Mutations in the TBC1D20 gene are responsible for approximately 5% of cases of Warburg micro syndrome. Other causative genes of Warburg micro syndrome are RAB3GAP1, RAB3GAP2 and RAB18, overall responsible for 50% of the cases. More than 40% of the cases of this syndrome are not yet attributable to any gene. Two siblings have also been described with TBC1D20 mutation and Martsolf syndrome, a condition clinically overlapping to Warburg micro syndrome, but less severe and more rare. The phenotype of patients with Warburg micro syndrome mutated in TBC1D20 is indistinguishable from that of patients with Warburg micro syndrome mutated in other genes.
The clinical phenotype of patients with biallelic mutations in TBC1D20 is characterized by ocular, nervous system and endocrine system abnormalities. Optic abnormalieties include congenital cataract, microphthalmia, microcornea, and small and atonic pupils. Despite cataract surgery, vision remains poor due to optic atrophy and cortical visual impairment. Many patients develop glaucoma. TBC1D20 mutated patients display generally severe to profound developmental delay with autistic features, they do not learn to walk, and speak few words (4-5 at most). Only known exception is a couple of Iranian siblings diagnosed with Martsolf syndrome showing mild to moderate developmental delay. Head circumference is normal at birth, but patients may develop postnatal microcephaly. Facial features include deep-set eyes, ptosis, wide nasal bridge, micrognathia, low anterior hairline, and prominent subnasal region. They show severe hypotonia in the first year of life and subsequently develop spasticity in the upper and lower limbs leading to spastic quadriplegia. Both patients with Warburg micro syndrome and those with Martsolf syndrome have hypogenitalism, which in males can manifest with micropenis and/or cryptorchidism. MRI analysis reveals in these patients severe brain abnormalities including frontal polymicrogyria, hypoplasia of the corpus callosum, widened lateral ventricles, megacisterna magna, and atrophy of the cerebellar vermis and hemispheres. Some individuals may have epilepsy. Generally, these patients have feeding difficulties, and may have gastroesophageal reflux, and/or dysphagia, and gastrostomy tube placement is required to improve nutrition.
TBC1D20