Disease burden by ALPL variant number in patients with non-life-threatening hypophosphatasia in the Global HPP Registry

Abstract

Background: Hypophosphatasia (HPP) is a rare metabolic disease caused by autosomal dominant or recessive inheritance of ALPL 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 ALPL variant versus two or more ALPL variants.

Methods: Patients were included if they had one or more ALPL 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 ALPL variant, 116 (16.9%) had two variants, and one (0.1%) had three variants. Patients with two or more ALPL 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 ALPL 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.

Keywords: gene frequency; genetic association studies; genetic diseases, inborn.

Figure 1. Patient flow chart. ALP, alkaline phosphatase; HPP, hypophosphatasia.

Figure 2. Reported history of baseline signs and symptoms of HPP by number of ALPL variants. Patients may have more than 1 sign and symptom within each category. *Prevalence ratio is statistically significant based on 95% CI of prevalence ratio not overlapping 1. ^†Excludes patients <6 months of age at enrolment. ^‡Includes loss of permanent teeth, loose teeth, poor dentition, hypodontia, dental implants, dental bridges and dentures. ^§Excludes patients <2 years of age at enrolment. HPP, hypophosphatasia.

Figure 3. BPI-SF scores (A) and HAQ-DI scores (B) in adults by number of ALPL variants. Box plots show median and IQR with whiskers representing 95% CIs; x denotes mean value. BPI-SF, Brief Pain Inventory-Short Form; HAQ-DI, Health Assessment Questionnaire-Disability Index.

Figure 4. 6MWT results in (A) children and (B) adults with disease onset >6 months of age by number of ALPL variants. Box plots show median and IQR with whiskers representing 95% CIs; x denotes mean value. 6MWT, 6-Min Walk Test. *p<0.005.

Figure 5. Quality of life in (A) children and (B) adults by number of ALPL variants. (A) PedsQL in children. Box plots show median and IQR with whiskers extending from minimum to maximum value; x denotes mean value. Per data from the California State Children’s Insurance programme, means (parent report) in general population are 81.34 for total score, 83.26 for physical health, 80.22 for psychosocial health, 80.28 for emotional functioning, 82.15 for social functioning and 76.91 for school functioning. HRQoL, health-related quality of life; PedsQL, Pediatric Quality of Life Inventory. (B) SF-36v2 in adults. Mean scores are shown. Higher scores indicate a more favourable health status; 50 is average for the general population. SF-36v2, 36-Item Short-Form Health Survey V.2.