GeneReviews^® [Internet].

Clinical characteristics.

ALPK1-related autoinflammatory disease (ALPK1-AD) is characterized by clinical findings that can include intraocular inflammation, retinal degeneration, recurrent fever, deforming arthritis, and headaches. Anhidrosis/hypohidrosis, dental caries, short dental roots, and hyposalivation are common. While most adults have ophthalmologic manifestations, vision loss is not universal. Although significantintrafamilial variability can occur, most individuals withALPK1-AD exhibit at least one clinical or laboratory feature (such as episodic low-grade fever or episodic elevation of serum markers of inflammation such as C-reactive protein). To date, 41 individuals from 19 families with apathogenic variant inALPK1 have been described.

Diagnosis/testing.

The diagnosis ofALPK1-AD is established in aproband with suggestive findings and aheterozygouspathogenic variant inALPK1 identified bymolecular genetic testing.

Management.

Treatment of manifestations: Supportive treatment involves the following: intraocular inflammation management; low vision services; systemic inflammation management (such as a rheumatologist); dental care of enamel defects; and orthodontic procedures for individuals with short dental roots.

Surveillance: Regular monitoring by specialists treating the ophthalmologic findings, systemic inflammatory disease, and systemic and dental manifestations of anhidrosis/hypohidrosis.

Genetic counseling.

ALPK1-AD is inherited in anautosomal dominant manner. If a parent of theproband has theALPK1pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Once theALPK1 pathogenic variant has been identified in an affected family member, prenatal andpreimplantation genetic testing are possible.

Suggestive Findings

ALPK1-related autoinflammatory disease (ALPK1-AD)should be suspected in aproband with the following clinical, laboratory, and imaging findings and family history.

Clinical findings

• Ophthalmologic findings (which vary between and within families) include the following:
  • Optic nerve edema (elevation) is often present on initial evaluation even in early childhood (i.e., age <10 years). Can be observed on fundoscopic evaluation and on measurement of retinal nerve fiber layer thickness obtained by optical coherence tomography (OCT).
  • Intraocular inflammation (uveitis, retinal vasculitis)
    • Limited data suggest that it is often present in adolescence and early adulthood.
    • Slit lamp examination and dilated fundoscopic examination can identify signs of ocular inflammation. Additional testing, including OCT and fluorescein angiography (FA), can further investigate cystoid macular edema and retinal vascular leakage, respectively.
  • Retinal dystrophy (degeneration)
    • Timing of onset varies.
    • Signs of retinal dystrophy (including retinal atrophy, vascular attenuation, and pigment migration) can be identified on fundus examination and retinal fundus autofluorescence (FAF) imaging.
    • Electroretinogram (ERG) can identify early changes in photoreceptor function before signs of retinal dystrophy are observed on examination.
• Recurrent low-grade, non-infectious fever. Fever episodes typically last <24 hours before resolving spontaneously.
• Episodic malaise. "Flu-like" episodes that last a few days. These seem to be more prominent in individuals with splenomegaly and cytopenias.
• Episodic abdominal pain. Typically, gastroesophageal reflux disease and constipation
• Joint involvement. Arthralgia (discomfort) in small and large joints and deforming arthritis of the hands (affecting the proximal interphalangeal and distal interphalangeal joints)
• Headaches. Some individuals experience daily headaches, which can have migraine-like qualities including sensitivity to light.
• Splenomegaly can present with abdominal fullness and/or cytopenias or be identified on screening of asymptomatic individuals. Some individuals develop massive splenomegaly with weight exceeding 3 kilograms. Pathology at the time of splenic resection typically reveals red pulp congestion.
• Anhidrosis/hypohidrosis, which can manifest as difficulty tolerating hot temperatures (including easy flushing)
• Dental findings include enamel defects / multiple dental caries and short dental roots.
• Dry mouth caused by decreased salivary flow. Includes difficulty tolerating dry foods (e.g., crackers or pretzels) without simultaneously drinking liquids and the need to drink water during the night.
• Inability of women to lactate after childbirth

Laboratory findings

• Transient (cyclical) cytopenias with absolute neutrophil count occasionally dropping below 1,000 cells/µL and platelets occasionally dropping below 100,000 cells/µL
• Intermittently elevated C-reactive protein (CRP) ranging from mild (>10 mg/L) to severe (>100 mg/L)
• The risk of AA amyloidosis (previously known as secondary [AA] amyloidosis) is unknown; however, it was noted on biopsy of one individual who presented with renal dysfunction [C Kozycki, personal observation].

