Paroxysmal central nervous system disorders

Gene: ALPK1

Red List (low evidence)

Comment on list classification: After NHS Genomic Medicine Service consideration, the rating of this gene has been updated to red. This is based on a red review from Ian Berry.

Created: 19 Feb 2025, 1:03 p.m. | Last Modified: 19 Feb 2025, 1:03 p.m.

Panel Version: 3.13

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Red List (low evidence)

ALPK1 causes a highly syndromic form of disease in which paroxysmal CNS features are not prominent or really present in any form that would present to a neurology clinic. This has been included due to migraines being present in the disorder, but these are not hemiplegic or otherwise neurological and the phenotype does not overlap with the classical familial hemiplegic migraine genes which make up a predominant proportion of the referrals for this criteria. Adding this gene to the panel is therefore not appropriate.

OMIM phenotype summary:
Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome (ROSAH) is an autosomal dominant disorder in which affected individuals present in childhood with reduced vision associated with papilledema and low-grade ocular inflammation. Progressive deterioration of visual acuity results in counting fingers to no light perception by the third decade of life. Patients also show anhidrosis, as well as splenomegaly and mild pancytopenia, and most experience headaches that may be migraine-like in nature

Created: 14 Feb 2025, 9:57 p.m. | Last Modified: 14 Feb 2025, 9:57 p.m.

Panel Version: 3.12

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

ALPK1 variants have been associated with ROSAH syndrome (OMIM:614979) and as strong Gen2Phen gene for the same condition. To date, 20 patients from 12 unrelated families carry NM_025144.4(ALPK1):c.710C>T (p.Thr237Met)(PMID: 30967659; 31939038; 35868845) and one case negative for this variant carried: ALPK1(NM_025144.4):c.761A>G (p.Tyr254Cys)(PMID: 35868845). These variants are in the ligand binding domain of ALPK1 and have a gain-of-function action, resulting in enhanced NF-κB activation in transfected cells and fibroblasts from patients with ROSAH syndrome (PMID: 35868845).

Created: 15 Aug 2023, 2:27 p.m. | Last Modified: 15 Aug 2023, 2:30 p.m.

Panel Version: 3.6

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Created: 15 Aug 2023, 1:56 p.m. | Last Modified: 15 Aug 2023, 1:56 p.m.

Panel Version: 3.5

Green List (high evidence)

ALPK1 is associated with ROSAH syndrome, which commonly include episodic migraine or other headaches.
Sources: Literature

Created: 18 Jul 2023, 6:14 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
ROSAH syndrome

Publications

• PMID: 30967659

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments