Disease burden by <i>ALPL</i> variant number in patients with non-life-threatening hypophosphatasia in the Global HPP Registry.

Abstract

Hypophosphatasia (HPP) is a rare metabolic disease caused by autosomal dominant or recessive inheritance of <i>ALPL</i> 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 <i>ALPL</i> variant versus two or more <i>ALPL</i> variants. Patients were included if they had one or more <i>ALPL</i> 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). Of 685 included patients, 568 (82.9%) had one <i>ALPL</i> variant, 116 (16.9%) had two variants, and one (0.1%) had three variants. Patients with two or more <i>ALPL</i> 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. HPP disease burden is high in patients with HPP, regardless of <i>ALPL</i> 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. NCT02306720; EUPAS13514.