Profound Neuropathy Target Esterase impairment results in Oliver-McFarlane syndrome. R. B. Hufnagel1, G. Arno2, N. D. Hein3, J. Hersheson4, L. A. Krueger1, T. J. Jaworek5, L. C. Gregory4, S. Hull2, V. Plagnol6, C. M. Willen7, T. M. Morgan8, C. A. Prows1, R. S. Hegde9, S. Riazuddin10, G. A. Grabowski1, R. J. Richardson11, J. P. Martinez-Barbera4, T. Huang1, M. T. Dattani12, R. A. Sisk5, H. Houlden4, J. K. Fink3, A. T. Moore2, Z. M. Ahmed1,5 1) Human Genetics, Cincinnati Children's Hospital, Cincinnati, OH; 2) Ophthalmology, Moorfields Eye Hospital, London, UK; 3) Neurology, University of Michigan, Ann Arbor, MI; 4) Neurology, University College London, London, UK; 5) Pediatric Ophthalmology, Cincinnati Children's Hospital, Cincinnati, OH; 6) Statistical Genetics, University College London, London, UK; 7) Ophthalmology, University of Kentucky, Lexington, KY; 8) Human Genetics, Vanderbilt University, Nashville, TN; 9) Developmental Biology, Cincinnati Children's Hospital, Cincinnati, OH; 10) Pediatric Otolaryngology, Cincinnati Children's Hospital, Cincinnati, OH; 11) Environmental Health Sciences, University of Michigan, Ann Arbor, MI; 12) Endocrinology, University College London, London, UK.

   A half century mystery elucidated. Oliver-McFarlane syndrome [MIM 275400], first described in 1965, is a rare disorder with the triad of congenital trichomegaly, chorioretinal atrophy, and hypopituitarism. In our patients, thyroid and growth hormone replacement during childhood successfully improved the pituitary sequelae of intellectual disability and short stature. However, vision loss was progressive and devastating. Designing therapeutic approaches first requires discovery of the genetic and biologic mechanisms. In this study, through whole exome sequencing, we identified seven novel mutations in the PNPLA6 gene in five patients with Oliver-McFarlane syndrome. PNPLA6 (19p13.2) encodes Neuropathy Target Esterase (NTE), a phospholipase that hydrolyzes phosphatidylcholine and maintains axonal integrity. Previously, recessive alleles of PNPLA6 have been reported for two adult onset neurologic disorders, Spastic Paraplegia type 39 (SPG39) and Boucher-Neuhäuser syndrome. Oliver-McFarlane syndrome is distinguished from these by the congenital onset, trichologic findings, childhood pituitary sequelae, and ocular disease severity. In accord with the clinical findings, we found PNPLA6 expression in the developing human eye, pituitary, and brain. Molecular modeling suggested impaired function of the NTE patatin domain in the Oliver-McFarlane alleles. Concurrently, we confirmed this hypothesis in two model systems. In zebrafish, the pnpla6 curly-tailed morphant phenotype was fully rescued by wild type human PNPLA6 mRNA but not with Oliver-McFarlane or SPG39 mutation-harboring human mRNAs. Second, NTE enzymatic activities were measured in patient fibroblast cell lines to determine if the congenital onset of Oliver-McFarlane correlates with reduced hydrolase activity compared to adult onset SPG39. Indeed, NTE activity was significantly decreased in individuals with Oliver-McFarlane (25% of normal activity) compared to SPG39 (73% of normal activity). In conclusion, Oliver-McFarlane syndrome is caused by PNPLA6 mutations that result in early and severe loss of NTE function. Identification and functional characterization of this new PNPLA6-opathy reveals a broad spectrum of neurodevelopmental and neurodegenerative disorders caused by NTE impairment, which appears to determine both age of onset and affected tissues in a dose-dependent manner. Ongoing studies will focus on the relationship between NTE activity and disease prognosis, as well as therapeutic strategies.

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