Residual rod function in CNGB1 mutant dogs.

PURPOSE: Mutations in the cyclic nucleotide-gated (CNG) channel beta subunit (CNGB1) are an important cause of recessive retinitis pigmentosa. We identified a large animal model with a truncating mutation of CNGB1. This study reports the persistence of small, desensitized rod ERG responses in this model. METHODS: Dark-, light-adapted and chromatic ERGs were recorded in CNGB1 mutant dogs and age and breed matched controls. Comparisons were made with a dog model known to completely lack rod function; young dogs with a mutation in the rod phosphodiesterase 6 alpha subunit (PDE6A-/-). Immunohistochemistry (IHC) to label the rod CNG alpha (CNGA1) and CNGB1 subunits was performed. RESULTS: The dark-adapted ERG of CNGB1 mutant dogs had a raised response threshold with lack of normal rod response and a remaining cone response. Increasing stimulus strength resulted in the appearance of a separate, slower positive waveform following the dark-adapted cone b-wave. With increasing stimulus strength this increased in amplitude and became faster to merge with the initial b-wave. Comparison of responses from PDE6A-/- (cone only dogs) with CNGB1 mutant dogs to red and blue flashes and between dark-adapted and light-adapted responses supported the hypothesis that the CNGB1 mutant dog had residual desensitized rod responses. CNGB1 mutant dogs had a small amount of CNGA1 detectable in the outer segments. CONCLUSIONS: CNGB1 mutant dogs have a residual ERG response from desensitized rods. This may be due to low levels of CNGA1 in outer segments.

Ammonium tetrathiomolybdate treatment of copper-associated hepatopathy in dogs.

BACKGROUND: Copper-associated hepatopathy (CAH) is a common cause of liver disease in dogs. Although d-penicillamine can be an effective treatment, some dogs fail treatment or develop adverse effects. Ammonium tetrathiomolybdate (TTM) has been used to treat pathologic copper accumulation in other species, but its therapeutic potential for CAH is unknown. OBJECTIVES: To investigate short-term safety and efficacy of TTM for treatment of CAH. ANIMALS: Ten dogs with CAH. METHODS: Prospective study. All dogs were treated with TTM PO for 6 weeks, and hepatic biopsies were performed after the treatment course. Dog experiencing initial decreases in hepatic copper concentrations ([Cu]H ) received 6 additional weeks of TTM treatment and underwent 1 additional biopsy. Physical and laboratory examinations were performed every 2 weeks for study duration. RESULTS: Eight of 10 dogs had decreases in [Cu]H . Compared to baseline (median, 1606 µg/g; range, 572-5158 µg/g), [Cu]H were decreased at 6 weeks (1033 µg/g, 450-2975 µg/g; P = .04) and 12 weeks (931 µg/g, 218-1677 µg/g; P = .02). Hepatic molybdenum concentrations increased >50-fold (P < 0.001). Changes in histologic scores and hematologic and biochemical test results were variable and not significantly different from baseline. One dog developed presumed immune-mediated anemia and thrombocytopenia, but it was unclear if this was related to TTM administration. CONCLUSIONS AND CLINICAL IMPORTANCE: Results suggest that TTM can effectively decrease [Cu]H in some dogs with CAH. Larger studies are needed to determine the overall safety and efficacy of TTM for treating CAH and how it compares with current treatments.