ROSAH syndrome
From Wikipedia, the free encyclopedia
| ROSAH syndrome | |
|---|---|
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| ROSAH syndrome is inherited via an autosomal dominant manner. | |
| Causes | Mutation in ALPK1 gene |
ROSAH syndrome is a genetic disease of innate immune activation.[1] ROSAH stands for retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis and headache. The name emphasizes some, but not all, of the features that can be associated with the syndrome.[2] The disease is inherited in an autosomal dominant manner and caused by heterozygous missense mutations in the ALPK1 gene, an innate immune sensor for bacterial sugars.[3]
While the initial descriptions of ROSAH syndrome emphasized the ocular manifestations of the disease, it is now clear that ROSAH syndrome can also present with a range of systemic features including recurrent fever, uveitis, deforming arthritis, AA amyloidosis, meningeal enhancement and premature mineralisation of the basal ganglia, substantia nigra and red nuclei on MRI.[2][1] Additionally, clinical features not conventionally attributed to inflammation have also been reported and included short dental roots, enamel defects and decreased salivary flow.[1]
Pathophysiology
ALPK1 is a pattern recognition receptor of the innate immune system that recognises the bacterial metabolite ADP-heptose.[3] ROSAH syndrome patients' primary samples and in vitro assays with mutated ALPK1 constructs have shown immune activation with increased NF-κB signaling, STAT1 phosphorylation and interferon gene expression signature.[1]
Genetics
This condition is caused by mutations in the ɑ-kinase gene (ALPK1) gene, most commonly changing the amino acid Threonine to Methionine at position 237 in the protein. This gene is located on the long arm of chromosome 4 (4q25). The inheritance of this condition is autosomal dominant.
Diagnosis
Currently, screening for ROSAH syndrome is initiated upon a physician's judgement. Genetic testing for ROSAH syndrome can be performed as either targeted, single-gene testing through Sanger sequencing or a multi-gene test through whole exome sequencing or whole genome sequencing.[2][1]
Management
Some features of the disease are amenable to immunomodulatory therapy.[1] However, additional studies will be need to determine if immunomodulation can mitigate the risk of progressive vision loss in this disease.