Disease Burden by Variant Number in Patients with Non-life-threatening Hypophosphatasia in the Global HPP Registry

Background: Hypophosphatasia (HPP) is a rare metabolic disease caused by autosomal dominant or recessive inheritance of variants resulting in low alkaline phosphatase activity. The objective of this analysis was to compare HPP disease burden between patients with non-life-threatening disease in the Global HPP Registry who have one variant versus two or more  variants.

Methods: Patients were included if they had one or more  variants identified through genetic testing and first HPP manifestations after 6 months of age. Assessments included history of HPP manifestations, Brief Pain Inventory-Short Form (BPI-SF), Health Assessment Questionnaire-Disability Index (HAQ-DI), 6-Min Walk Test (6MWT), Paediatric Quality of Life Inventory (PedsQL) and 36-Item Short-Form Survey V.2 (SF-36v2).

Results: Of 685 included patients, 568 (82.9%) had one variant, 116 (16.9%) had two variants, and one (0.1%) had three variants. Patients with two or more  variants had higher proportions of skeletal (52.1% vs 32.6%), dental (73.5% vs 56.0%), muscular (36.8% vs 23.6%) and neurological (22.2% vs 8.8%) manifestations at last assessment. BPI-SF, HAQ-DI, PedsQL and SF-36v2 scores were similar between groups. Distances walked on the 6MWT were similar between groups for children. Distance walked was lower among adults with two or more variants (293 m (n=8)) than adults with one variant (466 m (n=103)), although the former group was very small.

Conclusion: HPP disease burden is high in patients with HPP, regardless of variant number. While prevalence of HPP-specific manifestations was higher in patients with two or more variants than those with one variant, patient-reported outcomes were similar between groups.

Trial Registration Number: NCT02306720; EUPAS13514.