Mutations in ABHD12 Cause the Neurodegenerative Disease PHARC: An Inborn Error of Endocannabinoid Metabolism

Abstract

Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) is a neurodegenerative disease marked by early-onset cataract and hearing loss, retinitis pigmentosa, and involvement of both the central and peripheral nervous systems, including demyelinating sensorimotor polyneuropathy and cerebellar ataxia. Previously, we mapped this Refsum-like disorder to a 16 Mb region on chromosome 20. Here we report that mutations in the ABHD12 gene cause PHARC disease and we describe the clinical manifestations in a total of 19 patients from four different countries. The ABHD12 enzyme was recently shown to hydrolyze 2-arachidonoyl glycerol (2-AG), the main endocannabinoid lipid transmitter that acts on cannabinoid receptors CB1 and CB2. Our data therefore represent an example of an inherited disorder related to endocannabinoid metabolism. The endocannabinoid system is involved in a wide range of physiological processes including neurotransmission, mood, appetite, pain appreciation, addiction behavior, and inflammation, and several potential drugs targeting these pathways are in development for clinical applications. Our findings show that ABHD12 performs essential functions in both the central and peripheral nervous systems and the eye. Any future drug-mediated interference with this enzyme should consider the potential risk of long-term adverse effects.

Hereditary ataxias: overview

“…46 Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC), a syndrome similar to Refsum disease, is caused by mutations in ABHD12. 47 Coenzyme Q10 (CoQ10) deficiency is often associated with seizures, cognitive decline, pyramidal track signs, and myopathy but may also include prominent cerebellar ataxia. 48,49 The symptoms may respond to CoQ10 treatment.…”

Endocannabinoids via CB1receptors act as neurogenic niche cues during cortical development

“…In this regard, FAAH polymorphisms have been associated with drug abuse behaviours [90,91]. A recent proof of concept of this notion is the involvement of ABDH12 mutations that associate with the neurodegenerative disease polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataract (PHARC) that occurs with concomitant demyelination and cerebellar ataxia [92]. CB 1 receptor signalling can be influenced as well by prenatal exposure to marijuana-derived cannabinoids or by contact with drugs targeting either directly or indirectly the ECB system.…”

Dynamic changes to the endocannabinoid system in models of chronic pain

“…The effects of spinal or supra-spinal administration of JZL184 on nociceptive processing in control rats, or in models of chronic pain have yet to be reported. In the context of chronic pain states involving the activation of spinal glial cells, it is noteworthy that 2-AG signalling in microglia is thought to be terminated by ABHD12 [96], which is not sensitive to JZL184 [97].…”