Identifying hpp

tracking down
hypophosphatasia

11A0763

11A0763

Identify hypophosphatasia with 2 or more low alkaline phosphatase tests in the presence of clinical signs and symptoms1*

If your patient has confirmed persistently low alkaline phosphatase in the presence of other comorbidities (eg, osteoporosis, osteomalacia, nutritional rickets), they could have hypophosphatasia. Persistently low alkaline phosphatase,† the key marker for a hypophosphatasia diagnosis, can be found in a routine blood test.1-8

  • *ALP ranges must be age- and sex-adjusted. Patient should be evaluated for other symptoms of HPP and differential diagnoses should be ruled out.1,5-9
  • † Persistently low alkaline phosphatase can be defined as having 2 exams below normal value at intervals of more than 30 days.
Look back at what constitutes low alkaline phosphatase activity
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When persistently low levels of alkaline phosphatase intersect with a range of unexplained symptoms in other metabolic disorders, look for hypophosphatasia in new and existing patients6,8,9*


*Persistently low values may be defined as at least 2 values below normal at intervals of more than 30 days.6,8,9

Any clinical sign/symptom PLUS persistently low alkaline phosphatase* is sufficient for a hypophosphatasia diagnosis1,5,7,11†


*Persistently low values may be defined as at least 2 values below normal in intervals of more than 30 days.9

†Other causes of low alkaline phosphatase should be ruled out.1 Not all signs and symptoms need to be present for a hypophosphatasia diagnosis.5

what you may not know
about substrate testing

If a patient presents with low alkaline phosphatase and signs/symptoms of hypophosphatasia, a diagnosis can be confirmed with substrate testing. However, it’s important to be aware of the limitations that come with these tests. Elevated PLP and/or PEA can support a diagnosis of hypophosphatasia, but these tests are subject to certain limitations6,10:

Substrate Test and Limitations

PEA8-10,12,13

LIMITATIONS:
  • May be normal in some patients with hypophosphatasia
  • Can be collected via spot urine test or 24-hour urine collection test, which can result in unreliable results due to:
    • Incomplete collection (omission of one or more samples in 24 hours)
    • Incorrect collection time
    • Incomplete emptying of bladder
    • Poor storage of sample
    • Inclusion of first 2 morning samples

PLP (vitamin B6)6,11,14

LIMITATIONS:
  • May be elevated in individuals taking supplements containing B6
  • May appear normal or low in patients with hypophosphatasia. This does not invalidate the hypophosphatasia diagnosis.
  • PLP is light-sensitive and must be protected from light; will need to be collected with amber-colored tube
  • PLP decreases in samples stored at room temperature due to dephosphorylation to PL
  • PLP is bound to albumin; it can be affected by nutrition, smoking, inflammation, and drugs
  • PLP must be taken in fasting state as it may decrease after high-carbohydrate intake

PPi8

LIMITATIONS:
  • These tests are done in research settings only and are not commercially available

PEA=phosphoethanolamine; PLP=pyridoxal 5’-phosphate, the active form of vitamin B6; PPi=inorganic pyrophosphate.

what you may not know
about substrate testing

If a patient presents with low alkaline phosphatase and signs/symptoms of hypophosphatasia, a diagnosis can be confirmed with substrate testing. However, it’s important to be aware of the limitations that come with these tests. Elevated PLP and/or PEA can support a diagnosis of hypophosphatasia, but these tests are subject to certain limitations6,10:

Substrate Test Limitations

PEA8,10,12,13

  • May be normal in some patients with hypophosphatasia
  • Can be collected via spot urine test or 24-hour urine collection test, which can result in unreliable results due to:
    • Incomplete collection (omission of one or more samples in 24 hours)
    • Incorrect collection time
    • Incomplete emptying of bladder
    • Poor storage of sample
    • Inclusion of first 2 morning samples

PLP (vitamin B6)6,11,14

  • May be elevated in individuals taking supplements containing B6
  • May appear normal or low in patients with hypophosphatasia. This does not invalidate the hypophosphatasia diagnosis.
  • PLP is light-sensitive and must be protected from light; will need to be collected with amber-colored tube
  • PLP decreases in samples stored at room temperature due to dephosphorylation to PL
  • PLP is bound to albumin; it can be affected by nutrition, smoking, inflammation, and drugs
  • PLP must be taken in fasting state as it may decrease after high-carbohydrate intake

PPi8

  • These tests are done in research settings only and are not commercially available

PEA=phosphoethanolamine; PLP=pyridoxal 5’-phosphate,
the active form of vitamin B6; PPi=inorganic pyrophosphate.