Imaging findings. On brain MRI, meningeal enhancement and premature basal ganglia / brain stem mineralization/calcifications can be observed in the absence of extrapyramidal symptoms such as parkinsonism or involuntary movements.

Family history may suggestautosomal dominant inheritance (e.g., affected males and females in multiple generations) or theproband may have ade novoALPK1pathogenic variant and represent asimplex case (i.e., a single occurrence in a family). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis ofALPK1-ADis established in aproband withsuggestive findings and aheterozygous pathogenic (orlikely pathogenic) variant inALPK1 identified bymolecular genetic testing (seeTable 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in thisGeneReview is understood to include likely pathogenic variants. (2) Identification of aheterozygousALPK1 variant ofuncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination ofgene-targeted testing (single gene testing,multigene panel) andcomprehensivegenomic testing (exome sequencing,genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (seeOption 1), whereas comprehensive genomic testing does not (seeOption 2).

Clinical Description

ALPK1-related autoinflammatory disease (ALPK1-AD) is characterized by clinical findings that can include intraocular inflammation, retinal degeneration, recurrent fever, deforming arthritis, and headaches. Anhidrosis/hypohidrosis with associated findings of enamel and caries, short dental roots, and hyposalivation are common. Most adults have ophthalmologic manifestations; however, vision loss is not universal [Kozycki et al 2022].

Although significantintrafamilial variability can occur, most individuals withALPK1-AD exhibit at least one clinical or laboratory feature (e.g., episodic elevation of serum markers of inflammation such as C-reactive protein).

To date, 41 individuals from 19 families with apathogenic variant inALPK1 have been described [Williams et al 2019,Zhong et al 2020,Jamilloux et al 2021,Hecker et al 2022,Kozycki et al 2022]. The following description of the phenotypic features associated with this condition is based on these reports (seeTable 2).

Ocular manifestations include optic disc edema, retinal degeneration, and signs of ocular inflammation including uveitis, retinal vasculitis, and cystoid macular edema. Initial ophthalmologic examination may be prompted by subjective visual changes. However, in those with a family history of retinal disease, early evaluation may reveal ocular involvement prior to development of subjective changes.

Systemic inflammation. Most individuals reported to date have findings consistent with systemic inflammation including headaches, recurrent fever, malaise, joint pain, episodic abdominal pain, and transient cytopenias. The fevers are often low grade and brief, lasting less than 24 hours before resolving spontaneously.

Joint pain and arthritis can affect both small and large joints, including hands, wrists, elbows, spine, knees, ankles, and feet. Reported gastrointestinal involvement includes episodic abdominal pain, gastroesophageal reflux disease, dysphagia, constipation, and ileus. Abdominal discomfort can also occur in the setting of massive splenomegaly.

Although recurrent headaches are common, cognitive deficits have only been reported in individuals who have other unrelated neurologic issues.

Dental abnormalities include multiple dental caries and short dental roots. Dysfunctional production of saliva, sweat, and breast milk are also common features in individuals withALPK1-AD.

Genotype-Phenotype Correlations

Nogenotype-phenotype correlations have been identified.

Penetrance

To date, all individuals with anALPK1pathogenic variant have had at least one clinical feature or laboratory finding consistent withALPK1-AD. However, the highly variable clinical manifestations ofALPK1-AD require that clinicians examiningheterozygous family members obtain a thorough medical history and perform a detailed physical examination to ensure that they correctly identify individuals as clinically affected or unaffected (C Kozycki, personal obervations).

Nomenclature

ALPK1-AD is also referred to as ROSAH syndrome. ROSAH is an acronym for the following findings associated withALPK1-AD:retinal dystrophy,optic nerve edema,splenomegaly,anhidrosis, and migraineheadache.

