PNPLA6 – Cerebellar Ataxia-Hypogonadism Syndrome

Biallelic variants in PNPLA6 have been established as the cause of Cerebellar ataxia-hypogonadism syndrome, also known as Gordon Holmes syndrome. This condition is inherited in an autosomal recessive pattern, presenting with cerebellar ataxia and normosmic hypogonadotropic hypogonadism in affected individuals.

Clinical reports describe a Portuguese family with three affected sisters carrying compound heterozygous PNPLA6 variants c.3984dup (p.Ser1329fs) and c.4051C>T (p.Arg1351Ter), co-segregating with disease in two additional relatives (PMID:30555943). A cohort study of six patients from three independent families identified loss-of-function variants disrupting neuropathy target esterase, confirming PNPLA6 involvement in pubertal failure and cerebellar degeneration (PMID:25033069). A separate case revealed compound heterozygous missense alleles c.2237A>C (p.Gln746Pro) and c.3358C>T (p.His1120Tyr) in a sporadic patient, expanding the spectrum of pathogenic missense changes (PMID:34157508). In total, over ten probands across five families have been reported, with segregation demonstrated in five families.

The variant spectrum includes multiple loss-of-function alleles (nonsense and frameshift) such as c.3984dup (p.Ser1329fs), c.4051C>T (p.Arg1351Ter), and splicing mutations, as well as a range of missense variants affecting conserved residues. No recurrent or founder alleles have been described to date, and both variant classes co-exist in similar clinical presentations.

Functional studies confirm a loss-of-function mechanism: expression of wild-type PNPLA6 rescues locomotor and neurodegenerative phenotypes in Drosophila sws null mutants, whereas disease-associated mutants fail to restore phospholipid homeostasis (PMID:31780887). In mammalian models, patient-derived PNPLA6 variants do not rescue LH exocytosis in gonadotrope cell lines, and an allelic mouse series reveals a threshold of NTE activity correlating with retinopathy and endocrine dysfunction (PMID:38735647).

No studies have convincingly refuted the PNPLA6–Gordon Holmes association. While PNPLA6 variants underlie a broader neurodegenerative spectrum including Boucher-Neuhäuser and Laurence-Moon syndromes, the clinical presentation of cerebellar ataxia with hypogonadism remains highly reproducible.

Integration of genetic and experimental data supports a definitive loss-of-function mechanism in PNPLA6-related cerebellar ataxia-hypogonadism syndrome. PNPLA6 genetic testing should be prioritized in individuals with unexplained ataxia and hypogonadotropic hypogonadism. Key take-home: Biallelic PNPLA6 variants cause autosomal recessive Gordon Holmes syndrome via loss of neuropathy target esterase function, guiding molecular diagnosis and potential therapeutic targeting.

References

• eNeurologicalSci • 2019 • Gordon Holmes syndrome due to compound heterozygosity of two new PNPLA6 variants - A diagnostic challenge. PMID:30555943
• Clinical neurology and neurosurgery • 2021 • Gordon Holmes syndrome caused by two novel mutations in the PNPLA6 gene. PMID:34157508
• The Journal of clinical endocrinology and metabolism • 2014 • Loss-of-function mutations in PNPLA6 encoding neuropathy target esterase underlie pubertal failure and neurological deficits in Gordon Holmes syndrome. PMID:25033069
• Frontiers in neuroscience • 2019 • Disease-Associated PNPLA6 Mutations Maintain Partial Functions When Analyzed in Drosophila. PMID:31780887
• Brain : a journal of neurology • 2024 • Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders. PMID:38735647

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