Efficacy of asfotase alfa in a patient with adult-onset hypophosphatasia without obvious bone lesions: a case report with review of literature

Abstract

The use of asfotase alfa, a bone-targeted recombinant alkaline phosphatase (ALP) enzyme, for the treatment of adult-onset hypophosphatasia (HPP) remains controversial, particularly in patients without evident bone abnormalities. We report the case of a 41-year-old woman with a history of Graves’ disease, who presented with progressive joint pain and severe fatigue. Despite the absence of bone lesions, the patient was diagnosed with HPP based on persistently low alkaline phosphatase levels, family history, and a novel heterozygous ALPL variant (p.Ala205Thr). Functional analysis revealed a dominant-negative effect for this variant. Her symptoms significantly interfered with her daily activities owing to uncontrolled pain and loss of motor function and were so exacerbated that high doses of acetaminophen and NSAIDs were ineffective. Treatment with asfotase alfa was initiated based on multidisciplinary team consensus. Within 3 months of treatment initiation, her pain improved significantly, as indicated by reduced scores on the visual analog scale from 6.6 to 0.9, and elimination of the need for analgesics. Additionally, her grip strength increased, and her urinary phosphoethanolamine levels and serum pyridoxal 5'-phosphate/pyridoxal ratio decreased from 90.4 to 57.8 μmol/g·creatinine and from 4.6 to 0.4, respectively. These improvements have been maintained for more than 2 years. This case highlights the potential of asfotase alfa in effectively alleviating symptoms in patients with adult-onset HPP without bone lesions, emphasizing the importance of patient selection and outcome monitoring. We also discuss the key considerations for future treatment, supported by a literature review of asfotase alfa in adult patients with HPP.

Introduction

Hypophosphatemia (HPP) is a rare inherited metabolic bone disorder that manifests as impaired bone calcification. This impairment results from the decreased activity of tissue-nonspecific alkaline phosphatase (TNSALP) caused by loss-of-function variants of the ALPL gene [1]. A notable clinical feature of HPP is the persistent decrease in serum alkaline phosphatase (ALP) activity, which does not increase despite structural changes in the bones, akin to rickets or osteomalacia [2]. The disease is categorized into six clinical forms based on the age of onset and severity: severe perinatal, benign prenatal, infantile, childhood, adult, and odontohypophosphatasia [3, 4]. The prognosis for severe perinatal and infantile forms of HPP is notably poor, and the necessity for ALP enzyme replacement therapy (ERT) in these cases is well established [5, 6]. Conversely, the adult-onset form of HPP typically presents as a milder condition with a better prognosis, leading to an ongoing debate regarding the criteria for ERT. The various symptoms associated with HPP, such as bone fractures, osteomalacia, muscle weakness, myalgia, arthralgia, headache, pseudogout, decreased mobility, impaired physical function, and dental problems [3, 4, 7-9], significantly reduce the physical quality of life (QoL) of affected individuals [10]. Therefore, a reduction in these symptoms with pharmacotherapy could contribute to a significant improvement in the patients’ QoL.

In terms of prevalence, the frequency of severe HPP is thought to be extremely low; however, the frequency of mild forms, such as adult-onset HPP, has been reported to be approximately 1 in 1,692 in Europe [11]. According to a survey-based study, the prevalence of ALPL c.1559delT, the most common variant in Japanese patients, is estimated to be one in 480 carriers, suggesting that there are approximately 20,000 cases in Japan [12]. However, the prevalence of adult-onset HPP is unknown in Japan. This indicates that the prevalence of HPP, especially the adult-onset form, may have been underestimated.

