Objective:

To present a case of a combination of heterozygous PNPLA6 gene mutations with one gene mutation being previously unreported with a phenotype not fitting in the currently defined syndromic categories of PNPLA6 variants.

Background:

Pathogenic variants in PNPLA6 cause several autosomal recessive neurodevelopmental and neurodegenerative disorders with a spectrum of, at times, overlapping features. These include spastic paraplegia type 39 (SPG39), Gordon-Holmes syndrome, Boucher-Neuhäuser syndrome, Laurence-Moon syndrome, and Oliver-McFarlane syndrome.

Design/Methods:

Case report.

Results:

A case of a 51-year-old male with motor and cognitive delays since birth who was able to acquire some skills but then, since his adolescent years, has experienced motor regression. The patient has cognitive impairment, cerebellar ataxia, peripheral neuropathy, hypogonadism, and hair anomalies but no chorioretinal dystrophy or spasticity. This does not fully align with any of the currently defined syndromic categories of PNPLA6 variants. Whole genome sequencing was initially performed for diagnostic purposes and revealed two missense variants in PNPLA6: S1127C and D1077G.

Conclusions:

The biallelic PNPLA6 variants are typically associated with one of five major neurodegenerative syndromes, however, the clinical features in this case do not fully align with the diagnostic criteria for any of these established disorders. S1127C is a likely pathogenic variant. The D1077G variant has not been previously reported in the literature and is of uncertain significance. However, in silico analysis supports that it deleteriously affects protein structure/function. Both variants are inherited in an autosomal recessive pattern and the compound heterozygous state in our patient possibly resulted in a mixed phenotype. There is a growing perspective that PNPLA6-associated disorders fall under a pleiotropic spectrum of disease influenced by the activity of neuropathy target esterase (NTE) where the NTE activity level defines phenotypic expression among PNPLA6 disorders.