Prevalence

ALPK1-AD is rare. To date, 41 individuals from 19 families have been reported in the literature (seeClinical Description).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed withALPK1-AD, the evaluations summarized inTable 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure forALPK1-AD. Supportive treatment to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (seeTable 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized inTable 6 are recommended.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who may benefit from initiation of treatment with targeted immunomodulatory therapy.

SeeGenetic Counseling for issues related to testing of at-risk relatives forgenetic counseling purposes.

Pregnancy Management

To date, there is no evidence that a pregnant woman or fetus withALPK1-AD is at increased risk of adverse outcomes.

Therapies Under Investigation

SearchClinicalTrials.gov in the US andEU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

ALPK1-related autoinflammatory disease (ALPK1-AD) is inherited in anautosomal dominant manner.

Risk to Family Members

Parents of aproband

• Some individuals diagnosed withALPK1-AD have an affected parent.
• Some individuals diagnosed withALPK1-AD have the disorder as the result of ade novo ALPK1pathogenic variant.
• If theproband appears to be the only affected family member (i.e., asimplex case),molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and informrecurrence risk assessment.
• If thepathogenic variant identified in theproband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • Theproband has ade novopathogenic variant.
  • Theproband inherited apathogenic variant from a parent withgermline (or somatic and germline)mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances ofsomatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed withALPK1-AD may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unlessmolecular genetic testing has demonstrated that neither parent isheterozygous for thepathogenic variant identified in theproband.

Sibs of aproband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of theproband is affected and/or is known to have thepathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• Intrafamilial variability may be observed amongheterozygous family members. Affected family members may present with variable clinical features, and ophthalmologic involvement is not always present.
• If theALPK1pathogenic variant identified in theproband cannot be detected in the leukocyte DNA of either parent, therecurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parentalgermline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for theALPK1pathogenic variant but are clinically unaffected, the risk to the sibs of aproband appears to be low but still increased over that of the general population because of the possibility of failure to recognize manifestations in aheterozygous parent or the theoretic possibility of parentalgermline mosaicism.

Offspring of aproband. Each child of an individual withALPK1-AD has a 50% chance of inheriting theALPK1pathogenic variant.

Other family members. The risk to other family members depends on the status of theproband's parents: if a parent has theALPK1pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management,Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offergenetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

Prenatal Testing and Preimplantation Genetic Testing

Once theALPK1pathogenic variant has been identified in an affected family member, prenatal andpreimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal andpreimplantation genetic testing. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Table A.

View in own window

Table B.

View in own window

Molecular Pathogenesis

ALPK1 encodes alpha-protein kinase 1 (ALPK1), which is expressed in a wide range of cells. Although the complete role of ALPK1 in cellular function is still being investigated, it has been shown to act as an intracellular sensor for bacterial metabolites [Zhou et al 2018]. Specifically, the N-terminaldomain of ALPK1 binds bacterial sugars, including ADP-beta-D-manno-heptose (ADP-heptose). On activation, the kinase domain of ALPK1 phosphorylates TRAF-interacting protein with fork head-associated domain (TIFA), leading to enhanced NF-κB signaling. To date,ALPK1 pathogenic variants associated with autoinflammation have been restricted to the ligand-sensing domain [Kozycki et al 2022].

Of note, 40 of the 41 individuals identified in the literature withALPK1-related autoinflammatory disease to date areheterozygous forpathogenic variant p.Thr237Met (seeTable 7).

Mechanism of disease causation. Gain of function

Author Notes

Dr Christina Kozycki runs a clinical and translational research program focused onALPK1-related autoinflammatory disease (ALPK1-AD). In her work, she strives to improve clinical care for individuals living withALPK1-AD and leverage insights gained from caring for these individuals to drive basic science research that can further elucidate the role of ALPK1 in human biology. As part of this work, her team is actively engaged in the evaluation ofALPK1 variants ofuncertain significance. Dr Kozycki would be happy to communicate with persons who have any questions regarding diagnosis or treatment ofALPK1-related autoinflammatory disease.

Dr Kozycki is currently following individuals withALPK1-AD in the natural history protocol Familial Mediterranean Fever and Related Disorders: Genetics and Disease Characteristics (NCT00001373).

Acknowledgments

We express our greatest gratitude to patients and their families who have entrusted us with their care and dedicated their time and tissues to advancing our understanding of this rare disease.

