Abstract
Purpose :
The tub-/- (tubby) mouse (rd5) has long been known to express a complex retinal dystrophy-obesity phenotype with features abridging the Bardet-Biedl (BBS) and Alström (ALMS) syndromes, but to date there is only 1 report of a human counterpart (Borman et al. Hum. Mutat. 2014). Here we report the second ever family presenting with a tubby-like phenotype in association with TUB mutations in 2 affected Caucasian brothers, PT1 and PT2 (49 and 46 yo)
Methods :
Testing included visual acuity, semi-automated kinetic perimetries (SKPs), flash electroretinograms (ERGs), macular and retinal nerve fiber layer (RNFL) ocular coherence tomography (OCT), fundus autofluorescence, photos, and fluorescein angiography (FA). Smell function was also assessed (UPSIT scratch-and-sniff test). Whole exome sequencing genotyping was conducted within the Undiagnosed Disease Network project
Results :
Both patients exhibited photoreceptor degeneration with disseminated chorioretinal atrophic nummular lesions peripherally and at the arcades, bilateral bull’s eye maculopathy with partial foveal residue, and moderately to severely reduced acuity. SKPs were markedly constricted, and ERGs markedly reduced. In both patients a disproportionate vision loss compared to the retinal phenotype led to the identification of RNFL thickening and disc inflammation on FA, which were found to be linked to a secondary autoimmune involvement that responded in part to periocular/intravitreal steroids and oral immunosuppressives. Both patients had BMI>36, borderline cognition, decreased smell, and no dystrophic extremities. PT2 had dilated cardiomyopathy and hypertension. PT1 had sensorineural hearing loss. Both patients shared the c.1359_1360delAG, p.R453Sfs*10, and the splice site c.1380+1G>A TUB mutations. Heterozygous changes in other genes were also identified in both patients, and a novel change in the RP1L1 gene in PT2
Conclusions :
We provide further evidence that human TUB mutations are associated with a complex tubby-like syndromic retinal ciliopathy abridging the BBS and ALMS spectrum. The cause for the systemic phenotypic variability remains to be elucidated. Vision loss was augmented by secondary autoimmune phenomena that may be linked to the known role of TUB in regulating microglial phagocytosis through MERTK, a gene known to be associated with pathogenic secondary autoimmunity in both RCS rats and Mertk-/-mice
This is a 2021 ARVO Annual Meeting abstract.