Biochemical, clinical and genetic characteristics in adults with persistent hypophosphatasaemia; Data from an endocrinological outpatient clinic in Denmark

Abstract

Background Hypophosphatasia (HPP) is an inborn disease caused by pathogenic variants in ALPL. Low levels of alkaline phosphatase (ALP) are a biochemical hallmark of the disease. Scarce knowledge about the prevalence of HPP in Scandinavia exists, and the variable clinical presentations make diagnostics challenging. The aim of this study was to investigate the prevalence of ALPL variants as well as the clinical and biochemical features among adults with endocrinological diagnoses and persistent hypophosphatasaemia. Methods A biochemical database containing ALP measurements of 26,121 individuals was reviewed to identify adults above 18 years of age with persistently low levels of ALP beneath range (≤ 35 ± 2.7 U/L). ALPL genetic testing, biochemical evaluations and assessment of clinical features by a systematic questionnaire among included patients, were performed. Results Among 24 participants, thirteen subjects (54.2%) revealed a disease-causing variant in ALPL and reported mild clinical features of HPP, of which musculoskeletal pain was the most frequently reported ( n = 9). The variant c. 571G > A; p.(Glu191Lys) was identified in six subjects, and an unreported missense variant (c.1019A > C; p.(His340Pro)) as well as a deletion of exon 2 were detected by genetic screening. Biochemical analyses showed no significant differences in ALP ( p = 0.059), the bone specific alkaline phosphatase (BALP) ( p = 0.056) and pyridoxal-5′-phosphate (PLP) ( p = 0.085) between patients with an ALPL variant and negative genetic screening. Patients with a variant in ALPL had significantly higher PLP levels than healthy controls ( p = 0.002). We observed normal ALP activity in some patients classified as mild HPP, and slightly increased levels of PLP in two subjects with normal genetic screening and four healthy controls. Among 51 patients with persistent hypophosphatasaemia, fifteen subjects (29.4%) received antiresorptive treatment. Two patients with unrecognized HPP were treated with bisphosphonates and did not show complications due to the treatment. Conclusions Pathogenic variants in ALPL are common among patients with endocrinological diagnoses and low ALP. Regarding diagnostics, genetic testing is necessary to identify mild HPP due to fluctuating biochemical findings. Antiresorptive treatment is a frequent reason for hypophosphatasaemia and effects of these agents in adults with a variant in ALPL and osteoporosis remain unclear and require further studies.

Identifying adult hypophosphatasia in the rheumatology unit

“…Of these, 24 were genetically tested and more than 50% showed a mutation in the ALPL gene and musculoskeletal pain as leading symptom. PLP levels were higher in HPP than non-HPP subjects [ 15 ].…”

“…Established bone turnover markers are not indicative for HPP [ 16 ] and BMD by means of DXA is not necessarily reduced in HPP, as was shown in our population, and supported by other studies [ 35 ]. While not mandatory, genetic testing confirms the diagnosis of HPP because Sanger sequencing and MLPA allow the detection of 95% of all ALPL mutations [ 15 , 36 ].…”

“…In the event of low ALP activity, substrates of ALP, such as pyridoxal 5’-phosphate (PLP) accumulate [ 12 ]. Elevated PLP levels are indicative of HPP and can be used to differentiate from secondary reasons for low ALP levels [ 14 , 15 ]. Therefore concomitant PLP measurement in individuals with low ALP and clinical symptoms of HPP has been recommended [ 13 ].…”

Perspective on Dentoalveolar Manifestations Resulting From PHOSPHO1 Loss-of-Function: A Form of Pseudohypophosphatasia?

“…The nomenclature of pseudo-HPP has sometimes been used to describe apparent cases of HPP wherein clinical presentation overlaps with manifestations of HPP, but where ALP levels are within the normal range (23,24,26,27,(48)(49)(50). Many studies also report cases where clinical signs of HPP are present and ALP is low or normal, and no genetic variant in ALPL can be identified (51)(52)(53)(54)(55). By Sanger sequencing, up to 5% of suspected HPP cases resist the identification of a genetic factor (54)(55)(56)(57).…”

“…Many studies also report cases where clinical signs of HPP are present and ALP is low or normal, and no genetic variant in ALPL can be identified (51)(52)(53)(54)(55). By Sanger sequencing, up to 5% of suspected HPP cases resist the identification of a genetic factor (54)(55)(56)(57). These cases are sometimes attributed to ALPL variants that are difficult to locate by sequencing (e.g., in regulatory regions of the gene).…”