As a treatment for HPP, asfotase alfa, a human recombinant TNSALP ERT, was approved for use by the U.S. Food and Drug Administration and the Ministry of Health, Labour and Welfare (MHLW) in Japan in 2015 [13]. According to the The Japanese Society for Pediatric Endocrinology practice guidelines for HPP, ERT can improve symptoms and may be indicated for disease types with a relatively favorable prognosis, including the adult-onset type, if motor function and QoL are impaired due to bone symptoms and muscle weakness [14]. The treatment of adult-onset HPP using asfotase alfa is restricted in most countries. Therefore, reports of its efficacy in adult-onset HPP are limited. To date, most studies have focused on the effects of these compounds on bone lesions. Moreover, data on the optimal dosage, its adjustment, maintenance dose, and the possibility of treatment withdrawal are scarce.

To the best of our knowledge, this is the first report to provide a detailed account of asfotase alfa dosage, pain improvement, and quality of life enhancement in a patient with adult-onset HPP without obvious bone lesions. In addition, we conducted a functional analysis of the novel p.Ala205Thr variant, demonstrating its dominant-negative effect on ALP activity and further supporting its pathogenicity. We also provide a literature review of adult-onset HPP in patients treated with asfotase alfa.

Case Presentation

A 41-year-old woman with Graves’ disease who was receiving endocrinology care visited an orthopedic clinic with generalized pain and bone creaking. She reported that the pain was so severe that it interfered with her ability to work. No fractures were found, and the patient was referred to a rheumatologist for a thorough examination; however, no obvious abnormalities were noted. At the endocrine clinic, she complained of generalized bone pain and myalgia; increased pain in her ankles, knees, and hip joints when standing; increased pain in her wrists, elbows, and other joints with weight bearing; and generalized fatigue. No swelling or burning sensation was observed in these joints. Radiography of the wrist, elbow, hip, and knee joints revealed no fractures, bone deformities, or heterotopic calcifications. Dual-energy x-ray absorptiometry revealed bone mineral density (BMD) values of 1.075 g/cm² at the lumbar spine (L2–L4) with a Z-score of 0.6 and 0.659 g/cm² at the left femoral neck with a Z-score of –0.4, indicating no significant decrease in BMD. She had no history or evidence of dental abnormalities. Her height was 165.5 cm, and her weight was 55.8 kg. Laboratory tests related to bone metabolism showed that serum levels of corrected calcium (9.3 mg/dL), phosphate (3.8 mg/dL), and intact parathyroid hormone (19.3 ng/mL) were within the normal range, but serum ALP activity (105 IU/L; reference range: 109–321 IU/L), measured using the Japan Society of Clinical Chemistry method, was slightly below the lower normal limit, suggesting the possibility of HPP. Based on her serum 25(OH) vitamin D levels (19.3 ng/mL), she was diagnosed with vitamin D deficiency. Her urine phosphoethanolamine (PEA) levels, measured using high-performance liquid chromatography with ninhydrin reagent (conducted by BML General Laboratory, Saitama, Japan), were 90.4 μmol/g creatinine (reference range: 7–70 μmol/g creatinine), which warranted further investigation for HPP. Notably, the patient’s serum ALP activity, which was retrospectively evaluated, remained low even during the active phase of Graves’ disease, supporting the possibility of HPP. However, the patient had no obvious bone lesions or fractures, as assessed using bone scintigraphy, and ectopic calcification was screened using computed tomography. Genetic analysis of the patient’s blood revealed a novel ALPL c.613G>A (p.Ala205Thr) heterozygous variant (performed by direct sequencing using the Sanger method; commissioned to the Clinical Laboratory Division, Shimane University Hospital, Shimane, Japan). Alanine-205 is an amino acid that is conserved across species (Fig. 1a). The p.Ala205Thr variant was predicted to be pathogenic based on a PolyPhen2 score of 1.000 and the ClinVar classification. Structural and functional analyses demonstrated that the p.Ala205Thr variant significantly impaired the ALP enzymatic activity, confirming its pathogenicity.

Fig. 1  A novel ALPL gene variant identified in this case

(a) Alanine-205 is an amino acid that is conserved across species. (b) Structural analysis of TNSALP. (Top) The overall structure of wild-type TNSALP is presented as a homodimer, with one monomer in pink and the other in gray. Ala205 is highlighted in red. (Bottom) A zoomed-in view of the catalytic core showing the superimposed structures of wild-type (pink) and mutant (green) TNSALP. The Ala205 residue in the wild-type structure is red, while the Thr205 residue in the mutant is green. The predicted hydrogen bond between Thr205 and Asn170 is indicated by a yellow dashed line. (c) Reduced enzymatic activity and a dominant negative effect of the p.Ala205Thr variant of TNSALP. The indicated amounts of expression plasmids for GFP-tagged wild-type and p.Ala205Thr variant TNSALP (pcDNA-GFP-ALP[WT] and pcDNA-GFP-ALP[p.Ala205Thr], respectively) or VDR-GFP as a mock vector were introduced into COS7 cells plated in 6-well culture plates. Three days later, cell lysates were harvested to determine the enzymatic activity of TNSALP using p-nitrophenylphosphate as the substrate. The corrected activity in each sample was calculated by subtracting the activity of the cells transfected with 1.0 mg/well of the mock vector alone, which was considered the endogenous TNSALP activity. It was normalized based on the signal intensity in western blotting using lysates and anti-GFP antibody aliquots. The corrected activity in cells transfected with pcDNA-GFP-ALP[WT] alone was designated as 100%. The bottom panel shows a representative western blotting image. Data are shown as the mean ± S.D. (N = 3). *, p < 0.05 and **, p < 0.01 by a one-way ANOVA with the Tukey-Kramer method for post hoc tests.

Her mother had a low serum ALP activity of 22 IU/L (measured using the International Federation of Clinical Chemistry and Laboratory Medicine method; reference range: 38–113) and a history of multiple fractures, including a spontaneous pelvic fracture and ossification of the posterior longitudinal ligament. Her sister also exhibited low serum ALP activity, but no symptoms, including fractures. These findings, along with the genetic abnormalities, led to the diagnosis of HPP.

Our patient had no apparent bone lesions, but had poor QoL due to progressive symptoms that became severe and limited her daily activities, even with the use of acetaminophen 2,400 mg/day and naproxen 300 mg/day. Therefore, after a multidisciplinary team meeting, treatment with asfotase alfa was initiated at a dose of 1.6 mg/kg three times weekly. Lip edema and injection site reactions were observed immediately after administration, which persisted despite the use of antihistamines. Therefore, 2 weeks after initiation, the dose was reduced to 0.5 mg/kg and the frequency was increased to six times weekly, resulting in resolution of the side effects. After 2 weeks, the dose was increased to 0.7 mg/kg six times weekly. Her pain gradually improved, and the dose of pain medication was reduced. Six months after the initiation of asfotase alfa treatment, her pain almost disappeared, she no longer needed analgesics, and she was able to return to work. Although we attempted to reduce the dosage of asfotase alfa to 0.7 mg/kg four times weekly, it was increased back to 0.7 mg/kg six times weekly owing to intensified pain.

The patient’s motor function was continuously monitored in collaboration with the Department of Rehabilitation and the effects of asfotase alfa were assessed. For more than 2 years after treatment initiation, the patient maintained good control and was able to reduce the drug dose to 2.6 mg/kg/week (Fig. 2). Moreover, pain evaluated using a visual analog scale (VAS), numeric rating scale (NRS), and face rating scale (FRS) all showed significant improvement at 6 months after the initiation of treatment with asfotase alfa (VAS, from 6.6 to 1.1; NRS, from 7 to 1; and FRS, from 3 to 1). Additionally, motor function evaluation showed improvements in all tests. The 6-minute walk distance increased from 479 to 540 m, timed up and go test decreased from 7.62 to 5.70 seconds, and grip strength increased from 25 to 27 kg (right) and 20 to 24 kg (left). The QoL score evaluated by SF-36 [15-17], a widely used general health-related QoL questionnaire, also showed improvement, particularly in the physical QoL, with the Physical Component Summary score increasing from 9.3 to 31.0, Role Physical score increasing from 15.8 to 42.4, and Vitality score increasing from 27.4 to 49.8 (Table 1). Moreover, the percentage of vital capacity in the respiratory function tests improved from 87.5% to 89.9% 136 weeks after treatment. Both the serum pyridoxal 5'-phosphate (PLP) level and serum PLP-to-pyridoxal (PL) ratio decreased from 35.7 to 4.9 nmol/L (reference range: 20.5–151 nmol/L) and from 4.6 to 0.4 (reference range: 1.0–4.2), respectively, over 60 weeks of treatment. Levels were measured as described by Akiyama et al. [18].

