Bi-allelic variants in PNPLA6 possibly associated with Parkinsonian features in addition to spastic paraplegia phenotype.

Variants in the PNPLA6 gene are known to cause 4 distinct phenotypes. One known phenotype is Hereditary Spastic Paraplegia type 39 (HSP 39), a rare neurodegenerative condition characterized by variable onset of lower limb spasticity, weakness and ataxia. Little is known about complications of HSP 39 in adulthood. Here, we report a family of three siblings who presented with bilateral lower limb spasticity in childhood, consistent with HSP, with confirmed bi-allellic PNPLA6 mutations. Two siblings developed parkinsonian features in middle age, a novel finding in this sibship. The proband had a positive dopamine transporter scan, indicating degeneration in dopaminergic neurons, and dopa-responsive extrapyramidal symptoms. Testing for known genetic causes of Parkinsonism was negative. The PNPLA6 gene encodes neuropathy target esterase, an enzyme involved in lipid metabolism that is critical to the stability of cell membranes. We hypothesize that the development of Parkinsonism in these patients may be related to the PNPLA6 mutations, as lipid dysregulation has been implicated in the pathogenesis of Parkinson disease.