PNPLA6 disorders: what’s in a name?

ABSTRACT

Background

Variants in the patatin-like phospholipase domain containing 6 (PNPLA6) gene cause a broad spectrum of neurological disorders characterized by gait disturbance, visual impairment, anterior hypopituitarism, and hair anomalies. This review examines the clinical, cellular, and biochemical features found across the five PNPLA6-related diseases, with a focus on future questions to be addressed.

Materials and Methods

A literature review was performed on published clinical reports on patients with PNPLA6 variants. Additionally, in vitro and in vivo models used to study the encoded protein, Neuropathy Target Esterase (NTE), are summarized to lend mechanistic perspective to human diseases.

Results

Biallelic pathogenic PNPLA6 variants cause five systemic neurological disorders: spastic paraplegia type 39, Gordon-Holmes, Boucher-Neuhäuser, Laurence-Moon, and Oliver-McFarlane syndromes. PNPLA6 encodes NTE, an enzyme involved in maintaining phospholipid homeostasis and trafficking in the nervous system. Retinal disease presents with a unique chorioretinal dystrophy that is phenotypically similar to choroideremia and Leber congenital amaurosis. Animal and cellular models support a loss-of-function mechanism.

Conclusions

Clinicians should be aware of choroideremia-like ocular presentation in patients who also experience growth defects, motor dysfunction, and/or hair anomalies. Although NTE biochemistry is well characterized, further research on the relationship between genotype and the presence or absence of retinopathy should be explored to improve diagnosis and prognosis.

KEYWORDS:

• PNPLA6
• NTE
• Spastic paraplegia type 39
• Gordon-Holmes syndrome
• Boucher-Neuhäuser syndrome
• Laurence-Moon syndrome
• Oliver-McFarlane syndrome

Acknowledgments

We would like to thank the patients and their families, as well as the healthcare professionals involved in their care. We thank Dr. Laryssa Huryn for the clinical images in Figure 1.

Author contributions

JL and RBH wrote and prepared the manuscript and approved the final manuscript.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

This work was supported by National Eye Institute intramural funds.