Fig. 2  Clinical course after initiation and dose adjustment of asfotase alfa

Three months after treatment initiation, the patient stopped using analgesics, and 6 months later, each pain scale had significantly improved. The dose of asfotase alfa was adjusted according to the severity of pain, and at 2 years, treatment was continued with asfotase alfa 0.7 mg/kg, 6 times a week, by subcutaneous injection. VAS, visual analog scale; NRS, numerical rating scale; FRS, face rating scale; M, month.

Table 1 Trends in quality of life after treatment initiation

	0M	1M	3M	12M	24M
PF	14.5	18.1	10.9	39.8	18.1
RF	15.8	32.5	25.8	42.4	35.8
BP	31.4	35.8	35.4	44.7	41.2
GH	35.1	35.1	38.9	44.2	49.5
VT	27.4	37.0	40.2	49.8	49.8
SF	44.1	44.1	44.1	57.0	44.1
RE	47.7	39.4	47.7	56.1	35.3
MH	51.8	57.2	57.2	59.9	49.1
PCS	9.3	15.7	9.1	31.0	25.9
MCS	49.0	52.6	57.3	55.3	60.4
RCS	50.0	49.5	50.9	60.0	38.6

Health-related quality of life changes assessed with SF-36. Eight subscales and three summary scores are shown, converted to a score of 0–100, with higher scores indicating better quality of life.

PF, Physical functioning; RF, Role physical; BP, Bodily pain; GH, General health; VT, Vitality; SF, Social functioning; RE, Role emotional; MH, Mental health; PCS, Physical component summary; MCS, Mental component summary; RCS, Role/Social component summary.

Structural and Functional Analysis

Structural and functional analyses were performed to evaluate the pathogenicity of this novel p.Ala205Thr variant.

Methods

i. Structural Analysis of Wild-Type and Mutant Forms of TNSALP

The wild-type structure of TNSALP was modeled based on the crystal structure available in the Protein Data Bank (PDB ID: 7YIV). The predicted full-length structure of the mutant (p.Ala205Thr) was generated using the ColabFold platform [19]. The predicted mutant structure was superimposed on the wild-type crystal structure for direct comparison. Structural superimposition, binding detection, and figure preparation were performed using the PyMOL software (Schrödinger LLC, New York, NY, USA).

ii. Functional Analysis of the p.Ala205Thr variant of TNSALP

The expression plasmid for green fluorescent protein (GFP)-tagged TNSALP (pcDNA-GFP-ALP) was constructed as previously described [20]. Site-directed mutagenesis was performed using the QuikChange Lightning Site-Directed Mutagenesis Kit (Agilent Technologies, Palo Alto, CA, USA). The plasmids for wild-type (WT) and variant (p.Ala205Thr) TNSALP were introduced into COS7 cells using FuGENE HD Reagent (Roche Diagnostics, Indianapolis, IN, USA). An expression plasmid encoding GFP-tagged vitamin D receptor (pSG5-VDR-GFP) was used as a mock plasmid. To assess dominant-negative effects, cells were co-transfected with varying ratios of wild-type and p.Ala205Thr variant plasmids (1:1). Three days later, the cell lysates were harvested in 10 mM Tris-HCl buffer (pH 7.4) containing 0.05% Triton X-100. TNSALP activity in the cell lysates was determined using p-nitrophenylphosphate (Sigma-Aldrich, St. Louis, MO, USA) as the substrate. Aliquots of the lysates were subjected to western blotting with an anti-GFP rabbit polyclonal antibody (Proteintech, Rosemont, IL, USA), and densitometry was performed using ImageJ software. The corrected TNSALP activity in each sample was calculated by subtracting the activity in the cells transfected with the mock plasmid from the endogenous activity of COS7 cells and normalizing based on the signal intensity in western blotting.

