Hypophosphatasia is caused by reduced activity of the alkaline phosphatase (ALP) enzyme. The low ALP activity and accumulation of ALP substrates can lead to serious systemic complications. The progressive and systemic consequences of the disease are caused by altered bone metabolism, which often affects the skeleton and/or teeth. Symptoms may also be neurological, respiratory, muscle-related, rheumatological and/or kidney-related. Various tests can be conducted to assess the functional capacity of patients and how the disease changes over time.

Tests for assessing disease development and the patient's condition

Six-Minute Walk Test
This is a functional walk test which measures how far a patient can walk in six minutes. The test is used to assess and evaluate functional status. The result is presented as a percentage of the expected distance for a six-minute walk, based on age and gender-matched healthy individuals.
Patient Patient Patient


BOT-2 (Bruininks-Oseretsky Test of Motor Proficiency, 2nd edition)
BOT-2 is a standardised test of motor proficiency, which measures fine and gross motor skills in individuals aged 4 to 21.

BOT-2 comprises 4 parts:
  1. Fine motor response
  2. Arm and hand co-ordination
  3. Body co-ordination
  4. Strength and dexterity
In clinical trials of hypophosphatasia, the focus is on strength and dexterity.
Patient Patient


PDMS-2 (Peabody Development Motor Scales, 2nd edition)
PDMS-2 is a normed, standardised instrument that assesses fine and gross motor skills of children. The scale is designed for younger children – from birth up to age 5 – with suspected motor retardation.

PDMS-2 comprises 6 subtests:
  1. Reflexes (measures the child’s ability to automatically react to events in his/her environment)
  2. Stationary (measures the child’s ability to sustain control of his/her body and stay in balance
  3. Locomotion (measures the child’s ability to move from one place to another)
  4. Object Manipulation (measures a child’s ability to handle balls, e.g. catching, throwing and kicking)
  5. Grasping (measures the child’s ability to use his/her hands)
  6. Visual Motor Integration (measures the child’s ability to use his/her visual and perceptual skills to perform complex eye-hand co-ordination tasks)
In clinical trials of hypophosphatasia, the focus is on Stationary, Locomotion and Object Manipulation.
Sjukdomsmekanism


Clinical Assessment Tool and questionnaire for the patient/carer
The HPP Clinical Assessment Tool includes examples of a wide variety of tests and makes the asssessment of the disease development easier. The tests are categorised by symptoms or organs, to make it easy to find the most relevant test for the individual patient and his/her situation.

Accompanying the tool is a questionnaire which the patient (or carer) can complete ahead of each appointment. This can then be used as a foundation when discussing the patient’s life situation and everyday life.

Leung EC et al. JIMD Rep 2013; 11: 73-78.
Mornet E. Best Pract Res Clin Rheum 2008; 22: 113-127.
Mornet E et al. Ann Hum Genet 2011; 75: 439-445.
Rockman-Greenberg C. Ped Endocrinol Rev 2013; 10 (Suppl 2): 380-388.
Whyte MP. Ann N Y Acad Sci 2010; 1192: 190-200.
Goemans N et al. PLoS One. 2013;8(12):e84120
Deitz JC et al., Phys Occup Ther Pediatr. 2007;27(4):87–102
Folio R et al. Peabody Developmental Motor Scales-2 (2nd ed.). Austin, TX: Pro-Ed; 2000.
In 2015 an Enzyme Replacement Therapy (ERT) was approved in Europe for long-term enzyme replacement therapy in patients with paediatric-onset hypophosphatasia to treat the bone manifestations of the disease.

Supportive care
Earlier supportive care for hypophosphatasia was aimed at dealing with the systemic manifestations of the disease:
  • Analgesics for the management of bone, muscle and joint pain.
  • Surgery to reduce elevated intracranial pressure or repairment of fractures.
  • Vitamin B6 for seizures.
  • Dental care to maintain good dental health
  • Treatment of hypercalcemia/hypercalcuria
  • Respiratory support
Surgery
Treatment strategies for surgical repairs may differ for patients with hypophosphatasia. Fractures and pseudofractures are common for patients with hypophosphatasia and may require different types of surgical interventions.

Unsuitable (contraindicated) treatments
High doses of Vitamin D, calcium supplements and biphosphonates should not be given if hypophosphatasia can be suspected, as it has been shown that these agents may worsen symptoms of hypophosphatasia.

Mornet E et al. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993. http://www.ncbi.nlm.nih.gov/books/NBK1150/. Published November 20, 2007. Updated February 4, 2016. Accessed June 8, 2016.
Mohn A et al. Hypophosphatasia in a child with widened anterior fontanelle: lessons learned from late diagnosis and incorrect treatment. Acta Paediatr. 2011;100(7):e43-e46
Sutton RAL et al. “Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia. J Bone Miner Res. 2012;27(5):987-994.

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