ALPK1 – ROSAH syndrome

ROSAH syndrome (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache) is an autosomal dominant systemic disorder caused by heterozygous variants in ALPK1 (Gene Symbol). Initial discovery in five unrelated families established the inheritance pattern and clinical features, including juvenile-onset oculopathy and splenomegaly (PMID:30967659).

Genetic evidence includes 27 reported patients across multiple cohorts, with the recurrent missense variant c.710C>T (p.Thr237Met) segregating in all five discovery families and a second variant c.761A>G (p.Tyr254Cys) identified in a larger cohort (PMID:35868845). Segregation analysis demonstrated co-segregation in at least five affected relatives with de novo or familial occurrence. The prevalence of two gain-of-function missense variants confirms a narrow variant spectrum consistent with autosomal dominant inheritance.

The predominant variant, c.710C>T (p.Thr237Met), accounts for the majority of cases, with c.761A>G (p.Tyr254Cys) representing a second hotspot. Both variants alter the ADP-heptose binding pocket, triggering constitutive activation of ALPK1. A novel p.Ser277Phe variant has been reported but remains uncommon and functionally characterized in a single pedigree.

Functional studies reveal a gain-of-function mechanism: patient primary cells and in vitro kinase assays show enhanced NF-κB activation, increased STAT1 phosphorylation, and an interferon signature. Immunofluorescence of patient fibroblasts demonstrates defective ciliogenesis and ALPK1 localization to the photoreceptor ciliary base (PMID:30967659, PMID:35868845).

Animal models including ALPK1[T237M] knock-in mice recapitulate subclinical inflammation, supporting pathogenicity of gain-of-function variants. Additional cell-free and reporter assays confirm that mutant ALPK1 is activated by endogenous nucleotide sugars in the absence of bacterial ADP-heptose, explaining systemic autoinflammation (PMID:38060563).

Clinical manifestations respond variably to immunomodulatory therapy: anti-TNF and anti-IL-1 agents suppress systemic inflammation, while anti-IL-6 (tocilizumab) uniquely improves intraocular inflammation. The narrow variant spectrum and well-characterized mechanism support robust genetic testing and targeted immunotherapy in ROSAH syndrome.

Key Take-home: Heterozygous gain-of-function ALPK1 variants cause autosomal dominant ROSAH syndrome, an autoinflammatory ciliopathy amenable to immunomodulatory treatment.

References

• Journal of clinical immunology • 2020 • Juvenile Onset Splenomegaly and Oculopathy Due to Germline Mutation in ALPK1. PMID:31939038
• Genetics in medicine • 2019 • ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder. PMID:30967659
• Annals of the rheumatic diseases • 2022 • Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome PMID:35868845
• Proceedings of the National Academy of Sciences of the United States of America • 2023 • ALPK1 mutants causing ROSAH syndrome or Spiradenoma are activated by human nucleotide sugars. PMID:38060563

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