Results

i. Structural Analysis

TNSALP primarily forms homodimers or can further assemble into multimeric structures, enhancing its stability in extracellular environments [21, 22]. Ser110 plays a central role in phosphatase activity, and the two zinc ions and one magnesium ion within the catalytic core are essential for enzymatic function. Based on the overall structure of wild-type TNSALP, Ala205 is located within the catalytic core and positioned near Ser110 and metal ions (Fig. 1b).

The full-length structure of the p.Ala205Thr mutant was predicted using the AlphaFold2-based ColabFold platform and was superimposed onto the crystal structure of wild-type TNSALP (PDB:7YIV). Very few differences in the overall tertiary structures were observed between the wild-type and mutant forms (Fig. 1b). However, Thr205 in the mutant form was predicted to form a hydrogen bond with Asn170 at a distance of 2.9 Å, a bond that was not observed with Ala205 in the wild-type (Fig. 1b).

The p.Asn170Asp mutation is pathogenic, causing a severe phenotype [23], and affecting TNSALP protein stability and intracellular localization [24]. Based on these findings, we hypothesized that Thr205 interacts with the side chain of Asn170, inducing local structural changes around the catalytic core or altering the chemical properties of Asn170. These changes could reduce the enzymatic activity through a mechanism similar to the Asn170Asp mutation.

ii. Functional Analysis

The p.Ala205Thr variant exhibited significantly reduced enzymatic activity compared to the wild-type protein (p < 0.01). When cells were co-transfected with wild-type and p.Ala205Thr variant plasmids at varying ratios, enzymatic activity was further reduced compared to cells transfected with the wild-type plasmid alone. These findings indicated that the p.Ala205Thr variant exerted a dominant-negative effect on the enzymatic activity of TNSALP (Fig. 1c).

Review of Literature

We extensively searched PubMed using the terms “adult” and “hypophosphatasia” and “asfotase alfa” on July 9, 2024. Our search yielded 56 articles. After excluding articles that did not report treatment with asfotase alfa for adult-onset HPP, nine relevant articles remained. Detailed clinical descriptions were available for eight cases, and specific dosages of asfotase alfa were reported in five cases [3, 6, 25-27].

We summarized the clinical characteristics and dosages of asfotase alfa in patients with adult-onset HPP, including our case (Table 2). Of the eight reports with detailed clinical descriptions, seven involved pain [3, 6, 25, 27-29], five involved atypical fractures [3, 6, 25, 26, 28], and one reported refractory ectopic calcification [27]. In patients with fractures, asfotase alfa was administered at a dose of 3.0 to 6.0 mg/kg/week. The patient with ectopic calcification received half of this dose (1.5 mg/kg/week). Details of asfotase alfa treatment in patients without fractures or ectopic calcifications have not been reported [28, 29].

