Warburg Micro Syndrome 4

A number sign (#) is used with this entry because of evidence that Warburg Micro syndrome-4 (WARBM4) is caused by homozygous mutation in the TBC1D20 gene (611663) on chromosome 20p13.

Description

Warburg Micro syndrome is a rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism (summary by Morris-Rosendahl et al., 2010).

For a discussion of genetic heterogeneity of Warburg Micro syndrome, see 600118.

Clinical Features

Liegel et al. (2013) studied 7 patients from 5 families with Warburg Micro syndrome due to mutations in the TBC1D20 gene who showed the same range of clinical features observed in WARBM patients with mutations in the RAB3GAP1 (602536), RAB3GAP2 (609275), and RAB18 (602207) genes. Shortly after birth, patients presented with congenital cataracts, microphthalmia, microcornea, and small atonic pupils. Despite cataract surgery, they had poor vision due to optic atrophy, and several affected children also developed glaucoma. All patients with TBC1D20 mutations had severe to profound developmental delay: they did not learn to walk and spoke only 4 to 5 words at most. They also displayed autistic features. Patients had normal head circumferences at birth but developed postnatal microcephaly. Facial features included deep-set eyes, ptosis, wide nasal bridge, relatively narrow mouth, low anterior hairline, and prominent subnasal region. Affected boys exhibited micropenis and cryptorchidism. In the first year of life, all affected individuals had severe axial hypotonia, and then gradually developed lower and upper limb spasticity, resulting in spastic quadriplegia. Cranial MRIs in 4 patients showed predominantly frontal polymicrogyria, corpus callosum hypogenesis particularly involving the splenium, widened lateral ventricles, and megacisterna magna due to cerebellar vermis hypoplasia; follow-up MRIs in 2 of the patients showed atrophy of the cerebellar vermis and hemispheres.

Molecular Genetics

In a cohort of 77 patients with a spectrum of Warburg Micro disorders, Liegel et al. (2013) analyzed the candidate gene TBC1D20 and identified homozygous mutations in 7 patients diagnosed with WARBM from 5 families of different ethnic origins (611663.0001-611663.0005). The cohort included 59 cases of 'typical' WARBM, 5 cases diagnosed with Martsolf syndrome (212720), and 13 atypical cases that had been described by Handley et al. (2013).