Burden of Illness in Adults With Hypophosphatasia: Data From the Global Hypophosphatasia Patient Registry

Abstract

Hypophosphatasia (HPP) is a rare, inherited, metabolic disease caused by deficient tissue non-specific alkaline phosphatase activity. This study aims to assess patient-reported pain, disability and health-related quality of life (HRQoL) in a real-world cohort of adults with HPP who were not receiving asfotase alfa during the analysis. Adults (≥18 years old) with HPP (confirmed by ALPL gene mutation and/or low serum alkaline phosphatase activity for age/sex) were identified from the Global HPP Registry (NCT02306720). Demographics, clinical characteristics, and data on patient-reported pain, disability, and HRQoL (assessed by Brief Pain Inventory Short Form [BPI-SF], Health Assessment Questionnaire Disability Index [HAQ-DI], and 36-Item Short-Form Health Survey version 2 [SF-36v2], respectively) were stratified by pediatric-and adult-onset HPP and summarized descriptively. Of the 304 adults included (median [min, max] age 48.6 [18.8, 79.8] years; 74% women), 45% had adult-onset HPP and 33% had pediatric-onset HPP (unknown age of onset, 22%). Of those with data, 38% had experienced ≥5 HPP manifestations and 62% had a history of ≥1 fracture/pseudofracture. Median (Q1, Q3) BPI-SF scores were 3.5 (1.5, 5.3) for pain severity and 3.3 (0.9, 6.2) for pain interference. Median (Q1, Q3) disability on the HAQ-DI was 0.3 (0.0, 0.7). Median (Q1, Q3) physical and mental component summary scores on the SF-36v2 were 42.4 (32.7, 49.9) and 45.3 (36.3, 54.8), respectively. Greater numbers of HPP manifestations experienced/body systems affected correlated significantly with poorer scores on the BPI-SF, HAQ-DI, and SF-36v2 (all p < 0.05). No significant differences between adults with pediatric-and adult-onset HPP were observed for patient-reported outcomes, except for disability and the BPI-SF question "pain at its worst," which were significantly higher among adults with pediatric-versus adult-onset HPP (p = 0.03 and 0.04, respectively). These data from the Global HPP Registry show that adults with HPP have a substantial burden of illness that is associated with reduced patient-reported HRQoL, regardless of age of disease onset.

Tissue-Nonspecific Alkaline Phosphatase—A Gatekeeper of Physiological Conditions in Health and a Modulator of Biological Environments in Disease

“…As explicitly reviewed in a publication by Street and Sowa, TNAP influences the regulation of pain sensation by metabolizing ATP, which exhibits proand adenosine anti-nociceptive effects due to its enzymatic activity as an ectonucleotidase [177]. Going along with this, HPP patients often suffer from chronic pain that is, among others, treated with nonsteroidal anti-inflammatory drugs (NSAIDs) [178], but can only partially be attributed to an increase of inflammatory processes in their body as pain from prevalent (pseudo)fractures is also decreasing the patients' quality of life [179]. According to a study published by Seefried et al , pain is even the most prevalent symptom in the analyzed HPP patient cohort as more than 67% suffer from it [179].…”

“…Additionally, TNAP can degrade ATP in a stepwise manner to adenosine and, therefore, influence the availability of ligands for purinergic receptors, which is leading to effects on pain, sleep, inflammation, and other processes [148,177] (Figure 4C). even the most prevalent symptom in the analyzed HPP patient cohort as more than 67% suffer from it [179]. For further insights into TNAP's involvement in numerous pathways in the nervous system, like the purinergic signaling, which affects the functionality of diverse neuronal processes, we recommend reading the review by Negyessy et al [180].…”

Therapie der Hypophosphatasie

“…Während pathogene Veränderungen auf beiden Allelen im Sinne einer autosomal-rezessiven Erkrankung häufig mit sehr deutlichen Einschränkungen der Enzymaktivität und einer schwerwiegenden, frühzeitig klinisch manifesten Symptomatik einhergehen, sind heterozygote, monoallelische Veränderungen oftmals mit einer subtileren, klinisch weniger auffälligen Manifestation assoziiert [1][2][3][4]. Allerdings sind individuelle Verläufe auch über die Lebenszeit hinweg durchaus variabel und können insofern in beide Richtungen von dieser orientierenden Regel stark abweichen.…”

Multigenerational case examples of hypophosphatasia: Challenges in genetic counseling and disease management

“…Although morbidity and mortality are highest in perinatal and infantile forms, significant disease burden may exist at any age, with symptom overlap across the subtypes and worsening over time [ 14 ]. There are attenuated forms of HPP including benign perinatal HPP (also known as transient prenatal HPP) and odontohypophosphatasia.…”

“…Individuals with AD HPP, previously described as “mild” cases, may manifest symptoms at any point throughout the lifespan that can result in significant disease burden. It has been reported that some adults with a mild clinical presentation (or only biochemical evidence of disease) may appear asymptomatic for many years and subsequently develop fractures later in life, including after exposure to bisphosphonate therapy [ 14 , 20 ], thus representing a continuum of disease severity throughout the lifespan. Continued monitoring of symptom development over time is vital to the growing understanding of the clinical spectrum, and ongoing management of individuals with HPP, including those with a suspected attenuated form.…”