Table 2 Summary of cases reported in literature on adult-onset hypophosphatasia treated with asphotase alfa

First author (year)	Age (years)	Sex	bone fracture	muscle weakness and pain	fatigue	chondrocalcinosis	dental abnormalities	asfotase alfa dose
The present case	41	Female	–	+	+	–	–	0.7 mg/kg, 6 times/wk
Magdaleno AL et al. (2019)	52	Female	+	+	–	–	+	1.0 mg/kg, 3 times/wk
Hidaka N et al. (2023)	64	Female	+	+	+	–	+	1.7 mg/kg, 3 times/wk
Fanous N et al. (2020)	49	Female	+	–	+	–	–	1.0 mg/kg, 6 times/wk
Koga M et al. (2022)	64	Female	–	+	–	+	–	0.47 mg/kg, 3 times/wk
Kitaoka T et al. (2017)	34	Male	+	+	–	–	–	1.17 mg/kg, 3 times/wk
Klidaras P et al. (2018)	61	Male	+	+	–	–	+	No data on dosage
Alsarraf F et al. (2024)	48	Male	–	+	+	–	–	No data on dosage
Alsarraf F et al. (2024)	68	Male	–	+	+	–	+	No data on dosage*
Kishnani PS et al. (2019)	This report on the effects of asfotase alfa in adult and adolescent HPP patients includes one adult-onset HPP, but lacks detailed information on individual cases.
Kishnani PS et al. (2024)	This report on a registry of adult HPP treated with asfotase alfa notes that 17 out of 190 subjects had adult-onset HPP, but lacks details on individual cases.

* Ten days after starting treatment with asfotase alfa, the patient discontinued the therapy due to the development of the following symptoms: shortness of breath, irritability, nausea, generalized body pain, dryness and itchiness of the eyes, numbness in the left leg and ankle, and sharp back pain.

Discussion

We report a case demonstrating the remarkable efficacy of asfotase alfa for adult-onset HPP, even with no apparent bone lesions, but with severe pain and muscle weakness that impaired the patient’s QoL. Multifaceted evaluation by a multidisciplinary team is necessary to clarify the effects of ERT, particularly in cases with limited objective findings. Severe HPP is recessively inherited mainly because of homozygosity or compound heterozygosity of severe variants. However, moderate HPP may be inherited dominantly or recessively [1]. The dominant inheritance is thought to be due to the dominant-negative effects of missense variants derived from the functional homodimeric structure of TNSALP [30].

Mild adult-onset HPP is mainly caused by the dominant-negative effects of missense variants and is thought to be caused by a haploinsufficiency mechanism characterized by nonspecific signs [31]. In the present case, a novel ALPL heterozygous variant was detected in a patient with an obvious family history and progressively severe symptoms, which were alleviated by ERT, suggesting that the variant may have a dominant-negative effect. According to a survey of 125 adult patients with HPP, pain was reported in 95% of cases, pain was severe enough to limit activity in 76%, and bone pain was severe enough to require medication in 69% [10]. In addition, 60% of the patients required assistive devices for mobility and developed muscle disorders and joint symptoms related to mobility [10]. As many patients with adult-onset HPP present with generalized bone and muscle pain, limited activity, and require high doses of analgesics, this case report, in which treatment successfully improved QoL, provides an important message.

Although the exact indications for adult-onset HPP are still debated, Shapiro et al. proposed treatments for adult patients with HPP presenting with symptoms of persistent pain, chondrocalcinosis, atypical fractures, delayed fracture healing, repeated orthopedic surgeries, functional impairment, low BMD, and/or nephrocalcinosis due to HPP [32]. In the present case, the patient had persistent and worsening pain that affected her daily life, including work restrictions, and was, therefore, judged amenable to treatment.

A multicenter, randomized, open-label study of asfotase alfa in adults and adolescents with HPP revealed that ERT improved gait ability, gross motor function, muscle strength, and functional disability by decreasing PLP levels [33]. However, it is noteworthy that all participants had either pediatric- or infant-onset HPP, except for one with adult-onset HPP, and 95% of them had bone fractures.

