this hypothesis. Additionally, a mutation previously

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    Arrhinencephaly in Kallmann syndrome also is associated with anomalies of the ethmoid bone that can be demonstrated by computed tomography (Maione et al., 2013). Other genetic syndromes in which brain with dysplasia of the olfactory bulb or epithelium may occur include TUBA1A mutations (Myers et al., 2015), Prader–Willi syndrome (Khor et al., 2016), Bardet–Biedl syndrome (Suspitsin and Imyanitov, 2016), and various congenital heart malformations (Panigrahy et al., 2016). In Waardenburg syndrome due to SOX10 mutations, 7 of 8 patients were anosmic, and arrhinencephaly was demonstrated by imaging (Elmach-Bergès et al., 2013).

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    One isolated instance of Hirschsprung disease and Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH), in addition to agyria with microcephaly, has been described in a girl harbouring a novel TUBA1A variant predicted to cause a p. Cys200Tyr substitution (reported as p. Cys402Tyr) (Hikita et al., 2013). Two individuals with hydranencephaly-like cortical dysgeneses were identified as having p. Cys25Phe and p. Arg64Trp substitutions (Yokoi et al., 2015), and a p. Ala270Ser variant in a boy presenting with microphthalmia and congenital cataracts in addition to microcephaly and mildly simplified cerebral gyral patterning (Myers et al., 2015). At present, the vast majority of TUBA1A mutations described are de novo, heterozygous missense variations.

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Funding Source: No external funding was secured for this study.

Financial Disclosure Statement: The authors have no financial relationships relevant to this article to disclose.

Conflict of Interest Statement: The authors have no conflicts of interest to disclose.

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