Elevated PLP and/or PEA can support a diagnosis of hypophosphatasia. These tests are subject to certain limitations5,6:

  • restrictive costs/ affordability8,10,12,13,15
  • diagnostic services only available at certain laboratories8,10,12,13,15
  • results may be unreliable if sample collection is done incorrectly8,10,12,13,15

The role of genetic testing

Genetic testing rules in hypophosphatasia; it does not rule it out16,17

Insurance requirements and/or coverage for genetic testing vary by state and insurance provider. Verify with the patient's insurer to understand which type of services will be covered.

While genetic testing for hypophosphatasia can be a useful tool, it remains an evolving science with certain limitations and challenges.

400+

Since its initial discovery in 1988, the number of ALPL gene mutations have increased with over 400 identified; new discoveries are ongoing10,18-22

Family members with hypophosphatasia who have identical genotypes may express varying phenotypes due to factors beyond the ALPL gene mutation (eg, number of mutant enzyme synthesized, alkaline phosphatase enzymatic activity).24-26

Additional limitations16,22,23

  • restrictive costs/affordability
  • diagnostic services only available at certain laboratories
  • not all ALPL variants necessarily lead to the manifestation of hypophosphatasia or establish hypophosphatasia
  • diagnostic sensitivity of genetic tests that detect ALPL can vary by laboratory
  • ALPL sequencing is predicted to detect pathogenic variants of ~95% of severe perinatal and infantile hypophosphatasia cases; in milder forms, the detection rate is difficult to estimate
  • the milder the disease, the higher the likelihood that only one ALPL pathogenic variant is detected

If your patient has a variant of uncertain significance (VUS)

If the classification of the variant is VUS, it means that at the time of interpretation, there was insufficient evidence to determine if the variant was related to disease or not.27

“According to the ACMG* guidelines, a VUS should not be used in clinical decision-making. If a patient is identified to have a VUS, all clinical decisions should be based on personal and family history and not on the presence of the VUS.”28

-Jennifer Schleit, PhD, Senior Geneticist

*ACMG, American College of Medical Genetics and Genomics.

A VUS may be related to hypophosphatasia and does not rule out the diagnosis.29

calling for backup

Uncovering hypophosphatasia unlocks a world of answers for your patients and validates their long journey of perplexing symptoms. Once you’ve diagnosed hypophosphatasia, consider assembling a team of professionals similar to the example below to develop a comprehensive care plan for your patients.

Assemble a multidisciplinary disease management team to provide comprehensive care to your patients with hypophosphatasia.8,30