Asfotase alfa is effective in alleviating pain and may lead to significant improvements in life, even in adult-onset HPP without bone lesions. However, data on the optimal dosage, dose adjustment, treatment duration, and possible dosing cycles for treating adult-onset HPP with asfotase alfa are lacking. Therefore, further studies and data accumulation are required. According to the literature review of asfotase alfa treatment for adult-onset HPP, including our present case, the initiating dose ranged from 3.0 to 6.0 mg/kg/week, which is not significantly different from that of pediatric- or infant-onset HPP. In our case, we could not reduce the dosage or use of enzyme therapy to >24 months to maintain good long-term outcomes. In a report of six adult patients with HPP who were treated with asfotase alfa for 5 years and then withdrawn, the patients experienced worsening of clinical symptoms after withdrawal of ERT, which improved after the resumption of therapy [34]. However, further investigations are required.

In HPP, the loss of TNSALP activity results in the accumulation of its substrates, PEA, inorganic pyrophosphate, and PLP, as they are not degraded. Their accumulation causes systemic disorders such as nervous system disorders, impaired bone calcification and formation, and respiratory failure. Urinary PEA has been reported to be a useful specific biomarker for adult HPP, not only as a promising diagnostic marker, but also as a potentially useful monitoring marker during ERT [35]. PLP levels have been reported to correlate with the occurrence of fractures and number of symptoms, and PLP is a marker of disease severity in adults with HPP [8]. More recently, the serum PLP-to-PL ratio, when measured simultaneously with PL, a product of the enzymatic reaction of ALP with PLP as a substrate, was found to be a better indicator of the effect of ERT on HPP than serum PLP and urine PEA levels, with a PLP-to-PL ratio <4.0 considered a good indicator of HPP improvement and patient compliance with ERT [18]. In the present case, the urinary PEA level and serum PLP-to-PL ratio were high before treatment and decreased significantly after initiation of asfotase alfa.

Evaluation of treatment in mild HPP cases, which lack objective signs such as fractures or ectopic calcification, requires a comprehensive and multidimensional assessment, including pain scales, analgesic use, QoL scores, motor and respiratory functions, biomarkers such as urinary PEA and serum PLP levels, and the serum PLP-to-PL ratio. Using this method, we quantitatively assessed the therapeutic effects of asfotase alfa. Therefore, we propose that similar monitoring is essential to accurately determine the efficacy of asfotase alfa treatment in adult-onset HPP without bone lesions.

HPP may be latent in patients with unexplained fatigue, pain, or fragility fractures. Therefore, it should be considered in patients with suspected osteomalacia and low ALP levels. Even in adult-onset HPP without bone lesions, treatment with asfotase alfa may be a useful therapy to improve pain and QoL.

In conclusion, we presented a case of adult-onset HPP with a novel ALPL heterozygous variant without apparent bone lesions that was successfully treated with asfotase alfa. For monitoring, urinary PEA, serum PLP, and serum PLP-to-PL ratio were used, in addition to the pain scales and QoL scores evaluated by a multidisciplinary team (Graphical Abstract). Although further case accumulation is needed, establishing a multidisciplinary team is particularly important for assessing cases with few objective findings.

Graphical Abstract

Acknowledgment

We acknowledge Editage (www.editage.jp) for the English language editing. No external funding was received for the study.

Author Contributions

S.N. and H.F. managed the patient during hospitalization and outpatient follow-up, contributed to treatment decisions, and prepared the manuscript. M.Y. and Y.I. were involved in patient care during hospitalization and contributed to treatment planning. T.N. evaluated bone health and provided clinical insights as an orthopedic specialist. T.A. assessed the biochemical markers and contributed to patient evaluation. R.H. and Y.S. evaluated motor function as rehabilitation specialists. K.S. performed the structural analysis and prepared related sections and figures. K.T. and T.M. conducted the functional analyses, and T.M. drafted the related sections and figures. W. O. supervised the study and provided critical insights.

This version has been adjusted according to the journal’s specific requirements or preferences. It is more succinct but ensures that all authors’ contributions are recognized.

Disclosure

The authors declare no conflicts of interest in relation to this study. Toshimi Michigami and Hidenori Fukuoka are members of Endocrine Journal’s Editorial Board.

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