> Publications > Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders

OptoDrum

Publication

February 23, 2026 • ✎ STRIA TECH

Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders

Topics:

Optic Nerve Damage

Optic Neuritis

Rare and Inherited CNS and Eye Disorders

Rare Disease

Retinal Degeneration

Retinal Dystrophy

Publication

Brain (Jun 03, 2024) Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders

Liu J, He Y, Lwin C, Han M, Guan B, Naik A, Bender C, Moore N, Huryn LA, Sergeev YV, Qian H, Zeng Y, Dong L, Liu P, Lei J, Haugen CJ, Prasov L, Shi R, Dollfus H, Aristodemou P, Laich Y, Németh AH, Taylor J, Downes S, Krawczynski MR, Meunier I, Strassberg M, Tenney J, Gao J, Shear MA, Moore AT, Duncan JL, Menendez B, Hull S, Vincent AL, Sis-kind CE, Traboulsi EI, Blackstone C, Sisk RA, Miraldi Utz V, Webster AR, Michaelides M, Arno G, Synofzik M, Hufnagel RB

DOI: 10.1093/brain/awae055 >>

This study looked at a gene called PNPLA6, changes in which cause a range of rare neurological conditions affecting movement, hormones, and eyesight. Researchers measured how much of the PNPLA6 enzyme “NTE” is active and found that lower activity predicts more severe disease and eye damage. They tested many human genetic variants and used mice to show that less NTE activity leads to worse visual outcomes. To measure vision in mice, they used Striatech’s OptoDrum to get a reliable readout of visual ability.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker.