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Robert B Hufnagel, Sarah Hull, Jose Luiz Pedroso, Shuan Dai, Andrea Nemeth, Helene Dollfus, Brian Patrick Brooks, Robert Sisk, Michel Michaelides, Anthony T Moore, Zubair Ahmed; Survey of ophthalmic and systemic features in patients with PNPLA6-related disorders. Invest. Ophthalmol. Vis. Sci. 2016;57(12):6564. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Mutations in PNPLA6 result in neurodegenerative disorders with congenital, childhood, or adult onset due to dysfunction of the encoded protein, Neuropathy Target Esterase (NTE). These include Spastic Paraplegia type 39, Gordon-Holmes syndrome, Boucher-Neuhauser syndrome, Laurence-Moon syndrome, and Oliver-McFarlane syndrome. Here, we evaluate the natural history of retinal degeneration and systemic findings in PNPLA6-related disorders.
Twenty-three patients with clinical diagnosis of a PNPLA6-related disorder and/or biallelic PNPLA6 mutations were enrolled. DNA was analyzed for PNPLA6 mutations by Sanger sequencing or whole exome sequencing. Retinal phenotypes were analyzed by visual acuity and color vision testing, fundus photos, autofluorescence, optical coherence tomography (OCT), visual fields, and electroretinography (ERG). Brain MRI and hormone concentrations were obtained to assess hypopituitarism and spinocerebellar phenotypes.
Patient ages at last evaluation ranged from 4 years to 55 years. The majority of disease-causing variants in PNPLA6 altered the esterase domain. Chorioretinal atrophy with preserved macular and peripapillary pigment was noted in the majority of patients. Additionally, patients typically had constricted visual fields, macular atrophy on OCT, and reduced or absent cone and rod activity on ERG. Onset of retinal degeneration was typically in the 1st or 2nd decade, with onset as early as 1 year of age. Retinal degeneration was typically preceded by evidence of pituitary dysfunction, including short stature and pituitary atrophy. Thyroxine and growth hormone replacement improved developmental and growth delays when initiated during childhood. Hypogonadotropic hypogonadism commonly presented in adolescence. Ataxia and spastic paraplegia was present in nearly half of patients, with onset ranging from the first to third decades.
PNPLA6 mutations typically result in loss of NTE function. Chorioretinopathy is characteristic of PNPLA6-related conditions and is present in Boucher-Neuhauser, Laurence-Moon, and Oliver-McFarlane syndromes. The progression and severity of ocular and systemic features varied among our patients, although the typical order of symptom onset appeared to be pituitary, followed by retinal, and then spinocerebellar, regardless of age of onset. Ongoing studies will focus on natural history and correlations with genotype and NTE activity.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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