Multifaceted and Age-Dependent Phenotypes Associated With Biallelic PNPLA6 Gene Variants: Eight Novel Cases and Review of the Literature

Abstract

A wide spectrum of neurodegenerative diseases has been associated with pathogenic variants in the PNPLA6 (patatin-like phospholipase domain-containing protein 6) gene, including spastic paraplegia type 39, Gordon—Holmes, Boucher—Neuhauser, Oliver—Mc Farlane, and Laurence—Moon syndromes. These syndromes present variable and overlapping clinical symptoms, encompassing cerebellar ataxia, hypogonadotropic hypogonadism, chorioretinal dystrophy, spastic paraplegia, muscle wasting, peripheral neuropathy, and cognitive impairment. In the present study, we performed a wide genetic screening in 292 patients presenting with ataxia or spastic paraplegia using a probe-based customized gene panel, covering >200 genes associated with spinocerebellar diseases. We identified six novel and four recurrent PNPLA6 gene variants in eight patients (2.7%). Six patients presented an infantile or juvenile onset (age <18), and two patients had an adult onset. Cerebellar ataxia was observed in seven patients and spastic paraplegia in one patient. Progression of cerebellar symptoms was slow in all patients, who retained ambulation even after a mean disease duration of 15 years. Brain MRI showed cerebellar atrophy in 6/8 patients, more pronounced in superior and dorsal vermis lobules (I to VII). Additional clinical features included hypogonadotropic hypogonadism (5/8), growth hormone deficiency (2/8), peripheral axonal neuropathy (4/8), cognitive impairment (3/8), chorioretinal dystrophy (2/8), and bilateral vestibular areflexia with a reduced visual vestibule-ocular reflex (1/8). In accordance with previous studies, chorioretinal dystrophy was the most frequent presenting symptom in early onset patients, hypogonadotropic hypogonadism in juvenile onset cases, and cerebellar ataxia in adult patients. One patient had an initial clinical presentation compatible with Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS), but no pathological expansions in the RFC1 gene. In conclusion, patients with PNPLA6 variants present a variable age of onset spanning from infancy to adulthood, and each clinical symptom has an age-dependent manifestation thus requiring a multi-systemic diagnostic approach. The description of patients presenting very late-onset cerebellar ataxia suggests that PNPLA6 genetic screening should also be considered in the diagnostic workout of adult cerebellar ataxia.

Neuropathy target esterase activity predicts retinopathy amongPNPLA6disorders

“…114/116 genotyped individuals have at least 1 missense allele, implicating missense alleles as a key driver of residual NTE activity and thus disease severity. To date, there are two patients with two frameshift variants that predict to have 0% activity (15,41). Based on the results of this study, truncations prior to amino acid position 1177 produce 0% NTE activity, while truncations past this position produce relatively high residual esterase activity (e.g.…”

Whole-Genome and Long-Read Sequencing Identify a Novel Mechanism in RFC1 Resulting in CANVAS Syndrome

“…Alternative repeat disorders with ataxia and predicted damaging variants in PNPLA6 and ELF2 were excluded. 5 , 6 …”

A novel mutation in RNF216 gene in a Turkish case with Gordon Holmes syndrome

“…RNF216 and PNPLA6 are the most frequently mutated genes in GHS. RNF216 encodes the E3 ubiquitin-protein ligase that is responsible for regulation of autophagy and regulates synaptic transmission and plasticity in neurons [ 3 , 4 ]. In addition to GHS, RNF216 mutations have been detected in cases with Huntington-like disease (HLD), 4H syndrome (hypodontia, hypomyelination, ataxia and hypogonadotropic hypogonadism), and congenital hypogonadotropic hypogonadism (HH) [ 5 – 7 ].…”