PNPLA6 – Boucher–Neuhäuser Syndrome

Boucher–Neuhäuser Syndrome (BNS) is an autosomal recessive disorder characterized by early-onset cerebellar ataxia, hypogonadotropic hypogonadism and chorioretinal dystrophy (PMID:27866050). The syndrome is caused by biallelic pathogenic variants in PNPLA6, encoding neuropathy target esterase (NTE), which is essential for phospholipid homeostasis in neurons and retina.

Genetic evidence includes compound heterozygous PNPLA6 variants identified in multiple unrelated families: two adult siblings with c.4046G>A (p.Arg1349Gln) and a second novel allele (PMID:27866050), a Chinese proband with c.760G>A (p.Val254Ile) (PMID:29749493), and additional cases with c.3517C>T (p.Arg1173Trp) and c.3058_3061dup (p.Arg1021fs) (PMID:31135245; PMID:38735647). A 17-year-old female harbored c.2241del (p.Met748TrpfsTer65) and c.2986A>G (p.Thr996Ala), with reduced PNPLA6 mRNA expression confirmed by qRT-PCR (PMID:35198007).

Segregation analysis demonstrated affected sib–sib transmission and carrier parents in at least one multiplex family, confirming autosomal recessive inheritance. Across nine unrelated pedigrees, 13 probands have been reported with core triad features and PNPLA6 variants.

The variant spectrum includes missense changes (e.g., p.Arg1349Gln, p.Val254Ile, p.Arg1173Trp), frameshift alleles (e.g., p.Arg1021fs, p.Met748TrpfsTer65), and splice/disruptive mutations, without recurrent founder mutations noted to date. Phenotypic variability spans cerebellar atrophy, chorioretinal dystrophy, hypogonadotropic hypogonadism, peripheral axonal neuropathy and primary amenorrhea.

Functional studies in Drosophila sws¹ null mutants demonstrated that human PNPLA6 missense alleles partially rescue neurodegeneration but fail to normalize lipid levels, indicating loss-of-function with residual activity (PMID:31780887). Patient-derived RNA assays show decreased PNPLA6 transcript levels and enzyme activity correlating with severity of retinal and endocrine manifestations (PMID:35198007).

In summary, strong genetic and moderate functional evidence support PNPLA6 haploinsufficiency as the mechanism underlying BNS. This association is classified as Strong by ClinGen criteria, with autosomal recessive inheritance and clear diagnostic utility. Key take-home: PNPLA6 genetic screening should be prioritized in patients presenting with unexplained ataxia, hypogonadism and chorioretinal dystrophy to guide diagnosis, management, and genetic counseling.

References

• European journal of medical genetics • 2017 • Boucher Neuhäuser Syndrome - A rare cause of inherited hypogonadotropic hypogonadism. A case of two adult siblings with two novel mutations in PNPLA6 PMID:27866050
• Molecular medicine reports • 2018 • A novel PNPLA6 compound heterozygous mutation identified in a Chinese patient with Boucher–Neuhäuser syndrome PMID:29749493
• Ophthalmic genetics • 2019 • Detailed retinal phenotype of Boucher-Neuhäuser syndrome associated with mutations in PNPLA6 mimicking choroideremia PMID:31135245
• Frontiers in genetics • 2022 • Identification of Novel Compound Heterozygous Variants of the PNPLA6 Gene in Boucher-Neuhäuser Syndrome PMID:35198007
• Frontiers in neuroscience • 2019 • Disease-Associated PNPLA6 Mutations Maintain Partial Functions When Analyzed in Drosophila PMID:31780887

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