A Novel De Novo TUBB3 Variant Causing Developmental Delay, Epilepsy and Mild Ophthalmological Symptoms in a Chinese Child.

Heterozygous missense mutations in TUBB3 have been implicated in various neurological disorders encompassing either isolated congenital fibrosis of the extraocular muscles type 3 (CFEOM3) or complex cortical dysplasia with other brain malformations 1 (CDCBM1). The description of seizures in patients with TUBB3 mutations is rare. Here, we reported a patient who had febrile seizures before and focal seizure this time, which was diagnosed as epilepsy in combination with an abnormal EEG. MRI showed hypoplastic corpus callosum. Mutation analysis showed a novel de novo heterozygous variant of TUBB3 gene (NM_006086), c.763G>A (p.V255I). He had global developmental delay, photophobia and elliptic pupil, but lacking extraocular muscles involvement and malformations of cortical development, which might be a less severe phenotype of TUBB3 mutations. This was the first report of elliptic pupil in patients with TUBB3 mutations and expanded the spectrum of TUBB3 phenotypes. It indicated that the phenotypic range of TUBB3 mutations might be more continuous than discrete, with a severity ranging from mild to severe. Further studies are needed to elucidate the complete spectrum of TUBB3-related phenotypes.

TUBB3 M323V Syndrome Presents with Infantile Nystagmus

Variants in the TUBB3 gene, one of the tubulin-encoding genes, are known to cause congenital fibrosis of the extraocular muscles type 3 and/or malformations of cortical development. Herein, we report a case of a 6-month-old infant with c.967A>G:p.(M323V) variant in the TUBB3 gene, who had only infantile nystagmus without other ophthalmological abnormalities. Subsequent brain magnetic resonance imaging (MRI) revealed cortical dysplasia. Neurological examinations did not reveal gross or fine motor functions, which are inconsistent with the clinical characteristics of patients with the M323V syndrome reported so far. A protein modeling showed that the M323V mutation in the TUBB3 gene interferes with αβ heterodimer formation with the TUBA1A gene. This report emphasizes the importance of considering TUBB3 and TUBA1A tubulinopathy in infantile nystagmus. A brain MRI should also be considered for these patients, although in the absence of other neurologic signs or symptoms.

Optic Nerve Head and Retinal Abnormalities Associated with Congenital Fibrosis of the Extraocular Muscles

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduced in CFEOM patients compared to controls (p < 0.005). Situs inversus of retinal vessels was seen in five patients. Our study provides evidence of structural optic nerve and retinal changes in CFEOM. We show for the first time that there are widespread retinal changes beyond the retinal ganglion cells in patients with CFEOM. This study shows that the phenotype in CFEOM extends beyond the motor nerves.

Discovery of New Mutation Sites of KIF21A Gene in Chinese Patients with Congenital Fibrosis of the Extraocular Muscles

Background Congenital fibrosis of the extraocular muscles (CFEOM) is a rare hereditary nonprogressive disorder characterized by bilateral ptosis, which shows severely limited ocular motility. We reported a new mutation site of KIF21A gene in a Chinese family with congenital fibrosis of the extraocular muscles type 1 (CFEOM1).Methods A retrospective study of case series was conducted in this study. Standard ocular examinations were performed on 10 family members in a CFEOM1 family. Next-generation sequencing (NGS) was performed to sequence 828 genes related to oculopathy. The splice sites of the KIF21A gene were analyzed to detect the existence of mutations.Results The five patients with CFEOM1 were found in the family members of a Chinese family on three generations. A new KIF21A pathogenic SNP mutation site KIF21A-ex20 c.2821C > T (p.Arg941Trp) was identified by comparing with human genome reference genes and Sanger sequencing. .Conclusions A new KIF21A pathogenic SNP mutation site KIF21A-ex20 c.2821C > T (p.Arg941Trp) could possibly be a major disease‑causing gene for the Chinese family with CFEOM1.

New Mutation Sites of KIF21A Gene in Chinese Patients with Congenital Fibrosis of the Extraocular Muscles

Background Congenital fibrosis of the extraocular muscles (CFEOM) is a rare hereditary nonprogressive disorder characterized by bilateral ptosis, with severely limited ocular motility. We report a new mutation site of KIF21A gene in a Chinese family with congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Methods We conducted a retrospective study of case series. Standard ocular examinations were performed on 10 persons in a CFEOM1 family. Next-generation sequencing (NGS) was performed to sequence 828 genes related to oculopathy. To detect mutations, we determined the splice sites of the KIF21A gene. Results The five patients with CFEOM1 were found in the ten people of a Chinese family on three generations. A new KIF21A pathogenic SNP mutation site KIF21A-ex20 c.2821C> T (p.Arg941Trp) was identified by compared with human genome reference genes and Sanger sequencing. Conclusions A new KIF21A pathogenic SNP mutation site KIF21A-ex20 c.2821C> T (p.Arg941Trp) may be a major disease‑causing gene for the Chinese family with CFEOM1.