POS1205 BURDEN OF FATIGUE IN HYPOPHOSPHATASIA: FINDINGS FROM AN OBSERVATIONAL STUDY IN A TERTIARY CARE HOSPITAL IN THE UNITED KINGDOM

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Background: Hypophosphatasia (HPP) is a rare inherited condition caused by bi-allelic (recessive) or mono-allelic (dominant) pathogenic variants of the alkaline phosphatase ( ALPL ) gene causing deficiency of Tissue non-specific alkaline phosphatase (TNSALP). This leads to disorders of bone and teeth mineralisation [1]. Severity can vary widely, from perinatal lethal forms to mild forms affect babies in utero (perinatal benign) to onset in childhood or adulthood. In adults, the presentation varies from recurrent fractures, teeth mineralisation abnormalities to disabling chronic pain. Although severe HPP is very rare, a recent study by Mornet suggests an estimated prevalence of mild HPP in adults of 1:508 which is more common than previously estimated. Low alkaline phosphatase (ALP) levels remain the hallmark of the disease [1]. Thirty to forty percent of the affected patients experience fatigue, a major burden that contributes to a decline in both the physical and mental health domains of Health-Related Quality of Life (HRQOL) [2, 3]. We used the Fatigue Assessment Scale (FAS) in this study, a widely used and validated unidimensional scale to assess the severity of chronic fatigue [4]. Objectives: This abstract assesses fatigue in HPP, from the preliminary findings of a comprehensive single-centre observational study of HPP, conducted at a tertiary care hospital in England. This study examined the wider clinical manifestations and psychosocial impacts of the disease on adult HPP patients. Methods: Fifty-two symptomatic adults aged 18 years and older, fifty-one with confirmed genetic pathogenic variants in the ALPL gene, clinical symptoms of hypophosphatasia (HPP), low alkaline phosphatase (ALP) activity for their age and sex, and elevated fasting vitamin B6 levels, were recruited for the study. Demographic data, clinical manifestations, biochemical markers, self-reported symptoms, and standardised questionnaires on HRQOL were pseudonymously collected. The patients were divided into two groups for, those receiving Enzyme replacement therapy (ERT, n=12) with Asfotase Alfa and those not receiving ERT (n=40). The FAS was used as a standardised questionnaire, to assess the prevalence and severity of fatigue for our patient population. Thirty five of the fifty-two participants completed the FAS questionnaire (67%). Results: Table 1 . Table 1 shows that both groups had a median age over 40 at diagnosis. All ERT patients had paediatric-onset symptoms, compared to 80% in the non-ERT group. Females were more affected in both groups (75% in ERT, 85% in non-ERT), with most patients being Caucasian. A significant proportion (83% with ERT and 63% with non-ERT) self-reported fatigue as a predominant symptom. The study found similar ALP levels in both groups, but the ERT group had higher fasting B6 levels, which, along with Urine Phosphoethanolamine (PEA), is a diagnostic test. Overall, 100% of the ERT group reported some level of fatigue, while 75% of the non-ERT reported fatigue. This reinforces the earlier self-reported findings that a significant proportion of both groups experience fatigue, with the ERT group showing a notably higher prevalence. As assessed by the FAS questionnaire, 80% of the patients have fatigue. The FAS bar graph (n=35) compares fatigue levels between two groups. 71% of the ERT group reported ‘Mild to Moderate Fatigue', compared to 46% in the non-ERT group. Both cohorts showed equal percentages (29%) of participants with ‘Severe Fatigue'.A scatter plot examining the relationship between diagnostic ALP levels (X-axis) and FAS scores (Y-axis) showed a weak positive correlation in the non-ERT group. A similar plot for diagnostic B6 levels and FAS scores showed dispersed data points, indicating no clear linear relationship. Figure 1 Conclusion: In this predominantly female cohort of adults with HPP, fatigue assessed by FAS was very common, affecting eighty percentage of the patients overall. A one hundred percent of ERT group and seventy five percent from the non-ERT experience fatigue. The self-reported fatigue percentages align with these findings. The FAS results showed a broader range of fatigue scores with the non-ERT group compared to the ERT group. This underscores the importance of considering fatigue as a key feature when assessing for hypophosphatasia (HPP), especially in individuals with milder symptoms where these extra skeletal manifestations can be overlooked. REFERENCES: [1] Reis FS, Lazaretti-Castro M. Hypophosphatasia: from birth to adulthood. Arch Endocrinol Metab. 2023 May 25;67(5):e000626. doi: 10.20945/2359-3997000000626. PMID: 37249457; PMCID: PMC10665056. [2] Dahir, K.M., Seefried, L., Kishnani, P.S. et al. Clinical profiles of treated and untreated adults with hypophosphatasia in the Global HPP Registry. Orphanet J Rare Dis 17, 277 (2022). https://doi.org/10.1186/s13023-022-02393-8. [3] Behanova M, Medibach A, Haschka J, Kraus D, Raimann A, Mindler GT, Zwerina J, Kocijan R. Health-related quality of life and fatigue in adult rare bone disease patients: A cross-sectional study from Austria. Bone. 2024 Apr;181:117034. doi: 10.1016/j.bone.2024.117034. Epub 2024 Feb 2. PMID: 38311305. [4] de Kleijn WP, De Vries J, Lower EE, Elfferich MD, Baughman RP, Drent M. Fatigue in sarcoidosis: a systematic review. Curr Opin Pulm Med. 2009 Sep;15(5):499-506. doi: 10.1097/MCP.0b013e32832d0403. PMID: 19458531. [5] Reis FS, Lazaretti-Castro M. Hypophosphatasia: from birth to adulthood. Arch Endocrinol Metab. 2023 May 25;67(5):e000626. doi: 10.20945/2359-3997000000626. PMID: 37249457; PMCID: PMC10665056. Acknowledgements: NIL . Disclosure of Interests: Afzal Latheef: None declared, Nidhi Sofat: None declared, Muhammad Atif Rauf: None declared, Matthew Taylor: None declared, Sahar Mansour: None declared, Mohammad Ali Shah: None declared, Robbie Ramsden: None declared, Katie Moss Alexion, Alexion, Alexion. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.

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