Revision History

• 27 June 2024 (bp) Review posted live
• 2 June 2023 (ck) Original submission

Literature Cited

• HeckerJ, LetiziaM, LoescherBS, SiegmundB, WeidingerC. Early onset of TNFα-driven arthritis, auto-inflammation, and progressive loss of vision in a patient with ALPK1 mutation.J Clin Immunol.2022;42:880-4. [PMC free article: PMC9166835] [PubMed: 35235128]
• JamillouxY, MathisT, GrunewaldO, DollfussH, HenryT, SèveP, MeunierI.ALPK1 gene mutations drive autoinflammation with ectodermal dysplasia and progressive vision loss.J Clin Immunol.2021;41:1671-3. [PubMed: 34159509]
• KozyckiCT, KodatiS, HurynL, WangH, WarnerBM, JaniP, HammoudD, Abu-AsabMS, JittayasothornY, MattapallilMJ, TsaiWL, UllahE, ZhouP, TianX, SoldatosA, MoutsopoulosN, Kao-HsiehM, HellerT, CowenEW, LeeCR, ToroC, KalsiS, KhavandgarZ, BaerA, BeachM, Long PrielD, NehrebeckyM, RosenzweigS, RomeoT, DeuitchN, BrenchleyL, PelayoE, ZeinW, SenN, YangAH, FarleyG, SweetserDA, BriereL, YangJ, de Oliveira PoswarF, SchwartzIVD, Silva AlvesT, DusserP, Koné-PautI, TouitouI, TitahSM, van HagenPM, van WijckRTA, van der SpekPJ, YanoH, BennecheA, ApalsetEM, JanssonRW, CaspiRR, KuhnsDB, GadinaM, TakadaH, IdaH, NishikomoriR, VerrecchiaE, SangiorgiE, MannaR, BrooksBP, SobrinL, HufnagelRB, BeckD, ShaoF, OmbrelloAK, AksentijevichI, KastnerDL. 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.Ann Rheum Dis.2022;81:1453-64. [PMC free article: PMC9484401] [PubMed: 35868845]
• RahbariR, WusterA, LindsaySJ, HardwickRJ, AlexandrovLB, TurkiSA, DominiczakA, MorrisA, PorteousD, SmithB, StrattonMR, HurlesME, et al.Timing, rates and spectra of human germline mutation.Nat Genet.2016;48:126-33. [PMC free article: PMC4731925] [PubMed: 26656846]
• RichardsS, AzizN, BaleS, BickD, DasS, Gastier-FosterJ, GrodyWW, HegdeM, LyonE, SpectorE, VoelkerdingK, RehmHL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med.2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• StensonPD, MortM, BallEV, ChapmanM, EvansK, AzevedoL, HaydenM, HeywoodS, MillarDS, PhillipsAD, CooperDN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.Hum Genet.2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
• WilliamsLB, JavedA, SabriA, MorganDJ, HuffCD, GriggJR, HengXT, KhngAJ, HollinkI, MorrisonMA, OwenLA, AndersonK, KinardK, GreenleesR, NovacicD, Nida SenH, ZeinWM, RodgersGM, VitaleAT, HaiderNB, HillmerAM, NgPC, Shankaracharya, Cheng A, Zheng L, Gillies MC, van Slegtenhorst M, van Hagen PM, Missotten T, Farley GL, Polo M, Malatack J, Curtin J, Martin F, Arbuckle S, Alexander SI, Chircop M, Davila S, Digre KB, Jamieson RV, DeAngelis MM. ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder.Genet Med.2019;21:2103-15. [PMC free article: PMC6752478] [PubMed: 30967659]
• ZhongL, WangJ, WangW, WangL, QuanM, TangX, GouL, WeiM, XiaoJ, ZhangT, SuiR, ZhouQ, SongH. Juvenile onset splenomegaly and oculopathy due to germline mutation in ALPK1.J Clin Immunol.2020;40:350-8. [PubMed: 31939038]
• ZhouP, SheY, DongN, LiP, HeH, BorioA, WuQ, LuS, DingX, CaoY, XuY, GaoW, DongM, DingJ, WangDC, ZamyatinaA, ShaoF. Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose.Nature.2018;561:122-6. [PubMed: 30111836]