Don’t let hypophosphatasia GO UNDETECTED
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References: 1. Bishop N, Munns CF, Ozono K. Transformative therapy in hypophosphatasia. Arch Dis Child. 2016;101(6):514-515. 2. Desborough R, Nicklin P, Gossiel F, et al. Clinical and biochemical characteristics of adults with hypophosphatasia attending a metabolic bone clinic. Bone. 2021;144:115795. 3. Bloch-Zupan A. Hypophosphatasia: diagnosis and clinical signs - a dental surgeon perspective. Int J Paediatr Dent. 2016;26(6):426-438. 4. Shapiro JR, Lewiecki EM. Hypophosphatasia in adults: clinical assessment and treatment considerations. J Bone Miner Res. 2017;32(10):1977-1980. 5. Rockman-Greenberg C. Hypophosphatasia. Pediatr Endocrinol Rev. 2013;10(suppl 2):380-388. 6. McKiernan FE, Berg RL, Fuehrer J. Clinical and radiographic findings in adults with persistent hypophosphatasemia. J Bone Miner Res. 2014;29(7):1651-1660. 7. Whyte MP. Hypophosphatasia: nature's window on alkaline phosphatase function in humans. In: Bilezikian JP, Raisz LG, Martin TJ, eds. Principles of Bone Biology. 3rd ed. Academic Press; 2008:1573-1598. 8. Bianchi ML, Bishop NJ, Guañabens N, et al; Rare Bone Disease Action Group of the European Calcified Tissue Society. Hypophosphatasia in adolescents and adults: overview of diagnosis and treatment. Osteoporos Int. 2020;31(8):1445-1460. 9. Vieira LHR, Peixoto KC, Flósi CL, Fleiuss de Farias ML, Madeira M. Active search of adult patients with persistently low serum alkaline phosphatase levels for diagnosis of hypophosphatasia. Arch Endocrinol Metab. 2021;65(3):289-294. 10. NORD. Hypophosphatasia. Accessed March 30, 2023. https://rarediseases.org/rare-diseases/hypophosphatasia/ 11. Mornet E, Nunes ME. Hypophosphatasia. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews®. University of Washington; 2007. Accessed March 30, 2023. https://www.ncbi.nlm.nih.gov/books/NBK1150/ 12. Mornet E. Molecular genetics of hypophosphatasia and phenotype-genotype correlations. Subcell Biochem. 2015;76:25-43. 13. Kamińska J, Dymicka-Piekarska V, Tomaszewska J, Matowicka-Karna J, Koper-Lenkiewicz OM. Diagnostic utility of protein in creatinine ratio (P/C ratio) in spot urine sample within routine clinical practice. Crit Rev Clin Lab Sci. 2020;57(5):345-364. 14. Shajani-Yi Z, Ayala-Lopez N, Black M, Dahir KM. Urine phosphoethanolamine is a specific biomarker for hypophosphatasia in adults. Bone. 2022;163:116504. 15. Phillips KA, Deverka PA, Hooker GW, Douglas MP. Genetic test availability and spending: where are we now? Where are we going? Health Aff (Millwood). 2018;37(5):710-716. 16. Mornet E. Hypophosphatasia. Metabolism. 2018;82:142–155. 17. Khan AA, Josse R, Kannu P, et al. Hypophosphatasia: Canadian update on diagnosis and management. Osteoporos Int. 2019;30(9):1713-1722. 18. NIH MedlinePlus. ALPL gene. National Library of Medicine. 2018. Accessed March 30, 2023. https://medlineplus.gov/genetics/gene/alpl/ 19. Horton RH, Lucassen AM. Recent developments in genetic/genomic medicine. Clin Sci (Lond). 2019;133(5):697-708. 20. Weiss MJ, Cole DE, Ray K, et al. A missense mutation in the human liver/bone/kidney alkaline phosphatase gene causing a lethal form of hypophosphatasia. Proc Natl Acad Sci. 1988;85:7666-7669. 21. The ALPL Gene Variant Database. JKU Faculty of Medicine. Accessed March 30, 2023. https://alplmutationdatabase.jku.at/ 22. Jandl NM, Schmidt T, Rolvien T, et al. Genotype-phenotype associations in 72 adults with suspected ALPL-associated hypophosphatasia. Calc Tissue Int. 2021;108(3):288-301. 23. Nunes ME. Hypophosphatasia. GeneReviews®. 2007;1993–2002. 24. Whyte MP, Leung E, Wilcox WR, et al. Natural history of perinatal and infantile hypophosphatasia: a retrospective study. J Pediatr. 2019;209:116-124.e4. 25. Zurutuza L, Muller F, Gibrat JF, et al. Correlations of genotype and phenotype in hypophosphatasia. Hum Mol Genet. 1999;8(6):1039-1046. 26. Hofmann C, Girschick HJ, Mentrup B, et al. Clinical aspects of hypophosphatasia: an update. Clin Rev Bone Miner Metab. 2013;11:60-70. 27. Sanabria-de la Torre R, Martínez-Heredia L, González-Salvatierra S, et al. Characterization of genetic variants of uncertain significance for the ALPL gene in patients with adult hypophosphatasia. Front Endocrinol (Lausanne). 2022;13:863940. 28. Blueprint Genetics. VUS—the most maligned result in genetic testing. 2019. Accessed March 30, 2023. https://blueprintgenetics.com/resources/vus-the-most-maligned-result-in-genetic-testing/ 29. Beck NM, Sagaser KG, Lawson CS, et al. Not just a carrier: clinical presentation and management of patients with heterozygous disease-causing alkaline phosphatase (ALPL) variants identified through expanded carrier screening. Mol Genet Genomic Med. 2023;11(1):e2056. 30. Kishnani PS, Rockman-Greenberg C, Rauch F, et al. Five-year efficacy and safety of asfotase alfa therapy for adults and adolescents with hypophosphatasia. Bone. 2019;121:149-162.